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numbered

CONFIDENTIAL
CONFIDENTIAL
TheGlaxoSmithKline
GlaxoSmithKline
of companies
The
groupgroup
of companies

YM2008/00019/00
YM2008/00019/00
B2C109575
B2C109575

Division: Worldwide Development


Retention Category: GRS019
Information Type: Clinical Study Report
Title:

A randomised, double-blind, placebo-controlled, parallel group,


dose ranging study evaluating the efficacy and safety of
GW642444M administered once daily compared with placebo
for 28 days in adolescent and adult subjects with persistent
asthma

Phase:

IIb

Compound Number: GW642444M


Effective Date:

27 April 2009

Description: This study evaluated the efficacy, safety and pharmacokinetics (PK) of five
doses of GW642444M and placebo in adult and adolescent subjects with persistent
asthma. Following Screening and a 14-day Run-in period, subjects meeting eligibility
criteria were stratified in an approximately 1:1 ratio according to their baseline FEV1
expressed as a percentage of predicted normal (40% - 65% or >65% - 90%).
Subjects were randomised to one of six double-blind 28-day treatments (GW642444M 3
g, 6.25 g, 12.5 g, 25 g, 50 g, or placebo) administered via the Novel Dry Powder
Inhaler once-daily in the evening. At the end of the treatment period, subjects entered a
seven-day Follow-up period. Once-daily treatment with GW642444M for 28 days
resulted in dose-dependent improvements in lung function, with 12.5 g, 25 g, 50 g
GW642444M showing statistically significant increases of up to 0.162 L from baseline
compared with placebo in trough FEV1, measured 23-24 h after the last dose on Day 28
(the primary efficacy endpoint). FEV1 improved in a similar manner across the strata
The improvements in FEV1 measurements were also seen across other secondary efficacy
parameters including morning and evening peak expiratory flow (PEF) and percentage of
symptom- and rescue-free 24-h periods with the greatest improvements seen with 25 g
and 50 g. All GW642444M doses were well-tolerated throughout the study period. The
incidence of adverse events (AEs) was similar across the GW642444M treatment groups
and was comparable with placebo. Headache was most frequently reported across all
groups. No serious adverse events (SAEs) were reported on study treatment. No safety
concerns were noted from haematology, clinical chemistry (including liver function tests)
and urinalysis, vital signs or glucose and potassium assessments. There were no
clinically relevant increases from baseline versus placebo in serial, weighted mean or
maximum QTc(F) (0-4 h) for any treatment group at any time point. Increases in mean
serial QTc(B) from baseline versus placebo of 6 msec to 12.5 msec within 1 h of dosing
were seen with 50 g GW642444M on all clinic study days, and on Days 1 and 14 with
25 g GW642444M. GW642444M concentration-time data were too limited (high % NQ
values) for formal population PK analysis.
Copyright 2009 the GlaxoSmithKline group of companies. All rights reserved.
Unauthorised copying or use of this information is prohibited.

-1-

CONFIDENTIAL
CONFIDENTIAL
TheGlaxoSmithKline
GlaxoSmithKline
of companies
The
groupgroup
of companies

YM2008/00019/00
YM2008/00019/00
B2C109575
B2C109575

Systemic exposure could only be characterised at doses 12.5 g. Observed Cmax (an
estimate of systemic exposure) increased with dose with marginal increases on repeat
dosing. There was no clear covariate effect on Cmax and no clear correlation between
observed Cmax and any systemic pharmacodynamic endpoint (pulse rate, QTc, glucose
or potassium). At all doses and visits, concentrations of triphenylacetate (counterion)
were below limits of quantification (1 ng/mL) in the majority of subjects. GW642444M
metabolite (GW630200 and GSK932009) concentrations were below limits of
quantification for all doses and visits in the vast majority of subjects (99.8%). Based on a
predicted maximum effect (Emax) model of all the evaluable trough FEV1 data, an ED50
(dose achieving half predicted maximal response) is estimated as 16.1 g [95%CI: 12.519.7 g] and an Emax of 243 mL. The estimated half life of GW642444M was 26 h [95%
CI 23-29 h] in equilibrium with the lung biophase, consistent with a sustained duration of
action. This study demonstrated that, in subjects with moderate to severe persistent
asthma, once-daily treatment with GW642444M was well tolerated and produced a dosedependent and sustained bronchodilatory effect that was superior to placebo at 23-24 h
with the 12.5 g, 25 g and 50 g doses following 28-days treatment.
Subject: Asthma, dose ranging, efficacy, safety, pharmacokinetics, placebo.
Author(s):

Indication Studied: Asthma


Initiation Date:

29 Dec 2007

Completion Date:

10 Sep 2008

Date of Report:

April 2009

Sponsor Signatory:
(and Medical Officer)
Respiratory MDC
GlaxoSmithKline Research and Development
This study was performed in compliance with Good Clinical Practices and
GlaxoSmithKline Standard Operating Procedures for all processes involved, including
the archiving of essential documents.

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CONFIDENTIAL

YM2008/00019/00
B2C109575

TABLE OF CONTENTS
Page

Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11

1. ETHICS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.1. Independent Ethics Committee (IEC) or Institutional Review Board (IRB) .
1.2. Ethical Conduct of the Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.3. Subject Information and Consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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14
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2. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE . . . . . . . . . . .

14

3. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

15

4. STUDY OBJECTIVE(S) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

16

5. INVESTIGATIONAL PLAN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1. Overall Study Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1.1. Discussion of Study Design, Including the Choice of Control
Group(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2. Protocol Amendment(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.3. Selection of Study Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.3.1. Inclusion/Exclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.3.2. Predetermined Criteria for Subject Withdrawal . . . . . . . . . . . . . . . . .
5.4. Investigational Product(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.4.1. Description of Investigational Product(s) . . . . . . . . . . . . . . . . . . . . . .
5.4.2. Dosages and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.4.3. Dose Rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.4.4. Blinding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.4.5. Treatment Assignment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.4.6. Assessment of Compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.4.7. Treatment of Investigational Product Overdose . . . . . . . . . . . . . . . .
5.5. Prior and Concomitant Medications and Non-Drug Therapies . . . . . . . . . . .
5.5.1. Permitted Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.5.2. Prohibited Medications and Non-Drug Therapies . . . . . . . . . . . . . . .
5.5.3. Medical Device(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.6. Study Assessments and Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.6.1. Demographic and Baseline assessments . . . . . . . . . . . . . . . . . . . . .
5.6.2. Efficacy Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.6.3. Safety Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.6.4. Pharmacokinetic Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.6.5. Pharmacogenetic Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.7. Data Quality Assurance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.8. Data Analysis Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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5.8.1. Timings of Planned Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


5.8.2. Sample Size Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.8.3. Analysis Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.8.4. Treatment Comparisons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.8.5. General Considerations for Data Analyses . . . . . . . . . . . . . . . . . . . .
5.8.6. Data Handling Conventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.8.7. Study Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.8.8. Efficacy Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.8.9. Safety Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.8.10. Pharmacokinetic and Pharmacokinetic/Pharmacodynamic
Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.8.11. Pharmacogenetic Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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6. STUDY POPULATION RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


6.1. Disposition of Subjects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.2. Protocol Deviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.3. Populations Analysed . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.4. Demographics and Other Screening Characteristics . . . . . . . . . . . . . . . . . .
6.4.1. Demographic Characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.4.2. Other Characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.4.3. Other Current Medical Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.5. Concomitant Medications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.5.1. Concomitant Asthma Medications . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.5.2. Concomitant Non-Asthma Medications . . . . . . . . . . . . . . . . . . . . . . .
6.6. Treatment Compliance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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7. EFFICACY RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.1. Primary Efficacy Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.1.1. Analyses Supporting the Primary Efficacy Analysis . . . . . . . . . . . . .
7.2. Secondary Efficacy Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.2.1. Strata Analysis of Trough FEV1 . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.2.2. Weighted Mean 24-hour Serial FEV1 . . . . . . . . . . . . . . . . . . . . . . . .
7.2.3. Daily Evening PEF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.2.4. Daily Morning PEF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.2.5. Symptom-Free 24-hour periods. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.2.6. Rescue-free 24-hour periods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.2.7. Post-Salbutamol/Albuterol FEV1 . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.3. Other Efficacy Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.3.1. Repeated Measures Analysis of Serial FEV1 . . . . . . . . . . . . . . . . . .
7.3.2. FEV1 (0-4 hours) on Days 1 and 28 . . . . . . . . . . . . . . . . . . . . . . . . .
7.3.3. Symptom-Free Days and Symptom-Free Nights . . . . . . . . . . . . . . . .
7.3.4. Rescue-Free Days and Rescue-Free Nights . . . . . . . . . . . . . . . . . . .

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7.3.5. Withdrawals Due to Lack of Efficacy . . . . . . . . . . . . . . . . . . . . . . . . .


7.4. Efficacy Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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8. SAFETY RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.1. Extent of Exposure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.2. Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.2.1. Adverse Events during the Treatment Period . . . . . . . . . . . . . . . . . .
8.2.2. Post-Treatment Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.2.3. Drug-Related Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.3. Serious Adverse Events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.4. Adverse Events Related to Premature Discontinuation of Investigational
Product and/or Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.5. Clinical Laboratory Evaluations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.5.1. Laboratory Values over Time . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.5.2. Abnormalities of Potential Clinical Concern . . . . . . . . . . . . . . . . . . . .
8.6. Other Safety Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.6.1. Vital signs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.6.2. Twelve-Lead ECG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.6.3. Potassium and Glucose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.6.4. Asthma Exacerbations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.6.5. Medical Device/Product Incidents, Near-Incidents, Malfunctions
and Remedial Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.7. Safety Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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9. BIOANALYTICAL RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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10. PHARMACOKINETIC RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


10.1. Plasma Concentration-Time Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.1.1. GW642444 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.1.2. Triphenylacetate (counterion) . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.1.3. GW630200 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.1.4. GSK932009 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.2. Pharmacokinetic Analysis: GW642444 . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.2.1. Nonlinear Mixed Effects Modelling . . . . . . . . . . . . . . . . . . . . . . . . .
10.2.2. Noncompartmental Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.3. Pharmacokinetic Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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11. PHARMACOKINETIC/PHARMACODYAMIC RESULTS . . . . . . . . . . . . . . . . . . .


11.1. Systemic PK/PD Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.2. Pharmacodynamic modelling of dose-response and time course of FEV1
11.2.1. Trough FEV1 Dose Response Model . . . . . . . . . . . . . . . . . . . . . . .
11.2.2. Modelling the 24h time course of FEV1 . . . . . . . . . . . . . . . . . . . . . .
11.3. Pharmacokinetic/Pharmacodynamic Summary . . . . . . . . . . . . . . . . . . . . .

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12. DISCUSSION AND CONCLUSIONS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


12.1. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12.2. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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13. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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14. CASE NARRATIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


14.1. Serious Adverse Events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14.2. Pregnancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14.3. Withdrawals Due to Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14.4. Withdrawals Due to Protocol-Defined Stopping Criteria . . . . . . . . . . . . . .

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STUDY POPULATION DATA SOURCE FIGURES AND TABLES . . . . . . . . . . . . . .

134

EFFICACY DATA SOURCE FIGURES AND TABLES . . . . . . . . . . . . . . . . . . . . . . .

229

SAFETY DATA SOURCE FIGURES AND TABLES . . . . . . . . . . . . . . . . . . . . . . . . .

387

PHARMACOKINETIC DATA SOURCE FIGURES AND TABLES . . . . . . . . . . . . . . .

818

PHARMACOKINETIC & PHARAMCODYNAMIC DATA SOURCE FIGS AND


TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

836

ATTACHMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

864

Attachment 1. MEDICAL CONDITIONS AT SCREENING . . . . . . . . . . . . . . . . . . . .

864

Attachment 2. INDIVIDUAL POTASSIUM PROFILES FOR SUBJECTS WITH


VALUES >7 MMOL/L . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

865

Attachment 3. PHARMACOKINETIC ATTACHMENT . . . . . . . . . . . . . . . . . . . . . . . .

870

Attachment 4. PHARMACOKINETICS/PHARMACODYNAMICS . . . . . . . . . . . . . . .

872

Attachment 5. DATA LISTINGS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

900

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LIST OF FIGURES
Page

Figure 1 Study Schedule Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


Figure 2 Adjusted Means of Change from Baseline in Trough FEV1 (L) (LOCF) at
Day 28 (ITT Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 3 Adjusted Treatment Differences of Change from Baseline in Trough FEV1
(L) (LOCF) at Day 28 Difference from Placebo (ITT Population) . . . . . . . . . . .
Figure 4 Adjusted Treatment Differences of Change from Baseline in Trough FEV1
(L) (LOCF) at Day 28 Difference from Placebo (PP Population) . . . . . . . . . . .
Figure 5 Repeated Measures Analysis of Change from Baseline in Trough FEV1
(L) Differences from Placebo (ITT Population) . . . . . . . . . . . . . . . . . . . . . . . .
Figure 6 Adjusted Treatment Differences of Change from Baseline in Trough FEV1
(L) (LOCF) at Day 28 by Percent Predicted FEV1 Stratum Difference from
Placebo (ITT Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 7 Adjusted Treatment Differences of Weighted Mean 24-hour Serial FEV1
(L), Difference from Placebo (All Subjects, including 6-12 hour Time Points)
(ITT Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 8 Adjusted Treatment Differences from Sensitivity Analysis of Weighted
Mean 24-hour Serial FEV1 (L), Difference from Placebo, Day 28 (ITT
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 9 Adjusted Treatment Differences of Change from Baseline in PM PEF
(L/min), Days 1-28 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 10 Mean Change from Baseline in PM PEF (L/min) (ITT Population) . . . . . .
Figure 11 Mean Change from Baseline in AM PEF (L/min) (ITT Population) . . . . . .
Figure 12 Adjusted Treatment Differences of Change from Baseline in Percentage
of Symptom Free 24 Hour Periods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 13 Adjusted Treatment Differences of Change from Baseline in Percentage
of Rescue Free 24 Hour Periods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 14 Repeated Measures Adjusted Treatment Differences from Placebo in
Change from Baseline FEV1, Day 28 (L) (ITT Population) . . . . . . . . . . . . . . . . .
Figure 15 Absolute Change from Baseline in Serial FEV1 (L) 0-4 hours (ITT
Population), Day 28 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 16 Proportion of Subjects Obtaining 200 mL and
12% Increase from Baseline FEV1 (L), 0-24 h . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 17 Adjusted Treatment Differences of Peak Post-Dose FEV1 (L) (0-4
hours), Day 28 (ITT Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 18 Minimum Post-Baseline Potassium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 19 Maximum Post-Baseline Glucose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 20 Adjusted Treatment Differences (95% CI) of Change from Baseline in
Post-Dose Serial QTc(F) (msec) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Figure 21 Dose-Response for Trough FEV1 (ITT population) at Day 28


Overlay-Observed LSMean difference from Placebo with Model Simulated
LSMean Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 22 K-PD model based simulations versus observed time course of FEV1 for
placebo and GW642444M 25 g on Day 28 . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 23 Therapeutic Index mapping dose-response for efficacy and safety Day
28 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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LIST OF TABLES
Page

Table 1 Description of Investigational Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


Table 2 Time and Events Schedule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 3 Withdrawals prior to Randomisation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 4 End of Study Record (ITT Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 5 Summary of Demographic Characteristics (ITT Population) . . . . . . . . . . . . .
Table 6 Summary of Duration of Asthma and Asthma History (ITT Population) . . . .
Table 7 Summary of Screening Lung Function (ITT Population) . . . . . . . . . . . . . . . .
Table 8 Summary of on-treatment Asthma Concomitant Medications taken by
5% of Subjects (ITT Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 9 Post-hoc Analysis of Background Inhaled Steroid Dose during Treatment .
Table 10 Summary of Treatment Compliance (ITT Population). . . . . . . . . . . . . . . . .
Table 11 Linear Trend Test of Change from Baseline in Trough FEV1 (LOCF) (ITT
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 12 Statistical Analysis of Change from Baseline in Trough FEV1 (L) (LOCF)
at End of Treatment (ITT Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 13 Statistical Analysis of Change from Baseline in Trough FEV1 (L) at Day
28 by Percent Predicted Stratum (LOCF) (ITT Population) . . . . . . . . . . . . . . . .
Table 14 Statistical Analysis of Weighted Mean Change from Baseline in 24-hour
Serial FEV1 (L) (All Subjects, including 6-12 hour Time Points) (ITT
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 15 Statistical Analysis of Change from Baseline in PM PEF (L/min), Days
1-28 (ITT Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 16 Statistical Analysis of Change from Baseline in AM PEF (L/min), Days
1-28 (ITT Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 17 Statistical Analysis of Change from Baseline in Percentage of
Symptom-Free 24-h Periods, Days 1-28 (ITT Population) . . . . . . . . . . . . . . . . .
Table 18 Statistical Analysis of Change from Baseline in Percentage of
Rescue-Free 24-h Periods, Days 1-28 (ITT Population) . . . . . . . . . . . . . . . . . . .
Table 19 Statistical Analysis of Difference in Post-Salbutamol/Albuterol FEV1 (L)
(ITT Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 20 Statistical Analysis of Weighted Mean Change from Baseline in FEV1 (L)
(0-4 hours) (ITT Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 21 Statistical Analysis of Maximum Increase from Baseline in FEV1 (L) (0-4
hours) (ITT Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 22 Summary of Ratio of Peak Post-Dose FEV1 (L) to Trough FEV1 (L), Day
28 (ITT Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 23 Statistical Analysis of Change from Baseline in Percentage of
Symptom-Free Days (ITT Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

25
30
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Table 24 Statistical Analysis of Change from Baseline in Percentage of


Symptom-Free Nights (ITT Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 25 Statistical Analysis of Change from Baseline in Percentage of Rescue
Free Days (ITT Population). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 26 Statistical Analysis of Change from Baseline in Percentage of Rescue
Free Nights (ITT Population). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 27 Summary of Exposure (ITT Population) . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 28 Adverse Events (ITT Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 29 Most Frequent On-Treatment Adverse Events (ITT Population) . . . . . . . . .
Table 30 Drug-Related Adverse Events (2% or Greater Incidence in Any
Treatment Group) (ITT Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 31 Adverse Events Leading or Related to Permanent Discontinuation of
Study Drug, or Withdrawal from the Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 32 Summary of Absolute ECG findings at any Time Post-Baseline . . . . . . . . .
Table 33 Summary of ECG Changes at any Time Post-Baseline . . . . . . . . . . . . . . .
Table 34 Summary of Subjects with Asthma Exacerbations (ITT Population) . . . . . .
Table 35 GW642444: Summary of % of Not Quantifiable values by Treatment, Day
and Time . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 36 Triphenylacetate: Summary of % of NQ values by treatment, Day and
Time . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 37 Summary (Median [range]) GW642444 Cmax and tmax (estimated over
period 2-30 min post-dose) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 38 Summary (Median [range]) GW64244 Cmax (pg/mL) by Categorical
Covariate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 39 Dose Response Model Parameters for trough FEV1 change from
baseline on Day 28 (ITT Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abbreviations
AE
ALT
ANCOVA
AM
AST
AV
BD
BDP
BMI
Bpm
CI
COPD
CPK
Cmax
CSR
DMPK
ECG
eCRF
E0
ECG
ED50
eDiary
Emax
FEV1
GCP
GCSP
GINA
GSK
GW642444M
h
HARP
HPLC
IEC
HBsAg
HR
ICH
ICS
IgE
IND
INS
IRB
ITT
L
LABA

Adverse Event
Alanine aminotransferase
Analysis of covariance
Morning (ante meridiem)
Aspartate aminotransferase
Atrioventricular
Bis in die (twice daily)
Beclometasone dipropionate
Body Mass Index
Beats per Minute
Confidence interval
Chronic obstructive pulmonary disease
Creatine phosphokinase
Maximal plasma concentration
Clinical study report
Drug Metabolism and Pharmacokinetics
Electrocardiogram
Electronic case report form
Placebo Effect
Electrocardiogram
Potency; dose producing 50% of maximum predicted
response
Electronic diary
Maximum predicted effect
Forced expiratory volume in 1 second
Good Clinical Practice
Global Clinical Safety and Pharmacovigilance
Global Initiative for Asthma
GlaxoSmithKline
GW642444 formulated with the excipient magnesium
stearate
hour
Harmonisation for analysis and reporting program
High performance liquid chromatography
Independent Ethics Committee
Hepatitis B surface antigen
Heart Rate
International Conference on Harmonisation
Inhaled corticosteroid
Immunoglobulin E
Investigational New Drug
Intranasal corticosteroid
Institutional Review Board
Intent-to-treat
Litre
Long-acting -agonist
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LFT
LLQ
LLR
LOCF
LS Mean
LRT
MAO
MDC
MDI
MedDRA
Min
mL
MS
msec
N
n
NA
NC
ND
NHLBI
NIH
NONMEM
OBJ
OD
PGx
PK
PD
PEF
PGx
PK
PM
PP
PWRES
QC
QTc interval
QTc(B)
QTc(F)
RAMOS
RAP
SA
SAE
SD
SE
SOP
UK
ULN
USA

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Liver function test


Lower limit of quantification
Log-Likelihood Ratio
Last observation carried forward
Least Square mean
Likelihood ratio test
Monoamine oxidase
Medicine development centre
Metered dose inhaler
Medical dictionary for regulatory activities
Minutes
Millilitre
Mass spectrometry
Milliseconds
Number of subjects in the treatment group
Number of subjects with non-missing values
Not applicable
Not calculable
Not determined
National Heart, Lung and Blood Institute
National Institutes of Health
A nonlinear mixed effect modeling software
Loglikelihood ratio
Once-daily
Pharmacogenetics
Pharmacokinetics
Pharmacodynamics
Peak Expiratory Flow
Pharmacogenetics
Pharmacokinetics
Evening (post meridiem)
Per protocol
Population weight residuals
Quality control
Time between the start of the Q wave and the end of the T
wave in the heart's electrical cycle
QTc calculated using Bazetts formula
QTc calculated using Frederica formula
Registration and Medication Ordering System
Reporting and analysis plan
Safety Assessment
Serious adverse event
Standard deviation
Standard error
Standard operating procedure
United Kingdom of Great Britain and Northern Ireland
Upper limit of normal
United States of America
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Visual Predictive Check


Weighted Residuals

Trademark Information
Trademarks of the GlaxoSmithKline
group of companies

Trademarks not owned by the


GlaxoSmithKline group of companies

DISKUS

Inform
MONOLIX
NHANES
NONMEM
OBIWAN
RAMOS
SAS
WinNonlin

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1.

ETHICS

1.1.

Independent Ethics Committee (IEC) or Institutional Review


Board (IRB)

The study protocol, any amendments, the informed consent, and other information that
required pre-approval were reviewed and approved by a national, regional, or
investigational centre ethics committee or institutional review board.

1.2.

Ethical Conduct of the Study

This study was conducted in accordance with Good Clinical Practice (GCP) and all
applicable regulatory requirements, and the guiding principles of the Declaration of
Helsinki.

1.3.

Subject Information and Consent

Written informed consent was obtained from each subject prior to the performance of any
study-specific procedures. Electronic case report forms (eCRFs) were provided for each
subjects data to be recorded.

2.

INVESTIGATORS AND STUDY ADMINISTRATIVE


STRUCTURE

This multi-centre study was conducted by 88 investigators at 88 sites in 16 countries.


GSK was responsible for the administration, monitoring, analyses and reporting of this
study.
Central laboratory facilities were provided by Quest Diagnostics. Bioanalysis of PK
samples was performed by WorldWide Bioanalysis, Drug Metabolism and
Pharmacokinetics (DMPK), GSK. Cardinal Health Research Services (formerly
VIASYS) supplied spirometry, 12-lead ECG and electronic diary (eDiary) equipment.
Manual reading and calculation of the electrocardiographic parameters was done
centrally by a cardiologist independent from GSK. No independent data monitoring
committee was involved in this study.

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3.

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INTRODUCTION

Asthma is a chronic inflammatory condition characterised by wheeze, chest tightness,


cough and shortness of breath as a consequence of bronchoconstriction, airway
inflammation and airway hyperreactivity. Asthma is a problem worldwide, with an
estimated 300 million affected individuals [Masoli, 2004; Beasley, 2004]. The symptoms
of asthma can greatly impair a person's ability to function, as well as affect their healthrelated quality of life.
Inhaled corticosteroids (ICS; e.g., fluticasone propionate and budesonide) and long-acting
2-agonists (LABAs; e.g., salmeterol and formoterol) are used in combination as a
maintenance therapy to help prevent asthma symptoms and asthma exacerbations in
patients uncontrolled on ICS alone, as advocated by GINA (Global Initiative for Asthma)
[GINA, 2006] and the NHLBI [NIH, 2007]. The LABAs that are currently available
require twice-daily (BD) administration. There is a significant need for a once-daily
(OD) inhaled medication that can help to improve patient compliance and overall disease
management by providing sustained, 24-hour (h) bronchodilation.
GW642444 is a potent, inhaled LABA and is under development as part of an ICS/LABA
combination for use as a once-daily treatment in asthma and chronic obstructive
pulmonary disease (COPD), and also as a standalone product for the treatment of COPD.
GW642444 has previously been studied as the -phenylcinnamate H salt formulated
with lactose alone. Due to a taste disturbance with phenylcinnamate salt however, the
most recent clinical studies have been conducted with GW642444M (the triphenylacetate
salt of GW642444) blended with lactose, or lactose and magnesium stearate. Magnesium
stearate is used as a stabilising agent and is the excipient used, in this (and future) studies.
GW642444M is equipotent with salmeterol and is 1000- and 400-fold more selective for
2 than 1 and 3 receptors, respectively. It has a greater duration of action and a faster
onset of bronchodilatory action in human bronchus and guinea pig trachea preparations
than salmeterol. Systemic exposure is limited by a low oral bioavailability (lower than
salmeterol in the rat) and rapid breakdown. GW642444 has been engineered to be
metabolically labile and is rapidly broken down in human microsomes and hepatocytes
into products with 100-fold less activity at the human 2 receptor.
To date, GW642444M formulated with the excipient magnesium stearate has been
evaluated in phase I and IIA studies in healthy and asthmatic subjects which evaluated
the efficacy, safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of
this formulation. GW642444M is also being evaluated in COPD. Overall, inhaled
administration of GW642444M was well tolerated and showed a good safety profile:
adverse events (AEs) have generally been of mild or moderate intensity without any
obvious patterns of AEs related to the administration of GW642444M. Typical side
effects related to -2 adrenoceptor agonist treatment were seen at higher exposures of
inhaled GW642444M (100 g): increases in heart rate and systolic blood pressure,
decreases in diastolic blood pressure, increases in QTc intervals, hypokalemia and
hyperglycemia. The effects however were generally not clinically significant. All tested
doses of GW642444M induced a statistically and clinically significant improvement in
lung function compared with placebo in a single-dose study, with single doses of 25 g to
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100 g demonstrating a 24-h duration of action as confirmed by a 200 mL or greater


increase in mean 23 to 24 h post-dose FEV1 versus placebo. No clear dose-response was
observed over the dose range 25 g to 100 g, suggesting that these doses represent the
top of the efficacy dose-response curve.
This study evaluated the efficacy and safety of five doses of GW642444M versus
placebo, administered OD in the evening in subjects with persistent asthma over a 28-day
period. Pharmacokinetic samples were also collected. It was intended that these samples
would be analysed by a PK modelling approach to define the population PK of
GW642444 and its associated variability in the target population, which would help to
evaluate the pharmacokinetic variability in subjects representative of the target
population and the pharmacokinetic behaviour of the drug. The information obtained
from this study will be used to support selection of the optimum dose for future studies.
A model-based analysis of the dose-response for trough FEV1 response as well as time
course of FEV1 was undertaken after accounting for diurnal variation in placebo
response.

4.

STUDY OBJECTIVE(S)

The primary objective of this study was to evaluate the dose response, efficacy and safety
of five doses of GW642444M (3 g, 6.25 g, 12.5 g, 25 g and 50 g) over a 28-day
treatment period in subjects with persistent asthma. The secondary objective was to
characterise the population PK of GW642444 in subjects with persistent asthma.

5.

INVESTIGATIONAL PLAN

5.1.

Overall Study Design

This was a multi-centre, randomised, double-blind, parallel-group, placebo-controlled


study in adolescent and adult subjects with persistent asthma. Five doses of
GW642444M inhalation powder (3 g, 6.25 g, 12.5 g, 25 g and 50 g OD) were
investigated and compared with placebo. The study schematic is given in Figure 1.
At Visit 1, subjects were screened for eligibility, which included the inhaled
albuterol/salbutamol reversibility test. Subjects who failed the reversibility test were
allowed to return to the clinic within 4 days. Subjects meeting the eligibility criteria at
Visit 1 entered a 14 (-4/+2) day Run-in period. In order to investigate the consistency of
the dose-response relationship for the different disease severities, subjects were stratified
at the end of the run-in period (Visit 2) in an approximately 1:1 ratio according to their
baseline FEV1 as a percentage of the predicted normal. One stratum included subjects
with FEV1 percent predicted 40% - 65% and the other included those with FEV1
percent predicted > 65% - 90%. Once stratified, subjects were randomised at Visit 2 to
one of the following treatments before entering into a 28-day double-blind treatment
period (-4/+2 days):

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GW642444M 3 g OD in the evening.

GW642444M 6.25 g OD in the evening.

GW642444M 12.5 g OD in the evening.

GW642444M 25 g OD in the evening.

GW642444M 50 g OD in the evening.

Placebo OD in the evening.

The first dose of study medication was given in the clinic at the Visit 2. At the end of the
treatment period there was a 7-day follow-up period. Subjects who completed the study
(screening, Run-in, treatment period and Follow-up) participated in the study for a total
of 7 weeks. Subjects remained on their current ICS therapy (at fixed doses) throughout
the study (screening to follow-up inclusive).
A Time and Events schedule is presented in Table 2.
Figure 1

Clinic Visit 1
Study Day -14

Study Schedule Overview

2/2A*
1/2

3
7

4
14

5/5A
28/29

6
(+7)

* Randomisation.
Visit 2/2A and Visit 5/5A took place over 2 days. In selected centres, a proportion of subjects remained in the clinic
overnight (66% of subjects). In other centres, subjects returned to the clinic approximately mid-morning on Day 2 and
Day 29 (Visit 2A and 5A, respectively) to complete Day 1 and 28 serial FEV1 measurements.

5.1.1.

Discussion of Study Design, Including the Choice of Control


Group(s)

This study was designed to build on the experience gained from phase I and phase IIA
studies in healthy subjects and asthma patients and to provide efficacy and safety data in
subjects with persistent asthma.

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A placebo arm was included as suitable reference to establish the magnitude of effect of
GW642444M on efficacy and safety parameters.
Treatment duration of 28 days was considered to be sufficient to demonstrate that the
efficacy of GW642444M is maintained without the development of tolerance.

5.2.

Protocol Amendment(s)

Three protocol amendments were made to the original protocol dated 1 November 2007.
Overall, these amendments were largely for clarification. There was no significant
impact on the patient population before or after any of the amendments, and the
robustness and credibility of the results is unaltered.
Protocol amendment 01 (17 December 2007)

Most of the changes were corrections of inconsistencies within the protocol. The changes
to respiratory tract infections were made in order to allow subjects to enter the trial, with
mild symptoms that did not impact their asthma; this allowed a slightly wider patient
population into the study, but did not make any significant impact on the overall study
population.
The addition of severe milk allergy was made as an addition to lactose sensitivity, in
order to clarify for investigators that subjects with either of these sensitivities should be
excluded. This was a safety warning for a rare allergy, which did not affect the
robustness of the study.
Scope of the amendment:

Clarification that upper and lower respiratory tract infections were only an exclusion
criterion if they resulted in a change to subjects asthma management or if they
affected the subjects ability to participate in the study.

Exclusion criterion 7 was amended to clarify that subjects with severe milk protein
allergy should be excluded from the study1.

Clarification that long-acting anti-histamines only were prohibited for 14 days prior
to and during the study.

It was no longer necessary for Investigators to consult with the GSK Medical
Monitor prior to withdrawing a subject who had met any of the ECG withdrawal
criteria.

Correction of a formatting error that could potentially have led to the


misinterpretation of the protocol requirements for prohibited medications.

No symptoms related to milk protein allergy were identified in any of the subjects.

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Clarification that study-issued rescue salbutamol/albuterol was provided for use


during the Run-in, treatment period and Follow-up period.

Protocol amendment 02 (09 April 2008)

Most of the changes were clarifications of the protocol. These included a revision of
some ECG terms, to give greater clarity without changing the original intended exclusion
or withdrawal criteria.
Long-acting anti histamines were allowed because the original protocol allowed short
acting anti-histamines and this was an inconsistency, since multiple doses of a short
acting anti-histamine give a similar effect to a long acting anti-histamine.
Re-screening was introduced with Protocol Amendment 2, but only if the lung function
criteria of FEV1 percent predicted and/or reversibility following inhalation of
albuterol/salbutamol were not met at the original screening visit.
Scope of the amendment:

To amend the definition of evaluable subjects.

To allow subjects to re-screen for Visit 1 if they failed to meet lung function criteria
and to allow subjects who previously failed screening to be re-screened.

To clarify the exclusion of subjects with upper and lower respiratory tract infections
between Visit 1 and randomisation Visit 2.

To amend the ECG abnormality randomisation and withdrawal criteria.

To clarify blood pressure entry criteria

To clarify that pregnancy tests were required for all females.

To allow the use of long-acting anti-histamines.

To extend the permitted time deviation windows for serial measurements of lung
function in acknowledgement of the complexity of the study.

Protocol amendment 03 (21 April 2008)

Amendment 03 was a correction of a randomisation criterion, which had an error in the


text, following Amendment 01.
Scope of the amendment:

Correction of Randomisation Criterion no 7 to reflect that the subjects asthma status


or ability to participate in the study was not expected to be affected by the
occurrence of a viral infection of the respiratory tracts, sinus or middle ear during the
run-in period that led to a change in asthma management.

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5.3.

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Selection of Study Population

Approximately 1200 subjects were planned to be screened with the aim of achieving
randomisation of 594 evaluable subjects (99 subjects per group) with at least one predose or 23-24 h post-dose FEV1 assessment on or after nominal Day 7.
5.3.1.

Inclusion/Exclusion Criteria

5.3.1.1.

Inclusion Criteria

Subjects eligible for enrolment in the study had to meet all of the following criteria:
1.

Subjects were 12 years of age at Visit 1. In Germany, the Russian Federation and
South Africa, where local regulations or the regulatory status of study medication
permitted enrolment of adults only, subjects recruited were 18 years of age. In
Chile, subjects recruited by one centre were >15 years of age; subjects recruited by
another centre were >18 years of age.

2.

Subjects were male or eligible female. A urine pregnancy test was performed for all
female subjects prior to study participation. To be eligible for entry into the study,
females of childbearing potential had to commit to the consistent and correct use of
an acceptable method of birth control: commit to complete abstinence from
intercourse from screening until 2 weeks after the follow-up contact, sterile sole
partner prior to the subjects entry into the study, implants of levonorgestral,
injectable progestogen, oral contraceptives (combined or progestogen only), double
barrier method, intrauterine or vaginal devices or systems, or percutaneous
contraceptive patches. Female subjects were not enrolled if they were pregnant,
lactating, or planned to become pregnant during the time of study participation.
Females of non-child bearing potential, including females who were postmenopausal, were eligible.

3.

Subjects had a documented history of persistent asthma that was defined by the
National Institute of Health [NIH, 2007]. Their condition had to be first diagnosed at
least 6 months prior to Visit 1.

4.

Subjects had reversible airways disease as demonstrated at Screening Visit 1 by an


increase in FEV1 of 12% and 200 mL over the pre-salbutamol/albuterol FEV1 at
approximately 30 minutes after the inhalation of 400 g of salbutamol/albuterol via
metered dose inhaler (MDI) or one nebulised salbutamol/albuterol solution. If a
subject did not meet the inclusion criteria based upon FEV1 percent predicted and/or
reversibility, he/she was allowed to return once within 4 days to repeat the lung
function tests.

5.

Subjects had to use an ICS and had to have been maintained on a stable dose for 4
weeks prior to Visit 1.

6.

Subjects had a pre-bronchodilator FEV1 between 40 and 90% predicted at Visit 1,


as calculated using NHANES III.

7.

Subjects provided an appropriately signed and dated informed consent.

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8.

Subjects were capable of withholding salbutamol/albuterol use for 6 h prior to


clinic visits.

9.

In France, subjects were eligible for inclusion in the study only if they were either
affiliated to or a beneficiary of a social security category.

5.3.1.2.

Exclusion Criteria

Subjects meeting any of the following criteria were not enrolled in the study:
1.

Subjects with an exacerbation of asthma within 4 weeks of Visit 1, or a culture


documented or suspected bacterial or viral infection of the upper or lower respiratory
tract, sinus or middle ear within 4 weeks of Visit 1 that led to a change in asthma
management, or affected the subjects asthma status or the subjects ability to
participate in the study (as judged by the Investigator).

2.

Subjects with a history of life-threatening asthma.

3.

Subjects with an asthma exacerbation requiring treatment with oral corticosteroids


within 3 months prior to Visit 1.

4.

Subjects who were hospitalised for an asthma exacerbation within 6 months of Visit
1.

5.

Subjects who had participated in any study using an investigational drug during the
previous 30 days or participated simultaneously in another clinical trial.

6.

Subjects with any clinically significant, uncontrolled condition or disease state that
would put the subjects safety at risk through study participation or would confound
the interpretation of the efficacy results if the condition/disease exacerbated during
the study.

7.

Subjects with any adverse reaction including immediate or delayed hypersensitivity


to any 2-agonist or sympathomimetic drug, or known (i.e., severe milk protein
allergy) or suspected sensitivity to the constituents of GW642444M inhalation
powder (e.g., lactose or magnesium stearate).

8.

Subjects who were likely to be non-compliant with study medication and other
study-related requirements (e.g. attendance at clinic visits or completion of the daily
eDiary).

9.

Subjects with a neurological or psychiatric disease or history of drug or alcohol


abuse which would interfere with the subjects proper completion of the protocol
requirements.

10. Subjects who were current smokers or had a smoking history of 10 pack years or
more (e.g., 20 cigarettes/day for 10 years). Subjects were not allowed to have used
tobacco products within the one year prior to the study.
11. Subjects administered systemic, oral or depot corticosteroids or administration of
anti-IgE (e.g. omalizumab [Xolair]) within 12 weeks of Visit 1.
12. Subjects administered any of the asthma medications theophyllines, oral 2-agonists
(e.g. bambuterol), slow-release bronchodilators, short- or long-acting

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anticholinergics, oral leukotriene receptor antagonists (e.g. montelukast), inhaled


sodium cromoglicate, or inhaled nedocromil sodium within 14 days of Visit 1.
13. Subjects administered inhaled long-acting 2-agonists (e.g. salmeterol) within 7 days
of Visit 1.
14. Subjects administered any other prescription or over the counter medication which
could affect the course of asthma or interact with sympathomimetic amines, such as:
anticonvulsants (barbiturates, hydantoins, and carbamazepine); polycyclic
antidepressants; -adrenergic blocking agents; phenothiazines and monoamine
oxidase (MAO) inhibitors.
15. Subjects administered a potent P-glycoprotein inhibitor or potent Cytochrome P450
3A4 inhibitor within 4 weeks prior to Visit 1 (e.g. ritonavir and ketoconazole).
16. Subjects who were immediate family members of the participating Investigator, subInvestigator, study co-ordinator, or employees of the participating Investigator.
5.3.1.3.

Randomisation Criteria

At the end of the run-in period subjects had to fulfil the following additional criteria in
order to enter the treatment period of the study:
1.

Best baseline pre-dose FEV1 at Visit 2 40% and 90% of their predicted normal.

2.

Any combination of daily asthma symptom scores (day-time plus night-time) of 1


or salbutamol/albuterol use on at least four of the last seven consecutive days of the
run-in period (immediately preceding Visit 2).

3.

No evidence of a clinically significant abnormality in the haematological,


biochemical or urinalysis screen at Visit 1, as judged by the investigator.

4.

No diagnosis of chronic hepatitis B and C, as confirmed by positive Hepatitis B


surface antigen (HBsAg) or Hepatitis C antibody screen at Visit 1.

5.

No evidence of significant abnormality in the 12-lead ECG at Visit 1, as judged by


independent cardiologist.
Selected specific ECG findings that were considered to be significant and excluded
the subject from study participation included, but were not limited to, the following:

Ventricular rate <45 beats per minute or >90 beats per minute (bpm).

PR interval >240 msec.

Evidence of second or third degree atrioventricular (AV) block.

Pathological Q waves, defined as wide (> 0.04 sec) and deep (> 0.4mV [4 mm
with 10 mm/mV setting]) or >25% of the height of the corresponding R wave,
provided the R wave was >0.5mV (5 mm with 10mm/mV setting), appearing in
at least two contiguous leads. Other historical or electrocardiographic evidence
of prior myocardial infarction also excluded the subject.

Evidence of two or more supra-ventricular or ventricular ectopic beats, i.e.,


ANY couplets, bigeminy, trigeminy or multifocal premature ventricular
complexes. This was to be confirmed by 3 readings at least 5 minutes apart.
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QTc(B) >450 msec.

ST-T wave abnormalities (excluding non-specific ST-T wave abnormalities).

Right or left complete bundle branch block, or a QRS interval >120 msec.

Incomplete right bundle branch block (QRS interval >110 msec <120 msec with
right bundle branch block pattern). This was to be confirmed by three readings
at least 5 minutes apart.

6.

No changes in asthma medication (excluding rescue salbutamol/albuterol MDI


provided at Visit 1) during the run-in period.

7.

No occurrence of a culture-documented or suspected bacterial or viral infection of


the upper or lower respiratory tract, sinus or middle ear during the run-in period that
led to a change in asthma management, or in the opinion of the Investigator was
expected to affect the subjects asthma status or the subjects ability to participate in
the study.

8.

Able to correctly use the Novel Dry Powder Inhaler.

9.

No asthma exacerbation during the run-in period.


An exacerbation was defined as worsening asthma requiring any treatment other than
rescue salbutamol/albuterol or regular inhaled corticosteroid use. This included
requiring the use of systemic corticosteroids and/or emergency room visit,
hospitalisation or a change in subjects regular ICS dose.

10. Compliance with completion of the daily eDiary. Non-compliance with completion
of the Daily eDiary, defined as:

Completion of morning and evening symptom scores on less than 4 days out of
the last 7 days immediately preceding Visit 2.

Completion of morning and evening rescue use on less than 4 days out of the
last 7 days immediately preceding Visit 2.

Completion of morning and evening PEF measurements on less than four out of
the last seven days immediately preceding Visit 2.

5.3.2.

Predetermined Criteria for Subject Withdrawal

A subject was regarded as having completed the study if they completed all phases of the
study (screening, treatment period and follow-up).
Subjects could be withdrawn from study treatment at anytime by the Investigator if it was
considered to be detrimental for them to continue in the study. Reasons for withdrawal
could include: an AE, lost to follow-up, protocol violation, lack of efficacy, sponsor
terminated study, non-compliance, pregnancy, abnormal liver function test, abnormal
laboratory results, or any other reason. Subjects were also free to withdraw themselves at
anytime. Once withdrawn from the investigational product a subject was considered
withdrawn from the study.

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A subject was withdrawn from the investigational product if he/she:


1.

Experienced any of the following abnormalities in ECGs (as decided following


consultation with the medical monitor, unless there was an immediate safety concern
and this was not feasible):

An increase in heart rate from baseline of >40 bpm (relative to the pre-dose Day
1 value) or an absolute heart rate of >110 bpm during the treatment period. This
was to be confirmed by 3 readings at least 5 minutes apart.

A prolongation in absolute mean QTc(B) to >500 msec or uncorrected mean QT


>600 msec during the treatment period. This was to be the mean of three
measurements taken at least 5 minutes apart.

Ventricular rate <37 bpm. This was confirmed by 3 readings at least 5 minutes
apart on 3 or more ECGs.

PR interval >240 msec. This was confirmed by 3 readings at least 5 minutes


apart on 3 or more ECGs.

Evidence of second or third degree AV block.

Pathological Q waves, defined as wide [> 0.04 seconds] and deep (> 0.4mV [4
mm with 10mm/mV setting]) or > 25% of the height of the corresponding R
wave, provided the R wave was >0.5 mV (5 mm with 10mm/mV setting),
appearing in at least two contiguous leads. Subjects were also to be withdrawn
in case of historical or electrocardiographic evidence of prior myocardial
infarction.

Evidence of 2 or more supra-ventricular or ventricular ectopic beats, ie. ANY


couplets, bigeminy, trigeminy or multifocal premature ventricular complexes.
This should be confirmed by 3 readings at least 5 minutes apart.

ST-T wave abnormalities (excluding non-specific ST-T wave abnormalities).

Right or left complete bundle branch block, or a QRS interval >120 msec.

Incomplete right bundle branch block (QRS interval >110 msec <120 msec with
right bundle branch block pattern). This should be confirmed by three readings
at least 5 minutes apart.

2.

Met any of the lack of efficacy criteria:

a.

Clinic FEV1 below the FEV1 Stability Limit value calculated at Visit 2 pre-dose
FEV1 at Visit 2 x 80%.

b.

During the 7 days immediately preceding the visit, the subject experienced any of the
following:

More than 3 days in which PEF had fallen below the morning PEF Stability
Limit calculated at Visit 2 (Mean morning PEF from the 7 days preceding Visit
2 x 80%).

More than 2 days in which 12 inhalations/day of salbutamol/albuterol were


used.

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3.

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Clinical asthma exacerbation, defined as worsening asthma requiring any


treatment other than study medication or rescue salbutamol/albuterol or regular
ICS use. This included requiring the use of systemic corticosteroids and/or
emergency room visit or hospitalisation or a change in subjects regular ICS
dose.

Met the following liver chemistry threshold criteria:

ALT 3 x ULN and bilirubin 1.5 x ULN (>35% direct).

ALT 5 x ULN.

ALT 3 x ULN if associated with the appearance or worsening of hepatitis


symptoms or rash.

The investigational product had to be permanently withdrawn, additional testing


performed, and the subject monitored until liver chemistries resolved, stabilised, or
returned to baseline values. The subject then had to be permanently withdrawn from
the study.
Subjects who were withdrawn from the study were not replaced. The primary reason for
withdrawal was recorded in the eCRF and any data collected up until the point of
withdrawal were used in the analyses. If a subject was prematurely withdrawn from the
study, an Early Withdrawal Visit was conducted within 24 h of the subjects stopping
study medication, if possible. In the event a subject withdrew at, or during, a scheduled
visit, an Early Withdrawal Visit was not required. However, all study procedures
scheduled at an Early Withdrawal Visit had to be performed at this visit instead. A
follow-up visit was made 7 days (-4/+2days) after the Early Withdrawal Visit.

5.4.

Investigational Product(s)

5.4.1.

Description of Investigational Product(s)

GSK Clinical Trials Supplies, Ware, UK manufactured and supplied the study medication
as detailed in Table 1. GW642444M and placebo were administered via Novel Dry
Powder Inhalers each containing two foil blister strips.
Table 1

Description of Investigational Products

Compound
Formulation

GW642444M
First strip: GW642444X micronised drug (as the M salt
triphenylacetate) blended with lactose and magnesium stearate.
Second strip: placebo containing lactose.
Novel Dry Powder Inhaler 30 doses per device

Dosage Form
Unit Dose
Strength(s)

a.

3 g per blister (batch


6.25 g per blister (batch
12.5 g per blister (batch
25 g per blister (batch
50 g per blister (batch
These batches were from the same formulation.

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Placebo
First strip: blend of lactose
and magnesium stearate.
Second strip: lactose.
Novel Dry Powder Inhaler 30
doses per device
Batch
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All study medications were stored in a secure area under appropriate physical conditions.
The Novel Dry Powder Inhalers containing GW642444M or matching placebo were
stored between 2 and 8C prior to being dispensed to subjects. Following dispensing, the
study medication was stored below 25C.
Subjects were provided with salbutamol/albuterol MDIs for use as rescue medication
throughout the study. The MDIs were sourced locally or by GSK for sites in the USA
and Canada.
5.4.2.

Dosages and Administration

At Visit 2, subjects were randomised in equal numbers to one of the following dosing
regimens:

GW642444M 3 g (1 actuation) administered once-daily via the Novel Dry Powder


Inhaler in the evening.

GW642444M 6.25 g (1 actuation) administered once-daily via the Novel Dry


Powder Inhaler in the evening.

GW642444M 12.5 g (1 actuation) administered once-daily via the Novel Dry


Powder Inhaler in the evening.

GW642444M 25 g (1 actuation) administered once-daily via the Novel Dry Powder


Inhaler in the evening.

GW642444M 50 g (1 actuation) administered once-daily via the Novel Dry Powder


Inhaler in the evening.

Placebo (1 actuation) administered once-daily via the Novel Dry Powder Inhaler in
the evening.

At Visits 2/2A, 3, 4 and 5, subjects were required to take their dose of study medication
at the clinic. At Visits 3, 4, and 5, treatment was administered at approximately the same
time of day ( 1 h) as Day 1 (Visit 2). On the other days, subjects were instructed to take
their study medication within 1 h of their dose time on Day 1 (Visit 2).
5.4.3.

Dose Rationale

Five doses of GW642444M (3 g, 6.25 g, 12.5 g, 25 g and 50 g) were selected for


this phase IIb dose-ranging study. The doses were selected based upon results from two
Phase I studies (B2C10001 and B2C108784) and four Phase IIa studies (B2C101762,
B2C104604, B2C106093, and B2C106996). The 3 g dose was included as a potential
no-effect dose. The 50 g dose was included as a likely supra-therapeutic dose to help
establish the therapeutic index for GW642444M and to assess whether or not a plateau
had been achieved. The intervening doses of 6.25 g, 12.5 g and 25 g represented
doubling-dose increments between the lowest and highest doses.

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By evaluating a range of doses from 3 g to 50 g of GW642444M, it was possible to


assess the dose response of GW642444M as well as the potential effects of GW642444M
on typical pharmacological class effects (e.g., increased heart rate, decreased potassium
levels, increased glucose levels). These data will provide useful information in
determining the therapeutic index of GW642444M and in selecting the dose(s) of
GW642444M to be carried forward in the Phase III program in the ICS/LABA
combination product.
5.4.4.

Blinding

This was a double-blind study. Neither the subject nor the investigator knew which study
medication the subject was receiving. The placebo dry powder formulation was
indistinguishable from the GW642444M formulation.
The investigator or treating physician was able to unblind a subjects treatment
assignment only in the case of an emergency, when knowledge of the study treatment
was essential for the appropriate clinical management or welfare of the subject.
Furthermore, GSKs Global Clinical Safety and Pharmacovigilance (GCSP) staff could
unblind the treatment assignment for any subject with an SAE. Further details can be
found in the Protocol.
5.4.5.

Treatment Assignment

The central randomisation schedule was generated by GSK using RandAll, a web serverbased, clinical trials randomisation system. Subjects were randomised centrally using
Registration and Medication Ordering System (RAMOS), an automated, interactive
telephone based system which was used by the Investigator or designee to register the
subject, randomise the subject and receive medication assignment information. Prior to
randomisation, subjects were stratified by baseline FEV1 as a percentage of predicted
(FEV1 40% - 65% predicted and FEV1 > 65% - 90% predicted) in an approximately
1:1 ratio. Within each stratum, allocation was centralised, with a block size of 6.
5.4.6.

Assessment of Compliance

Subjects were required to take their study medication every evening of each day during
the treatment period. At clinic Visits 2/2A, 3, 4 and 5 study drug administration was
observed by appropriately trained site personnel. Compliance throughout the study was
assessed at Visits 2 through 5 by reviewing the dose counter on the Novel Dry Powder
Inhaler. Percentage treatment compliance was calculated for each subject based on the
total number of inhalations taken and the expected number of inhalations to be taken.
Subjects who were not compliant with study drug administration were counselled on
appropriate dosing of the study drug.

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5.4.7.

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Treatment of Investigational Product Overdose

GSK did not recommend specific treatment guidelines for overdose and toxicity
management relating to GW642444M. The investigator was asked to refer to the relevant
documents for detailed information regarding warnings, precautions, contraindications,
AEs, and other significant data pertaining to the study drug being used in this study, such
documents as the Investigators Brochure and to use clinical judgment in treating the
overdose.

5.5.

Prior and Concomitant Medications and Non-Drug Therapies

All concomitant medications taken during the study were recorded in the eCRF.
5.5.1.

Permitted Medications

The following medications were permitted in this study:

Short-acting 2-agonists, which were replaced by rescue salbutamol/albuterol MDIs


issued to subjects at Visit 1.

ICSs, provided the dose remained constant for 4 weeks prior to Visit 1 and
throughout the study.

Intranasal corticosteroids (INS), intranasal sodium cromoglicate, topical


corticosteroids, immunotherapy for treatment of allergies, hormonal replacement
therapy for the treatment of menopausal symptoms, if started prior to Visit 1 and
stabilised throughout the study.

Short- and long-acting antihistamines and antihistamine eye drops to control


symptoms of allergic disorders. Subjects were only allowed either one oral or one
intranasal antihistamine during the trial.

Medications for other disorders (other than those listed in Section 5.5.2) were permitted
provided the dose remained constant and their use would not be expected to affect the
subject's lung function. Subjects were allowed to use non-drug therapies for conditions
other than asthma during the study if their use was not considered likely to have an
impact on the subject's asthma.
If a subjects current medication was changed as a result of study participation, then
consent was obtained at this point and the subject was required to return to the clinic to
complete the screening visit (Visit 1) once the required washout had been completed.
5.5.2.

Prohibited Medications and Non-Drug Therapies

The following medications were not permitted during the study or within the specified
time prior to the study.

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Within 7 days of Visit 1:

Long-acting 2-agonists.

ICSs and long acting 2-agonist combination products.

Within 14 days of Visit 1:

Theophyllines.

Oral 2 agonists.

Slow-release bronchodilators.

Anticholinergics, short- or long-acting.

Oral leukotriene receptor antagonists.

Inhaled sodium cromoglicate.

Inhaled nedocromil sodium.

Within 4 weeks of Visit 1:

Potent P-glycoprotein inhibitors

Potent Cytochrome P 3A4 inhibitors.

Within 12 weeks of Visit 1:

Systemic, oral, parenteral or depot corticosteroids.

Anti-IgE therapy.

In addition, a subject was not concurrently allowed to use any other prescription or overthe-counter medication which could affect the course of asthma, or interact with
sympathomimetic amines throughout the study (Visit 1 to Visit 6 inclusive), such as:

Anticonvulsants.

Polycyclic antidepressants.

-adrenergic blocking agents.

Phenothiazines.

MAO inhibitors.

5.5.3.

Medical Device(s)

GSK provided the eDiary device with integrated peak flow meter (Asthma Monitor
AM2+, Cardinal Health Research Services).

5.6.

Study Assessments and Procedures

A Time and Events schedule is provided in Table 2.


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Table 2
Procedures

Time and Events Schedule


Screen/
Run-in
1
-14(-4/+2)
x

Visit
Day
Written Informed
Consent
Subject Demography
x
Medical History
x
Asthma History
x
Therapy History
x
Smoking History
x
Physical examination
x
Inclusion/Exclusion
x
Criteria
Randomisation Criteria
Efficacy Assessments
Clinic measured FEV1
x
FEV1 response to
x12
salbutamol/albuterol
x
Issue eDiary with
integral PEF meter9
Review eDiary data
Safety Assessments
Concomitant
x
Medication
Vital Signs
x
12-lead ECG
x
Adverse Events
Serious Adverse
x
Events
Laboratory Assessments
Haematology5
x
Chemistry5
x
Urinalysis5
x
PGx Sampling
Serum Pregnancy Test x

Treatment
2/2A1
1

Early
withdrawal

3
7(-4/+2)

4
14(-4/+2)

5/5A1
28(-4/+2)

Follow-up
6
D28+7(-4/+2)

x
x2
x3

x2

x2

x2
x3

x4
x4
x
x

x4
x4
x
x

x4
x4
x
x

x4
x4
x
x

x
x
x
x

x
x

x
x

x
x
x

x
x
x

x
x

13

Urine pregnancy Test13


HBsAg and hepatitis C x
antibody
Exploratory Lab Assessments
PK sampling6
Serum potassium and
plasma glucose
sampling

x5

x
x7

x10

x
x11

x
x11

x
x7
Continued

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Table 2
Procedures

Time and Events Schedule (Continued)


Screen/
Run-in
1
-14(-4/+2)

Visit
Day
Investigational product
Dispense Invest.
Product.
Assess Invest. Product
compliance
Collect invest. product
Issue rescue
x
salbutamol/albuterol
Collect used rescue
salbutamol/albuterol

Treatment
2/2A1
1

Early
withdrawal

3
7(-4/+2)

4
14(-4/+2)

5/5A1
28(-4/+2)

Follow-up
6
D28+7 (-4/+2)

x8

x8

1.

Visit 2/2A and Visit 5/5A took place over 2 days. In selected centres, a proportion of subjects remained in the
clinic overnight (66% of subjects). In other centres, subjects returned to the clinic approximately mid-morning on
Day 2 and Day 29 (Visit 2A and 5A, respectively) to complete Day 1 and 28 serial FEV1 measurements.

2.

On Day 1 (Visit 2) and Day 28 (Visit 5) serial measurements of FEV1 were made at pre-dose, 15, 30 and
60 minutes and 2, 3, 4, 6, 12, 16, 20, 22, 23 and 24 h post-dose. Measurements at 6 and 12 h post-dose were
only made in those subjects remaining at the clinic overnight. On Days 7 (Visit 3) and 14 (Visit 4) pre-dose FEV1
measurements were required only.

3.

Performed 24 h after the Day 1 (Visit 2) and Day 28 (Visit 5) administration of the investigational product.

4.

Measurements were made on Day 1 (Visit 2), Day 7 (Visit 3), Day 14 (Visit 4) and Day 28 (Visit 5): pre-dose, 10
minutes and 1, 2 and 4 h post-dose.

5.

Samples were taken pre-dose.

6.

Samples were taken as follows:


Day 1 (Visit 2): pre-dose, between 2-10 minutes, between 10-30 minutes, between 30 minutes -2 h and between
2-4 h post-dose;
Day 7 (Visit 3): pre-dose;
Day 14 (Visit 4): 2minutes 1h post-dose;
Day 28 (Visit 5): pre-dose, between 2-10 minutes, between 10-30 minutes, between 30 minutes -2 h and between
2-4 h post-dose.

7.

Samples were taken pre-dose and 10 minutes, 1, 2 and 4 h post-dose. Subject was fasted from at least 4 h prior
to the pre-dose blood sample until after the 4 h post-dose sample.

8.

If required.

9.

Morning and evening PEF, symptoms and rescue medication usage was recorded every day from Visit 1 through
Visit 6.

10. Taken 24 h post-dose Day 28.


11. Serum potassium only. Samples were taken pre-dose and 10 minutes, 1, 2 and 4 h post-dose. Subjects were not
required to fast for these samples.
12. Subjects not meeting the FEV1 and/or reversibility inclusion criteria were allowed to return to the site once within 4
days to repeat the lung function tests. The Visit 1 screening period ended and the 14 day Run-in period began
when subjects met all of the inclusion criteria.
13. Required for all females

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Where multiple post-dose assessments were scheduled at the same timepoint, the
sequence of assessments was to be vital signs followed by 12-lead ECG, blood sampling
and FEV1 measurements. FEV1 measurements were performed as close to the scheduled
timepoint as possible.
5.6.1.

Demographic and Baseline assessments

The information described in this section refers to the assessments made at Screening
(Visit 1).
At Screening, the following information was obtained: height and weight, gender, ethnic
origin, date of birth, asthma history (including duration of asthma and atopic status),
smoking history, severity of disease, reversibility to salbutamol/albuterol and concurrent
medical conditions. Subjects also underwent a physical examination, vital signs
assessment (heart rate, blood pressure), 12-lead ECG assessment, pre-dose blood
sampling for haematology, clinical chemistry, urinalysis, serum pregnancy test (all
female subjects), and HBsAg and hepatitis C antibody tests. All demographic and
baseline assessments were completed according to the Time and Events schedule
(Table 2).
Subjects who had at least one study procedure performed (in addition to signing a consent
form) and who were assigned a study number, but who were not randomised were
considered screen failures.
Subjects who had previously screen-failed for any reason prior to Protocol Amendment
02 were allowed to return to the site for re-screening. Subjects who failed to meet the
FEV1 and/or reversibility inclusion criteria during Screening Visit 1 were allowed to
return once within 4 days to repeat the lung function tests.
5.6.2.

Efficacy Assessments

Efficacy assessments and procedures included clinic measurements of FEV1, response to


rescue salbutamol/albuterol, diary parameters as recorded in the daily eDiary and
withdrawals due to lack of efficacy. The measurements are outlined in Table 2.
5.6.2.1.

Primary efficacy endpoint(s)

The primary efficacy endpoint was the mean change from baseline in clinic visit trough
(pre-bronchodilator and pre-dose) FEV1 at the end of the 28-day treatment period. The
trough FEV1 was defined as the mean of the FEV1 values obtained 23 and 24 h after
dosing on Day 28.

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Secondary efficacy endpoint(s)

The secondary efficacy endpoints included:

Change from baseline in weighted mean 24 h serial FEV1 on Days 1 and 28 (mean
post-dose FEV1 after 15, 30 and 60 minutes and 2, 3, 4, 6, 12, 16, 20, 22, 23 and 24
h). This endpoint was derived for all subjects but the 6 and 12 h time points were
only measured in a sub-group of subjects (66% of subjects).

Mean change from baseline in trough (pre-dose and pre-bronchodilator) daily


evening peak expiratory flow (PEF) averaged over the 28-day treatment period.

Mean change from baseline in daily morning PEF averaged over the 28-day
treatment period.

Mean change from baseline in the percentage of symptom-free 24-h periods during
the 28-day treatment period.

Mean change from baseline in the percentage of rescue-free 24-h periods during the
28-day treatment period.

Difference in post salbutamol/albuterol FEV1 (FEV1 30 minutes after a single dose


of 400 g salbutamol/albuterol) between 24 h after dosing on Day 1 (Visit 2) and on
Day 28 (Visit 5); between screening (Visit 1) and 24 h after dosing on Day 1 (Visit
2); and between screening (Visit 1) and 24 h after dosing on Day 28 (Visit 5).

5.6.2.3.

Other efficacy endpoint(s)

The other efficacy endpoints included:

Maximum increase in FEV1 (0-4 h) on Days 1 and 28 compared with baseline.

Proportion of subjects obtaining 200 mL and 12% increase from baseline in FEV1
(0-4 h) on Days 1 and 28.

Mean change from baseline in trough FEV1 at Visits 2/2A, 3 and 4 (i.e. after 23-24 h,
7 and 14 days of treatment).

Mean change from baseline in the percentage of symptom-free days during the 28day treatment period.

Mean change from baseline in the percentage of symptom-free nights during the 28day treatment period.

Mean change from baseline in the percentage of rescue-free days during the 28-day
treatment period.

Mean change from baseline in the percentage of rescue-free nights during the 28-day
treatment period.

Mean change from baseline in daily AM PEF during the first 14 days on study
treatment and over weeks 1, 2, 3, 4 and endpoint of the study.

Mean change from baseline in daily PM PEF during the first 14 days on study
treatment and over weeks 1, 2, 3, 4 and endpoint of the study.
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Withdrawals due to lack of efficacy.

5.6.2.4.

Exploratory efficacy endpoints

Exploratory endpoints, not specified in the protocol, but that were specified in the
Reporting and Analysis Plan (RAP), included:

Weighted mean change from baseline (0-4 h) for FEV1 on Days 1 and 28.

Proportion of subjects obtaining 15% increase from baseline in FEV1 (0-4 h) on


Days 1 and 28.

Mean peak FEV1 (0-4 h) on Day 28.

Ratio of peak to trough in FEV1 on Day 28. The trough FEV1 was defined as the
mean of the FEV1 values obtained 23 and 24 hours (h) after dosing on Day 28, with
no imputation.

5.6.2.5.

Assessments

Measurements are outlined in Table 2.


Clinic measurements of FEV1

FEV1 was measured electronically at all clinic visits in the evening prior to study
medication dosing. Subjects were instructed not to use their rescue albuterol/salbutamol
for at least 6 h prior to the clinic visit. The highest of three technically acceptable
measurements was recorded. At Visit 1 (Screening), FEV1 was measured between 5PM
and 10PM; at Visit 2, pre-dose FEV1 was obtained between 5PM and 8PM. At each
subsequent visit, pre-dose FEV1 was obtained within 1 h of the time of the measurement
of the pre-dose FEV1 at Visit 2. At Visits 3 and 4, FEV1 was measured 23-24 h after the
last dose of study medication.
At Visit 1 (Screening), subjects eligibility was determined by assessing FEV1
reversibility immediately before and 30 minutes after administration of 400 g
salbutamol/albuterol via MDI or 1 nebulised salbutamol/albuterol solution. Subjects who
failed to demonstrate a 12% and 200 mL increase in FEV1 at this visit were not
eligible to take part in the study; however, subjects were allowed to return once within 4
days to repeat this test. If the subject met the lung function entry criteria on the second
attempt, then other Visit 1 procedures were to be performed on this Visit. At Visit 2, the
best pre-dose FEV1 had to be 40% and 90% of the subjects predicted normal to ensure
eligibility.
For randomised subjects an FEV1 Stability Limit was determined, which was derived
from the best pre-dose FEV1 at Visit 2.
In addition to the pre-dose FEV1 measurements at Visits 2 and 5, serial 24-h FEV1
measurements were taken post-dose (see Table 2). At each time point, the highest of a
minimum of three technically acceptable measurements was recorded.

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Response to salbutamol/albuterol

Following completion of the serial 24-h FEV1 measurements at Visit 2 and Visit 5, post
salbutamol/albuterol FEV1 was measured. The subject was administered a single 400 g
dose of inhaled salbutamol/albuterol via MDI or 1 dose of nebulised salbutamol/albuterol
solution and FEV1 was measured 30 minutes after this administration. The highest of
three technically acceptable measurements was recorded. These assessments were
performed as follows:

Between 5PM and 10PM.

6 h after the last use of salbutamol/albuterol (compliance with this was recorded in
the spirometry equipment).

6 h after the last caffeine consumption.

2 h after exercise (or strenuous activity).

24 h after the first dose (Visit 2) or last dose (Visit 5) of study medication.

For Visit 2/2A only, before the dose of study medication was taken on treatment Day
2.

Diary parameters

Daily eDiary parameters were recorded in the electronic daily eDiary from Run-in to
Follow-up. These included morning and evening PEF, day-time and night-time asthma
symptom scores, number of inhalations of rescue salbutamol/albuterol usage during the
day and night, and whether they had taken their regular ICS medication. Subjects
returned their eDiaries to the investigator at each clinic visit. At Visit 2, the eDiary was
checked against the randomisation criteria. At Visits 3, 4 and 5 the Investigator reviewed
all eDiary data to confirm that the Subjects had not met the criteria for withdrawal due to
lack of efficacy.
Subjects were issued a paper medical conditions diary to record adverse events during the
study (see Section 5.6.3). On the paper diary subjects were asked to record the time of
dosing of their study medication on the day (evening) before the clinic visit.
Peak Expiratory Flow Measurements

Morning and evening PEF were measured each morning prior to any rescue
salbutamol/albuterol use and each evening prior to study medication dose (and if
possible, rescue salbutamol/albuterol use) using the eDiary which had a built-in peak
flow meter issued to subjects at Visit 1. Three PEF measurements were made within 30
minutes of each other for each PEF time point and the highest PEF value was recorded in
the daily eDiary. For randomised subjects, a PEF Stability Limit (derived from mean
morning PEF from the available 7 days preceding Visit 2) was calculated by the daily
eDiary.

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Asthma Symptom Scores

Asthma Symptom Scores were recorded BD in the daily eDiary prior to taking any rescue
salbutamol/albuterol or study medication (evening only), and prior to making any PEF
measurements. These reflected the symptoms for the previous day and night and used the
following scales:
Day-time Symptom Score (recorded each evening):
0.

No symptoms during the day.

1.

Symptoms for one short period during the day.

2.

Symptoms for two or more short periods during the day.

3.

Symptoms for most of the day which did not affect my normal daily activities.

4.

Symptoms for most of the day which did affect my normal daily activities.

5.

Symptoms so severe that I could not go to work or perform normal daily activities.

Night-time Symptom Score (recorded each morning):


0.

No symptoms during the night.

1.

Symptoms causing me to wake once (or wake early).

2.

Symptoms causing me to wake twice or more (including waking early).

3.

Symptoms causing me to be awake for most of the night.

4.

Symptoms so severe that I did not sleep at all.

Rescue Salbutamol/Albuterol Usage

Each morning and evening, subjects recorded in their daily eDiary the number of rescue
salbutamol/albuterol inhalations taken using the issued MDIs during the previous 12 h.
Use of spacer devices was not permitted.
Withdrawals Due to Lack of Efficacy

For withdrawals due to lack of efficacy, see Section 5.3.2.


5.6.3.

Safety Assessments

During the study, safety was assessed by monitoring AEs and SAEs, clinical laboratory
tests (haematology, chemistry and urinalysis), vital signs (pulse rate and systolic and
diastolic blood pressure), 12-lead ECGs, and potassium and glucose levels. The
measurements are outlined in Table 2.
From the time a subject consented to participate in and completed the study (including
any follow-up period), all SAEs assessed as related to study participation (e.g., protocolmandated procedures, invasive tests, or change in existing therapy) or related to a GSK
concomitant medication, were reported promptly to GSK. The time period for collection

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of AEs commenced from the time of randomisation (first receipt of investigational


product) and ended after the 7 days follow-up period had been completed.
5.6.3.1.

Adverse Events

An AE was defined as any untoward medical occurrence in a patient or clinical


investigation subject, temporally associated with the use of a medicinal product, whether
or not considered related to the medicinal product. An AE could therefore be any
unfavourable and unintended sign (including an abnormal laboratory finding), symptom,
or disease (new or exacerbated) temporally associated with the use of a medicinal
product.
5.6.3.2.

Serious adverse events

An SAE was defined as any untoward medical occurrence that, at any dose:
1.

Resulted in death;

2.

Was life-threatening;

3.

Required hospitalisation or prolongation of existing hospitalisation;

4.

Resulted in disability/incapacity; or

5.

Was a congenital anomaly/birth defect.

6.

Medical or scientific judgement was to be exercised in deciding whether reporting


was appropriate in other situations, such as important medical events that may not
have been immediately life-threatening or resulted in death or hospitalisation but
may jeopardised the subject or may have required medical or surgical intervention to
prevent one of the other outcomes listed in the above definition. These should also
have been considered serious. Examples of such events are invasive or malignant
cancers, intensive treatment in an emergency room or at home for allergic
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation,
or development of drug dependency or drug abuse.

5.6.3.3.

Asthma exacerbations

For the purposes of this study, a subject was withdrawn due to lack of efficacy if they
experienced a clinical exacerbation, or at the investigators discretion. An exacerbation
was defined as worsening asthma requiring any treatment other than study medication or
rescue salbutamol/albuterol or the subjects regular ICS use. This included requiring the
use of systemic corticosteroids and/or emergency room visit or hospitalisation or a
change in inhaled corticosteroid dose.
Asthma exacerbations were not to be recorded as an AE, unless they met the definition of
an SAE (See Section 5.6.3.2). For the purposes of this study, asthma exacerbations were
recorded on the exacerbations log in the eCRF. The time period for collection of asthma
exacerbations began from the time of randomisation (first receipt of investigational
product) and ended after the Follow-up period had been completed.

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Pregnancies

Pregnancy information was collected from randomisation until Follow-up. To ensure


subject safety, each pregnancy was to be reported to GSK within 2 weeks of learning of
its occurrence, and followed up to determine outcome (including premature termination)
and status of mother and child. Pregnancy complications and elective terminations for
medical reasons were to be reported as an AE or SAE. Spontaneous abortions were to be
reported as an SAE.
Any SAE occurring in association with a pregnancy, brought to the investigators
attention after the subject had completed the study and considered by the investigator as
possibly related to the investigational product, was to be promptly reported to GSK.
Subjects who became pregnant during the study were to discontinue the study medication
and were withdrawn from the study.
5.6.3.5.

Other safety assessments

Clinical laboratory tests

Haematology and clinical chemistry tests were performed after 14 days and 28 days of
treatment and dipstick urinalysis parameters after 28 days of treatment (Table 2). All
blood samples were sent to a central laboratory for analysis. A mid-stream urine sample
was collected for urinalysis tests. These were analysed in a central laboratory.
If the clinical laboratory tests were taken prior to performing the lung function testing and
the subject met the lung function entry criteria based on the second lung function attempt
(within 4 days of Visit 1), the investigator was to document that the laboratory results
were clinically acceptable within the 4-day screening period. Additional samples could
be taken for safety reasons at the discretion of the investigator.
Fasting serum potassium and plasma glucose were monitored to assess the PD effects of
GW642444M. Subjects were asked to fast for at least 4 h prior to the planned blood draw
at Screening (Visit 1) and for at least 4 h prior to the pre-dose blood samples and until
after the 4 h post-dose blood samples at Visits 2 and 5. Non-fasting potassium was
monitored at Visits 3 and 4. The following endpoints were derived:

Maximum decrease from baseline and from pre-dose (0-4 h) for potassium.

Weighted mean change from baseline and from pre-dose (0-4 h) for potassium.

Maximum increase from baseline and from pre-dose (0-4 h) for glucose.

Weighted mean change from baseline and from pre-dose (0-4 h) for glucose.

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12-Lead ECGs

12-lead ECGs were measured by the investigator or his/her suitably qualified designee at
Visits 2, 3, 4 and 5 (Table 1) to derive the following endpoints:

Weighted mean change from baseline and from pre-dose (0-4 h) in QTc(F) (QT
interval corrected by Fridericia's method).

Weighted mean change from baseline and from pre-dose (0-4 h) in QTc(B). (QT
interval corrected by Bazett's method).

Maximum change from baseline (0-4 h) for QTc(F) and QTc(B).

ECGs were recorded after 5 minutes rest, after measurement of vital signs and before
clinic lung function tests at the specified time. If the subject failed the lung function
criteria at the first attempt, and only became eligible for the study at the second screening
visit the investigator was to document that the ECG results were clinically acceptable
within the 4-day screening period.
A cardiologist who was independent from GSK and who was blinded to treatment
assignment was responsible for providing an official interpretation of all ECGs collected.
A hard copy of the results was sent to the study site. If there was a discrepancy between
the assessment by the investigator and that by the independent cardiologist, the
assessment of the latter was used in all analyses and data presentations.
At Visit 2, the manual reading and calculation of the ECG parameters was used to
determine whether a subject met the eligibility criteria for enrolment in the study. Also at
this visit, the pre-dose ECGs were interpreted by the independent cardiologist as: within
normal limits; abnormal, not clinically significant; or abnormal, clinically significant. If
the pre-dose ECG at Visit 2 was judged to be abnormal and clinically significant, the
subject was to be withdrawn from the study. If any of the abnormalities in ECGs
outlined in Section 5.3.2 (withdrawal criteria) were observed pre-dose Visit 2 or after
randomisation, the subject was withdrawn from treatment.
The ECG was repeated at the Follow-up visit if it was clinically significantly abnormal at
Visit 5.
Vital signs

At Visits 2, 3, 4 and 5, pulse rate and systolic and diastolic blood pressure measurements
were performed in the sitting position after 5 minutes rest. Measurements were taken
before any clinic lung function assessments or ECGs at the specified time point. The
following endpoints were derived:

Change from baseline and from pre-dose in maximum value (0 - 4 h) for systolic
blood pressure.

Change from baseline and from pre-dose in minimum value (0 - 4 h) for diastolic
blood pressure.

Change from baseline and from pre-dose in maximum value (0 - 4 h) for pulse rate.

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Weighted mean change from baseline and from pre-dose (0 - 4 h) for blood pressure
and pulse rate.

The additional assessments following finalisation of Protocol Amendment 3 are detailed


in Section 5.8.1.1.
5.6.4.

Pharmacokinetic Assessments

The pharmacokinetic endpoints were:

Plasma concentrations of GW642444, the triphenylacetate counter ion (GI179710)


and the GW642444 metabolites GW630200 and GSK932009; and derived
population PK parameters for GW642444 in subjects with persistent asthma
following once-daily treatment for 28 days.

Relationship between systemic exposure to GW642444 (Cmax) and systemic


pharmacodynamic endpoints.

Assessments

Blood samples for the determination of GW642444, GI179710, GW630200 and


GSK932009 concentrations were collected from all subjects over 4 visits (Visits 2, 3, 4
and 5) as outlined in Table 2 and summarised as follows:

Visits 2 and 5: subjects attended the evening clinic without having taken their study
medication. A pre-dose sample was collected at the beginning of their clinic visit.
Additional samples were then taken post-dose. Every attempt was made to collect
samples at times spread throughout the time window.

Visit 3: subjects attended the evening clinic without having taken their study
medication. A pre-dose sample was collected at the beginning of their clinic visit.

Visit 4: Subjects attended the evening clinic without having taken their study
medication. One sample was taken post-dose. Every attempt was made to collect
samples at times spread throughout the time window.

Only samples from subjects receiving GW642444 were analysed for GW642444,
GI179710, GW630200 and GSK932009. In a change from what is stated in the protocol,
samples from subjects on all dose levels of GW642444 were analysed for the metabolites
(GW630200 and GSK932009) and the triphenylacetate counterion.
PK Sample Assay: Human plasma samples were analysed for GW642444, GSK932009,
GW630200 and GI179710 using a validated analytical method based on protein
precipitation, followed by high performance liquid chromatography/mass
spectrometry/mass spectrometry (HPLC/MS/MS) analysis. Two methods were used, the
first method has a lower limit of quantification (LLQ) of 30 pg/mL for GW642444, 180
pg/mL for GSK932009 and 90 pg/mL for GW630200 using a 150 L aliquot of human
plasma [GlaxoSmithKline Document number: WD2006/02197/00, 2006]. The second
method has a LLQ of 1 ng/mL for GI179710 using a 100 L aliquot of human plasma
[GlaxoSmithKline Document number: WD2006/02527/00, 2006]. The computer systems

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that were used on this study to acquire and quantify data included Analyst Version 1.4.1
and 1.4.2 and SMS2000 version 2.0 and 2.1
Methods for the determination of GW642444, GSK932009, GW630200 and GI179710 in
human plasma (range 30 to 15000, 90 to 45000, 180 to 90000 pg/mL and 1 to 1000
ng/mL, respectively) using HPLC/MS/MS have been validated. Within-run precision and
accuracy of quantification during the validation for GW642444, GSK932009,
GW630200 and GI179710 was better than 15% across the concentration range.
Quality Control (QC) samples, prepared at three different analyte concentrations and
stored with study samples, were analysed with each batch of samples against separately
prepared calibration standards. For the analysis to be acceptable, no more than one-third
of the QC results were to deviate from the nominal concentration by more than 15%, and
at least 50% of the results from each QC concentration should be within 15% of nominal.
All applicable analytical runs met all predefined run acceptance criteria.
In total, 504 subjects provided 5564 PK samples (non-missing) following administration
of GW642444M (3 - 50 g).
5.6.5.

Pharmacogenetic Assessments

Written approval from the IEC/IRB and, where required, the applicable regulatory
agency was required before PGx assessments could be conducted at the site. If approval
of PGx assessments occurred after approval was obtained for the rest of the study, the
written approval was to clearly indicate that approval of the PGx assessments was being
deferred and that the study, except for PGx assessments, could be initiated. When PGx
assessments were not approved, then the approval for the rest of the study clearly
indicated this and therefore, PGx assessments were not conducted.
Subjects who consented to participate in the PGx research provided a blood sample at
Visit 2.

5.7.

Data Quality Assurance

In accordance with applicable regulations, GCP and GSK procedures, GSK monitors
contacted the site prior to the start of the study to review with the site staff the protocol,
study requirements, and their responsibilities to satisfy regulatory, ethical and GSK
requirements. GSK monitored the study to ensure that the data were authentic, accurate
and complete; safety and rights of subjects were being protected; and that the study was
conducted in accordance with the currently approved protocol and any other study
agreements, GCP and all applicable regulatory requirements. GSK could conduct a
quality assurance audit of the site records and the regulatory agencies could conduct a
regulatory inspection at any time during or after completion of the study.
Subject data were captured and completed within 7 days of the subject visit by the
investigator or his/her designee using an eCRF. This study used the InForm eCRF (Phase
Forward, UK), which is a web-based clinical trials data management system. Activities
performed using InForm include data entry, modification, review and validation of
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clinical data. Each activity performed carries a unique user identification code and a
date-time stamp. Study-specific training on eCRF completion was provided at the
monitors and investigator meetings. Additionally, an InForm interactive training
database was available to site staff and study monitors for independent follow-up
training.
The eCRF was fully validated using test data, prior to distributing the url for site use.
Encrypted clinical trial data were transmitted from the site via the internet to a firewallprotected network server, and then via an application server into the clinical database.
An electronic audit trail of all changes made to the eCRF was kept within the InForm
system. This audit trail identified the user making the change by user ID, and date and
time of change. Pre-defined data validation checks were run within the eCRF as the data
were entered and submitted by authorized site staff. The resulting data queries were then
resolved. Additional queries were generated within the eCRF by authorized GSK staff
following data review. All data queries issued were to be answered by the site within 7
days from the date of issue or sooner as the study came to an end or, for example if GCSP
required a quick turnaround on SAEs information or data queries were required for
regulatory reports.
The principal investigator electronically signed and dated each InForm casebook attesting
to his/her responsibility for the quality of all data included therein, and that the data
represented a complete and accurate record of each subject's participation in the study.
At the end of the study, once all data queries were resolved, a CD-ROM containing eCRF
PDFs (the PDF contained all of the patient's eCRF data, the data queries, and a copy of
the audit trail) was sent to site along with a letter explaining how to view the data on the
PDF. Upon delivery of the CD-ROM, the study site notified GSK of receipt of the CD.
After data management procedures were completed, the database was released on 20
October 2008. Following release the database was frozen on 22 October 2008. The
original validated data (eCRFs, etc.) were archived according to company standard
procedures.
Subjects were also provided with a paper medical conditions diary card on which they
recorded all medical problems which may have occurred and all medications (except
study-related medications) taken to treat medical problems, as well as the time of
previous days dose (for PK assessments). Sites were instructed to review the paper diary
card and record all medical problems, which were considered AEs, and record all
concomitant medications into the eCRF at every study visit. Once completed, sites were
required to tear out the diary card page from the previous period at each visit and store in
the patient notes.
Diary data were collected using Asthma Monitor 2+ (AM2+, Cardinal Health Services)
eDiary every day throughout the study from Visit 1 (Screening) to Visit 6 (Follow Up)
and downloaded to the Cardinal Health Research Services server at the clinic visits. The
Cardinal Health Research Services Masterscope CT Users manual had primary contact
information for subject help requests.

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GSK Data Management and Cardinal Health Research Services performed limited data
checking, comparing the eDiary visit information to the eCRF visit information to ensure
consistency across each subject's data. Any data queries that arose (e.g., if a visit had
occurred in InForm eCRF but there was no corresponding data from Cardinal Health
Research Services) was either sent directly from the vendor or generated in the InForm
system, and had the same turnaround timelines as those for other InForm data. All
queries had to be addressed and closed prior to releasing the database.
In addition to InForm eCRF data, electronic laboratory data (Quest Laboratories, UK),
electronic spirometry data, ECG and electronic diary data (Cardinal Health Research
Services) were delivered to GSK. These data were reconciled with the eCRF data and
any resulting discrepancies were queried either within the eCRF or by the vendor using
their own SOPs. All queries had to be addressed and closed prior to releasing the
database.
Quality Control (QC) tasks were conducted in accordance with existing data management
standard operating procedures to ensure database accuracy against the data collected in
the eCRF and any other subject-completed documents. QC procedures are in alignment
with the International Conference on Harmonisation of Good Clinical Practice (ICH
GCP).
AEs and concomitant medications terms were coded using the Medical Dictionary for
Regulatory Activities (MedDRA) and GSKDrug, an internal validated medication
dictionary. An appropriate medical dictionary that covered all approved drugs in the
region was referenced.
SAE data were documented according using the SAE data collection tool. Once an
investigator became aware that an SAE has occurred in a study subject, he/she was to
report the information to GSK within 24 h, as outlined in the Protocol.

5.8.

Data Analysis Methods

Further details are provided in the Reporting and Analysis Plan (RAP).
5.8.1.

Timings of Planned Analyses

All planned analyses were performed after the database freeze had taken place. No
interim analysis was planned or conducted.
5.8.1.1.

Changes in the conduct of the study or planned analyses

The following changes in analyses were made after RAP sign-off but before unblinding2:

Addition of a repeated measures analysis of serial FEV1 on Days 1 and 28.

These changes were documented in filenotes to the study file before unblinding.

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Addition of a box plot of the maximum increase from baseline in pulse rate.

The first two rules stated in Section 10.2 of the RAP for protocol deviations3 were
changed as follows:

With respect to failure of inclusion, exclusion, or randomisation criteria,


subjects from the Per Protocol (PP) Population4 were excluded if they failed on
any efficacy-related criteria. Failure on criteria that were deemed to be not
related to efficacy did not result in exclusion from the PP Population. The
following criteria were deemed to be efficacy-related:

Inclusion criteria 3, 4, 5, 6, 8.

Exclusion criteria 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14.

Randomisation criteria 1, 2, 6, 7, 8, 9, 10.

With respect to taking of prohibited medications, subjects from the PP


Population were excluded if they took prohibited medications that could affect
efficacy. Taking of prohibited medications that were deemed to be not related to
efficacy did not result in exclusion from the PP Population.

Post-Hoc Analyses

Post-hoc analyses described in the CSR include:

Listing of subject treatment compliance >110% (Listing 6.101, Attachment 5).

Summary of Background Steroid Dose During Treatment (Table 6.103).

Summary of the proportion of subjects obtaining 200mL and 12% increase from
baseline FEV1 (0-24 h) (Table 7.105 and Figure 7.109).

Potassium profiles for subjects with values >7 mmol/L (Figure 8.101).

5.8.2.

Sample Size Considerations

The sample size of 594 subjects (99 subjects per group) with at least one pre-dose or 2324 h post-dose FEV1 assessment on or after nominal Day 7 was based on the primary
endpoint of change from baseline in trough FEV1. This approach had 97% power to
detect a slope of 4 mL/g (a dose response effect of 200 mL improvement in FEV1 per 50
g of GW642444M), assuming a standard deviation of 430 mL based on previous studies
and significance declared at the two-sided 5% level.
Similarly, there was >99% power to detect slopes of 8 mL/g (200 mL improvement per
25 g dose), 16 mL/ g (200 ml improvement per 12.5 g dose) and 32 mL/g (200 mL

Subjects with protocol deviations were defined as those who were randomised or entered into the trial, but
deviated from the protocol. Protocol deviations could be either full or partial (see Section 10.2 of the
RAP).

The PP Population is defined in Section 5.8.3.

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improvement per 6.25 g dose). The 3 g dose was assumed to be a non-effective dose
and the study had approximately 96% power to detect a 200 mL effect between this dose
and the 50 g dose, excluding placebo from the dose-response analysis. Furthermore, the
study had 90% power to detect a difference of 200 mL in pair-wise comparisons of
change from baseline in trough FEV1 between any active dose and placebo. Pair-wise
tests of each dose versus placebo were only performed if the linear trend in dose-response
proved significant.
Any subject whose FEV1 measurement at Day 28 was missing was included in the
analysis of the primary endpoint by imputation using the preceding non-missing trough
FEV1 value (Last Observation Carried Forward [LOCF]). Trough values prior to Day 7
pre-dose were not carried forward. Similarly, the primary endpoint was also analysed
using Repeated Measures whereby missing data were not directly imputed but the
correlation between visits for all subjects was used to adjust the estimate of treatment
effect.
No sample size review was planned or was conducted for this study.
5.8.3.

Analysis Populations

Four subject populations were identified in this study:


Total Population: This population comprised all subjects who were screened and for
whom a record existed on the study database. The Total Population was used for the
tabulation and listing of reasons for withdrawal before randomisation and listing of SAEs
for non-randomised subjects.
Intent-to-Treat (ITT) Population: The ITT Population comprised all subjects who were
randomised to treatment and who received at least one dose of study medication.
Randomised subjects were assumed to have received trial medication unless definitive
evidence to the contrary existed. This constituted the primary population for all analyses
of efficacy measures and safety measures.
Per Protocol (PP) Population: The PP Population consisted of all subjects in the ITT
Population who did not have any full protocol deviations. Protocol deviations could be
either full or partial. Subjects with only partial deviations were considered part of the PP
Population but from the date of their deviation onwards, their data were excluded. The
decision to exclude a subject from the PP Population was made prior to breaking the
blind. Protocol deviations that would lead to full or partial exclusion from the PP
Population are detailed in Section 10.2 of the RAP; changes to the first two rules stated in
Section 10.2 of the RAP made prior to unblinding are detailed in Section 5.8.1.1.
The PP population was used for confirmatory analyses of the primary efficacy endpoint
only.
PK Population: The PK Population comprised those subjects in the ITT Population for
whom a pharmacokinetic sample was obtained and analysed.

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Treatment Comparisons

The primary treatment comparison was a test of linear trend in dose response in trough
(pre-bronchodilator and pre-dose) evening FEV1 derived from the mean of the 23 and 24
h post-dose assessments at Day 28 across the five doses of GW642444M and placebo in
order to demonstrate overall efficacy of GW642444M relative to placebo. If the test of
linear trend was statistically significant, pair-wise tests of each dose versus placebo were
to be performed to identify effective doses. These comparisons were performed using the
ITT Population using Analysis of Covariance (ANCOVA) with LOCF to impute missing
data. A supporting analysis was also performed using a Repeated Measures Mixed
Model. Missing data were not implicitly imputed in this analysis. However, all nonmissing data for a subject were used within the analysis to estimate the Day 28 treatment
effects.
Since the pair-wise comparisons with placebo were only to be performed if the trend test
demonstrated overall efficacy of GW642444M, no further multiplicity adjustments were
planned.
The primary comparisons were supported by the same tests performed using the PP
Population. Furthermore, the dose response across the five doses of GW642444M was
explored using the ITT Population excluding placebo from the analysis.
Pair-wise comparisons were performed for all of the secondary and other efficacy
endpoints.
5.8.5.

General Considerations for Data Analyses

All programming was performed in a Harmonisation for Analysis and Reporting Program
(HARP) environment using SAS Version 8.2 or a later release.
5.8.5.1.

Multicentre studies

This study was conducted in 88 centres (worldwide). All centres within the same country
were pooled. Countries enrolling less than 12 subjects in total were pooled with other
countries within a similar geographical region and these amalgamations were used
whenever country was included in the analysis. All summaries and analyses were of all
countries combined (analysis models included country as a covariate).
5.8.5.2.

Other strata and covariates

All models used for the efficacy and safety analyses were adjusted for baseline value,
country, sex, age, baseline percent predicted FEV1 stratum and treatment group. Any
stratum by treatment interaction was explored as part of the model-checking process.
5.8.5.3.

Examination of subgroups

No subgroup analyses were performed for this study.

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5.8.5.4.

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Multiple comparison/multiplicity

No multiplicity adjustments were applied, for the reasons stated in Section 5.8.4.
5.8.6.

Data Handling Conventions

Full details of analysis considerations and handling conventions can be found in


Section 9 of the RAP.
5.8.7.

Study Population

Summaries of subject disposition, protocol deviations (agreed upon prior to unblinding


the study), demographic and baseline characteristics (demography and race, history of
asthma and tobacco use, medical conditions and concomitant medications, summary of
screening lung functions test results) and treatment compliance are described in
Section 10 of the RAP.
5.8.8.

Efficacy Analyses

Full details can be found in Section 11 of the RAP.


5.8.8.1.

Primary efficacy measure(s)

The primary endpoint of mean change from baseline at Day 28 in trough (evening prebronchodilator and pre-dose) FEV1 was derived from the mean of the 23 and 24 h postdose assessments. The dose-response was evaluated for Day 28. Provided the doseresponse test was statistically significant, estimated treatment differences for all pair-wise
comparisons for Day 28 were presented. These primary analyses were performed using
ANCOVA models on the Day 28 data with effects due to baseline FEV1, centre grouping
(country), age, sex, baseline percent predicted FEV1 stratum and dose/treatment group,
imputing missing data using last observation carried forward (LOCF).
The primary analyses were also performed on the PP Population.
The primary comparisons were also performed in a sensitivity analysis using a repeated
measures model allowing for effects due to baseline FEV1, centre grouping, age, sex,
baseline percent predicted FEV1 stratum, visit and treatment group. Data from Day 7
(pre-dose assessment), Day 14 (pre-dose assessment), and Day 28 (pre-dose assessment
and the mean of the 23 and 24 h post-dose assessments) were included. This model also
contained a visit-by-treatment interaction term. A linear trend contrast was constructed
for Day 28 to evaluate the dose-response trend.

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5.8.8.2.

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Secondary efficacy measure(s)

Strata analyses of trough FEV1

The primary endpoint of change from baseline in trough FEV1 at the end of treatment
was analysed for each percent predicted FEV1 strata separately, in order to investigate the
consistency of the dose-response relationship for the different disease severities. An
ANCOVA model with effects due to baseline trough FEV1, centre grouping, age, sex and
dose was used to estimate the dose response slope for each baseline percent predicted
FEV1 stratum. An ANCOVA model with effects due to baseline trough FEV1, centre
grouping, age, sex, stratum, treatment group and treatment group-by-stratum interaction
was used to estimate the treatment differences for all pair wise comparisons for each
stratum. Statistical significance testing was not performed for the strata analyses.
Summaries of the as-randomised and actual stratum, and summaries by actual stratum of
Day 1 pre-dose percent predicted FEV1 were presented.
0-24 h Weighted mean serial FEV1

The 24-h serial FEV1 was measured on Days 1 and 28 (pre-dose, and 15, 30 and 60
minutes and 2, 3, 4, 6, 12, 16, 20, 22, 23 and 24 h post-dose), with the 6 and 12 h time
points only measured in a subgroup of subjects. The change from baseline in weighted
mean for 24-h serial FEV1 on Days 1 and 28 was compared using an ANCOVA model
for each GW642444M group versus placebo.
Additionally, three sensitivity analyses were performed to assess the impact of the 6-12
hour time points, as follows:

All subjects. The 6-12 h time points were excluded.

Subset of subjects who had the 6-12 h time points measured. All time points were
included.

Subset of subjects who had the 6-12 h time points measured. The 6-12 h time points
were excluded.

Pair-wise comparisons of each GW642444M dose with placebo were performed.


PEF

For PEF-related endpoints, the baseline value was derived from the last 7 days of the
daily eDiary prior to the randomisation of the subject.
Evening trough PEF
The change from baseline in daily trough (pre-dose and pre-rescue bronchodilator)
evening PEF averaged over the 28-day treatment period was compared using an
ANCOVA model for each GW642444M dose versus placebo.

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Morning PEF
The change from baseline in daily morning PEF averaged over the 28-day treatment
period was compared using an ANCOVA model for each GW642444M dose versus
placebo.
Percentage of symptom- and rescue-free 24-h periods

The change from baseline in the percentage of symptom-free 24-h periods and rescuefree 24-h periods over the 28-day treatment period was calculated for each subject.
Baseline was derived from the last 7 days of the daily eDiary prior to randomisation of
the subject. Comparisons were then made using an ANCOVA model of each
GW642444M dose versus placebo.
Response to salbutamol/albuterol

The post-salbutamol/albuterol FEV1, measured 30 minutes after a single dose of 400 g


albuterol/salbutamol, was summarised at Screening, 24 h after dosing on Day 1 and 24 h
after dosing on Day 28. The differences between Screening, 24h after dosing on Day 1
and 24h after dosing on Day 28 were also summarised.
The following were derived for each subject and compared using an ANCOVA model for
each GW642444M group vs. placebo:

The difference in post-salbutamol/albuterol FEV1 between 24 h after dosing on Day


1 (Visit 2) and on Day 28 (Visit 5).

The difference in post-salbutamol/albuterol FEV1 between Screening (Visit 1) and


24 h after dosing on Day 1 (Visit 2).

The difference in post-salbutamol/albuterol FEV1 between Screening (Visit 1) and


24 h after dosing on Day 28 (Visit 5).

Baseline in this analysis was defined as the pre-salbutamol FEV1 value taken at
Screening Visit 1.
5.8.8.3.

Other efficacy measure(s)

Details of other efficacy measures are provided in Section 11.3 of the RAP.
FEV1 (0-4 h) on Days 1 and 28

The maximum increase and weighted mean change in FEV1 (0-4 h) on Days 1 and 28
compared with baseline was calculated for each subject. Comparisons were then made of
each GW642444M dose versus placebo using an ANCOVA model with effects due to
baseline FEV1, centre grouping, age, sex, baseline percent predicted FEV1 stratum and
treatment group. Estimated treatment differences for all comparisons were presented.
Summaries were produced for the proportion and cumulative proportion of subjects
obtaining both 200 mL and 12% increase from baseline in FEV1 (0-4 h) at each
planned time point on Days 1 and 28; the proportion and cumulative proportion of
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subjects obtaining 15% increase from baseline in FEV1 (0-4 h) at each planned time
point on Days 1 and 28; and peak to trough FEV1 ratio on Day 28. Peak post-dose FEV1
(0-4 h) on Day 28 was also summarised and analysed as described above for maximum
increase in FEV1 (0-4 h).
Percentage of Symptom-free and Rescue-free Days and Nights

The mean change from baseline in the percentage of symptom-free days, symptom-free
nights, rescue-free days and rescue-free nights over the 28 day treatment period was
calculated for each subject. Comparisons were then made of each GW642444M dose
versus placebo using an ANCOVA model with effects due to baseline value, centre
grouping, age, sex, baseline percent predicted FEV1 stratum and treatment group.
Estimated treatment differences for all comparisons were presented.
Withdrawals Due to Lack of Efficacy

Fishers Exact test was used to compare the number of withdrawals due to lack of
efficacy between each GW642444M treatment group versus placebo.
5.8.9.

Safety Analyses

The analyses of the safety data are detailed in Section 12 of the RAP.
5.8.9.1.

Extent of Exposure

The extent of exposure was summarised by treatment group. Exposure was defined as
[date of last dose - date of first dose] + 1.
5.8.9.2.

Adverse Events

AEs were coded using the standard GSK dictionary MedDRA. AEs were classified as
pre-treatment, during active treatment (on-treatment) and post-treatment. Narratives for
withdrawals due to AEs were supplied.
5.8.9.3.

Clinical Laboratory Evaluations

Clinical laboratory evaluations, including haematology, clinical chemistry and dipstick


urinalysis parameters were summarised by treatment group. Baseline was defined as the
Screening Visit 1 value.
5.8.9.4.

Vital Signs Assessments

Vital signs (pulse rate, systolic blood pressure and diastolic blood pressure) were
summarised by treatment for each clinic visit. Additionally, the following derived vital
signs endpoints were analysed: change from baseline and pre-dose in maximum value (04 h) for systolic blood pressure, change from baseline and pre-dose in minimum value (04 h) for diastolic blood pressure, change from baseline and pre-dose in maximum value
(0-4 h) for pulse rate, and weighted mean change from baseline and pre-dose (0-4 h) for
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blood pressure and pulse rate. Pair-wise comparisons of each active treatment group
versus placebo were also performed.
The baseline for vital signs was defined as the Visit 2 pre-dose assessment. If the
baseline was missing, then the screening Visit 1 value was used in its place.
5.8.9.5.

12-Lead ECG

0-4 h post-dose QTc(F) and QTc(B), and maximum QTc(F) and QTc(B), were summarised
for Day 1, Day 7, Day 14 and Day 28. Maximum change from baseline, weighted mean
change from baseline and weighted mean change from pre-dose were also summarised.
Post-dose serial QTc(F) and QTc(B) and change from baseline endpoints were analysed
using ANCOVA as for derived vital signs endpoints (see Section 12.7.1 of the RAP).
Pair-wise comparisons of each active treatment versus placebo were performed and
treatment differences were presented.
Baseline was defined as Visit 2 pre-dose value. If the Visit 2 pre-dose assessment was
missing, then the screening Visit 1 value was used.
5.8.9.6.

Potassium and Glucose

Fasting serum potassium and plasma glucose data were summarised by treatment for Day
1 and Day 28 and for non-fasting potassium on Day 7 and 14, and were used to derive the
following endpoints:

Maximum decrease from baseline and pre-dose (0-4 h) for potassium.

Weighted mean change from baseline and pre-dose (0-4 h) for potassium.

Maximum increase from baseline and pre-dose (0-4 h) for glucose.

Weighted mean change from baseline and pre-dose (0-4 h) for glucose.

Baseline was defined as Visit 2 pre-dose value. Data were analysed using ANCOVA
with effects due to baseline value, centre grouping, age, sex, baseline-predicted FEV1
stratum and treatment group. Pair-wise comparisons of each treatment group versus
placebo and summaries of change from baseline and change from pre-dose were
presented.
5.8.9.7.

Exacerbations

The number and percentage of subjects who had an asthma exacerbation, who took oral
corticosteroids for an exacerbation, who were hospitalised due to an exacerbation or who
had an emergency room visit due to an exacerbation were summarised separately
alongside the primary causes of asthma exacerbations.

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5.8.9.8.

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Novel Dry Powder Inhaler Malfunction

Subjects with a Novel Dry Powder Inhaler malfunction were listed with the primary
reason for malfunction.
5.8.10.

Pharmacokinetic and Pharmacokinetic/Pharmacodynamic


Analyses

Details of the planned analysis can be found in Section 13 of the RAP.


Plasma concentrations of GW642444, GW630200, GSK932009 and triphenylacetate
counter-ion were listed by treatment, subject, day and relative time of sample collection.
For each analyte, the percentage (%) of samples which had concentrations below the limit
of quantification (30 pg/mL) were summarised by treatment and sample collection
window. GW642444 concentrations were summarised descriptively by treatment, visit
and sample collection window.
Samples excluded from the pharmacokinetic analysis (no sample, sample not analysed,
no result, insufficient sample for analysis or missing dosing/sampling information) were
listed.
As a consequence of the limited nature of the concentration-time data at lower doses (25
g), only plasma GW642444 concentration-time data following 50 g GW642444M
were subjected to nonlinear mixed effects modelling using the NONMEM software
(Version V.1 and VI, Globomax, MD) within the OBIWAN interface and database for
Version V.1 (GSK Validated System). Additional to what is stated in the RAP, plasma
GW642444 concentration-time data following all treatments were analysed using the
non-compartmental Model 200 (for extravascular administration) of WinNonlin
Professional Edition Version 5.2 (Pharsight Corporation, Mountain View, CA) according
to the standard operating procedures described in Standard Methods for the NonCompartmental Analysis of Pharmacokinetic Data (GUI-CPK-3001 v02, 17-Dec-08).
The noncompartmental analysis was conducted to estimate the first occurrence of the
maximum observed plasma concentration (Cmax) and the time at which Cmax was
observed (tmax) for evaluable subjects over the period 2-30 minutes post-dose on Days 1
and 28 (across 2-10 min and 10-30 min sample collections). Systemic exposure (Cmax)
estimates were summarised descriptively. The role of influential covariates on the PK
disposition (Cmax) was investigated.
The relationship between selected systemic PD endpoints (including pulse rate, QTc,
glucose and potassium) and systemic exposure to GW642444 (individual observed
Cmax) was explored graphically. Individual observed Cmax was merged with subject
demographics, treatment and systemic pharmacodynamic endpoints. Where individual
Cmax following active treatment was non-quantifiable (NC) it was set to 15pg/mL (1/2
LLQ). After placebo treatment Cmax was set to zero (0 pg/mL). Where the pair-wise
comparisons between active treatment and placebo for the systemic PD parameters
showed a statistically significant treatment effect and there was evidence for a
concentration-effect relationship (pulse rate and QTc(B)), a model-based evaluation of the
relationship between GW642444M systemic exposure (Cmax) and systemic safety
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endpoints was investigated. The systemic PK/PD analysis was conducted using the
NONMEM software (Version 5.1, Globomax, MD) within the OBIWAN interface and
database (GSK Validated System). Excel and R 2.6.2 were utilised for graphical and
summary evaluations for both PK and PK/PD analyses.
To supplement the information provided from the primary statistical analysis a
population mixed-effect dose-response analysis was performed using mean change from
baseline trough FEV1 data (evening pre-bronchodilator and pre-dose) derived from the
mean of the 23 and 24 h post-dose assessments. The ITT dataset containing observed
individual trough Day 28 FEV1 data with patient covariates was used for estimating the
dose response model parameters (including placebo effect and inter-patient variability,
potency (ED50) and maximum predicted effect (Emax). Non-linear mixed effects model
with the program NONMEM V1 Level 2.0 as implemented in PDxPop V3.10, ICON
Dev. Solns (2008) was used. Further details on the methodology and results are provided
in Attachment 4.
5.8.11.

Pharmacogenetic Analyses

No analysis of PGx samples was planned. If at any time a potential unexpected or


unexplained variation in drug handling or response is apparent that may be attributable to
genetic variation (e.g., PK, efficacy and/or safety), then PGx analysis will be considered
and will be the topic of a separate report.

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6.

STUDY POPULATION RESULTS

6.1.

Disposition of Subjects

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A total of 1140 subjects were screened of whom 614 (54%) were randomised (Table 3).
The most common reason for Screening failure was not meeting continuation criteria.
Table 3

Withdrawals prior to Randomisation

Number of Subjects screeneda (N)


Randomised, n (%)
Not randomised, n (%)
Primary reasons for subject not randomising, n (%)
Did not meet continuation criteria
Study closed/terminated
Withdrew consent
Source data: Table 6.1 and Table 6.2.
a.

1140
614 (54%)
526 (46%)
457 (40%)
29 (3%)
19 (2%)

Of the 614 randomised subjects, 607 (99%) were included in the ITT Population having
received at least one dose of study medication; 583 (95%) were included in the PP
Population (Table 4). In total, 539 (89%) subjects in the ITT Population completed the
study (Run-in to Follow-up). The most common primary reason for withdrawal from the
study was Lack of efficacy which was reported by 33 (5%) of subjects, followed by
Subject reached protocol-defined stopping criteria (18 subjects [3%]). Two (<1%)
subjects withdrew with the primary reason due to AEs.

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Table 4

End of Study Record (ITT Population)


Placebo

3 g
GW642444

6.25 g
GW642444

12.5 g
GW642444

25 g
GW642444

Totala
Randomised,N(%)
103
102
102
102
103
ITTb, n (%)
102 (>99)
101 (>99)
101 (>99)
100 (98)
101 (98)
Lower stratumc
44 (43)
46 (46)
43 (43)
42 (42)
47 (47)
Upper stratumd
58 (57)
55 (54)
58 (57)
58 (58)
54 (53)
PPe, n (%)
98 (95)
97 (95)
98 (96)
98 (96)
93 (90)
Completion status, n (%)
Completed
86 (84)
84 (83)
91 (90)
88 (88)
93 (92)
Withdrawn
16 (16)
17 (17)
10 (10)
12 (12)
8 (8)
Primary reason for withdrawalf, n (%)
Lack of Efficacy
9 (9)
12 (12)
3 (3)
5 (5)
4 (4)
Subject reached
3 (3)
1 (<1)
7 (7)
3 (3)
2 (2)
protocol-defined
stopping criteria
Subject withdrew
3 (3)
0
0
1 (1)
1 (<1)
consent
Investigator
0
1 (<1)
0
1 (1)
0
discretion
Protocol deviation
1 (<1)
2 (2)
0
1 (1)
0
AE
0
1 (<1)
0
0
1 (<1)
Lost to Follow-up
0
0
0
1 (1)
0
Source data: Table 6.1, Table 6.3, Table 6.23.
a. Total: all subjects screened and for whom a record exists on the study database.
b. ITT: all randomised subjects who received at least a single dose of study medication.
c. Lower Stratum: FEV1 percent predicted 40% - 65%.
d. Upper stratum: FEV1 percent predicted 65% - 90%.
e. PP: all subjects in the ITT Population who did not have any full protocol deviations.
f. The primary reason for withdrawal as determined by the Investigator.

50 g
GW642444

Total

102
102 (100)
46 (45)
56 (55)
99 (97)

1140
614 (54)
607 (99)
268 (44)
339 (56)
583 (95)

97 (95)
5 (5)

539 (89)
68 (11)

0
2 (2)

33 (5)
18 (3)

1 (<1)

6 (<1)

2 (2)

4 (<1)

0
0
0

4 (<1)
2 (<1)
1 (<1)

Within the ITT Population, attendance at each clinic visit for all treatment groups was
similar (>87%) and is summarised in Table 6.4. Twenty-seven (4%) subjects were 12-17
years of age (Listing 6.4, Attachment 5) and had been recruited by centres for which no
age limit had been set.

6.2.

Protocol Deviations

Few full protocol deviations were reported for the ITT Population (24 subjects [4%]).
These included failure to meet inclusion, exclusion or randomisation criteria, use of
prohibited medications, or any other deviations deemed to have the potential for
influencing the primary endpoint (Table 6.7). The treatment group with the highest
number of full protocol deviations was the 25 g GW642444M treatment group (8
subjects [8%] within this group).
Twenty two subjects (4%) in the ITT Population had part of their data excluded from the
PP analysis due to partial protocol deviations (Table 6.7). These subjects used prohibited
medications or remained in the study after falling below the FEV1 or PEF stability limit,
after an exacerbation, or after excessive use of rescue medication. The highest number of

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partial protocol deviations were reported for the 3 g GW642444M treatment group (8
subjects [8%] within this group).
Table 6.6 displays a summary of inclusion/exclusion criteria deviations. The incidence of
these deviations was similar across the treatment groups (0-2%).

6.3.

Populations Analysed

As defined in Section 5.8.3, four populations were used for analysis: the Total
Population, the ITT and PP Populations, and the PK Concentration Population. Of the
607 subjects in the ITT Population, 102 subjects were treated with placebo, 101 with 3 g
GW642444M, 101 with 6.25 g GW642444M, 100 with 12.5 g GW642444M, 101 with
25 g GW642444M, and 102 with 50 g GW642444M.

6.4.

Demographics and Other Screening Characteristics

6.4.1.

Demographic Characteristics

Demographic characteristics were similar across the treatment groups within the ITT
Population (Table 5). The majority of subjects were female (50% to 60% across
treatment groups) and White (73% to 81% across treatment groups). The mean age was
39.9 to 44.4 years across treatment groups.
Demographic characteristics of the Per Protocol Population were similar to those reported
for the ITT Population and are provided in Table 6.9.

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Table 5

Summary of Demographic Characteristics (ITT Population)


Placebo

Age (years) a
Mean
SD
Range
Sex, n (%)
Female
Male
Ethnicity
Hisp/Lat
Not Hisp/Lat
Race, n (%)
White
Asian
African American / African
heritage
American Indian or
Alaska Native
Native Hawaiian or other
Pacific Islander
African American/African
Heritage & American
Indian or Alaska Native
African American/African
Heritage & White
American Indian or
Alaska Native & White
Asian & White
Height (cm)
Mean
SD
Range
Weight (kg)
Mean
SD
Range

N=102

3 g
GW642444
N=101

6.25 g
GW642444
N=101

12.5 g
GW642444
N=100

25 g
GW642444
N=101

50 g
GW642444
N=102

39.9
15.60
12-68

44.4
13.50
15-74

42.4
14.13
16-80

41.3
15.33
12-72

42.2
14.27
12-70

44.0
15.22
13-73

61 (60)
41 (40)

52 (51)
49 (49)

51 (50)
50 (50)

56 (56)
44 (44)

61 (60)
40 (40)

57 (56)
45 (44)

9 (9)
93 (91)

13 (13)
88 (87)

10 (10)
91 (90)

13 (13)
87 (87)

12 (12)
89 (88)

22 (22)
80 (78)

81 (79)
11 (11)
4 (4)

74 (73)
13 (13)
11 (11)

77 (76)
11 (11)
8 (8)

75 (75)
8 (8)
12 (12)

75 (74)
9 (9)
14 (14)

83 (81)
9 (9)
8 (8)

3 (3)

2 (2)

3 (3)

2 (2)

2 (2)

1 (<1)

1 (<1)

1 (<1)

2 (2)

1 (<1)

1 (<1)

2 (2)

1 (<1)

1 (<1)

1 (1)

165.3
10.94
108-188

169.5
11.30
135-200

167.3
9.67
149-193

168.5
10.06
140-191

167.1
9.70
150-193

167.8
9.97
147-198

77.16
78.98
77.58
81.53
77.09
78.93
18.644
17.625
17.731
19.063
18.702
20.652
48.043.0-142.0
50.0-127.3
30.9-137.3
43.0-134.1
44.5-155.9
127.0
Source data: Table 6.8 and Table 6.10.
a. 27 subjects [4%] were 12 - 17 years of age: 7 in the placebo group, 2 in the 3 g GW642444M group, 2 in the
6.25 g GW642444M group, 7in the 12.5 g GW642444M group, 5 in the 25 g GW642444M group, 4 in the 50
g GW642444M group.
Hisp/Lat = Hispanic/Latino.

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6.4.2.

Other Characteristics

6.4.2.1.

Tobacco History

The history of tobacco use within the ITT Population captured at Screening is provided in
Table 6.12. The majority of subjects (79% to 86%) across all treatment groups reported
to have never smoked prior to taking part in the study.
6.4.2.2.

Asthma History

A summary of the duration of asthma and asthma history is summarised in Table 6. All
treatment groups had a similar duration of asthma and the majority of subjects across
treatment groups had a history of asthma 10 years or more in duration (64% to 74%).
The majority of subjects (67%) had a history of atopy (Table 6.13).
Table 6

Summary of Duration of Asthma and Asthma History (ITT


Population)
Placebo

<6 months
6 months to <1 year
1 year to <5 years
5 years to <10 years
10 years
Source Table 6.13.

6.4.2.3.

N=102
0
0
14 (14)
20 (20)
68 (67)

3 g
GW642444
N=101
0
2 (2)
11 (11)
13 (13)
75 (74)

6.25 g
GW642444
N=101
0
1 (<1)
19 (19)
11 (11)
70 (69)

12.5 g
GW642444
N=100
0
1 (1)
16 (16)
12 (12)
71 (71)

25 g
GW642444
N=101
0
2 (2)
11 (11)
14 (14)
74 (73)

50 g
GW642444
N=102
0
1 (<1)
16 (16)
20 (20)
65 (64)

Screening Lung Function

A summary of lung function at Screening is presented in Table 7. Lung function at


Screening was similar across the treatment groups:

Mean pre-bronchodilator FEV1 ranged from 2.127 L to 2.257 L.

Mean percent predicted pre-bronchodilator FEV1 ranged from 65.3% to 67.6%.

Mean percent reversibility in FEV1 ranged from 24.2 % to 27.4 %.

Mean absolute reversibility ranged from 517.8 mL to 562.7 mL.

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Table 7

Summary of Screening Lung Function (ITT Population)


Placebo

N=102
Pre-Bronchodilator FEV1, (L)
Mean
2.211
SD
0.6740
Min-Max
0.83-4.48
Percent Predicted FEV1, (%)
Mean
66.9
SD
11.97
Min-Max
41-90
Post-Bronchodilator FEV1, (L)
Mean
2.767
SD
0.8004
Min-Max
1.18-5.26
Percent Reversibility in FEV1, (%)
Mean
26.6
SD
15.37
Min-Max
7-86
Absolute Reversibility in FEV1, (mL)
Mean
555.5
SD
300.26
Min-Max
164-1697
Source data: Table 6.21.

3 g
GW642444
N=101

6.25 g
GW642444
N=101

12.5 g
GW642444
N=100

25 g
GW642444
N=101

50 g
GW642444
N=102

2.257
0.8031
1.04-4.54

2.243
0.6494
1.06-3.63

2.255
0.6315
1.03-4.02

2.127
0.6067
0.83-3.76

2.165
0.6143
0.86-4.37

65.8
13.48
40-90

66.5
10.75
42-88

67.6
11.79
41-90

65.3
12.08
42-89

65.9
12.29
40-89

2.775
0.9468
1.26-5.17

2.806
0.7814
1.45-4.59

2.792
0.7369
1.32-4.81

2.668
0.7027
1.32-4.23

2.702
0.7095
1.07-5.05

24.2
13.45
2-76

26.3
15.39
6-100

25.2
16.20
12-125

27.4
20.74
12-123

26.4
15.45
-12-102

517.8
271.20
29-1317

562.7
291.05
148-1564

537.0
280.18
201-1501

540.2
339.07
200-2207

537.0
253.50
-229-1427

When split by stratum based on percent predicted FEV1, 53% to 58% of subjects in the
ITT Population were included in the upper stratum (Table 6.23). Within the strata, mean
percent predicted FEV1 was similar across the treatment groups and ranged from 75.5%
to 78.3% within the upper stratum; for the lower stratum this was 54.2% to 57.8%
(Table 6.24).
6.4.3.

Other Current Medical Conditions

Medical conditions present within the ITT Population at Screening are presented in
Attachment 1. A total of 485 (80%) subjects presented with current medical conditions.
In general, the distribution of current medical disorders was similar across the treatment
groups. The most frequent medical conditions were Respiratory, thoracic and
mediastinal disorders (42% of ITT Population subjects), followed by nervous system
disorders (20% of subjects), musculoskeletal and connective tissue disorders (20% of
subjects) and hypersensitivity/anaphylaxis related disorders (18% of subjects).

6.5.

Concomitant Medications

6.5.1.

Concomitant Asthma Medications

The types of pre-, on- and post-treatment asthma medications are summarised in
Table 6.15, Table 6.16 and Table 6.17, respectively.

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Prior to study treatment, all subjects were taking asthma medication; the use of asthma
medication was similar across all treatment groups. The most frequently taken asthma
medications pre-study were salbutamol, fluticasone propionate and budesonide, which
were taken by 70%-79%, 32%-44% and 35%-48% of subjects across treatment groups,
respectively.
During treatment, asthma medications were taken by >99% to 100% of subjects across
the treatment groups (Table 8). In general, the percentage of subjects taking concomitant
asthma medications on-treatment was similar across the groups. This was also observed
for post-treatment asthma medications (Table 6.17). Both on- and post-treatment the
most frequently reported asthma medications were fluticasone propionate (32% - 44% of
subjects across treatment groups), budesonide (33%-48%), and beclomethasone
dipropionate and beclometasone (11%-22%).
During treatment, 3 subjects received oral corticosteroids. These subjects were excluded
from the PP Population.
Table 8
n (%)
Any medication

Summary of on-treatment Asthma Concomitant Medications taken


by 5% of Subjects (ITT Population)
Placebo
N=102
101
(>99)
43 (42)
36 (35)
13 (13)

3 g
GW642444
N=101
101 (100)

6.25 g
GW642444
N=101
101 (100)

12.5 g
GW642444
N=100
100 (100)

25 g
GW642444
N=101
100 (>99)

50 g
GW642444
N=102
102 (100)

Fluticasone propionate
37 (37)
41 (41)
44 (44)
42 (42)
33 (32)
Budesonide
48 (48)
35 (35)
35 (35)
33 (33)
36 (35)
Beclometasone
11 (11)
22 (22)
11 (11)
13 (13)
20 (20)
dipropionate and
beclometasone
Mometasone furoate
4 (4)
1 (<1)
1 (<1)
7 (7)
6 (6)
7 (7)
Ciclesonide
4 (4)
3 (3)
2 (2)
2 (2)
5 (5)
5 (5)
Salbutamola
2 (2)
6 (6)
2 (2)
4 (4)
4 (4)
0
Source Table 6.16.
Some subjects took more than one concomitant medication.
a. Although the Investigators were instructed not to record the use of rescue medication as concomitant medication,
the use of albuterol/salbutamol was recorded by some Investigators.

6.5.1.1.

Background Inhaled Corticosteroid Use during Treatment

A summary of post-hoc analyses of background ICS use during treatment is presented in


Table 6.103. As shown in Table 9, the mean dose of concomitant ICS (presented as BDP
equivalent daily dose) was highest in the placebo group (814.4 537.50 g).

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Table 9

Post-hoc Analysis of Background Inhaled Steroid Dose during


Treatment

BDP-equivalent daily
dose (g)

Placebo

N=102
n
94
Mean
814.4
SD
537.50
Median
800.0
Min-Max
100-2000
Source data: Table 6.103.
BDP = beclometasone dipropionate.

6.5.2.

3 g
GW642444
N=101
89
698.3
405.53
500.0
200-2000

6.25 g
GW642444
N=101
84
747.6
467.68
550.0
100-2000

12.5 g
GW642444
N=100
91
736.3
473.29
500.0
100-2000

25 g
GW642444
N=101
92
736.4
411.78
800.0
200-2000

50 g
GW642444
N=102
92
709.8
517.24
500.0
100-2000

Concomitant Non-Asthma Medications

The types of pre-, on- and post-treatment non-asthma medications are summarised in
Table 6.18, Table 6.19 and Table 6.20, respectively.
In general, prior to study treatment, non-asthma medications were taken by the majority
of subjects (48% to 68%) across the treatment groups. Paracetamol was the most
frequently taken (9% to 13% of subjects across treatment groups), followed by ibuprofen,
vitamins (NOS), fluticasone propionate, mometasone furoate and acetylsalicylic acid.
Intranasal and topical formulations of fluticasone propionate and mometasone furoate
were taken as a non-asthma medication. Pre-treatment non-asthma medications were
taken to a similar extent across treatment groups.
During treatment, non-asthma medications were taken by 57% - 72% of subjects across
treatment groups. The most frequently recorded concurrent non-asthma medication
during treatment was paracetamol (taken by 13% to 17% of subjects across treatment
groups), followed by ibuprofen, vitamins (NOS), fluticasone propionate (intranasal and
topical formulation) and acetylsalicylic acid. In general, the percentage of subjects taking
concurrent non-asthma medications during the treatment period was similar across the
treatment groups.
Non-asthma medications taken post-treatment were recorded for 50% to 67% of subjects
across treatment groups. As was observed during treatment, the most frequently recorded
post-treatment non-asthma medication was paracetamol (taken by 6% to 11% of subjects
across treatment groups). Ibuprofen, fluticasone propionate (intranasal and topical
formulation), vitamins (NOS), acetylsalicylic acid and mometasone furoate (intranasal
and topical formulation) were also frequently taken.

6.6.

Treatment Compliance

Treatment compliance, as assessed at Visits 2 through 5, was similar across all treatment
groups in the ITT Population. Mean overall compliance for the treatment groups was
high and similar across the treatment groups, and ranged from 98.9% to 107% (Table 10).

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Most of the over-compliance (>100%) was near 100%. Post-hoc analysis showed that
only 13 subjects recorded treatment compliance of greater than 110%, including one
subject with compliance of 633% in the placebo group who was withdrawn early due to
lack of efficacy (Listing 6.101, Attachment 5). This subject was in the study for a short
period of time (three days) and thus a few actuations more than the expected number
during the duration of treatment inflates the compliance level by a significant amount.
Approximately half (6 of 13) of the subjects with compliance values over 110% withdrew
early from the study either due to lack of efficacy (2 subjects), subject reaching protocoldefined stopping criteria (2 subjects) or withdrawn consent (2 subjects) (Listing 6.101,
Attachment 5). These subjects who withdrew early were in the study for 13 days.
Table 10

Summary of Treatment Compliance (ITT Population)

Novel dry Powder Inhaler (%)


n
Mean
SD
Median
Min-Max
n
<80%, n (%)
80% to 100%, n (%)
>100%, n (%)
Source data: Table 6.22.

Placebo
N=102
102
107.0
54.72
100.00
79-633

3 g
GW642444
N=101
101
99.3
4.83
100.00
83-115

6.25 g
GW642444
N=101
101
98.9
5.58
100.00
81-125

12.5 g
GW642444
N=100
100
99.5
4.03
100.00
83-111

25 g
GW642444
N=101
100
99.0
5.59
100.00
75-112

50 g
GW642444
N=102
101
99.6
4.08
100.00
83-107

102
1 (<1)
77 (75)
24 (24)

101
0
75 (74)
26 (26)

101
0
82 (81)
19 (19)

100
0
79 (79)
21 (21)

100
3 (3)
79 (79)
18 (18)

101
0
77 (76)
24 (24)

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7.

EFFICACY RESULTS

7.1.

Primary Efficacy Results

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The primary efficacy endpoint was the mean change from baseline in clinic visit trough
(pre-bronchodilator and pre-dose) FEV1 at the end of the 28-day treatment period, with
the trough FEV1 defined as the mean of the 23 and 24 h post-dose assessments at Day 28.
In order to demonstrate overall efficacy of GW642444M relative to placebo, the primary
treatment comparison was a test of linear dose response in trough (pre-bronchodilator and
pre-dose) FEV1 at Day 28 across the five doses of GW642444M and placebo. The ITT
Population was the primary population of interest for the primary efficacy analysis.
The results of the linear trend test of change from baseline in trough FEV1 at the end of
the treatment period using LOCF are summarised in Table 11. Overall efficacy of
GW642444M relative to placebo was demonstrated by a statistically significant linear
trend test (p=0.003), indicating that the slope of the dose-response relationship was not
zero. When the same linear trend test was performed excluding placebo to investigate the
dose response across the five doses of GW642444M, a significant dose response
(p=0.037) was found. The dose-response curve based on linear trend test is shown in
Figure 2.
Table 11

Linear Trend Test of Change from Baseline in Trough FEV1 (LOCF)


(ITT Population)

Day 28, including placebo


Linear Trend Test, p-value
Estimate of Slope
95% C.I.
Day 28, excluding placebo
Linear Trend Test, p-value
Estimate of Slope
95% C.I.
Source Table 7.2, Table 7.3.

0.003
2.545 mL/g
(0.893, 4.196)
0.037
1.924 mL/g
(0.120, 3.728)

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Figure 2

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Adjusted Means of Change from Baseline in Trough FEV1 (L) (LOCF)


at Day 28 (ITT Population)

Source Data: Figure 7.2.

Since the test of linear trend was statistically significant, pair-wise tests of each dose
versus placebo were performed to identify effective doses (Table 12). Although a
placebo effect was observed (LS mean change of 0.147 L in FEV1 from baseline), tests of
each GW642444M dose versus placebo demonstrated a statistically significant
superiority of the 12.5 g, 25 g and 50 g GW642444M doses relative to placebo (mean
treatment differences of 0.130 L, 0.121 L and 0.162 L, respectively).
The adjusted treatment differences and corresponding 95% confidence intervals (CIs) for
change from baseline in trough FEV1 at the end of the treatment period are shown in
Figure 3.
Figure 7.3 is a box plot of change from baseline in trough FEV1.

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Table 12

Statistical Analysis of Change from Baseline in Trough FEV1 (L)


(LOCF) at End of Treatment (ITT Population)

Day 28

Placebo

n
LS Mean
LS Mean Change
(SE)
Difference vs. placebo
95% CI
p-value
Source Table 7.4.

Figure 3

N=102
95
2.388
0.147
(0.036)

3 g
GW642444
N=101
98
2.452
0.212
(0.036)
0.064
-0.036,0.164
0.208

6.25 g
GW642444
N=101
99
2.458
0.217
(0.035)
0.069
-0.029,0.168
0.169

12.5 g
GW642444
N=100
97
2.518
0.278
(0.036)
0.130
0.030,0.230
0.011

25 g
GW642444
N=101
99
2.509
0.269
(0.035)
0.121
0.023,0.220
0.016

50 g
GW642444
N=102
100
2.550
0.309
(0.035)
0.162
0.062,0.261
0.001

Adjusted Treatment Differences of Change from Baseline in Trough


FEV1 (L) (LOCF) at Day 28 Difference from Placebo (ITT Population)

Source Data: Figure 7.1.

7.1.1.

Analyses Supporting the Primary Efficacy Analysis

7.1.1.1.

PP Population

The analyses of the primary endpoint (linear trend test and pair-wise comparisons of the
GW642444M doses with placebo) were repeated for the PP Population. Table 7.5
summarises the trough FEV1 for the PP Population and the change from baseline in
trough FEV1 at the end of the 28-day treatment period. Table 7.6 shows the results of the
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linear trend test of change from baseline in trough FEV1, and the statistical analysis of
change from baseline in trough FEV1 for the PP Population is summarised in Table 7.7.
These data are depicted graphically in Figure 4 and Figure 7.6 and Figure 7.7.
The results of the analyses of the primary efficacy measure for the PP Population were
consistent with those for the ITT Population and showed statistically significant
superiority of the 12.5 g, 25 g and 50 g GW642444M doses relative to placebo (mean
treatment differences of 0.118 L [p=0.022], 0.135 L [p=0.008], and 0.135 L [p=0.008],
respectively).
Figure 4

Adjusted Treatment Differences of Change from Baseline in Trough


FEV1 (L) (LOCF) at Day 28 Difference from Placebo (PP Population)

Source data: Figure 7.5.

7.1.1.2.

Repeated Measures Analysis supporting the Primary Endpoint

A supporting sensitivity analysis of the primary endpoint was performed using a


Repeated Measures Mixed Model. The ITT Population was the primary population of
interest for this analysis.
As was observed for the linear trend test using LOCF, the linear trend test of change from
baseline in trough FEV1 using repeated measures analysis was statistically significant
(p<0.05, Table 7.8).
Subsequent analysis of pair-wise comparisons of GW642444M doses versus placebo
(Table 7.9) demonstrated a dose-dependent response and a sustained bronchodilatory

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effect throughout the treatment period, with statistically significant improvements in


trough FEV1 compared with placebo for:

12.5 g GW642444M: 23 and 24 h post-dose on Day 28 (p=0.013).

25 g GW642444M: 23 and 24 h post-dose on Day 28 (p=0.010).

50 g GW642444M: pre-dose on Day 7 (p=0.015), Day 14 (p= 0.032) and Day 28


(p=0.010), as well as 23-24h post-dose on Day 28 (p=0.002).

These results are shown graphically in Figure 5. An increase in FEV1 was noted on Day
29 following dosing on Day 28, which may be due to this treatment being supervised on
Day 28 in contrast to the treatment taken before the Day 7 and Day 14 measurements.
Figure 5

Repeated Measures Analysis of Change from Baseline in Trough


FEV1 (L) Differences from Placebo (ITT Population)

Source data: Figure 7.10.


Day 29 p-values: 0.142 (3 g GW642444M), 0.191 (6.25 g GW642444M), 0.013 (12.5 g GW642444M), 0.010 (25
g GW642444M), 0.002 (50 g GW642444M).

7.2.

Secondary Efficacy Results

7.2.1.

Strata Analysis of Trough FEV1

In order to investigate the consistency of the dose-response relationship for the different
disease severities, the change from baseline in trough FEV1 at the end of the treatment
period was analysed for each stratum (Table 13). Within each GW642444M dose, the
upper and lower strata responded in a similar manner showing similar dose responses,
with the confidence intervals overlapping the LS mean change for all groups except 3 g.
The adjusted treatment differences for each stratum are presented in Figure 6.
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Table 13
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Statistical Analysis of Change from Baseline in Trough FEV1 (L) at


Day 28 by Percent Predicted Stratum (LOCF) (ITT Population)
Placebo

3 g
6.25 g
GW642444
GW642444
N=102
N=101
N=101
Lower stratum (FEV1 percent predicted 40% - 65%)
n
43
44
41
LS Mean
2.450
2.402
2.487
LS Mean
0.210(0.057) 0.161(0.056) 0.247(0.057)
Change (SE)
Difference
-0.049
0.037
vs. Placebo
95% CI
((0.198,0.100)
0.113,0.188)
Upper stratum (FEV1 percent predicted 65% - 90%)
n
52
54
58
LS Mean
2.338
2.495
2.435
LS Mean
0.098(0.049) 0.254(0.051) 0.194(0.048)
Change (SE)
Difference
0.156
0.097
vs. Placebo
95% CI
(0.022,0.291)
(0.035,0.228)
Source data: Table 7.13.

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12.5 g
GW642444
N=100

25 g
GW642444
N=101

50 g
GW642444
N=102

40
2.559
0.319(0.057)

46
2.522
0.281(0.054)

45
2.590
0.349(0.055)

0.109

0.072

0.139

(-0.044,0.262)

(-0.075,0.218)

(-0.009,0.287)

57
2.488
0.247(0.049)

53
2.499
0.259(0.049)

55
2.517
0.276(0.049)

0.149

0.161

0.178

(0.018,0.281)

(0.027,0.295)

(0.045,0.312)

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Figure 6

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Adjusted Treatment Differences of Change from Baseline in Trough


FEV1 (L) (LOCF) at Day 28 by Percent Predicted FEV1 Stratum
Difference from Placebo (ITT Population)

Source data: Figure 7.11.

7.2.2.

Weighted Mean 24-hour Serial FEV1

The change from baseline in weighted mean for 24-h serial FEV1 on Days 1 and 28 was
compared for each GW642444M group versus placebo, with the 6-12 h post-dose time
points only measured in a subset of subjects.
Analysis of all ITT Population subjects (including those with the additional time point
measurements at 6 and 12 h after dosing) demonstrated that all GW642444M treatments
showed statistically significant improvement in FEV1 compared with placebo on Days 1
and 28, with the exception of 6.25 g GW642444M on Day 1 (Table 14 and Figure 7).
On both Days, a dose response was observed with the greatest improvements from
baseline in 24-h serial FEV1 versus placebo in the 12.5 g GW642444M group (0.130 L
on Day 1 and 0.142 L on Day 28), the 25 g GW642444M group (0.193 L on Day 1 and
0.165 L on Day 28) and the 50 g GW642444M group (0.215 L on Day 1 and 0.172 L on
Day 28).
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A summary of the weighted mean change from baseline is presented in Table 7.19.
Table 14

Statistical Analysis of Weighted Mean Change from Baseline in 24hour Serial FEV1 (L) (All Subjects, including 6-12 hour Time Points)
(ITT Population)
Placebo
N=102

Day 1
n
101
LS Mean (SE)
0.137(0.029)
Difference vs.
Placebo
95% CI
p-value
Day 28
n
87
LS Mean (SE)
0.149(0.032)
Difference vs.
Placebo
95% CI
p-value
Source data: Table 7.20.

3 g
GW642444
N=101

6.25 g
GW642444
N=101

12.5 g
GW642444
N=100

25 g
GW642444
N=101

50 g
GW642444
N=102

100
0.239(0.029)
0.102

101
0.215(0.029)
0.078

99
0.267(0.029)
0.130

100
0.330(0.029)
0.193

100
0.352(0.029)
0.215

(0.020,0.183)
0.015

(-0.003,0.158)
0.059

(0.049,0.211)
0.002

(0.112,0.273)
<0.001

(0.134,0.296)
<0.001

83
0.300(0.033)
0.151

91
0.253(0.031)
0.103

88
0.292(0.032)
0.142

93
0.315(0.031)
0.165

97
0.321(0.031)
0.172

(0.059,0.242)
0.001

(0.014,0.192)
0.023

(0.052,0.232)
0.002

(0.077,0.253)
<0.001

(0.084,0.260)
<0.001

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Figure 7

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Adjusted Treatment Differences of Weighted Mean 24-hour Serial


FEV1 (L), Difference from Placebo (All Subjects, including 6-12 hour
Time Points) (ITT Population)

Day 1

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Figure 7

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Adjusted Treatment Differences of Weighted Mean 24-hour Serial


FEV1 (L), Difference from Placebo (All Subjects, including 6-12 hour
Time Points) (ITT Population). (Continued)

Day 28

Source data: Figure 7.13.

Impact of the 6-12 hour Time Points on Weighted Mean Serial FEV1

A sensitivity analysis was performed for the ITT Population on Days 1 and 28 to assess
the impact of the 6-12 h time points on the changes in weighted mean serial FEV1 from
baseline following treatment (Table 7.21, Table 7.22 and Table 7.23). This was
performed to assess the impact of the 34% of subjects not providing FEV1 measurements
at 6 h and 12 h post-dose5. The estimated treatment differences for the comparisons of
the GW642444M treatments with placebo for Day 28 are presented in Figure 8. These
analyses demonstrate that exclusion of the 6-12 h timepoints does not have a substantial
impact on the treatment differences.

In total, 66% of subjects stayed overnight to provide data.

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Figure 8

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Adjusted Treatment Differences from Sensitivity Analysis of


Weighted Mean 24-hour Serial FEV1 (L), Difference from Placebo,
Day 28 (ITT Population)

Source data: Figure 7.14.


All subjects were ITT Population subjects.
Analysis 1-2, and 3-4 were compared:
Analysis 1: All subjects; the 6-12 h time points are included.
Analysis 2: All subjects; the 6-12 h time points are excluded.
Analysis 3: Subset of subjects who had the 6-12 h time points measured; the 6-12 h time points are included.
Analysis 4: Subset of subjects who had the 6-12 h time points measured; the 6-12 h time points are excluded.
Note: 207 (34%) subjects did not have the 6-12 h time point measured, and 400 (66%) subjects had the 6-12 h time
point measured.

Impact of Rescue Medication on Weighted Mean 24-hour Serial FEV1

A further sensitivity analysis was performed to assess whether rescue medication affected
weighted mean 24-h serial FEV1 values measured following GW642444M treatment on
Days 1 and 28. The analysis as that described for weighted mean 24-h serial FEV1 was

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performed after removing the FEV1 measurements taken within 6 h after rescue
medication use6 (Table 7.24). These results were similar to those from the full analysis.
7.2.3.

Daily Evening PEF

The change from baseline in daily PM trough (pre-dose and pre-rescue bronchodilator)
PEF averaged over the 28-day treatment period was compared for each GW642444M
dose vs. placebo (Table 15 and Figure 9). Figure 10 shows the daily mean change from
baseline in PM PEF.
Statistical analysis of change from baseline over Days 1-28 (Table 15 and Figure 9)
showed that all GW642444M treatment groups had statistically significantly greater
improvements in PM PEF compared with placebo, demonstrating a sustained
bronchodilatory effect. The greatest increases in PM PEF were recorded for the 25 g
and 50 g GW642444M groups (33.6 L/min and 38.0 L/min, respectively. The
GW642444M treatments were numerically better than placebo from the first week of
treatment onwards (Table 7.39).
Table 15

Statistical Analysis of Change from Baseline in PM PEF (L/min),


Days 1-28 (ITT Population)
Placebo

n
LS Mean
LS Mean Change (SE)
Difference versus Placebo
LS Mean Difference
95% CI
p-value
Source data: Table 7.40.

N=102
99
378.3
0.4 (3.87)

3 g
GW642444
N=101
99
391.9
14.0 (3.87)

6.25 g
GW642444
N=101
101
402.4
24.5 (3.82)

12.5 g
GW642444
N=100
98
406.7
28.9 (3.87)

25 g
GW642444
N=101
101
411.8
34.0 (3.81)

50 g
GW642444
N=102
102
416.2
38.4 (3.82)

13.6
(2.8, 24.4)
0.014

24.1
(13.5, 34.8)
<0.001

28.5
(17.7, 39.3)
<0.001

33.6
(22.9, 44.2)
<0.001

38.0
(27.3, 48.7)
<0.001

Subjects were requested not to use their rescue albuterol/salbutamol for at least 6 h prior to the clinic visit
during which spirometry was performed, if possible. However some subjects had used rescue
medication within 6 h of the assessment. These subjects were not excluded from ITT analysis.

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Figure 9

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Adjusted Treatment Differences of Change from Baseline in PM PEF


(L/min), Days 1-28

Source data: Figure 7.113.

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Figure 10

Mean Change from Baseline in PM PEF (L/min) (ITT Population)

Source data: Figure 7.26.

7.2.4.

Daily Morning PEF

The statistical analysis of change from baseline in daily AM PEF averaged over the 28day treatment period for each GW642444M dose versus placebo is summarised in
Table 16. The daily mean change from baseline in AM PEF is presented graphically in
Figure 11.
As was observed for PM PEF, all GW642444M treatment groups experienced
statistically significantly greater improvements in AM PEF compared with placebo. AM
PEF increased with GW642444M dose, with the greatest improvements versus placebo in
the 25 g and 50 g GW642444M groups (36.2 L/min and 42.1 L/min, respectively) The
GW642444M treatments were numerically better than placebo from the first week of
treatment onwards (Table 7.41).
Table 16

Statistical Analysis of Change from Baseline in AM PEF (L/min),


Days 1-28 (ITT Population)
Placebo

n
LS Mean
LS Mean Change (SE)
Difference versus Placebo
LS Mean Difference
95% CI
p-value
Source data: Table 7.42.

N=102
98
364.7
1.9 (3.69)

3 g
GW642444
N=101
99
381.4
18.7 (3.67)

6.25 g
GW642444
N=101
101
389.5
26.8 (3.63)

12.5 g
GW642444
N=100
98
397.0
34.2 (3.68)

25 g
GW642444
N=101
101
400.9
38.1 (3.61)

50 g
GW642444
N=102
102
406.7
44.0 (3.63)

16.8
(6.5, 27.1)
0.001

24.9
(14.7, 35.1)
<0.001

32.3
(22.1, 42.6)
<0.001

36.2
(26.1, 46.4)
<0.001

42.1
(31.9, 52.2)
<0.001

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Figure 11

Mean Change from Baseline in AM PEF (L/min) (ITT Population)

Source data: Figure 7.27.

7.2.5.

Symptom-Free 24-hour periods

The changes from baseline in the percentage of symptom-free 24-h periods over the 28day treatment period were compared for each GW642444M dose versus placebo. The
statistical analysis of change from baseline in the percentage of symptom-free 24-h
periods over Days 1-28 is summarised in Table 17 and Figure 12. When compared with
placebo, the differences from baseline were statistically significant for all GW642444M
treatments except for 3 g GW642444M. A dose-response effect was observed with the
greatest increases in percentage symptom-free periods in the 25 g and 50 g
GW642444M groups (22.2% and 18.1%, respectively).
Table 17

Statistical Analysis of Change from Baseline in Percentage of


Symptom-Free 24-h Periods, Days 1-28 (ITT Population)
Placebo

n
LS Mean Change (SE)
Difference vs Placebo
LS Mean Difference
95% CI
p-value
Source data: Table 7.44.

N=102
98
14.2 (3.27)

3 g
GW642444
N=101
99
22.6 (3.25)

6.25 g
GW642444
N=101
101
23.6 (3.21)

12.5 g
GW642444
N=100
98
26.8 (3.26)

25 g
GW642444
N=101
101
36.4 (3.21)

50 g
GW642444
N=102
102
32.3 (3.21)

8.4
(-0.7, 17.5)
0.069

9.4
(0.4, 18.4)
0.040

12.7
(3.6, 21.8)
0.006

22.2
(13.3, 31.2)
<0.001

18.1
(9.1, 27.2)
<0.001

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Figure 12

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Adjusted Treatment Differences of Change from Baseline in


Percentage of Symptom Free 24 Hour Periods

Source data: Figure 7.111.

7.2.6.

Rescue-free 24-hour periods

The statistical analysis of change from baseline in the percentage of rescue-free 24-h
periods over Days 1-28 is summarised in Table 18 and Figure 13. When compared with
placebo, the differences from baseline were statistically significant for all GW642444M
treatments. A dose-response effect was observed with the greatest increases in
percentage rescue-free periods in the 25 g and 50 g GW642444M groups (28.4% and
19.0%, respectively).

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Table 18

Statistical Analysis of Change from Baseline in Percentage of


Rescue-Free 24-h Periods, Days 1-28 (ITT Population)
Placebo

n
LS Mean Change (SE)
Difference vs Placebo
LS Mean Difference
95% CI
p-value
Source data: Table 7.46.

Figure 13

N=102
99
15.0 (3.33)

3 g
GW642444
N=101
99
25.8 (3.33)

6.25 g
GW642444
N=101
101
27.3 (3.28)

12.5 g
GW642444
N=100
98
29.6 (3.34)

25 g
GW642444
N=101
101
43.4 (3.28)

50 g
GW642444
N=102
102
34.0 (3.28)

10.8
(1.5, 20.1)
0.023

12.3
(3.1, 21.5)
0.009

14.7
(5.4, 24.0)
0.002

28.4
(19.3, 37.6)
<0.001

19.0
(9.8, 28.3)
<0.001

Adjusted Treatment Differences of Change from Baseline in


Percentage of Rescue Free 24 Hour Periods

Source data: Figure 7.112.

7.2.7.

Post-Salbutamol/Albuterol FEV1

Post-salbutamol/albuterol FEV1 (FEV1 measured 30 minutes after a single dose of 400 g


albuterol/salbutamol) was compared for each GW642444M group versus placebo, on the
difference between the following time points:

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24 h after dosing on Day 1 (Visit 2) and on Day 28 (Visit 5) (Table 7.25,


Figure 7.22).

Screening (Visit 1) and 24 h after dosing on Day 1 (Visit 2) (Table 7.25,


Figure 7.23).

Screening (Visit 1) and 24 h after dosing on Day 28 (Visit 5) (Table 7.25,


Figure 7.24).

Statistical analysis (Table 19) showed no significant differences in postsalbutamol/albuterol FEV1 for any of the time intervals against placebo for any
GW642444M treatment. The fact that the mean treatment differences are close to zero
and the corresponding CIs surrounding zero indicates that tolerance had not developed
over the 28-day treatment period.
Table 19

Statistical Analysis of Difference in Post-Salbutamol/Albuterol FEV1


(L) (ITT Population)
Placebo

N=102
Day 28 - Day 1
n
83
LS Mean
-0.039(0.023)
(SE)
Difference vs
Placebo
95% CI
p-value
Day 1 Screening
n
97
LS Mean
-0.040(0.028)
(SE)
Difference vs
Placebo
95% CI
p-value
Day 28 Screening
n
84
LS Mean
-0.076(0.031)
(SE)
Difference vs
Placebo
95% CI
p-value
Source data: Table 7.27.

3 g
GW642444
N=101

6.25 g
GW642444
N=101

12.5 g
GW642444
N=100

25 g
GW642444
N=101

50 g
GW642444
N=102

80
-0.035(0.024)

87
-0.012(0.023)

86
-0.017(0.023)

86
-0.062(0.023)

92
-0.049(0.022)

0.004

0.027

0.022

-0.023

-0.010

(-0.062,0.069)
0.916

(-0.037,0.091)
0.410

(-0.042,0.087)
0.498

(-0.087,0.041)
0.482

(-0.074,0.054)
0.756

97
0.008(0.028)

98
-0.061(0.028)

99
-0.029(0.028)

96
-0.020(0.028)

98
-0.060(0.028)

0.047

-0.021

0.011

0.020

-0.020

(-0.032,0.126)
0.241

(-0.099,0.057)
0.598

(-0.067,0.089)
0.791

(-0.058,0.098)
0.619

(-0.099,0.058)
0.613

80
-0.022(0.031)

89
-0.055(0.030)

86
-0.048(0.030)

88
-0.086(0.030)

93
-0.104(0.029)

0.055

0.021

0.029

-0.009

-0.027

(-0.032,0.141)
0.217

(-0.062,0.105)
0.615

(-0.056,0.114)
0.507

(-0.093,0.075)
0.826

(-0.111,0.056)
0.519

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7.3.

Other Efficacy Results

7.3.1.

Repeated Measures Analysis of Serial FEV1

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Repeated measures analysis of the adjusted treatment differences from placebo over time
demonstrated a sustained, 24-h duration of action on Day 1 (Table 7.17, Figure 7.20), as
well as on Day 28 (Table 7.18, Figure 14) for all GW642444M treatments.
Figure 14

Repeated Measures Adjusted Treatment Differences from Placebo in


Change from Baseline FEV1, Day 28 (L) (ITT Population)

Source data: Figure: 7.21.

7.3.2.

FEV1 (0-4 hours) on Days 1 and 28

For each GW642444M dose, the weighted mean change and maximum increase in FEV1
(0-4 h) from baseline on Days 1 and 28 were compared with placebo.
Table 20 shows that on Days 1 and 28 weighted mean change from baseline in FEV1 (0-4
h) differences with placebo were statistically significant for all GW642444M treatments.
Compared with the 3 g, 6.25 g and 12.5 g GW642444M doses, consistently higher
increases in weighted mean FEV1 versus placebo were recorded for 25 g GW642444M
(0.226 L on Day 1 and 0.205 L on Day 28) and 50 g GW642444M (0.236 L on Day 1
and 0.213 L on Day 28).
For maximum increase from baseline in FEV1 (0-4 h) differences from placebo reached
statistical significance for 12.5 g, 25 g, and 50 g GW642444M on Day 1, and for all
doses except 6.25 g GW642444M on Day 28 (Table 21). As for weighted mean change
in FEV1 (0-4 h), consistently higher increases in maximum FEV1 were recorded for the
25 g and 50 g GW642444M groups compared with the other treatments.

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Plots of the absolute and percentage change from baseline in serial FEV1 (0-4 h) on Day 1
and 28 are presented in Table 7.15 and Table 7.16 and in Figure 7.16 and Figure 7.17,
and Figure 15).
Table 20

Statistical Analysis of Weighted Mean Change from Baseline in FEV1


(L) (0-4 hours) (ITT Population)
Placebo

N=102
Day 1
n
101
LS Mean (SE)
0.095(0.027)
Difference vs.
Placebo
95% CI
p-value
Day 28
n
87
LS Mean (SE)
0.136(0.033)
Difference vs.
Placebo
95% CI
p-value
Source data: Table 7.31.

Table 21

3 g
GW642444
N=101

6.25 g
GW642444
N=101

12.5 g
GW642444
N=100

25 g
GW642444
N=101

50 g
GW642444
N=102

101
0.202(0.027)
0.107

101
0.176(0.027)
0.081

99
0.268(0.027)
0.173

100
0.321(0.027)
0.226

101
0.331(0.027)
0.236

(0.031,0.183)
0.006

(0.005,0.156)
0.037

(0.097,0.249)
<0.001

(0.151,0.302)
<0.001

(0.160,0.312)
<0.001

83
0.281(0.034)
0.145

91
0.246(0.032)
0.110

88
0.296(0.033)
0.160

93
0.341(0.032)
0.205

98
0.349(0.031)
0.213

(0.051,0.238)
0.003

(0.019,0.201)
0.018

(0.068,0.252)
<0.001

(0.115,0.295)
<0.001

(0.123,0.302)
<0.001

Statistical Analysis of Maximum Increase from Baseline in FEV1 (L)


(0-4 hours) (ITT Population)
Placebo

N=102
Day 1
n
102
LS Mean (SE)
0.230(0.029)
Difference vs.
Placebo
95% CI
p-value
Day 28
n
87
LS Mean (SE)
0.253(0.034)
Difference vs.
Placebo
95% CI
p-value
Source data: Table 7.29.

3 g
GW642444
N=101

6.25 g
GW642444
N=101

12.5 g
GW642444
N=100

25 g
GW642444
N=101

50 g
GW642444
N=102

101
0.309(0.029)
0.079

101
0.291(0.029)
0.061

100
0.385(0.029)
0.155

101
0.439(0.029)
0.209

101
0.459(0.029)
0.228

(-0.003,0.161)
0.059

(-0.020,0.142)
0.142

(0.073,0.236)
<0.001

(0.128,0.290)
<0.001

(0.146,0.310)
<0.001

85
0.366(0.034)
0.113

91
0.333(0.033)
0.079

88
0.390(0.033)
0.137

93
0.430(0.032)
0.176

98
0.442(0.032)
0.189

(0.019,0.208)
0.019

(-0.013,0.172)
0.091

(0.044,0.230)
0.004

(0.085,0.268)
<0.001

(0.098,0.280)
<0.001

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Figure 15

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Absolute Change from Baseline in Serial FEV1 (L) 0-4 hours (ITT
Population), Day 28

Source data: Figure 7.16.

Proportion of subjects obtaining 200 mL and 12% increase from baseline in


FEV1 (0-4 hours)

The proportion and cumulative proportion of subjects obtaining both 200 mL and 12%
increase from baseline in FEV1 0-4 h post-dosing was calculated for Days 1 and 28. The
proportion of subjects obtaining 200 mL and 12% increase from baseline in FEV1
increased with GW642444M dose (Table 7.32). Within the 25 g GW642444M and 50
g GW642444M groups, 35%-36% of subjects obtained the 200 mL and 12% increase
in FEV1 by 15 minutes after dosing on Day 1. A similar dose-response effect was seen
on Day 28; of note is that on Day 28, in the highest GW642444M dose strengths 46% of
subjects in the 25 g and 50 g GW642444M groups had already obtained a 200 mL
and 12% increase from baseline in FEV1 at pre-dose (Table 7.32).
As a post-hoc analysis, the 0-4 h interval was expanded to calculate the proportion of
subjects obtaining 200 mL and 12% increase from baseline in FEV1 over 24 h
(Table 7.105 and Figure 16). On both Days 1 and 28, the majority of subjects (>50% for
most timepoints over this interval) in the 25 g GW642444M and 50 g GW642444M
groups maintained a 24-h duration of action of 200 mL and 12% above baseline.

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Figure 16

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Proportion of Subjects Obtaining 200 mL and 12% Increase from


Baseline FEV1 (L), 0-24 h

Source data: Figure 7.109

Proportion of subjects obtaining 15% increase from baseline in FEV1 (0-4 hours)

Results for the proportion of subjects obtaining 15% increase from baseline in FEV1 (04 h) were similar to those observed for 200 mL and 12% increase from baseline in
FEV1 (0-4 h) (Table 7.34).

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Peak Post-Dose FEV1 (0-4 hours)

A summary and statistical analysis of peak post-dose FEV1 0-4 h following dosing on
Day 28 is presented in Table 7.36 and Table 7.37. The difference in peak post-dose
FEV1 with placebo was statistically significant for all doses except 6.25 g
GW642444M. A dose-response effect was observed with the 25 g and 50 g
GW642444M groups recording the greatest peak post-dose FEV1 (0.177 L and 0.198 L,
respectively; both p<0.001) (Table 7.37 and Figure 17).
Figure 17

Adjusted Treatment Differences of Peak Post-Dose FEV1 (L) (0-4


hours), Day 28 (ITT Population)

Source data: Figure 7.25.

Peak to Trough Ratio

On Day 28, the mean ratio of peak post-dose to trough FEV1 was similar across the
treatment groups including placebo (ranging from 1.040 in the 6.25 g GW642444M
group to 1.060 in the 50 g GW642444M group), demonstrating sustained
bronchodilation at 24-h with GW642444M (Table 22).

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Table 22

Summary of Ratio of Peak Post-Dose FEV1 (L) to Trough FEV1 (L),


Day 28 (ITT Population)

Day 28

Placebo

N=102
Ratio
n
86
Mean
1.042
SD
0.0912
Median
1.031
Minimum
0.78
Maximum
1.36
Source data: Table 7.38.

7.3.3.

3 g
GW642444
N=101

6.25 g
GW642444
N=101

12.5 g
GW642444
N=100

25 g
GW642444
N=101

50 g
GW642444
N=102

84
1.045
0.0682
1.036
0.81
1.35

91
1.040
0.0533
1.028
0.97
1.25

88
1.043
0.0843
1.032
0.63
1.32

93
1.056
0.0718
1.048
0.92
1.34

96
1.060
0.0607
1.050
0.96
1.24

Symptom-Free Days and Symptom-Free Nights

A summary and statistical analysis of the change from baseline in the percentage of
symptom-free days over the treatment period is provided in Table 7.47 and Table 23,
respectively. For symptom-free nights this information is presented in Table 7.49 and
Table 24.
Over Days 1-28, the mean change from baseline in the percentage of symptom-free days
and nights generally increased across the GW642444M treatment groups. The difference
versus placebo was greatest for the 25 g GW642444M groups (20.3% for symptom-free
days and 17.1% for symptom-free nights).
Table 23

Statistical Analysis of Change from Baseline in Percentage of


Symptom-Free Days (ITT Population)
Placebo

N=102
n
99
LS Mean (SE)
15.8 (3.24)
Difference vs. Placebo
95% CI
p-value
Source data: Table 7.48.

Table 24

3 g
GW642444
N=101
99
22.5 (3.24)
6.7
(-2.3, 15.8)
0.146

6.25 g
GW642444
N=101
101
26.9 (3.20)
11.1
(2.2, 20.0)
0.015

12.5 g
GW642444
N=100
98
27.1 (3.25)
11.4
(2.3, 20.4)
0.014

25 g
GW642444
N=101
101
36.1 (3.20)
20.3
(11.4, 29.2)
<0.001

50 g
GW642444
N=102
102
34.4 (3.19)
18.6
(9.6, 27.6)
<0.001

Statistical Analysis of Change from Baseline in Percentage of


Symptom-Free Nights (ITT Population)
Placebo

N=102
n
98
LS Mean (SE)
13.2 (3.04)
Difference vs. Placebo
95% CI
p-value
Source data: Table 7.50.

3 g
GW642444
N=101
99
18.2 (3.02)
5.0
(-3.5, 13.4)
0.249

6.25 g
GW642444
N=101
101
19.7 (2.98)
6.5
(-1.9, 14.8)
0.128

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GW642444
N=100
98
23.1 (3.03)
9.9
(1.4, 18.3)
0.022

25 g
GW642444
N=101
101
30.3 (2.98)
17.1
(8.8, 25.4)
<0.001

50 g
GW642444
N=102
102
23.2 (2.98)
10.0
(1.6, 18.4)
0.020

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7.3.4.

Rescue-Free Days and Rescue-Free Nights

A summary and statistical analysis of the change from baseline in the percentage of
rescue-free days and rescue-free nights over the treatment period are provided in
Table 7.51, and Table 7.53 and Table 25 and Table 26.
Results for the percentage of rescue-free days and nights over Day 1-28 were similar to
those observed for symptom-free days and nights. For all GW642444M groups except 3
g GW642444M, the percentage of rescue-free days was statistically significantly greater
than placebo, with the greatest differences versus placebo recorded for the 25 g
GW642444M group (25.6%). Similar results were found for rescue-free nights, with a
24.1% increase in rescue-free nights with 25 g GW642444M.
Table 25

Statistical Analysis of Change from Baseline in Percentage of


Rescue Free Days (ITT Population)
Placebo

N=102
n
99
LS Mean (SE)
15.3 (3.29)
Difference vs. Placebo
95% CI
p-value
Source data: Table 7.52.

Table 26

6.25 g
GW642444
N=101
101
29.6 (3.25)
14.2
(5.2, 23.3)
0.002

12.5 g
GW642444
N=100
98
26.2 (3.30)
10.9
(1.7, 20.0)
0.020

25 g
GW642444
N=101
101
41.0 (3.24)
25.6
(16.6, 34.7)
<0.001

50 g
GW642444
N=102
102
34.5 (3.24)
19.2
(10.1, 28.3)
<0.001

Statistical Analysis of Change from Baseline in Percentage of


Rescue Free Nights (ITT Population)
Placebo

n
LS Mean (SE)
Difference vs. Placebo
95% CI
p-value
Source data: Table 7.54.

7.3.5.

3 g
GW642444
N=101
99
23.4 (3.29)
8.0
(-1.2, 17.2)
0.087

N=102
98
12.6 (3.05)

3 g
GW642444
N=101
99
19.2 (3.03)
6.7
(-1.8, 15.1)
0.123

6.25 g
GW642444
N=101
101
22.6 (2.99)
10.0
(1.6, 18.4)
0.020

12.5 g
GW642444
N=100
98
24.0 (3.04)
11.4
(3.0, 19.9)
0.008

25 g
GW642444
N=101
101
36.7 (2.98)
24.1
(15.7, 32.5)
<0.001

50 g
GW642444
N=102
102
27.5 (2.98)
14.9
(6.5, 23.3)
<0.001

Withdrawals Due to Lack of Efficacy

A numerically higher percentage of subjects were withdrawn due to lack of efficacy from
the 3 g GW642444M group (12 [12%] subjects) and the placebo group (9 [9%]
subjects), compared with the other treatment groups (0% to 5% of subjects) (Table 7.55).
No subjects were withdrawn due to lack of efficacy in the 50 g GW642444M group.

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7.4.

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Efficacy Summary

Once-daily treatment with 12.5 g, 25 g and 50 g GW642444M on a background of


ICS and rescue salbutamol as needed over 28 days resulted in statistically significant
dose-dependent improvements in lung function compared with placebo. This conclusion
is supported by the following efficacy results:

For the primary analysis, the test of linear trend in dose response in trough FEV1
showed a statistically significant linear trend.

Two-sided hypothesis tests of change from baseline in trough FEV1 of each


GW642444M dose against placebo showed superiority of the three highest
GW642444M doses (12.5 g, 25 g and 50 g) on Day 28. Treatment with 12.5 g,
25 g and 50 g GW642444M resulted in FEV1 increases of 0.130 L, 0.121 L and
0.162 L relative to placebo, respectively.

Supporting analyses of the primary efficacy measures (linear trend test and pair-wise
comparisons of the GW642444M doses with placebo) using the PP Population
confirmed the primary results, demonstrating a dose response with significant
superiority of the 12.5 g, 25 g and 50 g GW642444M doses relative to placebo.
Treatment with these doses resulted in FEV1 increases of 0.118 L, 0.135 L and 0.135
L relative to placebo, respectively.

The results of the supporting repeated measures analysis of the primary endpoint
were consistent with those of the LOCF analyses for this population and further
demonstrated a sustained, 24-h duration of action with GW642444M. The linear
trend test of change from baseline in trough FEV1 using repeated measures analysis
was statistically significant and subsequent analysis of pair-wise comparisons of
GW642444M doses with placebo showed a dose-dependent superiority of the 12.5
g, 25 g and 50 g GW642444M doses. There were statistically significant
improvements in trough FEV1 compared with placebo for 12.5 g and 25 g
GW642444M at 23 and 24 h post-dose on Day 28 as well as for 50 g GW642444M
pre-dose on Day 7, Day 14 and Day 28, and at 23-24 h post-dose on Day 28.

Repeated measures analysis of serial FEV1 supported a 24-h duration of


bronchodilatory action on Days 1 and Day 28 for all GW642444M treatments.

Additional evidence of sustained bronchodilation with GW642444M was


demonstrated by the ratio of peak post-dose to trough FEV1.. A mean peak to trough
ratio of <1.1 in all treatment groups indicated that the duration of response is not a
function of increasing dose but is an intrinsic property of the molecule.

Whilst all GW642444M doses significantly improved weighted mean change from
baseline in 24-h serial FEV1 compared with placebo on Days 1 and 28 (with the
exception of 6.25 g GW642444M on Day 1), the greatest improvements in lung
function were observed for the 12.5 g, 25 g and 50 g GW642444M groups
(0.130 L, 0.193 L and 0.215 L respectively on Day 1; and 0.142 L, 0.165 L and
0.172 L respectively on Day 28).

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All GW642444M doses significantly improved morning and evening PEF compared
with placebo, though the greatest improvements in morning and evening PEF over
Days 1-28 were recorded for subjects receiving 25 g GW642444M (36.2 L/min and
33.6 L/min in AM and PM PEF, respectively) and 50 g GW642444M (42.1 L/min
and 38.0 L/min in AM and PM PEF, respectively). Evening (trough) PEF
measurements further supported a sustained duration of bronchodilatory action.

The proportion of subjects obtaining 200 mL and 12% increase from baseline in
FEV1 (0-4 h) on Days 1 and 28 increased with GW642444M dose. Similar results
were found for the proportion of subjects obtaining 15% increase from baseline in
FEV1 (0-4 h) on Days 1 and 28. When expanding the time interval to 0-24 h, the
majority of subjects (>50%) in the 25 g and 50 g GW642444M groups were able
to maintain the 200 mL and 12% improvement in FEV1 for most timepoints over
this time interval.

Except for the 3 g GW642444M dose, for which no statistically significant increase
in symptom-free 24-h periods was found, all GW642444M treatments statistically
significantly increased the percentage of symptom-free and rescue-free 24 h periods
versus placebo over the 28-day treatment period. The greatest improvements were
recorded for the 25 g and 50 g GW642444M groups, with a dose-response effect
up to 25 g GW642444M for both symptom-free and rescue-free 24-h periods
(22.2% and 28.4%, respectively). No further increments were seen with 50 g
GW642444M treatment.

A dose-response was found for weighted mean change from baseline in FEV1 (0-4 h)
with all GW642444M doses showing significant improvements. The greatest
improvements versus placebo were recorded for subjects in the 25 g GW642444M
group (0.226 L on Day 1 and 0.205 L on Day 28) and the 50 g GW642444M group
(0.236 L on Day 1 and 0.213 L on Day 28). Maximum increases from baseline in 04 h FEV1 versus placebo were also greatest for the 25 g GW642444M group (0.209
L on Day 1 and 0.176 L on Day 28) and the 50 g GW642444M group (0.228 L on
Day 1 and 0.189 L on Day 28).

Analysis of the dose-response relationship for the upper and lower strata showed that
within each dose, FEV1 improved in a similar manner across the strata,
demonstrating similar dose responses for both disease severities.

Post-salbutamol/albuterol FEV1 for Day 28-Day1, Day 28-Screening, and Day 1Screening for any GW642444M dose was comparable with placebo, indicating that
tolerance to short-acting 2-agonists had not developed.

The mean change from baseline in the percentage of symptom-free days and nights
increased in a similar manner across the GW642444M groups over the 28-day
treatment period. A dose-response effect up to 25 g GW642444M was observed
with increases versus placebo in symptom-free days and nights of up to 20.3% and
17.1%, respectively. No further increments were seen with 50 g GW642444M
treatment. Results for the percentage of rescue-free days and nights over the
treatment period were similar to those observed for symptom-free days and nights.

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A numerically higher percentage of subjects were withdrawn due to lack of efficacy


from the 3 g GW642444M group (12% of subjects) and the placebo group (9% of
subjects) compared with other groups (0% to 5% of subjects). No subjects were
withdrawn due to lack of efficacy in the 50 g GW642444M group.

8.

SAFETY RESULTS

8.1.

Extent of Exposure

A summary of exposure to placebo and GW642444M administered via the Novel Dry
Powder Inhaler for the ITT Population is provided in Table 27. A total of 102 subjects
were exposed to placebo and 505 subjects were exposed across the five dosages of
GW642444M. Mean exposure to study medication was similar across the GW642444M
and placebo treatment groups. The mean exposure ranged from 25.5 days in the placebo
group to 27.6 days in the 50 g GW642444M group.
The majority of subjects were treated for 29 days (51% to 65% of subjects across
treatment groups), with a maximum of 36 days. As shown in Listing 8.1 (Attachment 5),
across the treatment groups, 13 subjects were exposed for 31 days, of whom 3 received a
replacement inhaler. The subjects who took 6.25 g GW642444M for 35 days (1
subject) and 12.5 g GW642444M for 36 days (1 subject) both received replacement
inhalers whilst one subject who took 25 g GW642444M for 32 days did not receive a
replacement inhaler.
Table 27

Summary of Exposure (ITT Population)


Placebo
N=102

3 g
GW642444
N=101

6.25 g
GW642444
N=101

(days)a

12.5 g
GW642444
N=100

25 g
GW642444
N=101

50 g
GW642444
N=102

Exposure
n
102
101
101
100
101
102
Mean
25.5
25.7
26.6
26.8
27.0
27.6
SD
7.06
7.03
5.92
5.96
5.17
4.08
Median
29.0
29.0
29.0
29.0
29.0
29.0
Min-Max
1-31
1-31
4-35
1-36
5-32
6-31
Range of exposure
n
102
101
101
100
101
102
8
(8)
5
(5)
4
(4)
2
(2)
3
(3)
1
(<1)
7 days, n(%)
8-14 days, n(%)
4 (4)
8 (8)
4 (4)
6 (6)
2 (2)
3 (3)
15-28 days, n(%)
38 (37)
30 (30)
33 (33)
27 (27)
39 (39)
35 (34)
52 (51)
58 (57)
60 (59)
65 (65)
57 (56)
63 (62)
29 days, n(%)
Source data: Table 8.1.
a. Exposure was calculated as [date of last dose date of first dose] +1.
Study drug was taken for a maximum of 36 days.
For subjects who withdrew prior to Day 7 and did not have a date of last dose, the date of withdrawal was used as the
last dose date.

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8.2.

Adverse Events

An overview of AEs for the ITT Population is presented in Table 28. The incidence of
AEs on-treatment was similar across the GW642444M groups and was comparable with
placebo; this was also found for post-treatment AEs.
The incidence of AEs having a reasonable possibility of being drug-related was also
comparable between the GW642444M groups and placebo (4%-8% versus 7%,
respectively). Few AEs led to withdrawal from the study (0%-2%).
As outlined in Section 8.4 and Section 14, of the six subjects who had AEs leading to
withdrawal from the study, 2 subjects were withdrawn due to AEs and 4 subjects were
withdrawn from the study primarily due to protocol-defined stopping criteria, with related
AEs as a sub reason.
Table 28
n (%)

Adverse Events (ITT Population)


Placebo

3 g
GW642444
N=101
37 (37)
4 (4)
8 (8)
1 (<1)

N=102
Any on-treatment AE
37(36)
Any post-treatment AE
6 (6)
Any drug-related AE
7 (7)
Any AE leading to
1 (<1)
permanent discontinuation
of drug or withdrawala
Source data: Table 8.2, Table 8.3, Table 8.5, Table 8.6.
a.

8.2.1.

6.25 g
GW642444
N=101
34 (34)
5 (5)
8 (8)
2 (2)

12.5 g
GW642444
N=100
25 (25)
0
5 (5)
1 (1)

25 g
GW642444
N=101
23 (23)
5 (5)
4 (4)
1 (<1)

50 g
GW642444
N=102
31 (30)
2 (2)
7 (7)
0

Adverse Events during the Treatment Period

AEs reported during the treatment period are presented in Table 8.2. The incidence of
on-treatment AEs was highest in the placebo, 3 g GW642444M and 6.25 g
GW642444M groups (34%-37%). The most commonly reported AEs occurred in the
nervous system disorders (8-14% of subjects across treatment groups including placebo)
and infections and infestations (3-12% of subjects across treatment groups including
placebo) categories.
A summary of the most frequent on-treatment AEs is presented in Table 29. Headache
was the most commonly observed AE in all groups and was comparable to placebo.
Other AEs included upper respiratory tract infection, nasopharyngitis, dizziness, back
pain, muscle spasms and dyspnoea.
The incidence of AEs potentially reflecting LABA class effects (such as tremor,
palpitations, glucose and potassium effects) was low.

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The incidence of AEs in Cardiac disorders category, including palpitations, was low and
similar between treatment arms and placebo.

This subject also


recorded the AEs of Upper respiratory tract infection, Worsening of elevated blood
pressure and Facial injury, of which only Worsening of elevated blood pressure was
deemed related to study drug (Listing 8.3 and Listing 8.4, Attachment 5).

There were no AE reports of low potassium.


Table 29

Most Frequent On-Treatment Adverse Events (ITT Population)

Preferred term, n (%)


Any event
Headache
Upper respiratory tract
infection
Nasopharyngitis
Dizziness
Back pain
Muscle spasms
Dyspnoea
Source data: Table 8.4.

8.2.2.

Placebo
N=102
37 (36)
8 (8)
2 (2)

3 g
GW642444
N=101
37 (37)
12 (12)
2 (2)

6.25 g
GW642444
N=101
34 (34)
7 (7)
1 (<1)

12.5 g
GW642444
N=100
25 (25)
9 (9)
3 (3)

25 g
GW642444
N=101
23 (23)
7 (7)
2 (2)

50 g
GW642444
N=102
31 (30)
8 (8)
2 (2)

4 (4)
2 (2)
0
0
3 (3)

2 (2)
1 (<1)
3 (3)
0
0

2 (2)
1 (<1)
0
2 (2)
0

0
1 (1)
1 (1)
0
0

0
0
1 (<1)
0
0

2 (2)
3 (3)
0
3 (3)
0

Post-Treatment Adverse Events

AEs reported for the ITT population during the post-treatment period are presented in
Table 8.3. The incidence of post-treatment AEs was similar across all treatment groups
(2%-6%) although no AEs were recorded for the 12.5 g GW642444M group following
treatment. The most frequently reported post-treatment AE was headache (2% in any
treatment group), followed by bronchitis, nasopharyngitis, upper respiratory tract
infection and pharyngolaryngeal pain (all <1% in any treatment group).
8.2.3.

Drug-Related Adverse Events

Drug-related AEs were AEs considered by the investigator to have a reasonable


possibility of being related to study drug. Drug-related AEs for the ITT population with
an incidence of 2% in any treatment group are summarised in Table 30.

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The incidence of on-treatment drug-related AEs was comparable between the


GW642444M groups and placebo. No more than 8 subjects on any treatment reported
individual AEs which were considered to be treatment-related. Headache was the most
frequently reported drug-related AE and was reported by 2 subjects on each of 6.25 g,
12.5 g and 25 g GW642444M treatments. In comparison, no subjects on placebo or 50
g GW642444M reported drug-related headache.
As mentioned in Section 8.2.1, drug-related AEs potentially reflecting LABA class
effects were reported on-treatment for few subjects. Tremor was reported in 1 subject in
the 6.25 g GW642444M group, although in this subject GW642444M plasma
concentrations were below the LLQ of 30 pg/mL (PK Listing 9.1, Attachment 5).
Palpitations were reported by <1% to 2% of subjects across the placebo, 3 g
GW642444M and 6.25 g GW642444M groups (Listing 8.2, Attachment 5) although
those in the 3 g GW642444M and 6.25 g GW642444M groups had NQ plasma
concentrations of GW642444M (Listing 8.2, Attachment 5).
Table 30

Drug-Related Adverse Events (2% or Greater Incidence in Any


Treatment Group) (ITT Population)

System organ class


preferred term, n (%)
Any event
Nervous system disorders
Any event
Headache
Dizziness
Cardiac disorders
Any event
Palpitationsa
a. Source data: Table 8.5.

8.3.

Placebo
N=102
7 (7)

3 g
GW642444
N=101
8 (8)

6.25 g
GW642444
N=101
8 (8)

12.5 g
GW642444
N=100
5 (5)

25 g
GW642444
N=101
4 (4)

50 g
GW642444
N=102
7 (7)

0
0
0

2 (2)
1 (<1)
1 (<1)

3 (3)
2 (2)
0

2 (2)
2 (2)
0

2 (2)
2 (2)
0

2 (2)
0
2 (2)

2 (2)
1 (<1)

2 (2)
2 (2)

1 (<1)
1 (<1)

1 (1)
0

1 (<1)
0

0
0

Serious Adverse Events

No deaths or non-fatal SAEs were reported during this study.

8.4.

Adverse Events Related to Premature Discontinuation of


Investigational Product and/or Study

In total, 6 subjects were withdrawn from the study due to AEs, with no more than 2
subjects withdrawing in any treatment group and no subjects withdrawing in the 50 g
GW642444M group (Table 31). In 2 subjects withdrawal due to AE was quoted as the
primary reason, and for the remaining 4 subjects the primary reason for withdrawal from
the study was subject reaching protocol-defined stopping criteria, with related AEs as a
sub reason for withdrawal. Detailed information is provided in Section 14 (Case
Narratives).

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These events were deemed not related to the study drug.

These subjects experienced related AEs as a sub-reason


for withdrawal from the study.
Only the events of prolonged PR interval and AV block
second degree were deemed related to the study drug.

Table 31

Adverse Events Leading or Related to Permanent Discontinuation of


Study Drug, or Withdrawal from the Study

System organ class


preferred term, n (%)

Placebo

3 g
GW642444
N=101
1 (<1)

N=102
Any event
1 (<1)
Cardiac disorders
Any event
1 (<1)
0
AV block second degree
0
0
Ventricular arrhythmia
1 (<1)
0
General disorders and administration site conditions
Any event
0
1 (<1)
Feeling jittery
0
1 (<1)
Pyrexia
0
0
Investigations
Any event
0
0
ECG PR prolongation
0
0
ECG T wave amplitude
0
0
decreased
Immune system disorders
Any event
0
0
Hypersensitivity
0
0
Nervous system disorders
Any event
0
1 (<1)
Psychomotor hyperactivity
0
1 (<1)
Psychiatric disorders
Any event
0
1 (<1)
Insomnia
0
1 (<1)
Source data: Table 8.6.

6.25 g
GW642444
N=101
2 (2)

12.5 g
GW642444
N=100
1 (1)

25 g
GW642444
N=101
1 (<1)

50 g
GW642444
N=102
0

0
0
0

1 (1)
1 (1)
0

0
0
0

0
0
0

0
0
0

0
0
0

1 (<1)
0
1 (<1)

0
0
0

2 (2)
1 (<1)
1 (<1)

0
0
0

0
0
0

0
0
0

0
0

0
0

1 (<1)
1 (<1)

0
0

0
0

0
0

0
0

0
0

0
0

0
0

0
0

0
0

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8.5.

Clinical Laboratory Evaluations

8.5.1.

Laboratory Values over Time

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Summaries of chemistry and haematology data including changes from baseline are
presented in Table 8.11 to Table 8.16.
Mean and median values at Days 14 and 28 of the study period were similar, with no
changes for haematology analytes and clinical chemistry analytes below predefined levels
of clinically relevant concern.
Urinalysis dipstick results are provided in Table 8.17. At Screening and Day 28, results
were similar across the treatment groups for all urinalysis parameters (glucose, ketones,
WBCs, protein, pH and specific gravity).
8.5.2.

Abnormalities of Potential Clinical Concern

8.5.2.1.

Clinical Chemistry and Haematology

The percentages of clinical chemistry values outside the normal range were generally
similar across treatment groups including placebo, across all analytes and throughout the
duration of the study (Screening, Days 14 and 28 and any Visit post-Screening)
(Table 8.12).
Small increases in the incidence of values outside the normal range for creatine
phosphokinase (CPK) were observed with active treatment arms combined (19.6%)
compared to placebo (10.7%). Most values were below twice the upper limit and no dose
response was observed. Six subjects (1.2 %) in the active arms combined compared to 0
subjects in placebo had CPK values above five times the upper limit (Listing 8.10,
Attachment 5). No more than 26% of subjects in any treatment group at any of the time
points reported analyte values outside the normal range (Table 8.12). Similar results
were found for the percentages of haematological values outside the normal range, with a
minor overall decrease in haematocrit, haemoglobin and red blood cell count across all
treatment groups with time (Table 8.15).
Clinical chemistry changes from baseline relative to the normal range by time point (Day
14 and Day 28) were classified as shifting to low, shifting to normal or no change, or
shifting to high. Analysis showed that for all clinical chemistry analytes, 86% or more
subjects in any treatment group had no change or experienced shifts into the normal range
during the treatment period (Table 8.13). For haematology this was 76% (Table 8.16).
Potassium and Glucose

Up to 2% and 11% of subjects in any treatment group at any of the pre-dose time points
recorded low potassium and high glucose levels outside the normal range, respectively
(Table 8.12 and Table 8.15). Overall, for potassium and glucose, maximum changes
from baseline and weighted mean changes from baseline (0-4 h), including changes

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versus placebo, did not exceed the predefined levels of clinically relevant concern (see
Section 8.6.3).

No AE reports of hypokalemia were reported.


Box plots of minimum potassium and maximum glucose are presented in Figure 18 and
Figure 19.
Figure 18

Minimum Post-Baseline Potassium

Source data: Figure 8.13.


Graph includes fasting and non-fasting samples, only shows subjects who were above LLN at baseline and shows
subjects minimum value divided by the lower limit of normal. The clinical concern level was defined as 0.9xLLN.

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Maximum Post-Baseline Glucose

Source data: Figure 8.15.


Graph includes fasting and non-fasting samples, only shows subjects who were below ULN at baseline, and shows
subjects maximum value divided by the upper limit of normal.
The clinical concern level was defined as 1.5xULN.

8.5.2.2.

Liver Function

A box plot of maximum post-baseline liver function test (LFT) results is presented in
Figure 8.2. Maximum post-baseline LFT values were similar across the GW642444M
treatment groups and comparable to placebo.
This event was deemed related to
study drug (Listing 8.10, Attachment 5). Bilirubin and alkaline phosphatase levels were
within normal range. This subject had recovered at the time of Database closure.

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8.6.

Other Safety Results

8.6.1.

Vital signs

8.6.1.1.

Systolic Blood Pressure

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Throughout the treatment period, mean maximum increases in systolic blood pressure
over 0-4 h after dosing were similar across the treatment groups including placebo and
ranged from 2.9 mmHg to 7.0 mmHg versus baseline (Table 8.20). Statistical analysis
showed that differences with placebo for maximum increase in systolic blood pressure
were not significant for any group throughout the treatment period (Table 8.22).
Summaries of weighted mean change from baseline and pre-dose in systolic blood
pressure (0-4 h) are presented in Table 8.29 and Table 8.30, respectively. There was no
evidence of a statistically significant difference in weighted mean change from baseline
with placebo for any group at any time point (Table 8.31).
8.6.1.2.

Diastolic Blood Pressure

Throughout the treatment period, mean maximum decreases (i.e., change from baseline in
minimum value) in diastolic blood pressure 0-4 h after dosing were similar across the
treatment groups including placebo and ranged from -2.5 mmHg to -6.6 mmHg versus
baseline (Table 8.23). Statistical analysis showed that differences with placebo for
maximum decrease in diastolic blood pressure were only significant for the 50 g
GW642444M group on Day 1 (-2.5 mmHg, p=0.004), and for the 6.25 g GW642444M
group on Day 14 (-2.1 mmHg, p=0.049) (Table 8.25).
Summaries of weighted mean change from baseline and pre-dose in diastolic blood
pressure (0-4 h) are presented in Table 8.32 and Table 8.33, respectively. Except for the
50 g GW642444M group on Day 1, there was no evidence of a statistically significant
difference in weighted mean change from baseline versus placebo 0-4 h after dosing for
any group at any time point (Table 8.34). For the 50 g GW642444M group, the
decrease in weighted mean diastolic blood pressure of -1.7 mmHg versus placebo on Day
1 was statistically significant (p=0.030), but unlikely to be of clinical relevance.

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8.6.1.3.

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Pulse Rate

Throughout the treatment period, mean maximum increases in pulse rate over 0-4 h after
dosing were similar across the treatment groups including placebo and ranged from 1.1
bpm to 7.1 bpm versus baseline (Table 8.26). Statistical analysis showed that differences
from placebo for maximum increases from baseline in pulse rate were significant for the
12.5 g group on Day 1 (-1.9 bpm, p=0.035) and for the 50 g GW642444M group on
Day 28 (2.7 bpm, p=0.026) (Table 8.28). However, a difference of 2.7 bpm was below
predefined levels of clinically relevant concern (6 bpm).
Summaries of weighted mean change from baseline and pre-dose in pulse rate (0-4 h) are
presented in Table 8.35 and Table 8.36, respectively. Except for the 50 g GW642444M
group on Day 28, there was no evidence of a statistically significant difference in
weighted mean change versus placebo 0-4 h after dosing for any group at any time point
(Table 8.37). For the 50 g GW642444M group, the increase in weighted mean pulse
rate of 2.2 bpm versus placebo on Day 28 was statistically significant (p=0.047) but
below predefined levels of clinically relevant concern.
8.6.2.

Twelve-Lead ECG

A summary of ECG values (heart rate, uncorrected QT interval, QTc(F) and QTc(B), PR
interval and QRS duration) on Days 1, 7, 14 and 28 is provided in Table 8.38.
Abnormal and clinically significant ECG findings over time as assessed by the
independent cardiologist are summarised in Table 8.39. At any time post-baseline, the
incidence of absolute clinically significant abnormal ECG findings was similar across the
GW642444M treatment groups (6% to 12% of subjects) and comparable to placebo (8%)
(Table 32).
A summary of ECG changes at any time post-baseline Table 33 shows that the incidence
of unfavourable clinically significant changes was similar across the GW642444M
treatment groups (17%-19%) and comparable with placebo (18%). Of note is that not all
the changes listed in Table 33 are considered to be a clinically significant abnormality: a
subject can have a clinically significant change at the same time s/he has a normal result;
Table 32 and Table 33 therefore do not correlate exactly.
As outlined in Section 8.4 and Section 14 (case narratives), 4 subjects were withdrawn
due to ECG protocol-defined stopping criteria: one subject receiving placebo (ventricular
tachycardia), two subjects receiving 6.25 g GW642444M (T-wave amplitude decreased
and PR prolongation), and one subject receiving 12.5 g GW642444M (AV block second
degree).
In general, a greater incidence of subjects with an absolute maximum post-dose QTc
prolongation >450 msec across all treatment groups and over time was found when QTc
was calculated using Bazett's formula (incidence of up to 11%) than if corrected using
Fridericia's formula (incidence of up to 5%) (Table 8.40 and Table 8.41). For both QTc(F)
and QTc(B) no dose response was found across the treatment groups on any of the days
studied, including no clinically relevant difference to placebo.
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Similarly, a greater incidence of subjects with a 30 msec 60 msec QTc prolongation


from baseline (0-4 h) across treatment groups and over time was found when QTc was
calculated using Bazett's formula (incidence of up to 27%) than if corrected using
Fridericia's formula (incidence of up to 17%) (Table 8.42 and Table 8.43). Neither for
QTc(F) nor QTc(B) evidence of a dose response was found across the treatment groups on
any of the days studied, including no clinically relevant difference to placebo.

Whilst no maximum post-dose QTc(F) intervals of >500 msec were recorded at any time
point (Table 8.40), two subjects recorded post-dose QTc(B) intervals of >500 msec
(Table 8.41 and Listing 8.14, Attachment 5).

Table 32
n (%)

Summary of Absolute ECG findings at any Time Post-Baseline


Placebo
N=102
102
49 (48)
45 (44)

3 g
GW642444
N=101
101
38 (38)
51 (50)

6.25 g
GW642444
N=101
101
41 (41)
54 (53)

12.5 g
GW642444
N=100
100
50 (50)
40 (40)

25 g
GW642444
N=101
101
42 (42)
47 (47)

N
Normal
Abnormal - not clinically
significant
Abnormal clinically
8 (8)
12 (12)
6 (6)
10 (10)
12 (12)
significant
Not available
0
0
0
0
0
Source data: Table 8.39.
Abnormality and clinical significance determined by the central cardiologist.
A subject can have a clinically significant change at the same time s/he has a normal result

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GW642444
N=102
102
50 (49)
45 (44)
7 (7)
0

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Table 33

Summary of ECG Changes at any Time Post-Baseline

n (%)

Placebo

3 g
GW642444
N=101
101
0

6.25 g
GW642444
N=101
101
0

12.5 g
GW642444
N=100
100
0

25 g
GW642444
N=101
101
0

50 g
GW642444
N=102
102
0

N=102
N
102
Clinically significant
1 (<1)
change: favourable
Clinically significant
18 (18)
19 (19)
17 (17)
17 (17)
18 (18)
17 (17)
change: unfavourable
No change or insignificant
77 (75)
79 (78)
80 (79)
81 (81)
76 (75)
82 (80)
change
No result
6 (6)
3 (3)
4 (4)
2 (2)
7 (7)
3 (3)
Source data: Table 8.39.
Abnormality and clinical significance determined by the central cardiologist.
A subject can have a clinically significant change at the same time s/he has a normal result.
This table does not correlate exactly with Table 32 since not all the changes listed in Table 33 are considered to be a
clinically significant abnormality: a subject can have a clinically significant change at the same time s/he has a normal
result. Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.

8.6.2.1.

Heart rate

A summary of heart rate findings is presented in Table 8.38.


Mean heart rate was broadly similar across all treatment groups over all timepoints on all
study days. Throughout the study no subject had an absolute heart rate above 140 bpm.
8.6.2.2.

QTc(F)

Weighted Mean Change from Baseline and Pre-Dose (0-4 hours)

Summaries of weighted mean change from baseline and pre-dose (0-4 h) in QTc(F)
interval are provided in Table 8.44 and Table 8.45, respectively. No statistically
significantly weighted mean change from baseline (0-4 h) in QTc(F) interval was reported
for any treatment comparison to placebo, at the study Days 1, 7, 14 and 28 (Table 8.52).
Change from Baseline 0-4 hours Post-Dose Serial QTc(F)

In contrast to the analysis of weighted mean change, the analysis of serial QTc(F)
measured at 10 minutes, 1, 2 and 4 h following dosing on Days 1, 7, 14 and 28 showed a
statistically significant difference in mean post-dose serial QTc(F) (0-4 h) change from
baseline for 50 g GW642444M compared with placebo. Ten minutes after dosing on
Day 1, subjects in the 50 g GW642444M group recorded a statistically significant
difference in mean QTc(F) increase from baseline versus placebo of 4.1 msec (p=0.030)
(Table 8.48). In addition, 10 minutes after dosing on Day 7, subjects in the 50 g
GW642444M group recorded a statistically significant difference in mean QTc(F) increase
from baseline versus placebo of 5.0 msec (p=0.035). A predefined level of clinical
concern for changes in QTc for this study was agreed at 5 msec based on FDA
Guidance for Industry for clinical evaluation of QT/QTc prolongation [FDA Guidance
for Industry, 2005].
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In addition, a statistically significant decrease in QTc(F) versus placebo was found for the
6.25 g group 4 h after dosing on Day 14 (-5.9 msec, p=0.014). At other time points, any
changes in QTc(F) versus placebo did not reach statistical significance in any treatment
group.
The adjusted treatment differences from placebo for serial QTc(F) on Days 1, 7, 14 and 28
are shown in Figure 20.
Figure 20

Adjusted Treatment Differences (95% CI) of Change from Baseline in


Post-Dose Serial QTc(F) (msec)

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Figure 20

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Adjusted Treatment Differences (95% CI) of Change from Baseline in


Post-Dose Serial QTc(F) (msec) (continued)

Source data: Figure 8.8

Maximum Change from Baseline in QTc(F) (0-4 hours)

A summary of maximum post-dose QTc(F) values on Days 1, 7, 14 and 28 is provided in


Table 8.40 and Figure 8.4. Individual maximum changes in QTc interval change from
baseline (0-4 h) were defined as normal if 30 msec, high if >30 60 msec, and a reason
for concern if >60 msec.
For the majority of subjects (57%-79% across all treatment groups), maximum changes
from baseline in QTc(F) (0-4 h) were within the normal range, and values for the
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GW642444M groups were comparable to placebo (Table 8.42 and Figure 8.4). Across
the study days, only 2 or fewer subjects (2%) in the 3 g, 6.25 g, 12.5 g and 25 g
GW642444M groups had maximum changes from baseline in QTc(F) (0-4 h) of 60 msec
(Table 8.42). No subjects in the placebo and 50 g GW642444M groups recorded
maximum changes from baseline 60 msec.
Although up to 17% of subjects in any treatment group at any time point were reported to
have high maximum increases in QTc(F) (0-4 h), statistical analysis showed that any
differences with placebo 0-4 h after dosing were not statistically significant for any group
throughout the treatment period (Table 8.50).
8.6.2.3.

QTc(B)

Weighted Mean Change from Baseline and Pre-Dose (0-4 hours)

Summaries of weighted mean change from baseline and pre-dose (0-4 h) in QTc(B)
interval are provided in Table 8.46 and Table 8.47, respectively.
Statistical analysis showed that there was evidence of an increase in QTc(B) interval
compared with placebo only on 50 g GW642444M treatment (Day 1, 4 msec increase
(p=0.034) (Table 8.53). However, this value was below the pre-defined threshold of
clinical concern.
There were no statistically significant treatment differences in weighted mean change
from baseline (0-4 h) in QTc(B) interval for any other treatments on any day (Table 8.53).
Change from Baseline 0-4 hours Post-Dose Serial QTc(B)

Analysis of change from baseline in post-dose serial QTc(B) showed that on several
occasions following dosing on all study Days, treatment with 6.25 g, 25 g and 50 g
GW642444M resulted in statistically significant increases versus placebo in post-dose
serial QTc(B) (Table 8.49). Adjusted treatment differences of change from baseline in
post-dose serial QTc(B) are depicted graphically in Figure 8.9.
Most of the statistically significant increases in post-dose serial QTc(B) were recorded for
the 50 g GW642444M group: on seven occasions, 10 minutes to 1 h post-dose on all
study Days, the 50 g GW642444M group had mean treatment differences greater than 5
msec (6 msec 12.5 msec) following dosing. Statistically significant treatment
differences greater than 5 msec were also found for the 25 g GW642444M group (6.1
msec at 10 minutes on Day 1 and 8.2 msec at 1 h on Day 14). As mentioned in
Section 8.6.2.2, a predefined level of clinical concern for changes in QTc for this study
was agreed at 5 msec based on FDA Guidance for Industry for clinical evaluation of
QT/QTc prolongation [FDA Guidance for Industry, 2005].
In addition, there was a statistically significant QTc(B) treatment difference of 4.9 msec
recorded for the 6.25 g GW642444M group on Day 1 at 10 minutes.

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Maximum Change from Baseline in QTc(B) (0-4 hours)

A summary of maximum change from baseline QTc(B) (0-4 h) values on Days 1, 7, 14


and 28 is provided in Table 8.43. Overall, 43%-68% of subjects across all treatment
groups at any time point had maximum changes from baseline in QTc(B) within the
normal range (30 msec). Compared with QTc(F), for QTc(B) generally more subjects had
high maximum changes (>30 60 msec) from baseline. Across the study days, 3 or
fewer subjects (3%) in the GW642444M and placebo groups had maximum changes
from baseline in QTc(B) (0-4 h) of 60 msec (Table 8.43).
Statistical analysis showed that maximum increases from baseline versus placebo in
QTc(B) of 5.2 to 6.3 msec were significant only for subjects in the 50 g GW642444M
group, on Days 7, 14 and 28 (Table 8.51).
8.6.2.4.

QTc(F) and QTc(B) Heart Rate Relationship

Scatter plots of serial QTc(F) and QTc(B) versus heart rate on Days 1, 7, 14 and 28 are
presented in Figure 8.10 and Figure 8.11. For QTc(F) and heart rate, there was no strong
evidence of an association between these parameters on any of the time points suggesting
QTc(F) values are independent of heart rate . The scatter plot of QTc(B) and heart rate
showed positive correlation for for QTc(B) versus heart rate, which suggests that QTc(B)
does not completely correct for heart rate at the extremes. This is in line with the known
observation that QTc(B) over-corrects at high heart rates and under-corrects at low heart
rates [FDA Guidance for Industry, 2005]. Consequently data corrected as QTc(F)was
considered to be the most relevant and accurate for this review.
8.6.3.

Potassium and Glucose

Summary statistics of fasting potassium and glucose on Days 1 and 28 and non-fasting
potassium on Days 7 and 14 only are provided in Table 8.54 and Table 8.55. Changes
from baseline relative to the normal range (shift tables) are presented in Table 8.56 and
Table 8.57.
Changes from baseline relative to the normal range were classified as shifting to low,
shifting to normal or no change, or shifting to high; with the levels of clinical concern set
at a difference of -0.3 mmol/L and 1.5 mmol/L versus placebo for potassium and glucose,
respectively.
8.6.3.1.

Potassium

For fasting potassium, 81% or more subjects in any treatment group had no change or
experienced shifts into the normal range during the treatment period (Table 8.56). For
non-fasting potassium this was 83% (Table 8.57).
Mean potassium treatment differences from placebo did not go below the 0.3 mmol/L
predefined level of clinically relevant concern. Several subjects recorded values of >7
mmol/L; individual profiles for these subjects and discussion are presented in Attachment

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2. Outlying values of >7 mmol/L were thought by Quest Laboratories and GSK to be due
to non-usable samples.
Fasting Potassium - Maximum Decrease from Baseline and from Pre-Dose (0-4
hours)

Summaries of maximum decrease from baseline and pre-dose in fasting potassium (0-4 h)
are provided in Table 8.58 and Table 8.59, respectively. Statistical analysis (Table 8.70)
showed that on Day 28, decreases of -0.14 mmol/L from baseline versus placebo for both
the 6.25 g and 50 g GW642444M groups were statistically significant. However,
these changes were below predefined levels of clinically relevant concern
Fasting Potassium - Weighted Mean Change from Baseline and from Pre-Dose (0-4
hours)

Summaries of weighted mean change from baseline and pre-dose in fasting potassium (04 h) are provided in Table 8.64 and Table 8.65, respectively. Apart from a statistically
significant weighted mean decrease in fasting potassium of -0.130 mmol/L versus
placebo in the 50 g GW642444M group on Day 1, which was below predefined levels
of clinically relevant concern, no weighted mean changes from baseline in any treatment
group at Day 1 or Day 28 reached statistical significance (Table 8.73).
Non-Fasting Potassium - Maximum Decrease from Baseline and from Pre-Dose (04 hours)

Summaries of maximum decrease from baseline and pre-dose in non-fasting potassium


(0-4 h) are provided in Table 8.60 and Table 8.61, respectively. Statistical analysis
showed that any maximum decreases in non-fasting potassium versus placebo in any
treatment group on Day 7 were not statistically significant (Table 8.71).
In contrast, on Day 14, statistically significant decreases of -0.11 mmol/L (p=0.049) and
0.17 mmol/L (p=0.002) versus placebo were recorded for the 25 g GW642444M and 50
g GW642444M groups, respectively. These changes were however below predefined
levels of clinically relevant concern
Non-Fasting Potassium - Weighted Mean Change from Baseline and from PreDose (0-4 hours)

Summaries of weighted mean change from baseline and pre-dose in non-fasting


potassium (0-4 h) are provided in Table 8.66 and Table 8.67, respectively. Apart from a
statistically significant weighted mean decrease in fasting potassium of 0.170 mmol/L
versus placebo in the 50 g GW642444M group on Day 14, no other weighted mean
changes from baseline in non-fasting potassium versus placebo reached statistical
significance in any other treatment group at Day 7 or Day 14 (Table 8.74).

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8.6.3.2.

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Glucose

For glucose, 78% or more subjects in any treatment group had no change or experienced
shifts into the normal range during the treatment period (Table 8.56). Mean treatment
differences from placebo did not go above the predefined level of clinically relevant
concern (1.5 mmol/L).
Maximum Increase from Baseline and from Pre-Dose in Glucose (0-4 hours)

Summaries of maximum increase from baseline and pre-dose in glucose (0-4 h) are
provided in Table 8.62 and Table 8.63, respectively. Statistical analysis showed that,
except for the 6.25 g GW642444M group on Day 1, maximum changes in glucose
versus placebo in any treatment group at any time point were not statistically significant
(Table 8.72). A statistically significant change versus placebo of -0.25 mmol/L in the
6.25 g GW642444M group on Day 1 (p=0.044) did not exceed predefined levels of
clinically relevant concern.
Weighted Mean Change from Baseline and from Pre-Dose in Glucose (0-4 hours)

Summaries of weighted mean change from baseline and pre-dose in glucose (0-4 h) are
provided in Table 8.68 and Table 8.69, respectively. Apart from a statistically significant
weighted mean change in glucose of -0.185 mmol/L versus placebo in the 6.25 g
GW642444M group on Day 1, which did not exceed predefined levels of clinically
relevant concern, no weighted mean changes from baseline in any treatment group at Day
1 or Day 28 reached statistical significance (Table 8.75).
8.6.4.

Asthma Exacerbations

A summary of asthma exacerbations experienced by subjects during treatment is


provided in Table 34. The incidence of asthma exacerbations was low and similar across
the treatment groups, with the highest percentage of events in the placebo and 3 g
GW642444M groups (4% and 7%, respectively), compared with 0%-3% in the other
groups. Most exacerbations were considered due to allergy (4 subjects) or unknown
etiology (3 subjects).

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Table 34

Summary of Subjects with Asthma Exacerbations (ITT Population)

n(%)

Placebo

Any Asthma Exacerbation


Took Corticosteroids for an
exacerbation
Hospitalised due to an
exacerbation
ER visit due to an exacerbation
Corticosteroids or hospitalised
or ER
None of the above
Primary cause of exacerbation
Cold air/cold water
Tobacco smoke
Upper respiratory infection
Air pollution
Allergy
Exercise
Stress/emotions
Beta-blockers
Aspirin
Other NSAIDS
Withholding/ reducing asthma
meds
Withholding or reducing COPD
meds
Unknown aetiology
Lack of efficacy
Lower respiratory infection
Common cold
Upper respiratory infection other
than common cold
Other
Source data: Table 8.76.

8.6.5.

N=102
4 (4)
1 (<1)

3 g
GW642444
N=101
7 (7)
3 (3)

6.25 g
GW642444
N=101
2 (2)
2 (2)

12.5 g
GW642444
N=100
0
0

25 g
GW642444
N=101
3 (3)
1 (<1)

50 g
GW642444
N=102
1 (<1)
0

1 (<1)
2 (2)

2 (2)
5 (5)

1 (<1)
2 (2)

0
0

0
1 (<1)

0
0

2 (2)

2 (2)

2 (2)

1 (<1)

0
0
0
0
1 (<1)
0
1 (<1)
0
0
0
1 (<1)

1 (<1)
0
2 (2)
0
3 (3)
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0

0
0
0
1 (<1)
1 (<1)
0
0
0
0
0
0

0
0
0
0
0
1 (<1)
0
0
0
0
0

1 (<1)
0
0
0
0

1 (<1)
0
0
0
0

1 (<1)
1 (<1)
1 (<1)
0
0

0
0
0
0
0

0
1 (<1)
0
0
0

0
0
0
0
0

Medical Device/Product Incidents, Near-Incidents, Malfunctions


and Remedial Action

No incidents, near incidents or malfunctions were reported with the use of the medical
device(s) manufactured or marketed by GSK or by a third party for GSK, for this study.
Five malfunctions were reported for the Novel Dry Powder Inhaler (1 malfunction in
each of the placebo, 3 g, 6.25 g, 25 g and 50 g GW642444M groups), which were
mainly due to mechanical reasons (Listing 8.18, Attachment 5).

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8.7.

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Safety Summary

Throughout the 28-day treatment period, GW642444M was well tolerated at all
doses. The overall incidence of AEs was similar across the GW642444M treatment
groups (ranging from 23% to 37%) and was comparable to placebo. Headache was
the most common AE in all treatment groups including placebo and occurred at an
incidence of 7-12%. Other, commonly reported AEs included upper respiratory tract
infection, nasopharyngitis and dizziness. There was no dose-related increase in the
frequency of the most commonly reported AEs across the GW642444M doses.

The incidence of on-treatment drug-related AEs was comparable between the


GW642444M groups and placebo, and individual AEs were reported by no more
than 8 subjects on any treatment. On-treatment drug-related AEs included headache
(most commonly reported), dizziness and the LABA class adverse effects
palpitations and tremor. Palpitations were reported by <1% to 2% of subjects across
the placebo, 3 g GW642444M and 6.25 g GW642444M groups; tremor was
reported by <1% subject in the 6.25 g GW642444M group only.

In total, 6 subjects (0%-2% across treatment groups, with no more than 2 subjects
per group) were withdrawn from the study due to AEs though in only two cases was
the AE the primary reason for the withdrawal. One subject was withdrawn due to
the AE of psychomotor hyperactivity, feeling jittery and insomnia (3 g
GW642444M) and another subject was withdrawn due to an increase in allergy
symptoms and pyrexia (25 g GW642444M). The other 4 subjects were withdrawn
due to protocol stopping criteria with related AEs as a sub reason.

No SAEs or pregnancies were reported in this study.

There were no clinically relevant changes in mean or median haematology, clinical


chemistry and urinalysis values over time. Small differences in incidence of values
outside normal range for CPK were observed for active groups compared to placebo.

Maximum post-baseline liver function tests were similar across the GW642444M
treatment groups and comparable to placebo.

For potassium, maximum decreases from baseline and weighted mean changes from
baseline (0-4 h), including changes versus placebo, did not exceed the predefined
levels of clinically relevant concern. No AEs of hypokalaemia were reported.

For glucose, maximum increases from baseline and weighted mean change from
baseline (0-4 h), including changes versus placebo, mean treatment differences from
placebo did not exceed the predefined levels of clinical concern.

No safety concerns were noted from the results of vital signs assessments. For pulse
rate and systolic and diastolic blood pressure, no treatment-related changes were
apparent and differences from baseline versus placebo were deemed not clinically
significant.

Any statistically significant increases from baseline versus placebo in serial QTc(F)
(0-4 h) were deemed not clinically relevant. There were no statistically or clinically
significant treatment differences in weighted mean or maximum change from
baseline (0-4 h) in QTc(F) for any treatment group, at any time point.
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In contrast, statistically significant changes from baseline in serial QTc(B) of >5 msec
10 minutes to 1 h following dosing on all study days in the 50 g GW642444M
group were recorded. Treatment differences >5 msec were also found for the 25 g
GW642444M group on Day 1 at 10 minutes post-baseline and Day 14 at 10 minutes
and 1 h post-baseline. However, the plots of QTc(B) versus heart rate suggest that
QTc(B tends to under-correct at low and over-correct at high heart rate.

No safety concerns were raised for heart rate values measured by ECG.

The incidence of asthma exacerbations was low and similar across the treatment
groups, with the highest percentage of events in the placebo and 3 g GW642444M
groups (4% to 7%, respectively), compared with 0% to 3% in the other groups.

9.

BIOANALYTICAL RESULTS

Quality Control (QC) samples for the analysis of GW642444, GW630200, GSK932009
and triphenylacetate counter-ion, prepared at three different analyte concentrations and
stored with study samples, were analysed with each batch of samples against separately
prepared calibration standards. For the analysis to be acceptable, no more than one-third
of the QC results and no more than one-half of the results from each concentration level
were to deviate from the nominal concentration by more than 15%. All applicable
analytical runs met all predefined run acceptance criteria.

10.

PHARMACOKINETIC RESULTS

10.1.

Plasma Concentration-Time Data

In total, 504 subjects provided 5564 PK samples (non-missing) following administration


of GW642444M (3 - 50 g).

10.1.1.

GW642444

The percentage (%) of samples analysed for GW642444 which were below the Lower
Limit of Quantification (LLQ 30 pg/mL) are summarised by pharmacokinetic sample
collection time window, visit and treatment in Table 35.

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Table 35
Visit
(Day +4/-2)

GW642444: Summary of % of Not Quantifiable values by Treatment,


Day and Time
Time Window

3 g
GW642444

2 (Day 1)

Pre-dose
2-10 min
10-30 min
30 min - 2h
2-4 h
3 (Day 7)
Pre-dose
4 (Day 14)
2 min -1 h
5 (Day 28)
Pre-dose
2-10 min
10-30 min
30 min - 2h
2-4 h
Source data: Table 9.1

10.1.1.1.

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100
97
99
100
100
100
90
99
88
94
99
100

6.25 g
12.5 g
25 g
GW642444
GW642444
GW642444
Total (%) sample below LLQ (30 pg/mL)
99
97
98
84
48
21
93
67
41
97
92
79
98
96
94
99
98
97
63
37
26
99
96
93
57
20
10
88
44
20
100
90
48
100
95
78

50 g
GW642444
99
13
10
20
58
89
23
92
10
3
3
18

3g GW642444M

Plasma concentrations of GW642444 were below the LLQ (30 pg/mL) in the majority
(88%) of samples analysed from subjects who received single and repeat doses of 3g
GW642444M. A minority of subjects had quantifiable plasma concentrations of
GW642444 which were generally observed at a single time point within 10 min of dosing
at concentrations just above the LLQ (30-45pg/mL; Figure 9.1). Plasma concentrations
( 90 pg/mL) were reported in 3 subjects. Higher levels (165 and 201 pg/mL) were
observed in 2 subjects approximately 0.5 h after dosing. Median concentrations (by PK
sample collection period) were below LLQ (Attachment 3). Based on the high % NQ
concentrations across all timepoints and visits (97%), the data were considered too
limited for nonlinear mixed effects modelling.
10.1.1.2.

6.25g GW642444M

GW642444 was quantifiable in 16% of the samples analysed from subjects following a
single dose and 43% of samples analysed after repeat (28 days) dosing with 6.25 g
GW642444M. Generally GW642444 was only quantifiable at a single time point within
15 min post-dose. A minority of asthmatics had quantifiable concentrations of
GW642444 in 2 consecutive post-dose samples and a single individual had quantifiable
concentrations up to 4 h post-dose on Day 1 (Visit 2) of the study.
Median concentrations (by PK sample collection period) were below LLQ (see
Attachment 3). Based on the high % NQ concentrations across all timepoints and visits
(90%; Table 35), the data were considered too limited for nonlinear mixed effects
modelling.

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10.1.1.3.

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12.5g GW642444M

GW642444 was quantifiable in 52% of the subjects after a single dose and 80% of
subjects following repeated administration (28 days) of 12.5 g GW642444M. However,
plasma concentration-time profiles were very limited (Figure 9.1) with 2 quantifiable
post-dose concentrations/individual/day. Plasma concentrations fell below the LLQ in the
majority of samples collected beyond 30 min post-dose (Table 35). Median
concentrations (by PK sample collection period) were just above the LLQ in early (0-30
min) time collection periods (Attachment 3). Based on the high % NQ values (74%;
Table 35) across all timepoints and visits, the data were considered too limited for
nonlinear mixed effects modelling.
10.1.1.4.

25g GW642444M

GW642444 was quantifiable in plasma of the majority of the subjects who received
single and repeat doses of 25 g GW642444M. Again profiles were limited; generally
2 quantifiable post-dose concentrations/individual/day. In majority of subjects plasma
concentrations of GW642444 fell below the LLQ beyond 30 min post-dose after a single
and 2 h following repeat (28 days) inhaled administration (Table 33). Maximum
observed concentrations were generally seen within 30 min post-dose and ranged from
30-328 pg/mL (Figure 9.1). Median concentrations (by PK sample collection period)
were above LLQ in early (0-30 mins) time collection periods (Attachment 3). Based on
the high % NQ concentrations across all timepoints and visits (59%; Table 35), the data
were considered too limited for nonlinear mixed effects modelling.
10.1.1.5.

50g GW642444M

GW642444 was quantifiable in plasma of the majority of the asthmatic patients who
received single and repeat doses of 50 g GW642444M. Profiles were still relatively
limited. Across all timepoints and visits 37% of the samples analysed for GW642444
were NQ. GW642444 was quantifiable in the majority (80%) of samples collected up to
2 h post-dose on Day 1, thereafter ( 2h post-dose) the majority of samples (58%) were
NQ. On Day 28 profiles were more extensive; 82% of samples collected up to 4 h postadministration on Day 28 had quantifiable levels of GW642444. Maximum observed
concentrations were generally seen within 30 min post-dose and ranged from 30-975
pg/mL (Figure 9.1). Median concentrations (by PK sample collection period) were 250
pg/mL (Attachment 3). Plasma GW642444 concentration-time data following 50 g
GW642444M were subjected to nonlinear mixed effects modelling.

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10.1.2.
Table 36
Visit
(Day +4/-2)

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Triphenylacetate (counterion)
Triphenylacetate: Summary of % of NQ values by treatment, Day and
Time
Time
Window

2 (Day 1)

Pre-dose
2-10 min
10-30 min
30 min 2h
2-4 h
3 (Day 7)
Pre-dose
4 (Day 14)
2min -1 h
5 (Day 28)
Pre-dose
2-10 min
10-30 min
30 min 2h
2-4 h
Source data: Table 9.1

3 g
GW642444
100
100
100
99
100
100
99
100
100
99
100
100

6.25 g
12.5 g
25 g
GW642444
GW642444
GW642444
Total (%) sample below LLQ (1ng/mL)
100
100
100
100
100
100
99
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
99
99
100
99
100
100
100
99
100
99
100
100

50 g
GW642444
100
98
100
100
99
100
99
100
95
100
99
98

Triphenylacetate was quantifiable in a minority of individuals following 3, 6.25, 12.5, 25


and 50 g doses (Table 36), however, in all cases concentrations were low (< 2ng/mL;
Listing 9.2, Attachment 5); just above the limit of quantification (1 ng/mL).
10.1.3.

GW630200

GW630200 was not quantifiable (LLQ 90 pg/mL) in any subject following 3, 6.25, 12.5,
25 or 50 g GW642444M (Table 9.1) The metabolite was only quantified in plasma
(191 pg/mL) in a single subject (approximately 0.2% of total population to receive active
treatment) 10 min post-administration of 12.5 g GW642444M on Visit 4 of the study
(Day 14).
10.1.4.

GSK932009

The metabolite, GW630209 was not quantifiable (LLQ 180 pg/mL) in plasma of any
subject following 3, 6.25, 12.5 or 25 g GW642444M (Table 9.1). A single subject
(approximately 0.2% of total population to receive active treatment) had quantifiable
concentrations (268-476 pg/mL) pre-dose and up to 4 h post-dose at Visit 5 following 50
g GW642444M. This subject had the highest GW642444 concentrations reported in the
study.

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10.2.

Pharmacokinetic Analysis: GW642444

10.2.1.

Nonlinear Mixed Effects Modelling

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Plasma concentration-time data following 3-25 g GW642444M had too high a % NQ


values (59%) for formal population PK analysis (Table 35). Although GW642444
concentration-time data following 50 g GW642444M was still relatively limited (37%
of the total data was NQ) it was subjected to nonlinear mixed effects modelling in an
attempt to define a population PK model for GW642444M following inhaled
administration from a novel dry powder device.
The process of model building started with trying to fit the simplest pharmacokinetic
model possible to the data proceeding towards more complex effects added one at a time.
A number of different models were investigated (first- and zero-order, one- and twocompartmental models with first-order elimination) using NONMEM V.1 and
NONMEM V (with F_Flag functionality). However, due to the limited nature of the
concentration-time data (sparse sampling up to 4 h post-dose and LLQ data censoring) it
was not possible to build a population PK model that was able to accurately and robustly
describe the observed PK profile following 50 g GW642444M.
10.2.2.

Noncompartmental Analysis

10.2.2.1.

GW642444 Cmax

An estimate of Cmax and tmax was obtained directly from the raw concentration-time
data collected over the period 2-30 minutes post-dose on days 1 and 28 (across 2-10 min
and 10-30 min samples). If tmax was outside this window, tmax and Cmax were
reported as not determined (ND) and set to missing. Across all doses 8% of tmax
values were outside the 2-30 min window. Observed Cmax and tmax are summarised by
dose and visit in Table 37.

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Table 37
Parameter
(units)
Cmax (pg/mL)

Tmax (h)

Summary (Median [range]) GW642444 Cmax and tmax (estimated


over period 2-30 min post-dose)
Dose
(g)
3

Visit

N*

95% CI

Median

Range

96
69

Geometric
mean
NA
NA

2
5

100
82

100
82

NA
NA

NC
NC

NC - 165.6
NC - 201.6

6.25

2
5

101
90

96
88

79
50

NA
NA

NA
NA

NC
NC

NC 121.7
NC - 170.0

12.5

2
5

100
89

97
86

40
14

NA
NA

NA
NA

41.0
59.9

NC - 215.1
NC 200.3

25

2
5

101
92

98
91

17
8

59.3
96.5

50.5 - 69.7
82.4 113.1

64.8
119.6

NC - 260.7
NC - 328.1

50

2
5
2
5

102
97
100
82

93
89
4
13

6
3
96
69

139.1
223.0
ND
ND

117.8164.1
189.6 262.4
ND
ND

142.1
267.4
0.15
0.15

NC - 623.6
NC - 975.6
0.05 - 0.48
0.05 - 0.50

6.25

2
5

101
90

17
38

79
50

ND
ND

ND
ND

0.20
0.17

0.05 - 0.42
0.05 - 0.37

12.5

2
5

100
89

57
72

40
14

ND
ND

ND
ND

0.17
0.17

0.03 - 0.45
0.03 - 0.45

25

2
5

101
92

81
83

17
8

ND
ND

ND
ND

0.17
0.17

0.03 - 0.53
0.05 - 0.47

50

2
5

102
97

87
86

6
3

ND
ND

ND
ND

0.17
0.17

0.05 0.52
0.05 - 0.48

Source data: Table 9.3


NC =non calculable due to NQ concentrations
NA = not applicable due to insufficient data to derive summary measure
n = Number of subjects with non-missing values (including NC values)
n* = Number of subjects for whom parameter cannot be derived because of NQ concentrations, NCs were imputed
prior to derivation of summary statistics; No NC values were computed for tmax. Cmax imputed with LLQ (15
pg/mL).

10.2.2.2.

Covariate Effects on observed Cmax

As observed Cmax (2-30 min post-dose) at low doses (6.25 g) was censored by LLQ
(>55% of data reported as NC), covariate effects were only investigated for 12.5 50 g
GW642444M.
There was no notable effect of patient sex or baseline FEV1 stratum ( 65%-90% or
40%-65%) on observed Cmax (Table 38). Ethnicity, race and smoking covariates were
not investigated as the majority patients at each dose of GW642444M were non-Hispanic
and had never smoked (Table 5 and Section 6.4.2.1). Similarly, 73% of patients at each
GW642444M dose were of white/Caucasian/European heritage with all other races
representing <14% of the population (Table 5). Data were also too limited to investigate

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the effect of CYP3A4 inhibitors; only five patients receiving active treatment (12.5 and
25 g) were administered a moderate inhibitor during the study.
Table 38

Summary (Median [range]) GW64244 Cmax (pg/mL) by Categorical


Covariate
SEX

Visit 2 (Day1)

Males
Females

Visit 5 (Day28)

Males
Females

STRATA
Visit 2 (Day1)

Lower
(65-90)
Upper
(40-65)

Visit 5 (Day28)

Lower
(65-90)
Upper
(40-65)

12.5 g GW642444
(M44/F56)
42.6
[NC-98.8]
39.6
[NC-215.1]
12.5 g
(M37/F52)
62
[NC-200.3]
59.5
[NC-128.5]

25 g GW642444
(M40/F61)
47.5
[NC-133.3]
74.8
[NC-260.7]
25 g
(M36/F57)
98.4
[NC-325.9]
127
[NC-328.1]

50 g GW642444
(M45/F56a)
133.6
[NC-412.4]
158.1
[NC-623.6]
50 g
(M44/F53)
215.1
[NC-647.4]
287.1
[NC-975.6]

12.5 g
(M58/F42)
47.8
[NC-215.1]
NC
[NC-98.8]
12.5 g
(M53/F36)
62.7
[NC-169.1]
49.5
[NC-200.3]

25 g
(M54/F47)
88.4
[NC-208.3]
44.2
[NC-260.7]
25 g
(M50/F43)
127.7
[NC-256.4]
92.3
[NC-328.1]

50 g
(M56/F45)
186.5
[NC-623.6]
131
[NC-423.4]
50 g
(M49/F40)
271.3
[NC-975.6]
266.9
[NC-471.9]

Source data: Table 9.4.


a. Versus 57 in Table 5.

There was no clear correlation between patient age, body weight or BMI and observed
Cmax (Figure 9.2).

10.3.

Pharmacokinetic Summary

GW64244 concentration-time data was too limited (high % NQ values at doses 25


g and limited concentration-time profiles at 50 g for formal population PK
analysis.

GW642444M systemic exposure could only be characterised at doses of 12.5 g.


At lower doses, plasma concentrations of GW642444 were generally at or below the
limit of quantification in plasma (30 pg/mL)

Observed Cmax (over period 2-30 min post-dose) provided an estimate of systemic
exposure to GW642444M and increased with dose and showed a tendency for higher
exposure on repeat dosing. There was no clear covariate effect on observed Cmax.

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At all doses and visits, concentrations of triphenyacetate (counterion) were below


limits of quantification (1 ng/ml) in the majority of subjects.

GW642444 metabolite (GW630200 and GSK932009) concentrations were below


limits of quantification (90 and 180 pg/mL, respectively) for all doses and visits in
99.8% of subjects.

11.

PHARMACOKINETIC/PHARMACODYAMIC RESULTS

11.1.

Systemic PK/PD Analysis

Pulse Rate and QTc(B)


Visual inspection of plots of individual observed GW642444 Cmax (over collection
period 2-30 min) and individual pulse rate (0-4 h), or QTc(B) (0-4 h) suggested a very
slight trend with increasing Cmax (Figure 9.3).
Based on small linear increases in systemic PD effects with Cmax and clear effect of
baseline, a linear, slope-intercept model with baseline effect was investigated. However,
over the narrow range of observed concentrations it was not possible to build a model
that was able to accurately describe the Cmax /PD relationship for either endpoint
(change from baseline maximum and weighted mean pulse rate or change from baseline
maximum and weighted mean QTc(B)).
Fasting Potassium and Glucose
Whilst the pair-wise comparisons between active treatment and placebo showed
statistically significant treatment effects there was no clear effect relationship based on
visual inspection (Figure 9.3) and no evidence that the slope was different from zero for
either maximum decrease (potassium) / increase (glucose) and weighted mean change
from baseline values (0-4 h).
QTc(F)
Based on visual inspection, there was no clear correlation between individual observed
Cmax (over collection period 2-30min) maximum and weighted mean QTc(F) (0-4 h) (and
corresponding change from baseline values) (Figure 9.3); consistent with lack evidence
from pair-wise comparisons between active treatment and placebo for a statistically
significant treatment effect.

11.2.

Pharmacodynamic modelling of dose-response and time


course of FEV1

All datasets were provided with the dose response modelling strategy predefined in
Section 13 of the RAP. Additional details of PK/PD analysis methodology are described
in Attachment 4

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The ITT dataset containing observed individual trough day 28 FEV1 data with patient
covariates was used for estimating the dose response model parameters (including
placebo effect and inter-patient variability, potency (ED50) and maximum predicted
effect (Emax). This analysis supplements the information provided from the primary
statistical analysis.
For modelling time course of FEV1 across all treatments, the dataset consists of all
patients who provided at least 1 profile for time course of FEV1 (Day 1 and/or Day 28)
with a minimum of at least 6 FEV1 measurements for each profile. The aim of the
analysis was to characterise the time course of FEV1 as a function of dose and regimen
(single and repeat dose) after accounting for the diurnal variation in placebo response.
The key model parameters to be estimated are: time for onset of effect, overall apparent
potency, Emax, elimination half life of drug in lung biophase, and parameters describing
the diurnal variations of pulmonary function (FEV1).
11.2.1.

Trough FEV1 Dose Response Model

There were a total of 588 subjects in the ITT population each contributing 1 trough FEV1
value on Day 28 for the dose response analysis. The model parameters E0 (placebo
effect), ED50 and Emax were estimated with good precision but inter-subject variability
could only be estimated for the placebo response. No estimation of inter-subject
variability on potency (ED50) or maximum effect (Emax) was possible; this is not
unexpected given the current parallel-dose study design with 1 datum per subject.
The covariates, namely, age, baseline FEV1 and gender showed statistically significant
effect and thus explain the inter-subject variability in the placebo response (intercept E0).
Based on statistical criteria for model selection, the parameters of the dose response for
the optimal model and the associated precision of the estimates is given below
(Table 39). This is also supported by the typical range of diagnostics as shown in
Attachment 4. The model simulated LS Mean profile has been overlaid with observed
LS Mean Difference from placebo in Figure 21.
Table 39

Dose Response Model Parameters for trough FEV1 change from


baseline on Day 28 (ITT Population)

Parameters
Emax (L)
ED50 (g)
E0 (L) Placebo
Age on E0 (L/yr)
Baseline on E0
Gender on E0
Residual Error

Value
% RSE
0.243
20
16.1
11
0.733
18
-0.392
12
2.65
21
-0.166
24
Proportional: CV 12%
Additive: Standard Deviation 0.16

Source data: Table 9.5

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0.149
12.5
0.480
-0.482
1.57
-0.245

95th CI
0.337
19.7
0.986
-0.302
3.73
-0.087

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Figure 21

Dose-Response for Trough FEV1 (ITT population) at Day 28


Overlay-Observed LSMean difference from Placebo with Model
Simulated LSMean Profile

LSMean difference from Placebo FEV1 (L)

0.30

LSMean [95 CIs]


Model fitted

0.25
0.20
0.15
0.10
0.05
0.00
-0.05
ED50: 16.1ug [95%CI: 12.5-19.7]

10

20

30

40

50

OD Dose (ug)

Source Data: Figure 9.4

11.2.2.

Modelling the 24h time course of FEV1

The dataset for modelling time course of FEV1 comprised 548 subjects giving a total of
14333 individual FEV1 values over time post dose for both Day 1 and Day 28 over the
dose range 0 g (placebo) to 50 g od. Separate analyses were performed for both Day
1, Day 28 and combined Day 1 and Day 28. There was no marked difference in model
parameters between the separate Day 1 and Day 28 analyses. The various models
explored with final model parameters are provided in Attachment 5 and the salient results
from the final model are summarised below.
One application of the population K-PD model was to simulate the time course of FEV1
after placebo and each treatment after adjusting for the diurnal variations in pulmonary
function. Figure 22 shows the reasonable predictions of the K-PD model for placebo and
one of the doses at 25 g. Additional results provided in Attachment 4.

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Figure 22

K-PD model based simulations versus observed time course of FEV1


for placebo and GW642444M 25 g on Day 28

0.40

LSMean Obs
Mean model

Day 28 Placebo

Change from baseline FEV1 (L)

0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
-0.05
0

10

12

14

16

18

20

22

24

26

Time (h)

0.40

Day 28 25ug

Change from baseline FEV1 (L)

0.35
0.30
0.25

LSMean Obs
Mean model

0.20
0.15
0.10
0.05
0.00
-0.05
0

10

12

14

16

18

20

22

24

26

Time (h)

Source data: Figure 9.6

Therapeutic Index based on dose and dose regimen of GW642444M

Some of the systemic effects of bronchodilators include decrease in potassium levels,


increase in glucose levels with the most sensitive effect on increase in pulse rate for
GW642444M. Previous studies have characterised the concentration-effect (pulse rate)
of GW642444 in healthy, asthmatics and in subjects with COPD [IND 74,696, 2007].
There was generally a shallow linear relationship of drug concentration and maximum
pulse rate increase. A plasma GW642444 level of 600 pg/mL (upper 95%CI) would be
associated with a weighted mean pulse rate change of 6 bpm. A plasma level of 700
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pg/mL (upper 95%CI) would be associated with a maximum pulse rate change of 10
bpm. In the present study, very limited plasma data showed measurable drug levels
(LLQ=30 pg/mL) at doses 6.25 g. Whilst the majority of subjects had evaluable peak
drug levels at 12.5 g (often based on n=1 data point), even at the highest dose of 50 g
the geometric mean peak drug levels were only 223 pg/mL (upper 95%CI for peak drug
levels was 262pg/mL). There were no clear relationships between peak drug levels and
change in pulse rate due to the limited and narrow range of measurable drug levels of
GW642444 in asthmatics.
Figure 23 maps the therapeutic index of GW642444 in asthmatics over the dose range up
50 g OD. It clearly shows the good margin of safety (maximum HR increase) versus
effective dose response (observed LSMean and overlay with model fitted curve). Even at
the highest dose of 50 g at steady state there is only a marginal increase of 2.7 bpm.
Therapeutic Index mapping dose-response for efficacy and safety
Day 28

15
14
13
12
11
10
9
8
7
6
5
4
3
2
1
0
-1
-2
-3

0.30

Trough LSMean FEV1 diff drom placebo (L)

FEV1 Obs LSMean [95CIs]


LSMean Model Fitted

0.25

Threshold

0.20
0.15
0.10
0.05
0.00

-0.05
0

10

20

30

OD Dose (ug)

Source data: Figure 9.8

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40

50

LSMean Max HR diff from placebo (bts/min)

Figure 23

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11.3.

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Pharmacokinetic/Pharmacodynamic Summary

GW642444M shows a good therapeutic margin over the dose range studied. There
were limited measurable drug levels above the quantification limit of 30 pg/mL in
doses < 25 g. There was no clear relationship between systemic exposure
(observed Cmax over period 2-30 min post-dose) and any systemic PD endpoint
(pulse rate, QTc, glucose or potassium).

Using a population dose response model, the potency (ED50) of GW642444M was
16.1 g [95%CI: 12.5-19.7 g]. The predicted maximum FEV1 (Emax- after
adjusting for placebo) was 243 mL [95%CI:149-337 mL].

Based on a population dose-time-response analysis of serial FEV1 data from all


evaluable patients on Day 1 and at steady state a long elimination half life (26h ,
95%CI: 23-29h) of GW642444M in equilibrium with the lung biophase was
estimated. The diurnal variation in FEV1 was adequately characterised.

The lower doses of 12.5 and 6.25 g also showed sustained and prolonged duration
of effect, albeit lower than that observed at and above 25 g. This consistency in
prolonged efficacy at all doses and the estimated peak to trough ratio close to unity
across all doses highlight the intrinsic prolonged bronchodilator activity of
GW642444 in asthma.

12.

DISCUSSION AND CONCLUSIONS

12.1.

Discussion

The aim of this Phase IIb study was to investigate the dose response, efficacy and safety
of GW642444M, administered OD in the evening to asthmatics, to generate data to
inform on the selection of dose of GW642444M to be carried forward into the Phase III
studies where GW642444M will be combined with the inhaled corticosteroid
GW685698X to form a once daily LABA/ICS combination product.
This placebo controlled study investigated five doses of GW642444M (3 g, 6.25 g,
12.5 g, 25 g and 50 g). The 3 g dose was included as a potential no-effect dose.
The 50 g dose was included as a likely supra-therapeutic dose to help establish the
therapeutic index for GW642444M and to assess whether or not a plateau had been
achieved. The population recruited were symptomatic subjects with persistent asthma
who had a percentage predicted FEV1 at baseline of between 40% and 90% and
reversibility as demonstrated by an increase in FEV1 of 12% and 200 mL following 400
g albuterol/salbutamol. Subjects were required to be symptomatic despite treatment
with background ICS, representing a population who are suitable for a step-up in therapy
according to national [NIH, 2007] and international [GINA, 2006] treatment guidelines.
Subjects were stratified at randomisation according to baseline percentage predicted
FEV1 (40 to 65% and >65 to 90%) to investigate if the dose response to GW642444M
was similar in subjects with different disease severities.

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The primary endpoint of mean change from baseline at Day 28 in trough (evening prebronchodilator and pre-dose) FEV1 was selected as a measure of 24-h bronchodilation
with FEV1 as an accepted reproducible measure of lung function.
Within the ITT Population, the baseline demographics across the six treatment groups
were similar with the mean age of the study population ranging from 39.9 years to 44.4
years (27 subjects [4%] were 12-17 years of age), and the majority of the subjects having
had asthma for longer than 10 years (64% to 74%). The baseline mean percent of
predicted normal FEV1 across groups ranged from 65.3% to 67.6% and subjects
demonstrated a high degree of reversibility (mean percent reversibility 24.2 % to 27.4 %
across the groups). All subjects were receiving ICS at baseline from 100 to 2000 g
daily of BDP or equivalent with the mean ICS dose across each of the treatment groups
ranging from 698 g to 814 g daily. As such, the subjects in the study represented a
population of moderately severe persistent asthmatics who were uncontrolled despite ICS
therapy.
Results from the primary efficacy endpoint demonstrate that OD treatment with
GW642444M provides bronchodilation out to 24-h supporting OD dosing. Dosedependent improvements in trough FEV1 following 28-days of treatment were
statistically significant compared to placebo at the 12.5 g (p=0.011), 25 g (p=0.016)
and 50 g (p=0.001) doses (mean treatment differences of 130 mL, 121 mL and 162 mL,
respectively). A statistically significant linear trend in dose response in trough FEV1
(p=0.003) demonstrated the overall efficacy of GW642444M, despite a placebo effect of
147 mL versus baseline. The results from the per protocol analysis and the repeated
measures analysis of the primary endpoint also confirmed a statistically significant
superiority for the 12.5 g, 25 g and 50 g doses relative to placebo (all p<0.05).
Although none of the doses produced an increase in the adjusted mean trough FEV1 of
200 mL this appeared to be related to the pronounced placebo response observed in the
study. The unadjusted mean changes from baseline were all well in excess of 200 mL for
the 12.5 g, 25 g and 50 g groups (278 mL, 269 mL and 309 mL, respectively). The
reason for the pronounced placebo effect is not entirely clear, though it may have been
related to timing of the trough measurement which was recorded in the evening at a time
when lung function tends to be higher as a result of the natural circadian rhythm in
airway tone. Alternatively it may have been difficult to show such a magnitude of effect
in a population who were already receiving, in some instances, high doses of ICS, and
who may have increased their compliance with ICS as a result of being in the study.
The analysis by percent predicted FEV1 stratum suggests a broadly similar dose response
between the lower stratum (40% - 65%) and upper stratum (>65% - 90%) with CIs
substantially overlapping for all doses except for the 3 g dose. This suggests that the
dose response relationship was similar in subjects with more severe airway obstruction
compared to those with milder obstruction.
Serial FEV1 measurements taken on both Days 1 and 28 showed statistically significant
increases versus placebo in weighted mean change from baseline FEV1 (0-24 h) for all
doses of GW642444M except the 6.25 g dose on Day 1. However, the greatest
improvements were seen in the 12.5 g, 25 g and 50 g GW642444M groups (0.130 L

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to 215 mL on Day 1, and 0.142 mL to 172 mL on Day 28) though separation between all
the doses was more evident on Day 1 than on Day 28.
The serial FEV1 profiles also provide evidence of the 24-h duration of GW642444M. An
analysis of the peak value in FEV1 taken over the first 4 h compared to the trough FEV1
value taken over hours 23-24 revealed that the ratio of peak to trough across all the five
doses studied was close to 1. The ratio did not differ greatly as the dose increased,
remaining at or below 1.06 for all doses, suggesting that the 24-h duration of action was
an intrinsic property of the molecule rather than a function of increasing dose.
Other analyses also provided evidence of a dose-response across the doses studied and
confirmed the 24-h bronchodilation achievable with once-daily dosing with
GW642444M. Repeated measures analysis of the primary endpoint demonstrated a dosedependent response with 24-h statistically significant improvements in trough FEV1
compared with placebo for 12.5 g and 25 g GW642444M at 23 and 24 h post-dose on
Day 28; as well as 50 g GW642444M pre-dose on Day 7, Day 14 and Day 28, and at
23-24 h post-dose on Day 28.
Evening PEF, measured before the administration of study medication and therefore 24-h
after the preceding dose, increased with ascending GW642444M dose. All doses
produced a statistically significant improvement in evening PEF min relative to placebo
with the 25 g and 50 g doses producing improvements in PEF in excess of >30 L/min
(AM and PM PEF all p<0.001 except for the 3 g dose). A sharp fall was seen in
evening PEF for all treatments, including placebo, from Day1 to Day 2. The reason for
this may relate to the timing of the measurements which on Day 1 were performed in the
clinic in the late afternoon as opposed to the recordings made on subsequent days which
were performed immediately prior to the subjects taking their study medication in the
evening. Thus the fall observed between Day 1 and Day 2 may therefore be due to the
circadian variation in airway tone which tends to result in the highest values for lung
function values being seen in the late afternoon before falling back later in the day. No
such fall between Day 1 and Day 2 was observed in morning PEF which was recorded at
a similar time of day throughout the study. Morning PEF also increased in a dosedependent fashion with the 12.5 g and 25 g doses producing improvements relative to
placebo in excess of 30 L/min and the 50 g dose increasing morning PEF above 40
L/min.
Symptom-free and rescue-free 24-h periods demonstrated a dose-dependent increase up
to 25 g. No additional improvements were seen at the 50 g dose. This pattern was
repeated when symptom-free nights and days and rescue-free nights and days were
looked at separately.
The weighted mean FEV1 over the first 4 h on Day 1 and Day 28 increased with
ascending dose. All doses were statistically significant compared to placebo (all
p0.037) but only the 25 g and 50 g doses achieved a >200 mL improvement both on
Day 1 and Day 28 (p<0.001). The maximum increase in FEV1 over the first 4 h also
improved in a dose-related fashion with greatest improvement seen with the 50 g dose.
Analysis of the proportion of subjects with a combined increase of 200 mL and 12%
over baseline FEV1 in the 4 h following the dose at the clinic, demonstrated that a
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consistently higher percentage of subjects achieved the threshold with the 25 g and 50
g GW642444M doses (50% of subjects at most timepoints) on Day 1 and Day 28
compared with the 3 g, 6.25 g and 12.5 g doses, although the proportion of subjects
between the 25 g and 50 g doses were very similar. Analysis of the proportion of
subjects with a combined increase of 200 mL and 12% over baseline FEV1 over 24 h
post-dosing showed that the majority of subjects (>50% at most timepoints) receiving the
25 g and 50 g doses consistently maintained the improvement in lung function over
this time interval.
Withdrawals due to efficacy were highest in the placebo (9%) and 3 g (12%) treatment
groups and 5% in the other treatment groups. No subjects were withdrawn due to lack
of efficacy in the 50 g GW642444M group suggesting that, with the exception of the 3
g dose all doses were efficacious though the efficacy tended to increase with increasing
dose.
The response to albuterol/salbutamol following treatment with GW642444M was
investigated comparing the response at Screening and Day 1 with Day 28. There was no
difference between any of the doses and placebo with regards to the response to
albuterol/salbutamol at any of the time points investigated suggesting that there was no
evidence of tolerance developing to the bronchodilator response from short-acting 2agonists with GW642444M.
The safety of GW642444M was assessed by the occurrence of AEs and routine
laboratory assessments including measures which are known to be affected by -2agonists including serum potassium and glucose levels. Potential signs of any cardiac
effects were assessed using 12-lead ECG measurements.
The incidence of AEs was similar across all the GW642444M treatment groups and
comparable to placebo and there was no dose-related increase in the frequency of the
most commonly reported AEs. Drug-related AEs were reported at a very low incidence
with no more than 8 subjects on any treatment reporting an individual event.
Pharmacologically predictable AEs such as palpitations and tremor were also infrequent
and were similar in frequency to placebo with <1% of subjects reporting tremor, seen in
the 6.25 g dose group only. A total of 4 subjects were withdrawn due to subject
reaching protocol-defined stopping criteria, with the events of ventricular tachycardia
(placebo), AV block second degree (12.5 g GW642444M), T-wave amplitude decreased
(6.25 g GW642444M), and PR prolongation (6.25 g GW642444M). These subjects
experienced related AEs as a sub reason for withdrawal. Two subjects withdrew due to
the AEs of Psychomotor hyperactivity wired, feeling jittery and insomnia (3 g
GW642444M), and Increase in allergy symptoms and Pyrexia (25 g GW642444M). No
SAEs were reported. Overall, the AE data are very reassuring in that the frequency was
similar to placebo with no evidence of the frequency increasing as the dose increased and
no unexpected AEs. Asthma exacerbations were infrequent, with the highest percentage
of events in the placebo and 3 g GW642444M groups (4% and 7%, respectively),
compared with 0% to 3% in the other groups.

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No clinically relevant changes were noted in any of the haemotology, clinical chemistry
and urinalysis assessments. Small differences in incidence of values outside normal
range for CPK were observed when comparing active treatment arms and placebo,
although there was no dose response and most of the values were within twice the upper
limit of normal. No safety concerns were observed with liver function tests and no
treatment related changes were apparent in the vital signs. Small increases in pulse rate
were observed with the 50 g dose but as these changes were within the predefined
clinically relevant threshold (6 bpm) no safety concerns were raised for pulse rate. For
potassium and glucose, maximum and weighted mean changes from baseline (0-4 h),
including changes versus placebo, did not exceed the predefined levels of clinically
relevant concern (-0.3 mmol/L and 1.5 mmol/L for potassium and glucose, respectively).
No AEs of hypokalaemia were reported.
Although for the 50 g dose a statistically significant difference in mean post-dose serial
QTc(F) (0-4 h) change from baseline versus placebo was recorded of 5.0 msec on Day 7 at
10 minutes post-dose, it is recognised that mean QT prolongation changes of 5-20 msec
would represent a grey zone with an unclear risk of arrhythmia, whilst agents causing
mean QT prolongation of >20 msec would substantially increase the risk of proarrhythmia [FDA Guidance for Industry, 2005]. Furthermore, the use of the stated
thresholds is most relevant for the conduct of a Thorough QT study [FDA Guidance for
Industry, 2005].
For QTc(B) some treatment differences were observed with the 50 g dose which were
above the 5 msec threshold of clinical concern for this study, although as stated above,
the clinical significance of this observation is unclear. Treatment differences 5 msec
(and 12.5 msec) were observed between 10 min and 1 h following dosing on all the
study visit days. Treatment differences of 5 msec (and 8.2 msec) were also observed
for the 25 g dose on Day 1 at 10 min and on Day 14 at 10 min and 1 h post-dose.
However, the QTc(B) has been suggested to overestimate the QTc when heart rate
increases [Milic M, 2008] which occurs with 2-agonists as the dose is increased.
Importantly no increase in QTc was seen when the more appropriate Fridericias
correction was used. The use of the more accurate measure QTc(F) is supported by
analysis of QTc(F) and QTc(B) heart rate relationship, which increased for QTc(B) whilst
remained unchanged for QTc(F).
Overall, GW642444M was well tolerated across all the doses in this study.
The results from this study support the 24-h duration of bronchodilation with OD evening
dosing GW64244M. A dose-response was seen which was consistent with the rationale
that the 3 g represented a no-effect dose and the results of the 25 g and 50 g were
very similar suggesting that 50 g may represent a plateauing of the dose response curve
with regards to some of efficacy endpoints. Although the 12.5 g dose and 25 g doses
were similar for trough FEV1 on Day 28, across a number of other efficacy endpoints
there was a small incremental benefit of the 25g over the 12.5g dose. The 25g and
12.5g doses separated on the proportion of subjects who achieved a 200 mL and 12%
improvement over baseline over 24 h with the majority of subjects at most time points
achieving this threshold with the 25 g dose, compared with 45% with the 12.5 g dose.
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Additionally, greater improvements in symptom-free and rescue- free 24-h periods and
morning and evening peak flow were observed with 25 g versus 12.5 g dose.
Maximum increase and peak FEV1 was also higher with 25 g than with 12.5 g.
In conclusion, the data from this study suggests that the minimally effective optimal
doses for GW642444M to be carried forward into Phase III would be either the 12.5g or
25 g dose representing doses with high efficacy and good tolerability.

Pharmacokinetics / Pharmacodynamics
Pharmacokinetics and Systemic Pharmacokinetics / Pharmacodynamics

Following doses 25 g, the majority (60%) of PK samples had non-quantifiable


concentrations of GW642444 based on a lower limit of quantification of 30 pg/mL. Even
after 50 g GW642444M, 37% of the sparse sampling dataset was non-quantifiable.
Hence it was not possible to define a population PK model for GW642444 (a secondary
objective of this Phase IIB study). In the absence of adequate characterisation of PK
model, the individual approximate observed Cmax values were used to further understand
the PK of the drug with increase in dose on Day 1 and at steady state.
GW642444M systemic exposure (median Cmax) following single dose 25 and 50 g
(Day 1)_tended to be lower, with a higher % of NQ values, compared to that observed on
Day 28; consistent with an apparent accumulation of GW642444 on repeat once daily
dosing. GW642444 accumulation (30%-35%) has been reported historically in
asthmatics (B2C106093). Despite higher Day 28 exposure, steady-state Cmax was still
generally comparable with that observed historically after single doses of 25 and 50 g to
asthmatic subjects (B2C106996) and well within limits in healthy volunteers
(B2C108784) following repeat daily administration of 25 g -100 g GW642444M via
DISKUS. The reason(s) for the lower Day 1 exposure compared to historical single
dose estimates, such as device (Novel Dry Power versus DISKUS), and/or time of dosing
or general variability, is unclear. There was no evidence to suggest that patient
demographics (sex, baseline FEV1 stratum, age, body weight or BMI) have a marked
effect on GW642444M exposure.
GW642444M shows a good therapeutic margin over the dose range studied. As
predicted from historical PK/PD modelling (Cmax of 600 pg/mL associated with a
weighted mean pulse rate change of 6 bpm), the low systemic exposure to GW642444M
(geometric mean of 223 pg/mL following 50 g) correlated with minor, clinically
insignificant effects on pulse rate. Indeed, the data in the current study were too limited
and concentration range too narrow to accurately define an exposure (Cmax) relationship
for either pulse rate or any other systemic PD endpoint (QTc, glucose or potassium).
A physiological population Emax model was optimal in characterising the trough FEV1
response (corrected for placebo) over the GW642444M dose range of 3 g to 50 g OD
in persistent asthmatics. GW642444M is a potent bronchodilator (ED50 16.1 g
[95%CI: 12.5-19.7 g) and showed a predicted maximum effect (Emax) for trough FEV1
of 243 mL [95% CI:149 337 mL]. This predicted (modelled) Emax is within the

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95%CI obtained at the highest dose of 50 g OD in the present study [LSMean 162 mL.
95%CI: 62-261 mL]. Based on a model for time course of FEV1 after accounting for
diurnal variation, GW642444M has long pulmonary residency with an estimated
elimination half life of the drug in the lung biophase (T=26h [95%CI 23-29h) based on
the dose-time-response analysis.
This sustained lung drug residency would also explain the observed peak to trough ratio
close to unity at all treatment doses. Thus the combination of high pulmonary potency of
GW642444M, sustained residency of the drug and peak to trough ratio close to unity
would support the rationale for once daily potential dosing regimen in asthmatics.

12.2.

Conclusions

Overall efficacy of GW642444M was demonstrated by a statistically significant


linear trend test in dose response in trough FEV1.

Once-daily treatment with GW642444M resulted in a sustained 24-hour


improvement in lung function which was statistically significantly greater than that
seen with placebo at 12.5 g, 25 g and 50 g doses, supporting once-daily dosing.

The Per Protocol and repeated measures analyses confirmed the results from the
primary analysis by demonstrating the superiority of 12.5 g, 25 g and 50 g doses
GW642444M relative to placebo.

Compared with the 3 g, 6.25 g and 12.5 g GW642444M doses, treatment with 25
g and 50 g GW642444M resulted in consistently greater improvements in lung
function (weighted mean 24-h serial FEV1, proportion of subjects achieving 200
mL and 12% increase in FEV1, 0-4 h weighted mean FEV1 and 0-4 h maximum and
peak FEV1), morning and evening PEF as well as symptoms and rescue use
(percentage of symptom- and rescue free 24-h periods).

The sustained 24-h duration of bronchodilatory action for GW642444M and


potential as a once-daily drug was confirmed by repeated measures analysis of the
primary endpoint, repeated measures analysis of serial FEV1 and analysis of PM
PEF. The ratio of peak post-dose FEV1 to trough FEV1 of approximately 1 across all
GW642444M doses suggested that the 24-h duration of action is an intrinsic property
of the molecule and not a function of dose.

A greater withdrawal rate due to lack of efficacy with the lower doses compared to
the higher GW642444M doses are consistent with the findings of the primary and
other efficacy analyses.

There was no evidence of development of tolerance to the bronchodilator response


from short-acting 2-agonist (albuterol/salbutamol) with GW642444M.

Broadly similar dose response effects were found for the lower and upper strata,
suggesting that different doses of GW642444M may not be required for different
severities of asthma.

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The review of AEs, vital signs, laboratory parameters (haematology, clinical


chemistry including liver function tests, and urinalysis) and ECG demonstrated that
GW642444M was well tolerated and the observed safety profile was similar across
the GW642444M treatments and placebo. No SAEs were reported.

There were no clinically relevant increases from baseline versus placebo in serial,
weighted mean or maximum QTc(F) (0-4 h) for any treatment group, at any time
point. Although increases in mean serial QTc(B) from baseline versus placebo of 6
msec to 12.5 msec in the 25 g and 50 g GW642444M groups were above the 5
msec threshold of clinical concern, QTc(F) was acknowledged as the more robust
correction for drugs that are associated with increased heart rate, with QTc(B) being a
poorer correction factor.

Potassium and glucose values did not exceed the predefined levels of clinically
relevant concern. No AEs of hypokalaemia were reported.

PK analysis showed that GW642444 shows a good therapeutic margin over the dose
range studied. There were limited measurable drug levels above the quantification
limit of 30 pg/mL up to 25 g dose, without a clear relationship between systemic
exposure (observed Cmax over period 2-30 min post-dose) and any systemic PD
endpoint (pulse rate, QTc, glucose or potassium).

The combination of good pulmonary potency of GW642444, sustained residency of


the drug in lung biophase and peak to trough ratio close to unity would support the
rationale for once daily potential dosing regimen in asthmatics.

In conclusion, the data from this study suggest that the minimally effective doses for
GW642444M to be carried forward into Phase III would be either the 12.5 g or 25
g dose representing doses with high efficacy and good tolerability.

- 125 -

129

CONFIDENTIAL
CONFIDENTIAL

13.

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B2C109575

REFERENCES

Beasley R. The Global Burden of Asthma Report, Global Initiative for Asthma (GINA).
Available from http://www.ginasthma.org 2004.
Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for
Non-Antiarrhythmic Drugs. FDA Guidance for Industry. October 2005. ICH. E14,
(2005).
Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and
Prevention 2006. Global Initiative for Asthma, www.ginasthma.org; 2006.
GlaxoSmithKline Document number: WD2006/02197/00. The Validation of a Method
for the Determination of GW642444 (range 30 to 15000 pg/mL), GW630200 (range 90 to
45000 pg/mL) and GSK932009 (range 180 to 90000 pg/mL) in Human Plasma using
HPLC-MS/MS. Validation Report, 5-Sept-2006.
GlaxoSmithKline Document number: WD2006/02527/00. Validation of a Method for
the Determination of GI179710 in Human Plasma (range 1 to 1000 ng/mL) using HPLC
MS/MS. Validation Report, 8-Nov-2006.
IND 74,696, 08 November 2007, SN0000, Vol. 60.
NIH. Guidelines for the Diagnosis and Management of Asthma (EPR-3) 2007. NHLBI,
August; 2007. NIH publication no. 08-4051.
Masoli M, Fabian D, Holt S, Beasley R. The global burden of asthma: executive
summary of the GINA Dissemination Committee report. Allergy 2004;59(5):469-78.
Milic M, Bao X, Rizos, D, et al. Literature Review and Pilot Studies of the Effect of QT
Correction Formulas on Reported 132-Agonist-Induced QTc Prolongation. Clinical
Therapeutics 2006;28(4):582-90.

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130

This section contained patient narratives which are textual descriptions of medical history,
treatment and outcome for individual patients who experienced a clinically important adverse
event including serious adverse events during the trial. They have been excluded to protect
patient privacy. This data may be made available subject to an approved research proposal and
a determination of the ability to provide information from the specific narratives whilst protecting
the patients privacy. For further information please see the Patient Level Data section of

the GSK Clinical Study Register.

CONFIDENTIAL

YM2008/00019/00
B2C109575

Study Population Data Source Figures and Tables


Page

Figure 6.1 Subject Withdrawals Over Time . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


Figure 6.2 Subject Withdrawals due to Lack of Efficacy Over Time . . . . . . . . . . . . .
Table 6.1 Summary of Subject Populations (Total Population) . . . . . . . . . . . . . . . . .
Table 6.2 Summary of Reasons For Withdrawal Prior to Randomisation (Total
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 6.3 Summary of End of Study Record (Intent-to-Treat Population) . . . . . . . . .
Table 6.4 Summary of Attendance at Each Clinic Visit (Intent-to-Treat Population) .
Table 6.5 Summary of Number of Subjects by Centre (Intent-to-Treat Population) .
Table 6.6 Summary of Inclusion/Exclusion Criteria Deviations (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 6.7 Summary of Protocol Deviations (Intent-to-Treat Population) . . . . . . . . . .
Table 6.8 Summary of Demographic Characteristics Intent-to-Treat (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 6.9 Summary of Demographic Characteristics Per Protocol (Per Protocol
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 6.10 Summary of Race and Racial Combinations (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 6.11 Summary of Race and Racial Combination Details (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 6.12 Summary of History of Tobacco Use at Screening (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 6.13 Summary of Duration of Asthma and Asthma History (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 6.14 Summary of Current Medical Conditions (Intent-to-Treat Population) . . .
Table 6.15 Summary of Asthma Concomitant Medications Taken Pre-Treatment
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 6.16 Summary of Asthma Concomitant Medications Taken During
Treatment (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 6.17 Summary of Asthma Concomitant Medications Taken Post Treatment
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 6.18 Summary of Non-Asthma Concomitant Medications Taken
Pre-Treatment (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 6.19 Summary of Non-Asthma Concomitant Medications Taken During
Treatment (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 6.20 Summary of Non-Asthma Concomitant Medications Taken Post
Treatment (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 6.21 Summary of Screening Lung Function Test Results (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 6.22 Summary of Treatment Compliance (%%) (Intent-to-Treat Population) .

134

136
137
138
139
140
141
142
154
155
157
158
159
160
161
162
163
165
167
168
169
187
207
223
225

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Table 6.23 Summary of Percent Predicted FEV1 Strata: As Randomised and


Actual (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 6.24 Summary of Percent Predicted FEV1 (%%) Day 1 Pre-Dose by Actual
Stratum (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 6.103 Summary of Background Steroid Dose During Treatment
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

135

226
227
228

Page 1 of 1

Protocol: B2C109575
Population: Intent-to-Treat
Figure 6.1
Subject Withdrawals Over Time
100

90

70

60

CONFIDENTIAL

136

Percentage of Subjects in Study

80

50

40

30

20

10

1 Week

2 Weeks

3 Weeks

4 Weeks

Time Since Randomisation


Treatment

Placebo
3mcg

6.25mcg
12.5mcg

25mcg
50mcg

Note: Kaplan-Meier Estimate of time to withdrawal. Subjects are represented from their date of randomisation to their date
of study drug discontinuation

YM2008/00019/00
B2C109575

0
Randomisation

Page 1 of 1

Protocol: B2C109575
Population: Intent-to-Treat
Figure 6.2
Subject Withdrawals due to Lack of Efficacy Over Time
30

20

CONFIDENTIAL

137

Percentage of Subjects Withdrawn

25

15

10

1 Week

2 Weeks

3 Weeks

4 Weeks

Time Since Randomisation


Treatment

Placebo
3mcg

6.25mcg
12.5mcg

25mcg
50mcg

Note: Subjects are represented from their date of randomisation to their date of study drug discontinuation due to lack of efficacy

YM2008/00019/00
B2C109575

0
Randomisation

Protocol: B2C109575
Population: Total

Page 1 of 1
Table 6.1
Summary of Subject Populations

Population
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
--------------------------------------------------------------------------------------------------------Total
1140
Randomised
103
102
102
102
103
102
614
Intent-to-Treat (ITT) 102 (>99%) 101 (>99%) 101 (>99%) 100 (98%) 101 (98%) 102 (100%) 607 (99%)
Per Protocol (PP)
98 (95%)
97 (95%)
98 (96%)
98 (96%)
93 (90%)
99 (97%) 583 (95%)

CONFIDENTIAL

138
Note: 92 subjects in the Total population were previously screened but are only counted once.

YM2008/00019/00
B2C109575

Total: All subjects screened and for whom a record exists on the study database.
ITT: All randomised subjects who received at least a single dose of trial medication.
PP: All subjects in the ITT population who do not have any full protocol deviations.

Protocol: B2C109575
Population: Total

Page 1 of 1
Table 6.2
Summary of Reasons For Withdrawal Prior to Randomisation
Total
(N=1140)
---------------------------------------------------Withdrawals prior to randomisation
525 (46%)
1
3
29
0
16
19
457

(<1%)
(<1%)
(3%)
(1%)
(2%)
(40%)

139
This subject is not included in

YM2008/00019/00
B2C109575

this summary.

CONFIDENTIAL

Primary reason for withdrawal


Adverse event
Protocol deviation
Study closed/terminated
Lost to follow-up
Investigator discretion
Withdrew consent
Did not meet continuation criteria

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Table 6.3
Summary of End of Study Record

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
-----------------------------------------------------------------------------------------------------------Completion Status
Completed
86 (84%)
84 (83%)
91 (90%)
88 (88%)
93 (92%)
97 (95%)
539 (89%)
Prematurely Withdrawn
16 (16%)
17 (17%)
10 (10%)
12 (12%)
8 (8%)
5 (5%)
68 (11%)
0
9
2
4
0

(9%)
(2%)
(4%)

1 (<1%)
12 (12%)
3 (3%)
7 (7%)
0

0
5
2
3
0

2
0
0
0
0
0

0
0
1
0
1
0

3
0
2
0
2
0

0
3

0
1 (<1%)

0
7

1 (<1%)
0
0
0
1 (<1%)
0

5
2
0
0
0
0

3
0
0
0
0
3

(3%)

(3%)

(2%)
(2%)

(2%)

(7%)
(5%)
(2%)

0
3
3
0
0
1
1
1

(5%)
(2%)
(3%)

(1%)
(1%)

(3%)
(3%)
(1%)
(1%)
(1%)

1 (<1%)
4 (4%)
3 (3%)
2 (2%)
0

0
0
0
0
0

2 (<1%)
33 (5%)
12 (2%)
17 (3%)
0

2
0
0
0
0
0

0
0
0
0
0
0

10 (2%)
0
4 (<1%)
0
4 (<1%)
0

0
2

(2%)

(2%)

2 (2%)
0
0
0
0
1 (<1%)

Note: Only 1 primary reason can be chosen, but there can be multiple sub reasons.

0
2

(2%)

0
18

2 (2%)
0
0
0
2 (2%)
1 (<1%)

16
2
0
1
4
6

(3%)
(3%)
(<1%)
(<1%)
(<1%)
(<1%)

YM2008/00019/00
B2C109575

3 (3%)
0
1 (<1%)
0
1 (<1%)
0
(3%)

(3%)

0
3 (3%)
2 (2%)
1 (<1%)
0

CONFIDENTIAL

140

Primary reason for withdrawal


Adverse event
Lack of efficacy
Below FEV1 stability limit
Below PEF stability limit
Exceeded rescue medication
use
Exacerbation
No subreasons
Protocol deviation
Pregnancy
Lack of adherence
Liver function test
abnormality
No subreasons
Subject reached
protocol-defined stopping
criteria
ECG abnormality
No subreasons
Study closed/terminated
Lost to follow-up
Investigator discretion
Withdrew consent

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Table 6.4
Summary of Attendance at Each Clinic Visit

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
Visit
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
----------------------------------------------------------------------------------------------------------Screening
102 (100%)
101 (100%)
101 (100%)
100 (100%)
101 (100%)
102 (100%)
607 (100%)
Day 1
102 (100%)
101 (100%)
101 (100%)
100 (100%)
101 (100%)
102 (100%)
607 (100%)
Day 7
95 (93%)
98 (97%)
99 (98%)
97 (97%)
100 (>99%)
100 (98%)
589 (97%)
Day 14
93 (91%)
92 (91%)
96 (95%)
92 (92%)
95 (94%)
98 (96%)
566 (93%)
Day 28
89 (87%)
87 (86%)
91 (90%)
90 (90%)
94 (93%)
98 (96%)
549 (90%)
Follow Up
99 (97%)
97 (96%)
99 (98%)
96 (96%)
99 (98%)
100 (98%)
590 (97%)

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141

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Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 12
Table 6.5
Summary of Number of Subjects by Centre

Country Amalgamation: Argentina


Country
Investigator
--------------Argentina

Centre Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
ID
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
--------------------------------------------------------------------------------3 (3%)
4 (4%)
4 (4%)
7 (7%)
6 (6%)
12 (12%)
36 (6%)
1 (<1%)
3 (3%)
0
4 (4%)
2 (2%)
5 (5%)
15 (2%)
0
0
1 (<1%)
2 (2%)
0
2 (2%)
5 (<1%)
1 (<1%)
0
0
1 (1%)
0
1 (<1%)
3 (<1%)
1 (<1%)
1 (<1%)
3 (3%)
0
1 (<1%)
3 (3%)
9 (1%)
0
0
0
0
3 (3%)
1 (<1%)
4 (<1%)

CONFIDENTIAL

142

YM2008/00019/00
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Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 12
Table 6.5
Summary of Number of Subjects by Centre

Country Amalgamation: Belgium & France


Country
Investigator
--------------Belgium

France

Centre Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
ID
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
---------------------------------------------------------------------------------2 (2%)
0
1 (<1%)
2 (2%)
1 (<1%)
1 (<1%)
7 (1%)
2 (2%)
0
1 (<1%)
1 (1%)
1 (<1%)
1 (<1%)
6 (<1%)
0
0
0
1 (1%)
0
0
1 (<1%)
1 (<1%)
0
1 (<1%)

1 (<1%)
1 (<1%)
0

4
0
4

(4%)
(4%)

4 (4%)
1 (<1%)
3 (3%)

1 (<1%)
0
1 (<1%)

14 (2%)
4 (<1%)
10 (2%)

143

CONFIDENTIAL

3 (3%)
2 (2%)
1 (<1%)

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Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 12
Table 6.5
Summary of Number of Subjects by Centre

Country Amalgamation: Canada


Country
Investigator
--------------Canada

144

CONFIDENTIAL

Centre Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
ID
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
---------------------------------------------------------------------------------4 (4%)
6 (6%)
3 (3%)
6 (6%)
4 (4%)
2 (2%)
25 (4%)
1 (<1%)
0
0
1 (1%)
1 (<1%)
0
3 (<1%)
0
0
0
1 (1%)
0
0
1 (<1%)
2 (2%)
4 (4%)
2 (2%)
2 (2%)
2 (2%)
0
12 (2%)
0
0
0
1 (1%)
0
0
1 (<1%)
0
0
0
0
1 (<1%)
1 (<1%)
2 (<1%)
0
0
1 (<1%)
0
0
1 (<1%)
2 (<1%)
1 (<1%)
0
0
0
0
0
1 (<1%)
0
2 (2%)
0
1 (1%)
0
0
3 (<1%)

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 12
Table 6.5
Summary of Number of Subjects by Centre

Country Amalgamation: Chile & Peru


Country
Investigator
--------------Chile
Peru

Centre Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
ID
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
---------------------------------------------------------------------------------2 (2%)
1 (<1%)
0
0
3 (3%)
1 (<1%)
7 (1%)
2 (2%)
1 (<1%)
0
0
3 (3%)
1 (<1%)
7 (1%)
3
0
0
3

(3%)
(3%)

4 (4%)
0
1 (<1%)
3 (3%)

4
0
2
2

(4%)
(2%)
(2%)

3 (3%)
1 (<1%)
1 (<1%)
1 (<1%)

3 (3%)
0
2 (2%)
1 (<1%)

21 (3%)
1 (<1%)
7 (1%)
13 (2%)

145

CONFIDENTIAL

4 (4%)
0
1 (<1%)
3 (3%)

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 5 of 12
Table 6.5
Summary of Number of Subjects by Centre

Country Amalgamation: Germany


Country
Investigator
--------------Germany

146

CONFIDENTIAL

Centre Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
ID
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
---------------------------------------------------------------------------------7 (7%)
13 (13%)
11 (11%)
12 (12%)
8 (8%)
12 (12%)
63 (10%)
1 (<1%)
1 (<1%)
3 (3%)
1 (1%)
0
2 (2%)
8 (1%)
1 (<1%)
2 (2%)
3 (3%)
4 (4%)
1 (<1%)
4 (4%)
15 (2%)
2 (2%)
2 (2%)
2 (2%)
4 (4%)
3 (3%)
3 (3%)
16 (3%)
2 (2%)
4 (4%)
0
3 (3%)
2 (2%)
1 (<1%)
12 (2%)
1 (<1%)
0
1 (<1%)
0
0
0
2 (<1%)
0
2 (2%)
0
0
0
0
2 (<1%)
0
2 (2%)
2 (2%)
0
2 (2%)
2 (2%)
8 (1%)

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 6 of 12
Table 6.5
Summary of Number of Subjects by Centre

Country Amalgamation: Korea


Country
Centre Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
Investigator
ID
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
------------------------------------------------------------------------------------------------Korea
4 (4%)
6 (6%)
5 (5%)
2 (2%)
2 (2%)
4 (4%)
23 (4%)
2 (2%)
2 (2%)
2 (2%)
1 (1%)
1 (<1%)
3 (3%)
11 (2%)
2 (2%)
4 (4%)
3 (3%)
1 (1%)
1 (<1%)
1 (<1%)
12 (2%)

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Protocol: B2C109575
Population: Intent-to-Treat

Page 7 of 12
Table 6.5
Summary of Number of Subjects by Centre

Country Amalgamation: Netherlands & South Africa


Country
Investigator
--------------Netherlands

South Africa

Centre Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
ID
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
---------------------------------------------------------------------------------4 (4%)
4 (4%)
5 (5%)
2 (2%)
1 (<1%)
3 (3%)
19 (3%)
1 (<1%)
2 (2%)
2 (2%)
1 (1%)
0
1 (<1%)
7 (1%)
0
2 (2%)
0
1 (1%)
0
0
3 (<1%)
3 (3%)
0
3 (3%)
0
1 (<1%)
2 (2%)
9 (1%)
2
0
2
0

(2%)
(2%)

2
0
2
0

(2%)
(2%)

1
0
1
0

(1%)
(1%)

1 (<1%)
0
0
1 (<1%)

1 (<1%)
1 (<1%)
0
0

10 (2%)
1 (<1%)
7 (1%)
2 (<1%)

148

CONFIDENTIAL

3 (3%)
0
2 (2%)
1 (<1%)

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 8 of 12
Table 6.5
Summary of Number of Subjects by Centre

Country Amalgamation: Philippines & Thailand


Country
Investigator
--------------Philippines

Thailand

Centre Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
ID
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
---------------------------------------------------------------------------------1 (<1%)
3 (3%)
0
2 (2%)
2 (2%)
0
8 (1%)
1 (<1%)
2 (2%)
0
2 (2%)
1 (<1%)
0
6 (<1%)
0
1 (<1%)
0
0
1 (<1%)
0
2 (<1%)
(2%)
(2%)

2 (2%)
1 (<1%)
1 (<1%)

5 (5%)
4 (4%)
1 (<1%)

1
1
0

(1%)
(1%)

3 (3%)
2 (2%)
1 (<1%)

5 (5%)
4 (4%)
1 (<1%)

18 (3%)
14 (2%)
4 (<1%)

149

CONFIDENTIAL

2
2
0

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 9 of 12
Table 6.5
Summary of Number of Subjects by Centre

Country Amalgamation: Poland


Country
Centre Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
Investigator
ID
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
------------------------------------------------------------------------------------------------Poland
15 (15%)
15 (15%)
18 (18%)
9 (9%)
15 (15%)
9 (9%)
81 (13%)
0
1 (<1%)
0
0
0
1 (<1%)
2 (<1%)
1 (<1%)
4 (4%)
2 (2%)
0
3 (3%)
2 (2%)
12 (2%)
1 (<1%)
6 (6%)
3 (3%)

0
8
8

(8%)
(8%)

1
6
2

(1%)
(6%)
(2%)

0
5
7

(5%)
(7%)

0
4
2

(4%)
(2%)

2 (<1%)
33 (5%)
32 (5%)

150

CONFIDENTIAL

0
4 (4%)
10 (10%)

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 10 of 12
Table 6.5
Summary of Number of Subjects by Centre

Country Amalgamation: Russian Federation

151

CONFIDENTIAL

Country
Centre Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
Investigator
ID
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
------------------------------------------------------------------------------------------------Russian
10 (10%)
3 (3%)
6 (6%)
6 (6%)
8 (8%)
8 (8%)
41 (7%)
Federation
1 (<1%)
2 (2%)
2 (2%)
1 (1%)
1 (<1%)
1 (<1%)
8 (1%)
0
1 (<1%)
1 (<1%)
0
1 (<1%)
0
3 (<1%)
3 (3%)
0
0
1 (1%)
0
2 (2%)
6 (<1%)
0
0
0
0
0
1 (<1%)
1 (<1%)
0
0
0
1 (1%)
2 (2%)
1 (<1%)
4 (<1%)
6 (6%)
0
1 (<1%)
3 (3%)
4 (4%)
2 (2%)
16 (3%)
0
0
2 (2%)
0
0
1 (<1%)
3 (<1%)

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 11 of 12
Table 6.5
Summary of Number of Subjects by Centre

Country Amalgamation: Sweden


Country
Centre Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
Investigator
ID
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
------------------------------------------------------------------------------------------------Sweden
2 (2%)
4 (4%)
1 (<1%)
3 (3%)
3 (3%)
2 (2%)
15 (2%)
1 (<1%)
2 (2%)
1 (<1%)
2 (2%)
0
1 (<1%)
7 (1%)
1 (<1%)
2 (2%)
0
1 (1%)
3 (3%)
1 (<1%)
8 (1%)

CONFIDENTIAL

152

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 12 of 12
Table 6.5
Summary of Number of Subjects by Centre

Country Amalgamation: United States


Country
Investigator
--------------United States

CONFIDENTIAL

153

YM2008/00019/00
B2C109575

Centre Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
ID
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
---------------------------------------------------------------------------------36 (35%)
34 (34%)
35 (35%)
39 (39%)
37 (37%)
38 (37%)
219 (36%)
0
2 (2%)
1 (<1%)
1 (1%)
1 (<1%)
1 (<1%)
6 (<1%)
1 (<1%)
0
3 (3%)
1 (1%)
0
3 (3%)
8 (1%)
0
0
1 (<1%)
0
0
0
1 (<1%)
0
0
0
1 (1%)
1 (<1%)
1 (<1%)
3 (<1%)
0
0
1 (<1%)
1 (1%)
0
0
2 (<1%)
1 (<1%)
0
0
1 (1%)
1 (<1%)
0
3 (<1%)
0
1 (<1%)
1 (<1%)
0
0
0
2 (<1%)
1 (<1%)
0
0
0
0
0
1 (<1%)
1 (<1%)
0
1 (<1%)
0
1 (<1%)
0
3 (<1%)
0
2 (2%)
0
0
1 (<1%)
2 (2%)
5 (<1%)
1 (<1%)
4 (4%)
2 (2%)
1 (1%)
0
2 (2%)
10 (2%)
1 (<1%)
1 (<1%)
3 (3%)
1 (1%)
2 (2%)
0
8 (1%)
3 (3%)
1 (<1%)
1 (<1%)
3 (3%)
0
1 (<1%)
9 (1%)
1 (<1%)
2 (2%)
2 (2%)
0
1 (<1%)
1 (<1%)
7 (1%)
1 (<1%)
0
1 (<1%)
0
0
0
2 (<1%)
0
0
1 (<1%)
1 (1%)
0
0
2 (<1%)
0
0
0
0
1 (<1%)
1 (<1%)
2 (<1%)
2 (2%)
2 (2%)
2 (2%)
3 (3%)
4 (4%)
4 (4%)
17 (3%)
2 (2%)
3 (3%)
0
1 (1%)
4 (4%)
3 (3%)
13 (2%)
3 (3%)
1 (<1%)
2 (2%)
3 (3%)
4 (4%)
1 (<1%)
14 (2%)
0
4 (4%)
5 (5%)
4 (4%)
2 (2%)
2 (2%)
17 (3%)
1 (<1%)
0
0
0
1 (<1%)
2 (2%)
4 (<1%)
2 (2%)
1 (<1%)
1 (<1%)
2 (2%)
0
1 (<1%)
7 (1%)
2 (2%)
0
0
2 (2%)
1 (<1%)
1 (<1%)
6 (<1%)
2 (2%)
3 (3%)
2 (2%)
7 (7%)
4 (4%)
4 (4%)
22 (4%)
2 (2%)
2 (2%)
1 (<1%)
0
3 (3%)
1 (<1%)
9 (1%)
1 (<1%)
0
0
0
0
0
1 (<1%)
2 (2%)
1 (<1%)
1 (<1%)
2 (2%)
1 (<1%)
0
7 (1%)
2 (2%)
3 (3%)
2 (2%)
1 (1%)
1 (<1%)
7 (7%)
16 (3%)
4 (4%)
1 (<1%)
1 (<1%)
3 (3%)
3 (3%)
0
12 (2%)

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Table 6.6
Summary of Inclusion/Exclusion Criteria Deviations

Placebo 3mcg
6.25mcg 12.5mcg 25mcg
50mcg
Total
(N=102) (N=101) (N=101) (N=100) (N=101) (N=102) (N=607)
--------------------------------------------------------------------------------------------------------Any criteria deviations
0
1 (<1%) 2 (2%) 0
2 (2%) 0
5 (<1%)
Exclusion to Run-In:
Systemic corticosteroids or anti-IgE
medications within 12 weeks of Visit 1
Asthma exacerbation requiring OCS within
3 months of Visit 1

1 (<1%)

1 (<1%)

1 (<1%)

1 (<1%)

1 (<1%)

3 (<1%)

(2%)

154

CONFIDENTIAL

Randomisation Criteria:
No 12-lead ECG abnormalities

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 2
Table 6.7
Summary of Protocol Deviations

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
-----------------------------------------------------------------------------------------------------------Full Deviations
4 (4%)
4 (4%)
3 (3%)
2 (2%)
8 (8%)
3 (3%)
24 (4%)
1 (<1%)

0
0
1 (<1%)
0
0
2 (2%)
1 (<1%)

(3%)

(2%)

(2%)

1 (<1%)

(1%)

0
1 (<1%)
2 (2%)
1 (<1%)
1 (<1%)
2 (2%)

0
0
2 (2%)
0
0
1 (<1%)

0
0
0
0
0
2

1 (<1%)
0
0
1 (<1%)
0
3 (3%)

0
0
1 (<1%)
0
0
2 (2%)

1
1
6
2
1
12

(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(2%)

155

(3%)

4 (<1%)

YM2008/00019/00
B2C109575

Note: A subject may have more than one protocol deviation

(2%)

CONFIDENTIAL

Failure of inclusion/exclusion/
randomisation criteria
Exclusion Criteria 3
Exclusion Criteria 11
Inclusion Criteria 4
Randomisation 1
Randomisation 2
Received protocol prohibited
medications during the study
Treatment compliance < 80%

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 2
Table 6.7
Summary of Protocol Deviations

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
-----------------------------------------------------------------------------------------------------------Partial Deviations
4 (4%)
8 (8%)
4 (4%)
4 (4%)
1 (<1%)
1 (<1%)
22 (4%)
2

(2%)

(3%)

(2%)

(1%)

1 (<1%)

(1%)

1 (<1%)

(3%)

(2%)

(2%)

(1%)

1 (<1%)

1 (<1%)

2 (<1%)

4 (<1%)

1 (<1%)

1 (<1%)

(3%)

YM2008/00019/00
B2C109575

Note: A subject may have more than one protocol deviation

(1%)

CONFIDENTIAL

156

Received protocol prohibited


medications during the study
Remained in the study after
falling below the FEV1
stability limit
Remained in the study after an
exacerbation
Remained in the study after
falling below the PEF stability
limit for more than 3 days in
the 7 prior to a visit
Remained in the study after >=
12 puffs of rescue a day for
more than 2 days in the 7 prior
to a visit

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Table 6.8
Summary of Demographic Characteristics
Intent-to-Treat

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
-----------------------------------------------------------------------------------------------------------Age (y)
n
102
101
101
100
101
102
607
Mean
39.9
44.4
42.4
41.3
42.2
44.0
42.4
SD
15.60
13.50
14.13
15.33
14.27
15.22
14.72
Median
42.0
45.0
44.0
43.5
45.0
45.5
44.0
Min.
12
15
16
12
12
13
12
Max.
68
74
80
72
70
73
80
7 (7%)
89 (87%)
6 (6%)

2 (2%)
92 (91%)
7 (7%)

2 (2%)
94 (93%)
5 (5%)

7 (7%)
86 (86%)
7 (7%)

5 (5%)
93 (92%)
3 (3%)

4 (4%)
90 (88%)
8 (8%)

27 (4%)
544 (90%)
36 (6%)

157

Sex

n
Female
Male

102
61 (60%)
41 (40%)

101
52 (51%)
49 (49%)

101
51 (50%)
50 (50%)

100
56 (56%)
44 (44%)

101
61 (60%)
40 (40%)

102
57 (56%)
45 (44%)

607
338 (56%)
269 (44%)

Ethnicity

n
102
Hispanic/Latino
9 (9%)
Not Hispanic/Latino 93 (91%)

101
13 (13%)
88 (87%)

101
10 (10%)
91 (90%)

100
13 (13%)
87 (87%)

101
12 (12%)
89 (88%)

102
22 (22%)
80 (78%)

607
79 (13%)
528 (87%)

102
165.3
10.94
165.0
108
188

101
169.5
11.30
170.0
135
200

101
167.3
9.67
167.0
149
193

100
168.5
10.06
170.0
140
191

101
167.1
9.70
167.0
150
193

102
167.8
9.97
168.0
147
198

607
167.6
10.33
168.0
108
200

Weight (kg) n
Mean
SD
Median
Min.
Max.

101
77.16
18.644
72.00
48.0
127.0

100
78.98
17.625
75.65
43.0
142.0

101
77.58
17.731
74.70
50.0
127.3

99
81.53
19.063
82.00
30.9
137.3

101
77.09
18.702
74.30
43.0
134.1

102
78.93
20.652
76.00
44.5
155.9

604
78.53
18.752
75.75
30.9
155.9

YM2008/00019/00
B2C109575

Height (cm) n
Mean
SD
Median
Min.
Max.

CONFIDENTIAL

<=17 years
18-64 years
>=65 years

Protocol: B2C109575
Population: Per Protocol

Page 1 of 1
Table 6.9
Summary of Demographic Characteristics
Per Protocol

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
(N=98)
(N=97)
(N=98)
(N=98)
(N=93)
(N=99)
(N=583)
-----------------------------------------------------------------------------------------------------------Age (y)
n
98
97
98
98
93
99
583
Mean
39.9
44.3
42.3
41.2
43.0
43.8
42.4
SD
15.54
13.62
14.27
15.43
13.84
15.35
14.72
Median
42.0
45.0
44.0
43.5
46.0
45.0
44.0
Min.
12
15
16
12
12
13
12
Max.
68
74
80
72
70
73
80
7 (7%)
85 (87%)
6 (6%)

2 (2%)
88 (91%)
7 (7%)

2 (2%)
91 (93%)
5 (5%)

7 (7%)
84 (86%)
7 (7%)

3 (3%)
87 (94%)
3 (3%)

4 (4%)
87 (88%)
8 (8%)

25 (4%)
522 (90%)
36 (6%)

Sex

n
Female
Male

98
60 (61%)
38 (39%)

97
49 (51%)
48 (49%)

98
51 (52%)
47 (48%)

98
55 (56%)
43 (44%)

93
55 (59%)
38 (41%)

99
57 (58%)
42 (42%)

583
327 (56%)
256 (44%)

Ethnicity

n
Hispanic/Latino
Not Hispanic/Latino

98
9 (9%)
89 (91%)

97
13 (13%)
84 (87%)

98
10 (10%)
88 (90%)

98
12 (12%)
86 (88%)

93
12 (13%)
81 (87%)

99
21 (21%)
78 (79%)

583
77 (13%)
506 (87%)

98
165.6
9.36
165.0
142
188

97
169.6
11.32
171.0
135
200

98
167.0
9.66
165.5
149
193

98
168.4
10.14
169.5
140
191

93
167.5
9.90
167.0
150
193

99
167.6
10.00
168.0
147
198

583
167.6
10.11
167.0
135
200

Weight (kg) n
Mean
SD
Median
Min.
Max.

97
77.21
18.863
72.00
48.0
127.0

96
78.85
17.529
75.15
43.0
142.0

98
77.66
17.893
74.35
50.0
127.3

98
81.50
19.159
82.00
30.9
137.3

93
77.49
18.334
75.30
43.0
134.1

99
78.66
20.709
76.00
44.5
155.9

581
78.57
18.763
75.50
30.9
155.9

YM2008/00019/00
B2C109575

Height (cm) n
Mean
SD
Median
Min.
Max.

CONFIDENTIAL

158

<=17 years
18-64 years
>=65 years

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Table 6.10
Summary of Race and Racial Combinations

CONFIDENTIAL

159

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
-----------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
607
African American/African
4
(4%)
11 (11%)
8
(8%)
12 (12%)
14 (14%)
8
(8%)
57
(9%)
Heritage
American Indian or
3
(3%)
2
(2%)
3
(3%)
2
(2%)
2
(2%)
1 (<1%)
13
(2%)
Alaska Native
Asian
11 (11%)
13 (13%)
11 (11%)
8
(8%)
9
(9%)
9
(9%)
61 (10%)
Central/South Asian
1 (<1%)
0
0
0
1 (<1%)
0
2 (<1%)
Heritage
Japanese/East Asian
10 (10%)
13 (13%)
11 (11%)
8
(8%)
8
(8%)
9
(9%)
59 (10%)
Heritage/South East
Asian Heritage
Native Hawaiian or other
0
0
1 (<1%)
0
0
0
1 (<1%)
Pacific Islander
White
81 (79%)
74 (73%)
77 (76%)
75 (75%)
75 (74%)
83 (81%) 465 (77%)
African American/African
0
1 (<1%)
0
0
0
0
1 (<1%)
Heritage & American
Indian or Alaska Native
African American/African
2
(2%)
0
0
0
0
0
2 (<1%)
Heritage & White
American Indian or
1 (<1%)
0
1 (<1%)
2
(2%)
1 (<1%)
1 (<1%)
6 (<1%)
Alaska Native & White
Asian & White
0
0
0
1
(1%)
0
0
1 (<1%)

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Table 6.11
Summary of Race and Racial Combination Details

CONFIDENTIAL

160

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
-----------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
607
African American/African
4
(4%)
11 (11%)
8
(8%)
12 (12%)
14 (14%)
8
(8%)
57
(9%)
Heritage
American Indian or
3
(3%)
2
(2%)
3
(3%)
2
(2%)
2
(2%)
1 (<1%)
13
(2%)
Alaska Native
Asian - Central/South
1 (<1%)
0
0
0
1 (<1%)
0
2 (<1%)
Asian Heritage
Asian - East Asian
5
(5%)
6
(6%)
5
(5%)
3
(3%)
2
(2%)
4
(4%)
25
(4%)
Heritage
Asian - Japanese
0
0
0
1
(1%)
0
0
1 (<1%)
Heritage
Asian - South East Asian
5
(5%)
7
(7%)
6
(6%)
4
(4%)
6
(6%)
5
(5%)
33
(5%)
Heritage
Asian - Mixed Race
0
0
0
0
0
0
0
Native Hawaiian or other
0
0
1 (<1%)
0
0
0
1 (<1%)
Pacific Islander
White - Arabic/North
0
2
(2%)
0
3
(3%)
0
0
5 (<1%)
African Heritage
White 81 (79%)
72 (71%)
77 (76%)
72 (72%)
75 (74%)
83 (81%) 460 (76%)
White/Caucasian/European
Heritage
White - Mixed Race
0
0
0
0
0
0
0
Mixed Race
3
(3%)
1 (<1%)
1 (<1%)
3
(3%)
1 (<1%)
1 (<1%)
10
(2%)

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Table 6.12
Summary of History of Tobacco Use at Screening

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
--------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
607
Never smoked
86 (84%)
80 (79%)
82 (81%)
83 (83%)
87 (86%)
83 (81%)
501 (83%)
Former smoker
16 (16%)
21 (21%)
19 (19%)
17 (17%)
14 (14%)
19 (19%)
106 (17%)

CONFIDENTIAL

161

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Table 6.13
Summary of Duration of Asthma and Asthma History

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
------------------------------------------------------------------------------------------------------Duration of Asthma:
n
102
101
101
100
101
102
607
<6 months
0
0
0
0
0
0
0
>=6 months to <1 year
0
2 (2%)
1 (<1%)
1 (1%)
2 (2%)
1 (<1%)
7 (1%)
>=1 year to <5 years
14 (14%)
11 (11%)
19 (19%)
16 (16%)
11 (11%)
16 (16%)
87 (14%)
>=5 years to <10 years
20 (20%)
13 (13%)
11 (11%)
12 (12%)
14 (14%)
20 (20%)
90 (15%)
>=10 years
68 (67%)
75 (74%)
70 (69%)
71 (71%)
74 (73%)
65 (64%) 423 (70%)

102
30 (29%)
72 (71%)

101
34 (34%)
67 (66%)

101
37 (37%)
64 (63%)

100
33 (33%)
67 (67%)

101
34 (34%)
67 (66%)

102
33 (32%)
69 (68%)

607
201 (33%)
406 (67%)

CONFIDENTIAL

162

Does the subject have a


history of atopy?
n
No
Yes

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 2
Table 6.14
Summary of Current Medical Conditions

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
Classification
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
----------------------------------------------------------------------------------------------------------Any Condition
84 (82%)
79 (78%)
76 (75%)
86 (86%)
78 (77%)
82 (80%)
485 (80%)
4

(4%)

20 (20%)
2

(2%)

23 (23%)

23 (23%)
2

(3%)

20 (20%)

(2%)

1 (<1%)

15 (15%)

23 (23%)

(3%)

26 (26%)
2

(2%)

20 (20%)

8
5

(8%)
(5%)

6 (6%)
1 (<1%)

5
3

(5%)
(3%)

8
6

(8%)
(6%)

(8%)

(7%)

(5%)

45 (44%)

38 (38%)

13 (13%)

16 (16%)
5
0

(5%)

(5%)

16 (16%)
0

(6%)

18 (18%)
1 (<1%)

22 (22%)
4
2

21 (21%)

21

(3%)

123 (20%)
8

(1%)

124 (20%)

(4%)
(2%)

6 (6%)
1 (<1%)

37
18

(6%)
(3%)

(9%)

15 (15%)

12 (12%)

56

(9%)

49 (49%)

36 (36%)

48 (47%)

257 (42%)

16 (16%)

73 (12%)

(7%)

12 (12%)

(9%)

8
0

(8%)

11 (11%)
0

10 (10%)
1 (<1%)

9
2

(9%)
(2%)

56 (9%)
3 (<1%)

14 (14%)
5 (5%)

18 (18%)
1 (<1%)

13 (13%)
3 (3%)

11 (11%)
3 (3%)

15 (15%)
2 (2%)

13 (13%)
6 (6%)

84 (14%)
20 (3%)

20 (20%)

15 (15%)

15 (15%)

15 (15%)

17 (17%)

25 (25%)

107 (18%)

10 (10%)
11 (11%)

5 (5%)
11 (11%)

10 (10%)
10 (10%)

8
5

(8%)
(5%)

4
8

(4%)
(8%)

12 (12%)
12 (12%)

49
57

(8%)
(9%)

YM2008/00019/00
B2C109575

13 (13%)
0

41 (41%)

CONFIDENTIAL

163

Blood and lymphatic


system disorders
Musculoskeletal and
connective tissue
disorders
Neoplasms benign,
malignant and
unspecified (incl cysts
and polyps)
Nervous system
disorders
Psychiatric disorders
Renal and urinary
disorders
Reproductive system and
breast disorders
Respiratory, thoracic
and mediastinal
disorders
Skin and subcutaneous
tissue disorders
Vascular disorders
Infections and
infestations
Cardiac disorders
Ear and labyrinth
disorders
Hypersensitivity/anaphy
laxis related
Endocrine disorders
Eye disorders

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 2
Table 6.14
Summary of Current Medical Conditions

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
Classification
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
----------------------------------------------------------------------------------------------------------Gastrointestinal
16 (16%)
12 (12%)
12 (12%)
19 (19%)
13 (13%)
17 (17%)
89 (15%)
disorders
Hepatobiliary disorders
3 (3%)
3 (3%)
4 (4%)
1 (1%)
4 (4%)
4 (4%)
19 (3%)
Immune system disorders
9 (9%)
21 (21%)
12 (12%)
15 (15%)
13 (13%)
16 (16%)
86 (14%)
Metabolism and
7 (7%)
5 (5%)
5 (5%)
6 (6%)
9 (9%)
5 (5%)
37 (6%)
nutrition disorders

CONFIDENTIAL

164

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 2

Table 6.15
Summary of Asthma Concomitant Medications Taken Pre-Treatment

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Any medication
102 (100%) 101 (100%) 101 (100%) 100 (100%) 101 (100%) 102 (100%)
(75%)
(42%)
(35%)
(23%)

71
37
48
16

(70%)
(37%)
(48%)
(16%)

78
40
35
24

(77%)
(40%)
(35%)
(24%)

77
44
36
24

(77%)
(44%)
(36%)
(24%)

80
43
35
18

(79%)
(43%)
(35%)
(18%)

77
33
36
18

(75%)
(32%)
(35%)
(18%)

9
11
7
4
1
4
5
4
2
1
1
3
0

(9%)
(11%)
(7%)
(4%)
(<1%)
(4%)
(5%)
(4%)
(2%)
(<1%)
(<1%)
(3%)

10
9
7
1
6
3
1
1
4
4
4
1
1

(10%)
(9%)
(7%)
(<1%)
(6%)
(3%)
(<1%)
(<1%)
(4%)
(4%)
(4%)
(<1%)
(<1%)

17
6
6
1
8
2
2
5
0
0
0
1
1

(17%)
(6%)
(6%)
(<1%)
(8%)
(2%)
(2%)
(5%)

11
14
4
7
5
2
4
1
1
1
1
0
0

(11%)
(14%)
(4%)
(7%)
(5%)
(2%)
(4%)
(1%)
(1%)
(1%)
(1%)

12
7
9
6
2
5
4
1
4
3
2
0
3

(12%)
(7%)
(9%)
(6%)
(2%)
(5%)
(4%)
(<1%)
(4%)
(3%)
(2%)

17
9
7
8
3
5
0
3
3
3
2
2
1

(17%)
(9%)
(7%)
(8%)
(3%)
(5%)

1
1
2
2

(<1%)
(<1%)
(2%)
(2%)

0
0
1
0

1
0
0
0

(<1%)

1
0
0
0

(1%)

2
1
0
0

(2%)
(<1%)

0
0
0

0
0
1

0
0
0

0
1
0

(<1%)

(<1%)
(<1%)

(<1%)
(<1%)

0
0
0
1
0
0

(<1%)

0
2
0
0

0
0
0

1
1
0

0
0
1

0
0
0

(1%)

(3%)
(2%)

(<1%)
(<1%)

0
0
0
0
0
0

(3%)
(3%)
(3%)
(2%)
(2%)
(<1%)

YM2008/00019/00
B2C109575

77
43
36
23

CONFIDENTIAL

165

SALBUTAMOL
FLUTICASONE PROPIONATE
BUDESONIDE
SALMETEROL XINAFOATE+FLUTICASONE
PROPIONATE
BECLOMETASONE DIPROPIONATE
BUDESONIDE+FORMOTEROL FUMARATE
FORMOTEROL FUMARATE
MOMETASONE FUROATE
SALMETEROL XINAFOATE
CICLESONIDE
MONTELUKAST SODIUM
BECLOMETASONE
FORMOTEROL
THEOPHYLLINE
TERBUTALINE SULFATE
FENOTEROL HYDROBROMIDE
FENOTEROL HYDROBROMIDE+IPRATROPIUM
BROMIDE
FLUTICASONE
LEVOSALBUTAMOL HYDROCHLORIDE
IPRATROPIUM BROMIDE
SALBUTAMOL SULFATE+IPRATROPIUM
BROMIDE
CETIRIZINE
CETIRIZINE HYDROCHLORIDE
CROMOGLICATE SODIUM+REPROTEROL
HYDROCHLORIDE
PIRBUTEROL ACETATE
PREDNISOLONE
SALBUTAMOL SULFATE

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 2

Table 6.15
Summary of Asthma Concomitant Medications Taken Pre-Treatment

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------SALMETEROL
0
0
0
0
1 (<1%)
0
SALMETEROL+FLUTICASONE PROPIONATE
0
0
0
0
1 (<1%)
0
TIOTROPIUM BROMIDE
0
0
0
0
1 (<1%)
0
TRIAMCINOLONE ACETONIDE
0
1 (<1%)
0
0
0
0

CONFIDENTIAL

166

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 6.16
Summary of Asthma Concomitant Medications Taken During Treatment

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Any medication
101 (>99%) 101 (100%) 101 (100%) 100 (100%) 100 (>99%) 102 (100%)
43
36
9
4
4
2
4
1
0
0
0
0
1
0

(42%)
(35%)
(9%)
(4%)
(4%)
(2%)
(4%)
(<1%)

(<1%)

37
48
10
1
3
6
1
0
1
0
0
0
0
1

(37%)
(48%)
(10%)
(<1%)
(3%)
(6%)
(<1%)
(<1%)

(<1%)

41
35
17
1
2
2
5
1
0
0
1
1
0
0

(41%)
(35%)
(17%)
(<1%)
(2%)
(2%)
(5%)
(<1%)
(<1%)
(<1%)

44
35
10
7
2
4
1
1
0
1
0
0
0
0

(44%)
(35%)
(10%)
(7%)
(2%)
(4%)
(1%)
(1%)
(1%)

42
33
12
6
5
4
1
0
1
0
0
0
0
0

(42%)
(33%)
(12%)
(6%)
(5%)
(4%)
(<1%)
(<1%)

33
36
17
7
5
0
3
2
0
0
0
0
0
0

(32%)
(35%)
(17%)
(7%)
(5%)
(3%)
(2%)

CONFIDENTIAL

167

FLUTICASONE PROPIONATE
BUDESONIDE
BECLOMETASONE DIPROPIONATE
MOMETASONE FUROATE
CICLESONIDE
SALBUTAMOL
BECLOMETASONE
FLUTICASONE
PREDNISOLONE
FORMOTEROL FUMARATE
METHYLPREDNISOLONE
SALMETEROL XINAFOATE
THEOPHYLLINE
TRIAMCINOLONE ACETONIDE

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 6.17
Summary of Asthma Concomitant Medications Taken Post Treatment

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Any medication
101 (>99%) 101 (100%) 101 (100%) 100 (100%) 100 (>99%) 102 (100%)
(42%)
(35%)
(9%)
(4%)
(4%)
(2%)
(4%)
(2%)
(<1%)

37
48
10
1
3
5
1
1
1

1
2
1
0
0
0
0
0
0
0
0
0
1
0
0
0

(<1%)
(2%)
(<1%)

0
0
0
0
1
1
0
1
1
1
1
1
0
1
0
1

(<1%)

(37%)
(48%)
(10%)
(<1%)
(3%)
(5%)
(<1%)
(<1%)
(<1%)

(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)

41
35
17
1
2
1
4
1
2

(41%)
(35%)
(17%)
(<1%)
(2%)
(<1%)
(4%)
(<1%)
(2%)

44
35
10
7
2
3
1
1
1

(44%)
(35%)
(10%)
(7%)
(2%)
(3%)
(1%)
(1%)
(1%)

42
33
12
6
5
4
1
1
1

1
0
1
0
1
1
1
0
0
0
0
0
0
0
1
0

(<1%)

1
1
0
1
0
0
0
0
0
0
0
0
0
0
0
0

(1%)
(1%)

0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0

(<1%)
(<1%)
(<1%)
(<1%)

(<1%)

(1%)

(42%)
(33%)
(12%)
(6%)
(5%)
(4%)
(<1%)
(<1%)
(<1%)

33
36
17
7
5
0
3
0
0

(32%)
(35%)
(17%)
(7%)
(5%)

2
0
0
1
0
0
0
0
0
0
0
0
0
0
0
0

(2%)

(3%)

(<1%)

YM2008/00019/00
B2C109575

43
36
9
4
4
2
4
2
1

CONFIDENTIAL

168

FLUTICASONE PROPIONATE
BUDESONIDE
BECLOMETASONE DIPROPIONATE
MOMETASONE FUROATE
CICLESONIDE
SALBUTAMOL
BECLOMETASONE
MONTELUKAST SODIUM
SALMETEROL XINAFOATE+FLUTICASONE
PROPIONATE
FLUTICASONE
BUDESONIDE+FORMOTEROL FUMARATE
CLARITHROMYCIN
FORMOTEROL FUMARATE
METHYLPREDNISOLONE
PREDNISOLONE
AMBROXOL HYDROCHLORIDE
BEPOTASTINE
CARBOCISTEINE+SOBREROL
DEFLAZACORT
DEXAMETHASONE SODIUM PHOSPHATE
FEXOFENADINE HYDROCHLORIDE
PREDNISONE
ROXITHROMYCIN
SALMETEROL XINAFOATE
TRIAMCINOLONE ACETONIDE

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 18

Table 6.18
Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Any medication
68 (67%)
58 (57%)
48 (48%)
68 (68%)
62 (61%)
58 (57%)
31
4
5
2
4
1
2
1
2
1
1
0
2
1
1
0

(30%)
(4%)
(5%)
(2%)
(4%)
(<1%)
(2%)
(<1%)
(2%)
(<1%)
(<1%)
(2%)
(<1%)
(<1%)

28
4
6
1
2
2
2
1
1
2
1
0
1
2
3
1

(28%)
(4%)
(6%)
(<1%)
(2%)
(2%)
(2%)
(<1%)
(<1%)
(2%)
(<1%)
(<1%)
(2%)
(3%)
(<1%)

22
11
1
3
4
2
1
2
2
1
2
1
1
0
1
1

(22%)
(11%)
(<1%)
(3%)
(4%)
(2%)
(<1%)
(2%)
(2%)
(<1%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)

33 (33%)
6 (6%)
4 (4%)
8 (8%)
0
1 (1%)
1 (1%)
2 (2%)
1 (1%)
1 (1%)
0
4 (4%)
2 (2%)
0
1 (1%)
2 (2%)

1 (<1%)
0
0
0
1 (<1%)

1 (<1%)
1 (<1%)
2 (2%)
1 (<1%)
0

1
0
0
1
1

2 (2%)
1 (<1%)

0
0

0
0

0
1

1 (<1%)
0

0
0

1 (<1%)
0

0
0

(1%)

(23%)
(4%)
(4%)
(2%)
(3%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)

29
4
5
3
3
4
1
2
2
2
2
1
1
2
0
2

(28%)
(4%)
(5%)
(3%)
(3%)
(4%)
(<1%)
(2%)
(2%)
(2%)
(2%)
(<1%)
(<1%)
(2%)
(2%)

(1%)
(1%)

0
1 (<1%)
0
0
0

2 (2%)
0
1 (<1%)
2 (2%)
0

(1%)

1 (<1%)
1 (<1%)

0
0

0
2

0
0

(2%)

Note: A medication may be included in more than one ATC Level category and appear more than once.

YM2008/00019/00
B2C109575

0
2 (2%)
1 (<1%)
0
1 (<1%)

23
4
4
0
2
3
2
1
0
0
1
1
0
1
0
0

CONFIDENTIAL

169

RESPIRATORY SYSTEM
Any medication
FLUTICASONE PROPIONATE
MOMETASONE FUROATE
LORATADINE
AZELASTINE HYDROCHLORIDE
CETIRIZINE HYDROCHLORIDE
BECLOMETASONE DIPROPIONATE
BENADRYL (NOS)
PHENIRAMINE
BROMHEXINE
BUDESONIDE
RHINOCORT (NOS)
TRIAMCINOLONE ACETONIDE
FEXOFENADINE HYDROCHLORIDE
FLUTICASONE FUROATE
PSEUDOEPHEDRINE
HYDROCHLORIDE+FEXOFENADINE
HYDROCHLORIDE
COUGH COLD PREPARATIONS NOS
DESLORATADINE
LEVOCETIRIZINE HYDROCHLORIDE
PSEUDOEPHEDRINE HYDROCHLORIDE
DIPHENHYDRAMINE
HYDROCHLORIDE+PARACETAMOL
MONTELUKAST SODIUM
PSEUDOEPHEDRINE
SULFATE+LORATADINE
ACETYLCYSTEINE
CETIRIZINE

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 18

Table 6.18
Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment

YM2008/00019/00
B2C109575

Note: A medication may be included in more than one ATC Level category and appear more than once.

CONFIDENTIAL

170

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------CHLORPHENAMINE
0
1 (<1%)
0
0
1 (<1%)
0
CHLORPHENAMINE MALEATE
0
0
1 (<1%)
0
1 (<1%)
0
EPINEPHRINE
1 (<1%)
0
1 (<1%)
0
0
0
HYOSCINE
0
0
0
2 (2%)
0
0
METHONITRATE+CHLORPHENAMINE
MALEATE+PHENYLEPHRINE
HYDROCHLORIDE
MEQUITAZINE
1 (<1%)
0
0
0
0
1 (<1%)
PARACETAMOL+CHLORPHENAMINE
0
0
0
2 (2%)
0
0
MALEATE+PSEUDOEPHEDRINE
HYDROCHLORIDE
TRIAMCINOLONE
0
2 (2%)
0
0
0
0
TYLENOL SINUS (NOS)
0
0
0
1 (1%)
0
1 (<1%)
ASCORBIC
0
1 (<1%)
0
0
0
0
ACID+PARACETAMOL+CHLORPHENAMINE
MALEATE+PHENYLPROPANOLAMINE
HYDROCHLORIDE
BETAMETHASONE DIPROPIONATE
1 (<1%)
0
0
0
0
0
BUCKLEY'S MIXTURE (NOS)
0
1 (<1%)
0
0
0
0
CARDIOSPERMUM+GALPHIMIA
0
0
0
0
1 (<1%)
0
GLAUCA+LUFFA OPERCULATA
DEXTROMETHORPHAN
0
0
0
0
0
1 (<1%)
TANNATE+MEPYRAMINE
TANNATE+PHENYLEPHRINE TANNATE
DIMENHYDRINATE
0
1 (<1%)
0
0
0
0
DIPHENHYDRAMINE
0
0
0
1 (1%)
0
0
DIPHENHYDRAMINE HYDROCHLORIDE
0
1 (<1%)
0
0
0
0
EBASTINE
1 (<1%)
0
0
0
0
0
FLUNISOLIDE
0
0
0
0
1 (<1%)
0
FLUTICASONE
0
1 (<1%)
0
0
0
0
GUAIFENESIN
0
0
0
1 (1%)
0
0

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 18

Table 6.18
Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment

28 (27%)
8 (8%)
3 (3%)
2 (2%)

24 (24%)
5 (5%)
4 (4%)
3 (3%)

20 (20%)
5 (5%)
2 (2%)
3 (3%)

32 (32%)
7 (7%)
5 (5%)
2 (2%)

28 (28%)
5 (5%)
6 (6%)
0

Note: A medication may be included in more than one ATC Level category and appear more than once.

27 (26%)
3 (3%)
8 (8%)
0

YM2008/00019/00
B2C109575

ALIMENTARY TRACT AND METABOLISM


Any medication
VITAMINS NOS
ACETYLSALICYLIC ACID
CALCIUM CARBONATE

CONFIDENTIAL

171

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------GUAIFENESIN+DEXTROMETHORPHAN
0
0
0
0
0
1 (<1%)
HYDROBROMIDE
GUAIFENESIN+PSEUDOEPHEDRINE
0
1 (<1%)
0
0
0
0
HYDROCHLORIDE
HYDROCODONE
0
0
0
0
1 (<1%)
0
HYOSCINE
0
0
0
0
1 (<1%)
0
METHONITRATE+CHLORPHENAMINE
MALEATE+PSEUDOEPHEDRINE
HYDROCHLORIDE
NEOZEP NOS
0
0
0
0
1 (<1%)
0
OXYMETAZOLINE HYDROCHLORIDE
1 (<1%)
0
0
0
0
0
PARACETAMOL+CHLORPHENAMINE
0
0
0
0
0
1 (<1%)
MALEATE+PHENYLEPHRINE
HYDROCHLORIDE
PARACETAMOL+HYDROCODONE
0
0
0
0
0
1 (<1%)
POTASSIUM IODIDE
1 (<1%)
0
0
0
0
0
PREDNISOLONE
0
0
0
0
0
1 (<1%)
PROMETHAZINE
0
0
1 (<1%)
0
0
0
PSEUDOEPHEDRINE SULFATE+AZATADINE
0
0
0
0
0
1 (<1%)
MALEATE
PSEUDOEPHEDRINE
0
0
0
0
0
1 (<1%)
HYDROCHLORIDE+TRIPROLIDINE
HYDROCHLORIDE
SODIUM BICARBONATE+SODIUM
1 (<1%)
0
0
0
0
0
CHLORIDE
XYLOMETAZOLINE HYDROCHLORIDE
0
0
0
1 (1%)
0
0

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 18

Table 6.18
Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment

YM2008/00019/00
B2C109575

Note: A medication may be included in more than one ATC Level category and appear more than once.

CONFIDENTIAL

172

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------BECLOMETASONE DIPROPIONATE
2 (2%)
2 (2%)
1 (<1%)
1 (1%)
2 (2%)
1 (<1%)
OMEPRAZOLE
3 (3%)
0
1 (<1%)
1 (1%)
3 (3%)
1 (<1%)
ESOMEPRAZOLE MAGNESIUM
2 (2%)
1 (<1%)
0
3 (3%)
1 (<1%)
1 (<1%)
LANSOPRAZOLE
1 (<1%)
0
0
1 (1%)
4 (4%)
2 (2%)
BUDESONIDE
1 (<1%)
1 (<1%)
2 (2%)
0
1 (<1%)
2 (2%)
METFORMIN
0
1 (<1%)
1 (<1%)
1 (1%)
2 (2%)
2 (2%)
MINERALS NOS+VITAMINS NOS
4 (4%)
0
0
0
2 (2%)
1 (<1%)
RANITIDINE HYDROCHLORIDE
0
1 (<1%)
2 (2%)
2 (2%)
1 (<1%)
1 (<1%)
RHINOCORT (NOS)
0
0
1 (<1%)
4 (4%)
1 (<1%)
1 (<1%)
TRIAMCINOLONE ACETONIDE
2 (2%)
1 (<1%)
1 (<1%)
2 (2%)
0
1 (<1%)
ASCORBIC ACID
0
1 (<1%)
0
1 (1%)
1 (<1%)
2 (2%)
CALCIUM
1 (<1%)
2 (2%)
0
0
1 (<1%)
1 (<1%)
VITAMIN D NOS
0
1 (<1%)
3 (3%)
0
0
1 (<1%)
BISMUTH SUBSALICYLATE
0
1 (<1%)
0
0
1 (<1%)
1 (<1%)
DOCUSATE SODIUM
2 (2%)
0
0
0
0
1 (<1%)
HYDROCORTISONE
0
1 (<1%)
1 (<1%)
0
1 (<1%)
0
EPINEPHRINE
1 (<1%)
0
1 (<1%)
0
0
0
FAMOTIDINE
1 (<1%)
0
0
0
0
1 (<1%)
GLIBENCLAMIDE
0
1 (<1%)
1 (<1%)
0
0
0
GLIMEPIRIDE
0
0
0
1 (1%)
0
1 (<1%)
INSULIN ASPART
0
1 (<1%)
0
0
0
1 (<1%)
INSULIN GLARGINE
0
1 (<1%)
0
0
0
1 (<1%)
METFORMIN HYDROCHLORIDE
0
0
0
1 (1%)
0
1 (<1%)
PANTOPRAZOLE SODIUM
1 (<1%)
0
0
0
1 (<1%)
0
RABEPRAZOLE SODIUM
1 (<1%)
0
1 (<1%)
0
0
0
TOCOPHEROL
0
0
0
1 (1%)
1 (<1%)
0
TRIAMCINOLONE
0
2 (2%)
0
0
0
0
ALMAGATE
0
0
0
1 (1%)
0
0
ALUMINIUM HYDROXIDE GEL+MAGNESIUM
1 (<1%)
0
0
0
0
0
HYDROXIDE
ALUMINIUM HYDROXIDE+MAGNESIUM
0
0
0
0
0
1 (<1%)
HYDROXIDE+DIMETICONE, ACTIVATED

Protocol: B2C109575
Population: Intent-to-Treat

Page 5 of 18

Table 6.18
Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment

YM2008/00019/00
B2C109575

Note: A medication may be included in more than one ATC Level category and appear more than once.

CONFIDENTIAL

173

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------ALUMINIUM PHOSPHATE+AGAR+PECTIN
0
0
0
0
0
1 (<1%)
BETAMETHASONE DIPROPIONATE
1 (<1%)
0
0
0
0
0
CALCIUM CARBONATE+COLECALCIFEROL
0
0
0
1 (1%)
0
0
CALCIUM D3 (NOS)
1 (<1%)
0
0
0
0
0
CALCIUM+MAGNESIUM
0
0
1 (<1%)
0
0
0
CAROTENOIDS
0
0
1 (<1%)
0
0
0
CIMETIDINE
0
1 (<1%)
0
0
0
0
CINNAMOMUM VERUM
0
0
0
1 (1%)
0
0
DIMENHYDRINATE
0
1 (<1%)
0
0
0
0
DIMETICONE, ACTIVATED
0
0
0
0
1 (<1%)
0
DOMPERIDONE
0
0
1 (<1%)
0
0
0
ERGOCALCIFEROL+CALCIUM
0
0
0
1 (1%)
0
0
ESOMEPRAZOLE
0
1 (<1%)
0
0
0
0
GAVISCON NOS
0
0
0
1 (1%)
0
0
INSULIN DETEMIR
0
1 (<1%)
0
0
0
0
INSULIN HUMAN INJECTION, ISOPHANE
0
0
1 (<1%)
0
0
0
INSULIN LISPRO
0
0
1 (<1%)
0
0
0
INSULIN NOS
1 (<1%)
0
0
0
0
0
ITOPRIDE HYDROCHLORIDE
0
0
0
0
0
1 (<1%)
LINUM USITATISSIMUM
0
0
0
0
1 (<1%)
0
LOPERAMIDE HYDROCHLORIDE
0
0
0
0
0
1 (<1%)
MESALAZINE
0
0
0
1 (1%)
0
0
METFORMIN
0
0
0
0
0
1 (<1%)
HYDROCHLORIDE+GLIBENCLAMIDE
METOCLOPRAMIDE HYDROCHLORIDE
0
0
0
0
1 (<1%)
0
MISOPROSTOL
0
0
0
0
0
1 (<1%)
NYSTATIN
0
0
0
0
0
1 (<1%)
PANTOPRAZOLE
0
0
0
0
0
1 (<1%)
POTASSIUM NOS
0
0
1 (<1%)
0
0
0
PREDNISOLONE
0
0
0
0
0
1 (<1%)
PREDNISONE
1 (<1%)
0
0
0
0
0
PROMETHAZINE
0
0
1 (<1%)
0
0
0

Protocol: B2C109575
Population: Intent-to-Treat

Page 6 of 18

Table 6.18
Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment

29 (28%)
13 (13%)
9 (9%)
3 (3%)
0
0
2 (2%)
1 (<1%)
1 (<1%)
0
1 (<1%)
0

30 (30%)
13 (13%)
12 (12%)
4 (4%)
2 (2%)
1
0
1
0
1
1
1

(<1%)
(<1%)
(<1%)
(<1%)
(<1%)

16 (16%)
8 (8%)
6 (6%)
2 (2%)
0
1 (<1%)
0
0
0
1 (<1%)
0
1 (<1%)

31 (31%)
8 (8%)
8 (8%)
5 (5%)
3 (3%)
1
1
2
3
1
0
0

(1%)
(1%)
(2%)
(3%)
(1%)

27 (27%)
13 (13%)
5 (5%)
6 (6%)
1 (<1%)

26 (25%)
9 (9%)
2 (2%)
8 (8%)
0

2 (2%)
0
0
0
0
0
1 (<1%)

0
1 (<1%)
0
0
1 (<1%)
1 (<1%)
0

Note: A medication may be included in more than one ATC Level category and appear more than once.

YM2008/00019/00
B2C109575

NERVOUS SYSTEM
Any medication
PARACETAMOL
IBUPROFEN
ACETYLSALICYLIC ACID
ACETYLSALICYLIC
ACID+PARACETAMOL+CAFFEINE
ALPRAZOLAM
CLONAZEPAM
ESCITALOPRAM OXALATE
FLUOXETINE HYDROCHLORIDE
SERTRALINE HYDROCHLORIDE
BUPROPION HYDROCHLORIDE
CITALOPRAM HYDROBROMIDE

CONFIDENTIAL

174

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------RANITIDINE
0
0
0
1 (1%)
0
0
REPAGLINIDE
0
0
0
1 (1%)
0
0
RIFAXIMIN
0
0
0
1 (1%)
0
0
SENNA
1 (<1%)
0
0
0
0
0
SITAGLIPTIN
0
1 (<1%)
0
0
0
0
SODIUM BICARBONATE+SODIUM
1 (<1%)
0
0
0
0
0
CHLORIDE
THIAMINE
0
0
0
0
0
1 (<1%)
MONONITRATE+CYANOCOBALAMIN+PYRIDO
XINE
HYDROCHLORIDE+NICOTINAMIDE+TOCOPH
ERYL ACETATE+RIBOFLAVIN+CHOLINE
ALFOSCERATE
VITAMIN B NOS
0
1 (<1%)
0
0
0
0
VITAMIN B SUBSTANCES NOS
0
0
1 (<1%)
0
0
0
ZINC
0
1 (<1%)
0
0
0
0

Protocol: B2C109575
Population: Intent-to-Treat

Page 7 of 18

Table 6.18
Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment

YM2008/00019/00
B2C109575

Note: A medication may be included in more than one ATC Level category and appear more than once.

CONFIDENTIAL

175

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------DIPHENHYDRAMINE
1 (<1%)
1 (<1%)
0
1 (1%)
0
0
HYDROCHLORIDE+PARACETAMOL
EXCEDRIN (NOS)
0
0
0
0
0
3 (3%)
HYDROXYZINE
0
1 (<1%)
0
0
1 (<1%)
1 (<1%)
SUMATRIPTAN
1 (<1%)
0
1 (<1%)
1 (1%)
0
0
ACETYLSALICYLIC
0
0
0
1 (1%)
1 (<1%)
0
ACID+CAFFEINE+CINNAMEDRINE
HYDROCHLORIDE
AMFETAMINE SULFATE+AMFETAMINE
0
1 (<1%)
0
0
0
1 (<1%)
ASPARTATE+DEXAMFETAMINE
SULFATE+DEXTROAMPHETAMINE
SACCHARATE
KETOROLAC TROMETAMOL
0
0
1 (<1%)
1 (1%)
0
0
METAMIZOLE SODIUM
1 (<1%)
0
1 (<1%)
0
0
0
MODAFINIL
1 (<1%)
0
0
0
0
1 (<1%)
PARACETAMOL+HYDROCODONE
0
1 (<1%)
1 (<1%)
0
0
0
BITARTRATE
PREGABALIN
1 (<1%)
0
0
1 (1%)
0
0
RIZATRIPTAN BENZOATE
0
0
1 (<1%)
0
0
1 (<1%)
TRAZODONE
0
1 (<1%)
0
1 (1%)
0
0
ACETYLSALICYLIC
0
0
0
1 (1%)
0
0
ACID+CAFFEINE+SALICYLAMIDE
ASCORBIC
0
1 (<1%)
0
0
0
0
ACID+PARACETAMOL+CHLORPHENAMINE
MALEATE+PHENYLPROPANOLAMINE
HYDROCHLORIDE
CLONIDINE HYDROCHLORIDE
1 (<1%)
0
0
0
0
0
CYCLOBENZAPRINE HYDROCHLORIDE
0
0
0
0
1 (<1%)
0
DEXTROPROPOXYPHENE
1 (<1%)
0
0
0
0
0
HYDROCHLORIDE+PARACETAMOL
DEXTROPROPOXYPHENE
0
0
1 (<1%)
0
0
0
NAPSILATE+PARACETAMOL

Protocol: B2C109575
Population: Intent-to-Treat

Page 8 of 18

Table 6.18
Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment

YM2008/00019/00
B2C109575

Note: A medication may be included in more than one ATC Level category and appear more than once.

CONFIDENTIAL

176

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------ERGOTAMINE TARTRATE
0
0
0
0
0
1 (<1%)
ERGOTAMINE TARTRATE+CAFFEINE
0
0
0
0
0
1 (<1%)
ERGOTAMINE TARTRATE+METAMIZOLE
0
0
0
0
1 (<1%)
0
SODIUM+CAFFEINE+CHLORPHENAMINE
MALEATE
GABAPENTIN
0
0
0
0
1 (<1%)
0
HYDROCODONE
0
0
0
0
1 (<1%)
0
IBUPROFEN LYSINATE
0
0
0
0
1 (<1%)
0
LORAZEPAM
0
1 (<1%)
0
0
0
0
MEFENAMIC ACID
0
0
0
0
1 (<1%)
0
METHADONE
0
1 (<1%)
0
0
0
0
METHYLPHENIDATE HYDROCHLORIDE
0
0
0
1 (1%)
0
0
MIDAZOLAM MALEATE
0
0
0
0
0
1 (<1%)
MORPHINE
0
1 (<1%)
0
0
0
0
NARATRIPTAN HYDROCHLORIDE
1 (<1%)
0
0
0
0
0
ORPHENADRINE CITRATE
1 (<1%)
0
0
0
0
0
OXIRACETAM
0
0
0
1 (1%)
0
0
OXYCODONE
0
1 (<1%)
0
0
0
0
PARACETAMOL+CHLORPHENAMINE
0
0
0
0
0
1 (<1%)
MALEATE+PHENYLEPHRINE
HYDROCHLORIDE
PARACETAMOL+HYDROCODONE
0
0
0
0
0
1 (<1%)
PAROXETINE HYDROCHLORIDE
0
0
1 (<1%)
0
0
0
PROMETHAZINE
0
0
1 (<1%)
0
0
0
SERTRALINE
1 (<1%)
0
0
0
0
0
TOPIRAMATE
0
0
0
1 (1%)
0
0
VENLAFAXINE HYDROCHLORIDE
0
0
0
0
1 (<1%)
0
ZOLMITRIPTAN
1 (<1%)
0
0
0
0
0
ZOLPIDEM
0
0
1 (<1%)
0
0
0
ZOLPIDEM TARTRATE
0
0
0
1 (1%)
0
0
ZOPICLONE
0
0
0
1 (1%)
0
0

Protocol: B2C109575
Population: Intent-to-Treat

Page 9 of 18

Table 6.18
Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment

YM2008/00019/00
B2C109575

Note: A medication may be included in more than one ATC Level category and appear more than once.

CONFIDENTIAL

177

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------CARDIOVASCULAR SYSTEM
Any medication
23 (23%)
20 (20%)
21 (21%)
20 (20%)
20 (20%)
16 (16%)
ENALAPRIL
2 (2%)
0
2 (2%)
3 (3%)
3 (3%)
1 (<1%)
HYDROCHLOROTHIAZIDE
2 (2%)
5 (5%)
1 (<1%)
0
2 (2%)
1 (<1%)
AMLODIPINE BESILATE
1 (<1%)
2 (2%)
1 (<1%)
3 (3%)
1 (<1%)
2 (2%)
SIMVASTATIN
1 (<1%)
2 (2%)
0
0
2 (2%)
2 (2%)
VERAPAMIL
3 (3%)
1 (<1%)
0
1 (1%)
2 (2%)
0
AMLODIPINE
1 (<1%)
1 (<1%)
0
0
4 (4%)
0
VERAPAMIL HYDROCHLORIDE
1 (<1%)
0
1 (<1%)
3 (3%)
1 (<1%)
0
ENALAPRIL MALEATE
1 (<1%)
1 (<1%)
1 (<1%)
0
1 (<1%)
1 (<1%)
LISINOPRIL
0
0
2 (2%)
1 (1%)
1 (<1%)
1 (<1%)
PERINDOPRIL
0
1 (<1%)
0
0
4 (4%)
0
ATORVASTATIN CALCIUM
1 (<1%)
0
0
1 (1%)
0
2 (2%)
HYDROCHLOROTHIAZIDE+LOSARTAN
0
1 (<1%)
1 (<1%)
1 (1%)
0
1 (<1%)
POTASSIUM
INDAPAMIDE
0
0
1 (<1%)
1 (1%)
0
2 (2%)
VALSARTAN
1 (<1%)
1 (<1%)
1 (<1%)
1 (1%)
0
0
FISH OIL
0
0
2 (2%)
0
0
1 (<1%)
FOSINOPRIL SODIUM
1 (<1%)
1 (<1%)
0
0
0
1 (<1%)
HYDROCORTISONE
0
1 (<1%)
1 (<1%)
0
1 (<1%)
0
IRBESARTAN
0
1 (<1%)
1 (<1%)
1 (1%)
0
0
LOSARTAN
1 (<1%)
0
0
0
2 (2%)
0
LOSARTAN POTASSIUM
1 (<1%)
0
1 (<1%)
1 (1%)
0
0
RAMIPRIL
1 (<1%)
2 (2%)
0
0
0
0
TELMISARTAN
0
1 (<1%)
1 (<1%)
0
0
1 (<1%)
CANDESARTAN CILEXETIL
0
1 (<1%)
0
0
1 (<1%)
0
DIOSMIN
1 (<1%)
0
0
0
1 (<1%)
0
EPINEPHRINE
1 (<1%)
0
1 (<1%)
0
0
0
FELODIPINE
1 (<1%)
1 (<1%)
0
0
0
0
HYDROCHLOROTHIAZIDE+VALSARTAN
0
0
1 (<1%)
0
0
1 (<1%)
MOXONIDINE
1 (<1%)
0
0
0
1 (<1%)
0
OLMESARTAN
0
0
0
1 (1%)
0
1 (<1%)

Protocol: B2C109575
Population: Intent-to-Treat

Page 10 of 18

Table 6.18
Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment

YM2008/00019/00
B2C109575

Note: A medication may be included in more than one ATC Level category and appear more than once.

CONFIDENTIAL

178

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------ACETAZOLAMIDE
0
0
0
1 (1%)
0
0
ATORVASTATIN
1 (<1%)
0
0
0
0
0
BETAMETHASONE DIPROPIONATE
1 (<1%)
0
0
0
0
0
CAPTOPRIL
1 (<1%)
0
0
0
0
0
CHLORTALIDONE+ATENOLOL
0
0
0
1 (1%)
0
0
CIPROFIBRATE
0
0
0
1 (1%)
0
0
CLONIDINE HYDROCHLORIDE
1 (<1%)
0
0
0
0
0
DILTIAZEM
0
0
0
1 (1%)
0
0
DIOSMIN+HESPERIDIN
0
1 (<1%)
0
0
0
0
DOXAZOSIN
1 (<1%)
0
0
0
0
0
FENOFIBRATE
0
0
1 (<1%)
0
0
0
HYDROCHLOROTHIAZIDE+AMILORIDE
0
0
1 (<1%)
0
0
0
HYDROCHLORIDE
HYDROCHLOROTHIAZIDE+CANDESARTAN
0
0
1 (<1%)
0
0
0
CILEXETIL
HYDROCHLOROTHIAZIDE+ENALAPRIL
1 (<1%)
0
0
0
0
0
HYDROCHLOROTHIAZIDE+RAMIPRIL
0
0
0
0
1 (<1%)
0
INDOMETACIN
0
1 (<1%)
0
0
0
0
ISOSORBIDE MONONITRATE
0
0
0
0
0
1 (<1%)
LOVASTATIN
0
0
0
0
1 (<1%)
0
METOPROLOL SUCCINATE
0
1 (<1%)
0
0
0
0
MOEXIPRIL
0
0
1 (<1%)
0
0
0
NICOTINIC ACID
0
0
0
0
0
1 (<1%)
OMEGA-3 MARINE TRIGLYCERIDES
0
0
0
0
0
1 (<1%)
PENTOSAN POLYSULFATE SODIUM
0
0
0
1 (1%)
0
0
PREDNISOLONE
0
0
0
0
0
1 (<1%)
QUINAPRIL HYDROCHLORIDE
0
1 (<1%)
0
0
0
0
ROSUVASTATIN CALCIUM
0
0
0
0
1 (<1%)
0
SIMVASTATIN+EZETIMIBE
0
0
1 (<1%)
0
0
0
SPIRONOLACTONE
1 (<1%)
0
0
0
0
0
SPIRONOLACTONE+ALTIZIDE
1 (<1%)
0
0
0
0
0
TOCOPHEROL+FISH OIL
0
1 (<1%)
0
0
0
0

Protocol: B2C109575
Population: Intent-to-Treat

Page 11 of 18

Table 6.18
Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------TORASEMIDE
0
0
0
0
1 (<1%)
0
TRIAMTERENE+HYDROCHLOROTHIAZIDE
0
0
0
0
1 (<1%)
0
TRIMETAZIDINE HYDROCHLORIDE
1 (<1%)
0
0
0
0
0
UBIDECARENONE
0
0
1 (<1%)
0
0
0
17
4
5
2
1
1
0
2
0
1

(17%)
(4%)
(5%)
(2%)
(<1%)
(<1%)
(2%)
(<1%)

(19%)
(4%)
(6%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)

0
2 (2%)
0
0
0
0
0
0
1 (<1%)
0
1 (<1%)
0
0
0
0

18
11
1
1
2
2
1
1
1
0

(18%)
(11%)
(<1%)
(<1%)
(2%)
(2%)
(<1%)
(<1%)
(<1%)

0
0
0
0
0
0
0
0
0
0
0
1 (<1%)
0
0
1 (<1%)

25 (25%)
6 (6%)
4 (4%)
1 (1%)
2 (2%)
0
4 (4%)
2 (2%)
0
0
1
0
0
1
1
1
1
1
0
1
0
0
0
0
0

(1%)
(1%)
(1%)
(1%)
(1%)
(1%)
(1%)

14
4
4
2
1
1
1
0
1
0

(14%)
(4%)
(4%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)

1 (<1%)
0
0
0
0
0
0
0
0
0
0
0
0
0
0

Note: A medication may be included in more than one ATC Level category and appear more than once.

17
4
5
1
2
2
1
1
0
1

(17%)
(4%)
(5%)
(<1%)
(2%)
(2%)
(<1%)
(<1%)
(<1%)

0
0
0
0
0
0
0
0
0
0
0
0
1 (<1%)
1 (<1%)
0

YM2008/00019/00
B2C109575

0
0
1 (<1%)
0
0
0
0
0
0
0
0
0
0
0
0

19
4
6
2
1
1
0
1
1
0

CONFIDENTIAL

179

DERMATOLOGICALS
Any medication
FLUTICASONE PROPIONATE
MOMETASONE FUROATE
BECLOMETASONE DIPROPIONATE
BENADRYL (NOS)
BUDESONIDE
RHINOCORT (NOS)
TRIAMCINOLONE ACETONIDE
HYDROCORTISONE
ETHINYLOESTRADIOL+CYPROTERONE
ACETATE
TOCOPHEROL
TRIAMCINOLONE
BETAMETHASONE DIPROPIONATE
BETAMETHASONE+CALCIPOTRIOL
CLINDAMYCIN PHOSPHATE+TRETINOIN
CLINDAMYCIN+BENZOYL PEROXIDE
DESOXIMETASONE
DIPHENHYDRAMINE
DIPHENHYDRAMINE HYDROCHLORIDE
FLUCONAZOLE
FLUTICASONE
HYALURONIC ACID
NYSTATIN
PREDNISOLONE
PROMETHAZINE

Protocol: B2C109575
Population: Intent-to-Treat

Page 12 of 18

Table 6.18
Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------RIFAXIMIN
0
0
0
1 (1%)
0
0
TERBINAFINE
0
0
0
1 (1%)
0
0

25
9
3
3
4
1
0
0
1
1

(25%)
(9%)
(3%)
(3%)
(4%)
(<1%)

2
0
0

(2%)

(<1%)
(<1%)

18
12
2
0
0
1
1
0
0
0

(18%)
(12%)
(2%)
(<1%)
(<1%)

12 (12%)
6 (6%)
1 (<1%)
1 (<1%)
0
0
0
0
0
0

18 (18%)
8 (8%)
0
2 (2%)
0
1 (1%)
1 (1%)
1 (1%)
1 (1%)
0

15
5
1
2
0
1
0
2
0
1

(15%)
(5%)
(<1%)
(2%)

(<1%)

16
2
4
1
2
0
1
0
1
1

0
0
1 (<1%)

0
0
0

(<1%)
(2%)

(16%)
(2%)
(4%)
(<1%)
(2%)
(<1%)
(<1%)
(<1%)

0
1 (<1%)
0

0
0
1

1 (<1%)

1 (<1%)

0
0
1 (<1%)
0
0
0
0

0
0
0
1 (<1%)
0
0
1 (<1%)

0
2 (2%)
1 (<1%)
0
0
0
0

0
0
0
0
1
0
0

2 (2%)
0
0
0
0
1 (<1%)
0

0
0
0
0
0
0
0

(1%)

(1%)

Note: A medication may be included in more than one ATC Level category and appear more than once.

YM2008/00019/00
B2C109575

1 (<1%)
2 (2%)
0

CONFIDENTIAL

180

GENITO URINARY SYSTEM AND SEX


HORMONES
Any medication
IBUPROFEN
ETHINYLOESTRADIOL+LEVONORGESTREL
ETHINYLOESTRADIOL+DROSPIRENONE
ETHINYLOESTRADIOL+NORGESTIMATE
NAPROXEN SODIUM
ESTRADIOL
ESTROGENS CONJUGATED
ETHINYLOESTRADIOL+DESOGESTREL
ETHINYLOESTRADIOL+NORETHISTERONE
ACETATE
MEDROXYPROGESTERONE ACETATE
NAPROXEN
ACETYLSALICYLIC
ACID+CAFFEINE+CINNAMEDRINE
HYDROCHLORIDE
ETHINYLOESTRADIOL+CYPROTERONE
ACETATE
ETHINYLOESTRADIOL+GESTODENE
ETHINYLOESTRADIOL+NORETHISTERONE
LEVONORGESTREL
CYPROTERONE ACETATE
DESOGESTREL
ESTRADIOL VALERATE
ESTRADIOL+DYDROGESTERONE

Protocol: B2C109575
Population: Intent-to-Treat

Page 13 of 18

Table 6.18
Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment

17 (17%)
9 (9%)
3 (3%)
2 (2%)
0
1 (<1%)
1 (<1%)
0
0
0

20
12
4
1
1
1
1
2
0
1

(20%)
(12%)
(4%)
(<1%)
(<1%)
(<1%)
(<1%)
(2%)
(<1%)

12
6
2
0
1
0
1
1
0
1

(12%)
(6%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)

18 (18%)
8 (8%)
5 (5%)
0
1 (1%)
1 (1%)
0
0
0
0

16 (16%)
5 (5%)
6 (6%)
0
0
1 (<1%)
0
0
1 (<1%)
0

Note: A medication may be included in more than one ATC Level category and appear more than once.

12
2
8
1
1
0
0
0
1
0

(12%)
(2%)
(8%)
(<1%)
(<1%)

(<1%)

YM2008/00019/00
B2C109575

MUSCULO-SKELETAL SYSTEM
Any medication
IBUPROFEN
ACETYLSALICYLIC ACID
ALENDRONATE SODIUM
DICLOFENAC
NAPROXEN SODIUM
DICLOFENAC SODIUM
NAPROXEN
ALLOPURINOL
CHONDROITIN+GLUCOSAMINE

CONFIDENTIAL

181

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------ESTRADIOL
1 (<1%)
0
0
0
0
0
VALERATE+MEDROXYPROGESTERONE
ACETATE
ESTROGEN NOS
0
0
1 (<1%)
0
0
0
ESTROGENS
1 (<1%)
0
0
0
0
0
CONJUGATED+MEDROXYPROGESTERONE
ACETATE
ETHINYLOESTRADIOL+ETONOGESTREL
0
0
0
0
0
1 (<1%)
ETHINYLOESTRADIOL+FERROUS
0
0
0
1 (1%)
0
0
FUMARATE+NORETHISTERONE ACETATE
IBUPROFEN LYSINATE
0
0
0
0
1 (<1%)
0
METHYLTESTOSTERONE
0
0
0
0
1 (<1%)
0
MISOPROSTOL
0
0
0
0
0
1 (<1%)
NORETHISTERONE ACETATE+ESTRADIOL
0
0
0
1 (1%)
0
0
NYSTATIN
0
0
0
0
0
1 (<1%)
PROGESTERONE
0
0
1 (<1%)
0
0
0
SERENOA REPENS
0
0
0
0
0
1 (<1%)
TAMSULOSIN
0
0
0
1 (1%)
0
0
TAMSULOSIN HYDROCHLORIDE
0
0
0
1 (1%)
0
0
TESTOSTERONE
0
0
1 (<1%)
0
0
0

Protocol: B2C109575
Population: Intent-to-Treat

Page 14 of 18

Table 6.18
Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment

10 (10%)
4 (4%)
1 (<1%)
2 (2%)
0
0
0

9
3
1
1
1
1
2

(9%)
(3%)
(<1%)
(<1%)
(<1%)
(<1%)
(2%)

9 (9%)
3 (3%)
2 (2%)
1 (<1%)
2 (2%)
1 (<1%)
0

7
5
0
2
0
0
0

(7%)
(5%)
(2%)

3 (3%)
1 (<1%)
1 (<1%)
0
0
1 (<1%)
0

Note: A medication may be included in more than one ATC Level category and appear more than once.

8 (8%)
4 (4%)
2 (2%)
1 (<1%)
1 (<1%)
0
0

YM2008/00019/00
B2C109575

SYSTEMIC HORMONAL PREPARATIONS,


EXCL. SEX HORMONES AND INSULINS
Any medication
LEVOTHYROXINE SODIUM
BUDESONIDE
TRIAMCINOLONE ACETONIDE
LEVOTHYROXINE
HYDROCORTISONE
TRIAMCINOLONE

CONFIDENTIAL

182

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------KETOROLAC TROMETAMOL
0
0
1 (<1%)
1 (1%)
0
0
CAPSAICIN+DIPROPYLENE GLYCOL
0
0
0
0
0
1 (<1%)
SALICYLATE
CELECOXIB
0
0
0
1 (1%)
0
0
CHONDROITIN SULFATE SODIUM
0
0
0
1 (1%)
0
0
COLCHICUM AUTUMNALE
0
1 (<1%)
0
0
0
0
COLECALCIFEROL+ALENDRONIC ACID
1 (<1%)
0
0
0
0
0
CYCLOBENZAPRINE HYDROCHLORIDE
0
0
0
0
1 (<1%)
0
HYALURONIC ACID
0
0
1 (<1%)
0
0
0
HYDROXYCHLOROQUINE SULFATE
1 (<1%)
0
0
0
0
0
IBUPROFEN LYSINATE
0
0
0
0
1 (<1%)
0
INDOMETACIN
0
1 (<1%)
0
0
0
0
KETOPROFEN
0
0
1 (<1%)
0
0
0
MEFENAMIC ACID
0
0
0
0
1 (<1%)
0
MELOXICAM
0
0
0
0
1 (<1%)
0
METHYL
0
0
1 (<1%)
0
0
0
SALICYLATE+LEVOMENTHOL+EUCALYPTUS
GLOBULUS OIL
NABUMETONE
0
0
0
0
1 (<1%)
0
ORPHENADRINE CITRATE
1 (<1%)
0
0
0
0
0
PIROXICAM
0
0
1 (<1%)
0
0
0
TROLAMINE SALICYLATE
0
0
0
1 (1%)
0
0

Protocol: B2C109575
Population: Intent-to-Treat

Page 15 of 18

Table 6.18
Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------BETAMETHASONE DIPROPIONATE
1 (<1%)
0
0
0
0
0
LIOTHYRONINE
0
0
1 (<1%)
0
0
0
LIOTHYRONINE SODIUM
0
0
1 (<1%)
0
0
0
POTASSIUM IODIDE
1 (<1%)
0
0
0
0
0
PREDNISOLONE
0
0
0
0
0
1 (<1%)
PREDNISONE
1 (<1%)
0
0
0
0
0
THYROID
0
0
1 (<1%)
0
0
0
6 (6%)
4 (4%)
1 (<1%)
1 (<1%)
0
0
0
0
0
0
1 (<1%)
0
0
0

5
2
1
1
1
0
0
0
0
0
0
0
0
1

(5%)
(2%)
(<1%)
(<1%)
(<1%)

SENSORY ORGANS
Any medication
TRIAMCINOLONE ACETONIDE
DICLOFENAC
DICLOFENAC SODIUM
HYDROCORTISONE
ACETYLCYSTEINE
EPINEPHRINE

8 (8%)
2 (2%)
0
1 (<1%)
0
1 (<1%)
1 (<1%)

8
1
1
1
1
0
0

8
1
1
1
1
1
1

(8%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)

(8%)
(<1%)
(<1%)
(<1%)
(<1%)

(<1%)

10 (10%)
5 (5%)
1 (1%)
0
0
1 (1%)
0
1 (1%)
0
0
0
1 (1%)
1 (1%)
0
7
2
1
0
0
0
0

(7%)
(2%)
(1%)

8 (8%)
6 (6%)
0
0
0
0
1 (<1%)
0
0
1 (<1%)
0
0
0
0

9 (9%)
8 (8%)
0
0
0
1 (<1%)
0
0
0
0
0
0
0
0

CONFIDENTIAL

5 (5%)
3 (3%)
0
0
1 (<1%)
0
0
0
1 (<1%)
0
0
0
0
0

1 (<1%)
0
0
0
1 (<1%)
0
0

3 (3%)
1 (<1%)
1 (<1%)
0
0
0
0

YM2008/00019/00
B2C109575

183

BLOOD AND BLOOD FORMING ORGANS


Any medication
ACETYLSALICYLIC ACID
FOLIC ACID
CYANOCOBALAMIN
EPINEPHRINE
FERROUS SULPHATE
CALCIUM CHLORIDE
CLOPIDOGREL BISULFATE
FERROUS GLYCINE SULFATE
IRON
LYSINE
PENTOSAN POLYSULFATE SODIUM
PHENPROCOUMON
POTASSIUM NOS

Note: A medication may be included in more than one ATC Level category and appear more than once.

Protocol: B2C109575
Population: Intent-to-Treat

Page 16 of 18

Table 6.18
Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment

184

3 (3%)
1 (<1%)
0
0
2 (2%)
0

4 (4%)
2 (2%)
1 (<1%)
0
1 (<1%)
0

2
2
0
0
0
0

(2%)
(2%)

2
0
1
1
0
0

(2%)

VARIOUS
Any medication
ALLERGENS (NOS)
LINUM USITATISSIMUM OIL
ACETYLCYSTEINE
CHONDROITIN+GLUCOSAMINE
ALLIUM SATIVUM

4 (4%)
0
1 (<1%)
1 (<1%)
0
0

2 (2%)
1 (<1%)
0
0
1 (<1%)
0

2 (2%)
0
1 (<1%)
1 (<1%)
1 (<1%)
0

3
1
0
0
0
1

(3%)
(1%)

(1%)
(1%)

(1%)

2 (2%)
0
0
2 (2%)
0
1 (<1%)

3 (3%)
2 (2%)
1 (<1%)
0
0
0

2 (2%)
0
1 (<1%)
0
0
0

2 (2%)
1 (<1%)
0
0
0
0

Note: A medication may be included in more than one ATC Level category and appear more than once.

YM2008/00019/00
B2C109575

ANTINEOPLASTIC AND IMMUNOMODULATING


AGENTS
Any medication
IMMUNOTHERAPY{NOS}
ESTRADIOL
ESTROGENS CONJUGATED
MEDROXYPROGESTERONE ACETATE
ESTRADIOL VALERATE

CONFIDENTIAL

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------KETOROLAC TROMETAMOL
0
0
1 (<1%)
1 (1%)
0
0
OLOPATADINE HYDROCHLORIDE
0
1 (<1%)
0
1 (1%)
0
0
TRIAMCINOLONE
0
2 (2%)
0
0
0
0
ACETAZOLAMIDE
0
0
0
1 (1%)
0
0
CLONIDINE HYDROCHLORIDE
1 (<1%)
0
0
0
0
0
HYALURONIC ACID
0
0
1 (<1%)
0
0
0
INDOMETACIN
0
1 (<1%)
0
0
0
0
OXYMETAZOLINE HYDROCHLORIDE
1 (<1%)
0
0
0
0
0
PIROXICAM
0
0
1 (<1%)
0
0
0
POTASSIUM IODIDE
1 (<1%)
0
0
0
0
0
PREDNISOLONE
0
0
0
0
0
1 (<1%)
XYLOMETAZOLINE HYDROCHLORIDE
0
0
0
1 (1%)
0
0

Protocol: B2C109575
Population: Intent-to-Treat

Page 17 of 18

Table 6.18
Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment

1 (<1%)
0
1 (<1%)
0
0
0
0
0

0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0

3
0
0
0
0
1
1
1

ANTIPARASITIC PRODUCTS,
INSECTICIDES AND REPELLENTS
Any medication
HYDROXYCHLOROQUINE SULFATE

1 (<1%)
1 (<1%)

0
0

0
0

0
0

(3%)

(1%)
(1%)
(1%)

1 (<1%)
1 (<1%)
0
0
0
0
0
0

1 (<1%)
0
0
1 (<1%)
1 (<1%)
0
0
0

1 (<1%)
0

0
0

Note: A medication may be included in more than one ATC Level category and appear more than once.

YM2008/00019/00
B2C109575

ANTIINFECTIVES FOR SYSTEMIC USE


Any medication
AMOXICILLIN
CEFALEXIN
CEFUROXIME
CLARITHROMYCIN
FLUCONAZOLE
RIFAMPICIN
SULFAMETHOXAZOLE+TRIMETHOPRIM

CONFIDENTIAL

185

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------ALOE
0
0
0
1 (1%)
0
0
BARBADENSIS+GINSENG+CAMPHOR+LEVOM
ENTHOL+HAMAMELIS
VIRGINIANA+ANGELICA+LAVENDAR OIL
AMBIGUOUS MEDICATION
0
0
0
0
0
1 (<1%)
CHONDROITIN SULFATE SODIUM
0
0
0
1 (1%)
0
0
CINNAMOMUM VERUM
0
0
0
1 (1%)
0
0
DOCOSAHEXANOIC
0
0
0
0
1 (<1%)
0
ACID+EICOSAPENTAENOIC
ACID+ALPHA-LINOLENIC ACID+MOROTIC
ACID+HENEICOSAPENTAENIC
ACID+CLUPANODONIC
ACID+EICOSATETRAENOIC ACID
LINUM USITATISSIMUM
0
0
0
0
1 (<1%)
0
MEDICATION UNKNOWN
0
0
0
0
1 (<1%)
0
POTASSIUM IODIDE
1 (<1%)
0
0
0
0
0
VITIS VINIFERA
1 (<1%)
0
0
0
0
0

Protocol: B2C109575
Population: Intent-to-Treat

Page 18 of 18

Table 6.18
Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------PERMETHRIN
0
0
0
0
1 (<1%)
0

CONFIDENTIAL

186

YM2008/00019/00
B2C109575

Note: A medication may be included in more than one ATC Level category and appear more than once.

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 20

Table 6.19
Summary of Non-Asthma Concomitant Medications Taken During Treatment

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Any medication
72 (71%)
64 (63%)
58 (57%)
72 (72%)
63 (62%)
67 (66%)
34 (33%)
17 (17%)
11 (11%)
4 (4%)
0

(37%)
(16%)
(16%)
(6%)
(<1%)

29 (29%)
16 (16%)
9 (9%)
2 (2%)
0

0
2 (2%)
1 (<1%)

1 (<1%)
0
1 (<1%)

1 (<1%)
0
1 (<1%)

1
1
1

1
0
1
0
1
0
0
0
1
0

1
0
0
1
1
1
1
1
0
0

0
0
0
1 (<1%)
0
1 (<1%)
0
0
1 (<1%)
0

2
1
3
1
0
0
0
0
1
1

(<1%)
(<1%)
(<1%)

(<1%)

37
16
16
6
1

(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)

32 (32%)
10 (10%)
7 (7%)
3 (3%)
3 (3%)

34 (34%)
17 (17%)
11 (11%)
6 (6%)
0

32 (31%)
13 (13%)
7 (7%)
8 (8%)
0

(1%)
(1%)
(1%)

1 (<1%)
0
0

0
1 (<1%)
0

(2%)
(1%)
(3%)
(1%)

0
0
0
0
0
1
1
1
0
1

0
3
0
1
1
0
1
1
0
0

(1%)
(1%)

(<1%)
(<1%)
(<1%)
(<1%)

(3%)
(<1%)
(<1%)
(<1%)
(<1%)

1 (<1%)

1 (<1%)

0
1 (<1%)
0

0
0
0

1 (<1%)
0
1 (<1%)

0
0
1

1 (<1%)
0
0

0
1 (<1%)
0

Note: A medication may be included in more than one ATC Level category and appear more than once.

YM2008/00019/00
B2C109575

(1%)

CONFIDENTIAL

187

NERVOUS SYSTEM
Any medication
PARACETAMOL
IBUPROFEN
ACETYLSALICYLIC ACID
ACETYLSALICYLIC
ACID+PARACETAMOL+CAFFEINE
ALPRAZOLAM
CLONAZEPAM
DIPHENHYDRAMINE
HYDROCHLORIDE+PARACETAMOL
ESCITALOPRAM OXALATE
EXCEDRIN (NOS)
FLUOXETINE HYDROCHLORIDE
SERTRALINE HYDROCHLORIDE
BUPROPION HYDROCHLORIDE
CITALOPRAM HYDROBROMIDE
DIAZEPAM
HYDROXYZINE
SUMATRIPTAN
ACETYLSALICYLIC
ACID+CAFFEINE+CINNAMEDRINE
HYDROCHLORIDE
AMFETAMINE SULFATE+AMFETAMINE
ASPARTATE+DEXAMFETAMINE
SULFATE+DEXTROAMPHETAMINE
SACCHARATE
CYCLOBENZAPRINE HYDROCHLORIDE
ERGOTAMINE TARTRATE+CAFFEINE
KETOROLAC TROMETAMOL

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 20

Table 6.19
Summary of Non-Asthma Concomitant Medications Taken During Treatment

YM2008/00019/00
B2C109575

Note: A medication may be included in more than one ATC Level category and appear more than once.

CONFIDENTIAL

188

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------METAMIZOLE SODIUM
0
0
1 (<1%)
1 (1%)
0
0
MODAFINIL
1 (<1%)
0
0
0
0
1 (<1%)
PARACETAMOL+HYDROCODONE
0
1 (<1%)
1 (<1%)
0
0
0
BITARTRATE
PREGABALIN
1 (<1%)
0
0
1 (1%)
0
0
PROCAINE HYDROCHLORIDE
0
1 (<1%)
1 (<1%)
0
0
0
RIZATRIPTAN BENZOATE
0
0
1 (<1%)
0
0
1 (<1%)
TRAMADOL
0
0
1 (<1%)
0
1 (<1%)
0
TRAZODONE
0
1 (<1%)
0
1 (1%)
0
0
ACETYLSALICYLIC ACID+CALCIUM
0
0
1 (<1%)
0
0
0
CARBONATE
ACETYLSALICYLIC ACID+PARACETAMOL
0
0
0
1 (1%)
0
0
ACETYLSALICYLIC ACID+SODIUM
0
0
0
1 (1%)
0
0
BICARBONATE+CITRIC ACID
ACETYLSALICYLIC
0
0
0
1 (1%)
0
0
ACID+CAFFEINE+SALICYLAMIDE
ACETYLSALICYLIC
0
0
0
0
0
1 (<1%)
ACID+PHENACETIN+CAFFEINE+CITRIC
ACID+THEOBROMA CACAO
CAFFEINE
1 (<1%)
0
0
0
0
0
CHOLINE SALICYLATE
0
0
1 (<1%)
0
0
0
CLONIDINE HYDROCHLORIDE
1 (<1%)
0
0
0
0
0
DEXTROPROPOXYPHENE
1 (<1%)
0
0
0
0
0
HYDROCHLORIDE+PARACETAMOL
DEXTROPROPOXYPHENE
0
0
1 (<1%)
0
0
0
NAPSILATE+PARACETAMOL
EPINEPHRINE+ARTICAINE
0
0
0
0
1 (<1%)
0
HYDROCHLORIDE
ERGOTAMINE TARTRATE
0
0
0
0
0
1 (<1%)
ERGOTAMINE TARTRATE+METAMIZOLE
0
0
0
0
1 (<1%)
0
SODIUM+CAFFEINE+CHLORPHENAMINE
MALEATE

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 20

Table 6.19
Summary of Non-Asthma Concomitant Medications Taken During Treatment

YM2008/00019/00
B2C109575

Note: A medication may be included in more than one ATC Level category and appear more than once.

CONFIDENTIAL

189

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------FIORINAL NOS
0
1 (<1%)
0
0
0
0
FLUNARIZINE
0
0
0
0
1 (<1%)
0
GABAPENTIN
0
0
0
0
1 (<1%)
0
HYDROCODONE
0
0
0
0
1 (<1%)
0
IBUPROFEN LYSINATE
0
0
0
0
1 (<1%)
0
LIDOCAINE
0
1 (<1%)
0
0
0
0
LORAZEPAM
0
0
1 (<1%)
0
0
0
MED-LEMON (NOS)
1 (<1%)
0
0
0
0
0
MEFENAMIC ACID
0
0
0
0
1 (<1%)
0
METHADONE
0
1 (<1%)
0
0
0
0
METHYLPHENIDATE HYDROCHLORIDE
0
0
0
1 (1%)
0
0
MIDAZOLAM MALEATE
0
0
0
0
0
1 (<1%)
MORPHINE
0
1 (<1%)
0
0
0
0
NARATRIPTAN HYDROCHLORIDE
1 (<1%)
0
0
0
0
0
OXYCODONE
0
1 (<1%)
0
0
0
0
OXYCODONE HYDROCHLORIDE
0
0
0
0
1 (<1%)
0
PARACETAMOL+CAFFEINE+BUTALBITAL
0
0
0
0
1 (<1%)
0
PARACETAMOL+CAFFEINE+MEPYRAMINE
0
1 (<1%)
0
0
0
0
MALEATE
PARACETAMOL+CHLORPHENAMINE
0
0
0
0
0
1 (<1%)
MALEATE+PHENYLEPHRINE
HYDROCHLORIDE
PAROXETINE HYDROCHLORIDE
0
0
1 (<1%)
0
0
0
PROMETHAZINE
0
0
1 (<1%)
0
0
0
SERTRALINE
1 (<1%)
0
0
0
0
0
TOPIRAMATE
0
0
0
1 (1%)
0
0
VENLAFAXINE HYDROCHLORIDE
0
0
0
0
1 (<1%)
0
ZOLMITRIPTAN
1 (<1%)
0
0
0
0
0
ZOLPIDEM
0
0
1 (<1%)
0
0
0
ZOLPIDEM TARTRATE
0
0
0
1 (1%)
0
0
ZOPICLONE
0
0
0
1 (1%)
0
0

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 20

Table 6.19
Summary of Non-Asthma Concomitant Medications Taken During Treatment

YM2008/00019/00
B2C109575

Note: A medication may be included in more than one ATC Level category and appear more than once.

CONFIDENTIAL

190

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------RESPIRATORY SYSTEM
Any medication
35 (34%)
29 (29%)
22 (22%)
32 (32%)
24 (24%)
28 (27%)
FLUTICASONE PROPIONATE
4 (4%)
4 (4%)
11 (11%)
6 (6%)
4 (4%)
3 (3%)
MOMETASONE FUROATE
5 (5%)
6 (6%)
1 (<1%)
4 (4%)
3 (3%)
4 (4%)
LORATADINE
2 (2%)
2 (2%)
3 (3%)
7 (7%)
0
2 (2%)
BENADRYL (NOS)
2 (2%)
1 (<1%)
3 (3%)
0
1 (<1%)
3 (3%)
BECLOMETASONE DIPROPIONATE
2 (2%)
2 (2%)
1 (<1%)
1 (1%)
2 (2%)
1 (<1%)
PHENIRAMINE
2 (2%)
1 (<1%)
2 (2%)
1 (1%)
0
2 (2%)
PSEUDOEPHEDRINE HYDROCHLORIDE
1 (<1%)
2 (2%)
1 (<1%)
0
0
4 (4%)
BUDESONIDE
1 (<1%)
1 (<1%)
2 (2%)
0
1 (<1%)
2 (2%)
RHINOCORT (NOS)
0
0
1 (<1%)
4 (4%)
1 (<1%)
1 (<1%)
TRIAMCINOLONE ACETONIDE
2 (2%)
1 (<1%)
1 (<1%)
2 (2%)
0
1 (<1%)
FLUTICASONE FUROATE
1 (<1%)
3 (3%)
1 (<1%)
1 (1%)
0
0
AZELASTINE HYDROCHLORIDE
2 (2%)
2 (2%)
0
0
1 (<1%)
0
CETIRIZINE HYDROCHLORIDE
1 (<1%)
2 (2%)
0
0
1 (<1%)
1 (<1%)
PSEUDOEPHEDRINE
0
1 (<1%)
1 (<1%)
2 (2%)
0
1 (<1%)
HYDROCHLORIDE+FEXOFENADINE
HYDROCHLORIDE
PSEUDOEPHEDRINE
1 (<1%)
0
0
0
1 (<1%)
3 (3%)
HYDROCHLORIDE+TRIPROLIDINE
HYDROCHLORIDE
BROMHEXINE
1 (<1%)
0
1 (<1%)
1 (1%)
0
1 (<1%)
COUGH COLD PREPARATIONS NOS
0
2 (2%)
0
1 (1%)
0
1 (<1%)
DIPHENHYDRAMINE
1 (<1%)
1 (<1%)
1 (<1%)
1 (1%)
0
0
HYDROCHLORIDE+PARACETAMOL
FEXOFENADINE HYDROCHLORIDE
1 (<1%)
1 (<1%)
0
0
1 (<1%)
1 (<1%)
GUAIFENESIN
0
1 (<1%)
1 (<1%)
1 (1%)
0
1 (<1%)
PARACETAMOL+DEXTROMETHORPHAN
1 (<1%)
1 (<1%)
1 (<1%)
0
1 (<1%)
0
HYDROBROMIDE+PSEUDOEPHEDRINE
HYDROCHLORIDE+DOXYLAMINE
SUCCINATE
CHLORPHENAMINE
0
1 (<1%)
1 (<1%)
0
1 (<1%)
0

Protocol: B2C109575
Population: Intent-to-Treat

Page 5 of 20

Table 6.19
Summary of Non-Asthma Concomitant Medications Taken During Treatment

YM2008/00019/00
B2C109575

Note: A medication may be included in more than one ATC Level category and appear more than once.

CONFIDENTIAL

191

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------CHLORPHENAMINE MALEATE
0
1 (<1%)
1 (<1%)
0
1 (<1%)
0
PARACETAMOL+CHLORPHENAMINE
0
0
0
2 (2%)
0
1 (<1%)
MALEATE+PSEUDOEPHEDRINE
HYDROCHLORIDE
TYLENOL SINUS (NOS)
0
0
1 (<1%)
1 (1%)
0
1 (<1%)
DESLORATADINE
1 (<1%)
0
0
0
1 (<1%)
0
DIMENHYDRINATE
1 (<1%)
0
0
0
1 (<1%)
0
EPINEPHRINE
1 (<1%)
0
1 (<1%)
0
0
0
FLUNISOLIDE
0
0
0
1 (1%)
1 (<1%)
0
GUAIFENESIN+DEXTROMETHORPHAN
1 (<1%)
0
0
0
0
1 (<1%)
HYDROBROMIDE+PSEUDOEPHEDRINE
HYDROCHLORIDE
GUAIFENESIN+PSEUDOEPHEDRINE
1 (<1%)
0
0
0
0
1 (<1%)
HYDROCHLORIDE
HYOSCINE
0
0
0
2 (2%)
0
0
METHONITRATE+CHLORPHENAMINE
MALEATE+PHENYLEPHRINE
HYDROCHLORIDE
LEVOMENTHOL+EUCALYPTUS GLOBULUS
2 (2%)
0
0
0
0
0
PARACETAMOL+DEXTROMETHORPHAN
0
1 (<1%)
0
0
1 (<1%)
0
HYDROBROMIDE+PSEUDOEPHEDRINE
HYDROCHLORIDE
PSEUDOEPHEDRINE
1 (<1%)
1 (<1%)
0
0
0
0
SULFATE+LORATADINE
TRIAMCINOLONE
0
2 (2%)
0
0
0
0
TYLENOL COLD NOS
0
1 (<1%)
0
0
1 (<1%)
0
XYLOMETAZOLINE HYDROCHLORIDE
0
1 (<1%)
0
1 (1%)
0
0
BENZALKONIUM
1 (<1%)
0
0
0
0
0
CHLORIDE+THYMOL+LEVOMENTHOL+EUCAL
YPTUS GLOBULUS OIL
BETAMETHASONE DIPROPIONATE
1 (<1%)
0
0
0
0
0

Protocol: B2C109575
Population: Intent-to-Treat

Page 6 of 20

Table 6.19
Summary of Non-Asthma Concomitant Medications Taken During Treatment

YM2008/00019/00
B2C109575

Note: A medication may be included in more than one ATC Level category and appear more than once.

CONFIDENTIAL

192

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------CARDIOSPERMUM+GALPHIMIA
0
0
0
0
1 (<1%)
0
GLAUCA+LUFFA OPERCULATA
CETIRIZINE
0
0
0
0
1 (<1%)
0
DEXAMETHASONE
0
0
0
1 (1%)
0
0
DEXTROMETHORPHAN
1 (<1%)
0
0
0
0
0
DIABETIC TUSSIN (NOS)
0
1 (<1%)
0
0
0
0
DICHLOROBENZYL
0
1 (<1%)
0
0
0
0
ALCOHOL+AMYLMETACRESOL
DIPHENHYDRAMINE
0
0
0
1 (1%)
0
0
EBASTINE
1 (<1%)
0
0
0
0
0
FLUTICASONE
0
1 (<1%)
0
0
0
0
GUAIFENESIN+DEXTROMETHORPHAN
0
1 (<1%)
0
0
0
0
HYDROCODONE
0
0
0
0
1 (<1%)
0
HYOSCINE
0
0
0
0
1 (<1%)
0
METHONITRATE+CHLORPHENAMINE
MALEATE+PSEUDOEPHEDRINE
HYDROCHLORIDE
LIDOCAINE
0
1 (<1%)
0
0
0
0
MED-LEMON (NOS)
1 (<1%)
0
0
0
0
0
MONTELUKAST SODIUM
1 (<1%)
0
0
0
0
0
NEOZEP NOS
0
0
0
0
1 (<1%)
0
PARACETAMOL+CHLORPHENAMINE+PHENYL
0
0
0
0
1 (<1%)
0
EPHRINE HYDROCHLORIDE
PARACETAMOL+CHLORPHENAMINE
0
0
0
0
0
1 (<1%)
MALEATE+PHENYLEPHRINE
HYDROCHLORIDE
POTASSIUM IODIDE
1 (<1%)
0
0
0
0
0
POTASSIUM
0
1 (<1%)
0
0
0
0
BICARBONATE+CAMPHOR+LEVOMENTHOL+A
MMONIUM CARBONATE
PROMETHAZINE
0
0
1 (<1%)
0
0
0

Protocol: B2C109575
Population: Intent-to-Treat

Page 7 of 20

Table 6.19
Summary of Non-Asthma Concomitant Medications Taken During Treatment

30
8
4
2
3
2
2
1
0
1
0
4
0
2
0
1

(29%)
(8%)
(4%)
(2%)
(3%)
(2%)
(2%)
(<1%)
(<1%)
(4%)
(2%)
(<1%)

25
5
6
3
0
2
1
0
1
1
1
0
0
1
1
2

(25%)
(5%)
(6%)
(3%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(2%)

21
5
2
3
2
1
0
0
3
2
1
0
1
1
0
0

(21%)
(5%)
(2%)
(3%)
(2%)
(<1%)
(3%)
(2%)
(<1%)
(<1%)
(<1%)

31 (31%)
7 (7%)
3 (3%)
2 (2%)
1 (1%)
1 (1%)
3 (3%)
1 (1%)
2 (2%)
0
1 (1%)
0
4 (4%)
2 (2%)
1 (1%)
0

28
5
6
0
3
2
1
4
1
1
2
2
1
0
1
1

(28%)
(5%)
(6%)
(3%)
(2%)
(<1%)
(4%)
(<1%)
(<1%)
(2%)
(2%)
(<1%)
(<1%)
(<1%)

Note: A medication may be included in more than one ATC Level category and appear more than once.

30
3
8
0
1
1
1
2
1
2
2
1
1
1
2
1

(29%)
(3%)
(8%)
(<1%)
(<1%)
(<1%)
(2%)
(<1%)
(2%)
(2%)
(<1%)
(<1%)
(<1%)
(2%)
(<1%)

YM2008/00019/00
B2C109575

ALIMENTARY TRACT AND METABOLISM


Any medication
VITAMINS NOS
ACETYLSALICYLIC ACID
CALCIUM CARBONATE
OMEPRAZOLE
BECLOMETASONE DIPROPIONATE
ESOMEPRAZOLE MAGNESIUM
LANSOPRAZOLE
RANITIDINE HYDROCHLORIDE
BUDESONIDE
METFORMIN
MINERALS NOS+VITAMINS NOS
RHINOCORT (NOS)
TRIAMCINOLONE ACETONIDE
ASCORBIC ACID
CALCIUM

CONFIDENTIAL

193

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------PSEUDOEPHEDRINE SULFATE+AZATADINE
0
0
0
0
0
1 (<1%)
MALEATE
PSEUDOEPHEDRINE+NAPROXEN
0
1 (<1%)
0
0
0
0
PSEUDOEPHEDRINE+TRIPROLIDINE
0
0
0
0
0
1 (<1%)
PSEUDOEPHEDRINE
0
0
0
1 (1%)
0
0
HYDROCHLORIDE+IBUPROFEN
ROBITUSSIN (NOS)
0
0
0
0
1 (<1%)
0
TETRYZOLINE HYDROCHLORIDE
0
1 (<1%)
0
0
0
0
THIETHYLPERAZINE
1 (<1%)
0
0
0
0
0
TOCOPHEROL+THYMOL+AZULENE+EUCALYP
1 (<1%)
0
0
0
0
0
TUS GLOBULUS OIL+OLEUM PINI
SYLVESTRIS+MENTHA PIPERATA OIL
VICKS VAPORUB NOS
1 (<1%)
0
0
0
0
0
ZIPEPROL HYDROCHLORIDE
0
0
1 (<1%)
0
0
0

Protocol: B2C109575
Population: Intent-to-Treat

Page 8 of 20

Table 6.19
Summary of Non-Asthma Concomitant Medications Taken During Treatment

YM2008/00019/00
B2C109575

Note: A medication may be included in more than one ATC Level category and appear more than once.

CONFIDENTIAL

194

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------VITAMIN D NOS
0
1 (<1%)
3 (3%)
0
0
1 (<1%)
LOPERAMIDE HYDROCHLORIDE
1 (<1%)
1 (<1%)
0
1 (1%)
0
1 (<1%)
DOCUSATE SODIUM
2 (2%)
0
0
0
0
1 (<1%)
HYDROCORTISONE
0
1 (<1%)
1 (<1%)
0
1 (<1%)
0
RABEPRAZOLE SODIUM
1 (<1%)
0
1 (<1%)
0
0
1 (<1%)
DIMENHYDRINATE
1 (<1%)
0
0
0
1 (<1%)
0
EPINEPHRINE
1 (<1%)
0
1 (<1%)
0
0
0
FAMOTIDINE
1 (<1%)
0
0
0
0
1 (<1%)
GLIBENCLAMIDE
0
1 (<1%)
1 (<1%)
0
0
0
GLIMEPIRIDE
0
0
0
1 (1%)
0
1 (<1%)
INSULIN ASPART
0
1 (<1%)
0
0
0
1 (<1%)
INSULIN GLARGINE
0
1 (<1%)
0
0
0
1 (<1%)
METFORMIN HYDROCHLORIDE
0
0
0
1 (1%)
0
1 (<1%)
PANTOPRAZOLE SODIUM
1 (<1%)
0
0
0
1 (<1%)
0
TOCOPHEROL
0
0
0
1 (1%)
1 (<1%)
0
TRIAMCINOLONE
0
2 (2%)
0
0
0
0
ACETYLSALICYLIC ACID+SODIUM
0
0
0
1 (1%)
0
0
BICARBONATE+CITRIC ACID
ACTIVATED CHARCOAL
1 (<1%)
0
0
0
0
0
ALUMINIUM HYDROXIDE+MAGNESIUM
0
0
0
0
0
1 (<1%)
HYDROXIDE+DIMETICONE, ACTIVATED
ANTACIL NOS
0
0
0
0
0
1 (<1%)
BACILLUS LICHENIFORMIS
1 (<1%)
0
0
0
0
0
BETAMETHASONE DIPROPIONATE
1 (<1%)
0
0
0
0
0
CALCIUM CARBONATE+COLECALCIFEROL
0
0
0
1 (1%)
0
0
CALCIUM D3 (NOS)
1 (<1%)
0
0
0
0
0
CALCIUM+MAGNESIUM
0
0
1 (<1%)
0
0
0
CAMOMILE
1 (<1%)
0
0
0
0
0
CAROTENOIDS
0
0
1 (<1%)
0
0
0
CINNAMOMUM VERUM
0
0
0
1 (1%)
0
0
DEXAMETHASONE
0
0
0
1 (1%)
0
0
DIMETICONE, ACTIVATED
0
0
0
0
1 (<1%)
0

Protocol: B2C109575
Population: Intent-to-Treat

Page 9 of 20

Table 6.19
Summary of Non-Asthma Concomitant Medications Taken During Treatment

YM2008/00019/00
B2C109575

Note: A medication may be included in more than one ATC Level category and appear more than once.

CONFIDENTIAL

195

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------ERGOCALCIFEROL+CALCIUM
0
0
0
1 (1%)
0
0
ESOMEPRAZOLE
0
1 (<1%)
0
0
0
0
GAVISCON NOS
0
0
0
1 (1%)
0
0
HYOSCINE BUTYLBROMIDE
0
0
1 (<1%)
0
0
0
INSULIN DETEMIR
0
1 (<1%)
0
0
0
0
INSULIN HUMAN INJECTION, ISOPHANE
0
0
1 (<1%)
0
0
0
INSULIN LISPRO
0
0
1 (<1%)
0
0
0
INSULIN NOS
1 (<1%)
0
0
0
0
0
ITOPRIDE HYDROCHLORIDE
0
0
0
0
0
1 (<1%)
LINUM USITATISSIMUM
0
0
0
0
1 (<1%)
0
MANNITOL
1 (<1%)
0
0
0
0
0
MESALAZINE
0
0
0
1 (1%)
0
0
METFORMIN
0
0
0
0
0
1 (<1%)
HYDROCHLORIDE+GLIBENCLAMIDE
METOCLOPRAMIDE HYDROCHLORIDE
0
0
0
0
1 (<1%)
0
METRONIDAZOLE
0
0
0
1 (1%)
0
0
PANTOPRAZOLE
0
0
0
0
0
1 (<1%)
PARGEVERINE HYDROCHLORIDE
0
0
0
0
0
1 (<1%)
PHLOROGLUCINOL+TRIMETHYLPHLOROGLU
1 (<1%)
0
0
0
0
0
CINOL
POTASSIUM NOS
0
0
1 (<1%)
0
0
0
PROMETHAZINE
0
0
1 (<1%)
0
0
0
RANITIDINE
0
0
0
1 (1%)
0
0
REPAGLINIDE
0
0
0
1 (1%)
0
0
RIFAXIMIN
0
0
0
1 (1%)
0
0
SENNA
1 (<1%)
0
0
0
0
0
SITAGLIPTIN
0
1 (<1%)
0
0
0
0
SODIUM
0
0
1 (<1%)
0
0
0
BICARBONATE+THIAMINE+CALCIUM
CARBONATE+AMYLASE+SCOPOLIA
CARNIOLICA+SYZYGIUM
AROMATICUM+FOENICULUM VULGARE OIL

Protocol: B2C109575
Population: Intent-to-Treat

Page 10 of 20

Table 6.19
Summary of Non-Asthma Concomitant Medications Taken During Treatment

196

23
2
2
1
1
3
1
1
1
0
0
1
0

(23%)
(2%)
(2%)
(<1%)
(<1%)
(3%)
(<1%)
(<1%)
(<1%)
(<1%)

0
0
1 (<1%)
1 (<1%)
0

24
0
4
2
2
1
1
0
1
0
1
0
1

(24%)

(21%)
(2%)
(<1%)
(<1%)

(<1%)

21
2
1
1
0
0
0
1
1
2
0
0
1

0
2 (2%)
1 (<1%)
1 (<1%)
0

1
1
1
1
2

(<1%)
(<1%)
(<1%)
(<1%)
(2%)

(4%)
(2%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)

(<1%)
(<1%)
(2%)
(<1%)

19 (19%)
3 (3%)
1 (1%)
3 (3%)
0
1 (1%)
0
3 (3%)
0
1 (1%)
0
1 (1%)
1 (1%)
1
1
1
1
0

(1%)
(1%)
(1%)
(1%)

21
3
2
1
2
2
4
1
1
1
4
0
0

(21%)
(3%)
(2%)
(<1%)
(2%)
(2%)
(4%)
(<1%)
(<1%)
(<1%)
(4%)

0
0
0
0
0

Note: A medication may be included in more than one ATC Level category and appear more than once.

16
1
1
2
2
0
0
0
1
1
0
2
1

(16%)
(<1%)
(<1%)
(2%)
(2%)

(<1%)
(<1%)
(2%)
(<1%)

2 (2%)
0
0
0
1 (<1%)

YM2008/00019/00
B2C109575

CARDIOVASCULAR SYSTEM
Any medication
ENALAPRIL
HYDROCHLOROTHIAZIDE
AMLODIPINE BESILATE
SIMVASTATIN
VERAPAMIL
AMLODIPINE
VERAPAMIL HYDROCHLORIDE
ENALAPRIL MALEATE
LISINOPRIL
PERINDOPRIL
ATORVASTATIN CALCIUM
HYDROCHLOROTHIAZIDE+LOSARTAN
POTASSIUM
INDAPAMIDE
IRBESARTAN
LOSARTAN POTASSIUM
VALSARTAN
FISH OIL

CONFIDENTIAL

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------THIAMINE
0
0
0
0
0
1 (<1%)
MONONITRATE+CYANOCOBALAMIN+PYRIDO
XINE
HYDROCHLORIDE+NICOTINAMIDE+TOCOPH
ERYL ACETATE+RIBOFLAVIN+CHOLINE
ALFOSCERATE
TRIMEBUTINE MALEATE
1 (<1%)
0
0
0
0
0
TRIMETHOBENZAMIDE
0
1 (<1%)
0
0
0
0
VITAMIN B NOS
0
1 (<1%)
0
0
0
0
VITAMIN B SUBSTANCES NOS
0
0
1 (<1%)
0
0
0
ZINC
0
1 (<1%)
0
0
0
0

Protocol: B2C109575
Population: Intent-to-Treat

Page 11 of 20

Table 6.19
Summary of Non-Asthma Concomitant Medications Taken During Treatment

YM2008/00019/00
B2C109575

Note: A medication may be included in more than one ATC Level category and appear more than once.

CONFIDENTIAL

197

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------FOSINOPRIL SODIUM
1 (<1%)
1 (<1%)
0
0
0
1 (<1%)
HYDROCORTISONE
0
1 (<1%)
1 (<1%)
0
1 (<1%)
0
LOSARTAN
1 (<1%)
0
0
0
2 (2%)
0
RAMIPRIL
1 (<1%)
2 (2%)
0
0
0
0
TELMISARTAN
0
1 (<1%)
1 (<1%)
0
0
1 (<1%)
CANDESARTAN CILEXETIL
0
1 (<1%)
0
0
1 (<1%)
0
DIOSMIN
1 (<1%)
0
0
0
1 (<1%)
0
EPINEPHRINE
1 (<1%)
0
1 (<1%)
0
0
0
FELODIPINE
1 (<1%)
1 (<1%)
0
0
0
0
HYDROCHLOROTHIAZIDE+VALSARTAN
0
0
1 (<1%)
0
0
1 (<1%)
MOXONIDINE
1 (<1%)
0
0
0
1 (<1%)
0
OLMESARTAN
0
0
0
1 (1%)
0
1 (<1%)
PROCAINE HYDROCHLORIDE
0
1 (<1%)
1 (<1%)
0
0
0
ATORVASTATIN
1 (<1%)
0
0
0
0
0
BETAMETHASONE DIPROPIONATE
1 (<1%)
0
0
0
0
0
CAPTOPRIL
1 (<1%)
0
0
0
0
0
CIPROFIBRATE
0
0
0
1 (1%)
0
0
CLONIDINE HYDROCHLORIDE
1 (<1%)
0
0
0
0
0
DEXAMETHASONE
0
0
0
1 (1%)
0
0
DILTIAZEM
0
0
0
1 (1%)
0
0
DIOSMIN+HESPERIDIN
0
1 (<1%)
0
0
0
0
DOXAZOSIN
1 (<1%)
0
0
0
0
0
FENOFIBRATE
0
0
1 (<1%)
0
0
0
FLUNARIZINE
0
0
0
0
1 (<1%)
0
FUROSEMIDE
0
0
0
0
0
1 (<1%)
HEPARIN SODIUM
0
1 (<1%)
0
0
0
0
HYDROCHLOROTHIAZIDE+AMILORIDE
0
0
1 (<1%)
0
0
0
HYDROCHLORIDE
HYDROCHLOROTHIAZIDE+CANDESARTAN
0
0
1 (<1%)
0
0
0
CILEXETIL
HYDROCHLOROTHIAZIDE+ENALAPRIL
1 (<1%)
0
0
0
0
0
HYDROCHLOROTHIAZIDE+RAMIPRIL
0
0
0
0
1 (<1%)
0

Protocol: B2C109575
Population: Intent-to-Treat

Page 12 of 20

Table 6.19
Summary of Non-Asthma Concomitant Medications Taken During Treatment

26
11
3
3
4
1
0
0
0
1

(25%)
(11%)
(3%)
(3%)
(4%)
(<1%)

(<1%)

22
16
2
0
0
1
2
1
0
0

(22%)
(16%)
(2%)
(<1%)
(2%)
(<1%)

16 (16%)
9 (9%)
1 (<1%)
1 (<1%)
0
0
2 (2%)
0
0
0

18 (18%)
7 (7%)
0
2 (2%)
0
1 (1%)
0
1 (1%)
1 (1%)
1 (1%)

20
11
1
2
0
1
0
0
2
0

(20%)
(11%)
(<1%)
(2%)
(<1%)
(2%)

Note: A medication may be included in more than one ATC Level category and appear more than once.

18
7
4
1
2
1
0
1
0
1

(18%)
(7%)
(4%)
(<1%)
(2%)
(<1%)
(<1%)
(<1%)

YM2008/00019/00
B2C109575

GENITO URINARY SYSTEM AND SEX


HORMONES
Any medication
IBUPROFEN
ETHINYLOESTRADIOL+LEVONORGESTREL
ETHINYLOESTRADIOL+DROSPIRENONE
ETHINYLOESTRADIOL+NORGESTIMATE
NAPROXEN SODIUM
NAPROXEN
ESTRADIOL
ESTROGENS CONJUGATED
ETHINYLOESTRADIOL+DESOGESTREL

CONFIDENTIAL

198

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------INDOMETACIN
0
1 (<1%)
0
0
0
0
ISOSORBIDE MONONITRATE
0
0
0
0
0
1 (<1%)
LIDOCAINE
0
1 (<1%)
0
0
0
0
LOVASTATIN
0
0
0
0
1 (<1%)
0
MOEXIPRIL
0
0
1 (<1%)
0
0
0
NICOTINIC ACID
0
0
0
0
0
1 (<1%)
NIFEDIPINE
0
1 (<1%)
0
0
0
0
OMEGA-3 MARINE TRIGLYCERIDES
0
0
0
0
0
1 (<1%)
PENTOSAN POLYSULFATE SODIUM
0
0
0
1 (1%)
0
0
QUINAPRIL HYDROCHLORIDE
0
1 (<1%)
0
0
0
0
ROSUVASTATIN CALCIUM
0
0
0
0
1 (<1%)
0
SIMVASTATIN+EZETIMIBE
0
0
1 (<1%)
0
0
0
SPIRONOLACTONE
1 (<1%)
0
0
0
0
0
SPIRONOLACTONE+ALTIZIDE
1 (<1%)
0
0
0
0
0
TOCOPHEROL+FISH OIL
0
1 (<1%)
0
0
0
0
TORASEMIDE
0
0
0
0
1 (<1%)
0
TRIAMTERENE+HYDROCHLOROTHIAZIDE
0
0
0
0
1 (<1%)
0
TRIMETAZIDINE HYDROCHLORIDE
1 (<1%)
0
0
0
0
0
UBIDECARENONE
0
0
1 (<1%)
0
0
0

Protocol: B2C109575
Population: Intent-to-Treat

Page 13 of 20

Table 6.19
Summary of Non-Asthma Concomitant Medications Taken During Treatment

YM2008/00019/00
B2C109575

Note: A medication may be included in more than one ATC Level category and appear more than once.

CONFIDENTIAL

199

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------ETHINYLOESTRADIOL+NORETHISTERONE
1 (<1%)
0
0
0
1 (<1%)
1 (<1%)
ACETATE
MEDROXYPROGESTERONE ACETATE
2 (2%)
1 (<1%)
0
0
0
0
ACETYLSALICYLIC
0
0
0
1 (1%)
1 (<1%)
0
ACID+CAFFEINE+CINNAMEDRINE
HYDROCHLORIDE
ETHINYLOESTRADIOL+CYPROTERONE
1 (<1%)
0
0
0
0
1 (<1%)
ACETATE
ETHINYLOESTRADIOL+GESTODENE
0
0
0
0
2 (2%)
0
ETHINYLOESTRADIOL+NORETHISTERONE
0
0
2 (2%)
0
0
0
CYPROTERONE ACETATE
0
1 (<1%)
0
0
0
0
DESOGESTREL
0
0
0
1 (1%)
0
0
ESTRADIOL VALERATE
0
0
0
0
1 (<1%)
0
ESTRADIOL+DYDROGESTERONE
0
1 (<1%)
0
0
0
0
ESTRADIOL
1 (<1%)
0
0
0
0
0
VALERATE+MEDROXYPROGESTERONE
ACETATE
ESTROGEN NOS
0
0
1 (<1%)
0
0
0
ESTROGENS
1 (<1%)
0
0
0
0
0
CONJUGATED+MEDROXYPROGESTERONE
ACETATE
ETHINYLOESTRADIOL+ETONOGESTREL
0
0
0
0
0
1 (<1%)
ETHINYLOESTRADIOL+FERROUS
0
0
0
1 (1%)
0
0
FUMARATE+NORETHISTERONE ACETATE
IBUPROFEN LYSINATE
0
0
0
0
1 (<1%)
0
LEVONORGESTREL
0
0
1 (<1%)
0
0
0
METHYLTESTOSTERONE
0
0
0
0
1 (<1%)
0
METRONIDAZOLE
0
0
0
1 (1%)
0
0
NORETHISTERONE ACETATE+ESTRADIOL
0
0
0
1 (1%)
0
0
PROGESTERONE
0
0
1 (<1%)
0
0
0
SERENOA REPENS
0
0
0
0
0
1 (<1%)
TAMSULOSIN
0
0
0
1 (1%)
0
0

Protocol: B2C109575
Population: Intent-to-Treat

Page 14 of 20

Table 6.19
Summary of Non-Asthma Concomitant Medications Taken During Treatment

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------TAMSULOSIN HYDROCHLORIDE
0
0
0
1 (1%)
0
0
TESTOSTERONE
0
0
1 (<1%)
0
0
0
20
11
4
1
1
2
0
1
0
0
0
0
0

(20%)
(11%)
(4%)
(<1%)
(<1%)
(2%)
(<1%)

(26%)
(16%)
(6%)
(<1%)
(<1%)
(<1%)
(2%)
(<1%)
(<1%)

0
0
0
1 (<1%)
0
1 (<1%)
0
0
0
1 (<1%)
0
0
0

17
9
2
1
0
0
2
1
0
1
1
1
0

(17%)
(9%)
(2%)
(<1%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)

0
1 (<1%)
0
0
0
0
1 (<1%)
0
0
0
1 (<1%)
0
0

15 (15%)
7 (7%)
3 (3%)
2 (2%)
1 (1%)
0
0
0
0
0
0
1 (1%)
0
1
0
1
0
0
0
0
0
0
0
0
0
0

(1%)
(1%)

23
11
6
1
1
0
0
0
1
0
1
0
0

(23%)
(11%)
(6%)
(<1%)
(<1%)

(<1%)
(<1%)

0
0
0
0
0
0
0
0
1 (<1%)
0
0
1 (<1%)
1 (<1%)

Note: A medication may be included in more than one ATC Level category and appear more than once.

16
7
8
1
1
1
0
0
1
0
0
0
1
0
0
0
0
0
0
0
0
0
0
0
0
0

(16%)
(7%)
(8%)
(<1%)
(<1%)
(<1%)
(<1%)

(<1%)

YM2008/00019/00
B2C109575

0
0
0
0
1 (<1%)
0
0
1 (<1%)
0
0
0
0
0

26
16
6
1
1
1
2
1
0
1
0
0
0

CONFIDENTIAL

200

MUSCULO-SKELETAL SYSTEM
Any medication
IBUPROFEN
ACETYLSALICYLIC ACID
DICLOFENAC
NAPROXEN SODIUM
ALENDRONATE SODIUM
NAPROXEN
DICLOFENAC SODIUM
ALLOPURINOL
CHONDROITIN+GLUCOSAMINE
CYCLOBENZAPRINE HYDROCHLORIDE
KETOROLAC TROMETAMOL
CAPSAICIN+DIPROPYLENE GLYCOL
SALICYLATE
CELECOXIB
CHLORZOXAZONE
CHONDROITIN SULFATE SODIUM
COLCHICUM AUTUMNALE
COLECALCIFEROL+ALENDRONIC ACID
GLUCOSAMINE SULFATE
HYALURONIC ACID
HYDROXYCHLOROQUINE SULFATE
IBUPROFEN LYSINATE
INDOMETACIN
KETOPROFEN
MEFENAMIC ACID
MELOXICAM

Protocol: B2C109575
Population: Intent-to-Treat

Page 15 of 20

Table 6.19
Summary of Non-Asthma Concomitant Medications Taken During Treatment

201

17 (17%)
4 (4%)
5 (5%)
2 (2%)
2 (2%)
1 (<1%)
0
2 (2%)
0
1 (<1%)

18
4
6
1
2
1
0
1
1
0

0
0
0
1 (<1%)
0
0
0
0
0
0

0
2
0
0
0
0
0
0
0
0

(18%)
(4%)
(6%)
(<1%)
(2%)
(<1%)
(<1%)
(<1%)

(2%)

19
11
1
3
1
2
1
1
1
0
0
0
0
0
0
0
0
0
0
0

(19%)
(11%)
(<1%)
(3%)
(<1%)
(2%)
(<1%)
(<1%)
(<1%)

22 (22%)
6 (6%)
4 (4%)
0
1 (1%)
0
4 (4%)
2 (2%)
0
0
1
0
0
0
1
1
1
1
1
1

(1%)

(1%)
(1%)
(1%)
(1%)
(1%)
(1%)

13
4
3
1
2
1
1
0
1
0

(13%)
(4%)
(3%)
(<1%)
(2%)
(<1%)
(<1%)
(<1%)

1 (<1%)
0
0
0
0
0
0
0
0
0

Note: A medication may be included in more than one ATC Level category and appear more than once.

17
3
4
3
1
2
1
1
0
1

(17%)
(3%)
(4%)
(3%)
(<1%)
(2%)
(<1%)
(<1%)
(<1%)

0
0
1 (<1%)
0
0
0
0
0
0
0

YM2008/00019/00
B2C109575

DERMATOLOGICALS
Any medication
FLUTICASONE PROPIONATE
MOMETASONE FUROATE
BENADRYL (NOS)
BECLOMETASONE DIPROPIONATE
BUDESONIDE
RHINOCORT (NOS)
TRIAMCINOLONE ACETONIDE
HYDROCORTISONE
ETHINYLOESTRADIOL+CYPROTERONE
ACETATE
TOCOPHEROL
TRIAMCINOLONE
ACYCLOVIR
BETAMETHASONE DIPROPIONATE
BETAMETHASONE+CALCIPOTRIOL
BUTOCONAZOLE NITRATE
CLINDAMYCIN PHOSPHATE+TRETINOIN
CLINDAMYCIN+BENZOYL PEROXIDE
DESOXIMETASONE
DEXAMETHASONE

CONFIDENTIAL

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------METHYL
0
0
1 (<1%)
0
0
0
SALICYLATE+LEVOMENTHOL+EUCALYPTUS
GLOBULUS OIL
NABUMETONE
0
0
0
0
1 (<1%)
0
PIROXICAM
0
0
1 (<1%)
0
0
0
PSEUDOEPHEDRINE+NAPROXEN
0
1 (<1%)
0
0
0
0
QUININE
0
0
0
0
0
1 (<1%)
RISEDRONATE SODIUM
0
0
0
0
1 (<1%)
0
TROLAMINE SALICYLATE
0
0
0
1 (1%)
0
0

Protocol: B2C109575
Population: Intent-to-Treat

Page 16 of 20

Table 6.19
Summary of Non-Asthma Concomitant Medications Taken During Treatment

7
4
0
0
1
0
0
0
1
1
1
0
0
0
1
0

(7%)
(4%)
(<1%)

(<1%)
(<1%)
(<1%)

(<1%)

8 (8%)
6 (6%)
1 (<1%)
1 (<1%)
0
0
0
0
0
0
0
0
1 (<1%)
0
0
0

5 (5%)
2 (2%)
1 (<1%)
1 (<1%)
1 (<1%)
0
0
0
0
0
0
0
0
0
0
0

9
3
1
0
0
1
0
1
0
0
0
1
0
0
0
1

(9%)
(3%)
(1%)
(1%)
(1%)

(1%)

(1%)

8 (8%)
6 (6%)
0
0
0
0
1 (<1%)
0
0
0
0
0
0
1 (<1%)
0
0

Note: A medication may be included in more than one ATC Level category and appear more than once.

9 (9%)
8 (8%)
0
0
0
1 (<1%)
0
0
0
0
0
0
0
0
0
0

YM2008/00019/00
B2C109575

BLOOD AND BLOOD FORMING ORGANS


Any medication
ACETYLSALICYLIC ACID
FOLIC ACID
CYANOCOBALAMIN
EPINEPHRINE
FERROUS SULPHATE
CALCIUM CHLORIDE
CLOPIDOGREL BISULFATE
ELECTROLYTES NOS
FERROUS GLYCINE SULFATE
GLUCOSE
GLYCINE
HEPARIN SODIUM
IRON
MANNITOL
PENTOSAN POLYSULFATE SODIUM

CONFIDENTIAL

202

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------DIPHENHYDRAMINE
0
0
0
1 (1%)
0
0
FLUCONAZOLE
0
0
0
1 (1%)
0
0
FLUTICASONE
0
1 (<1%)
0
0
0
0
HYALURONIC ACID
0
0
1 (<1%)
0
0
0
LIDOCAINE
0
1 (<1%)
0
0
0
0
METRONIDAZOLE
0
0
0
1 (1%)
0
0
PROMETHAZINE
0
0
1 (<1%)
0
0
0
RIFAXIMIN
0
0
0
1 (1%)
0
0
TERBINAFINE
0
0
0
1 (1%)
0
0
TOCOPHERYL
0
0
0
0
0
1 (<1%)
ACETATE+ALLANTOIN+HYALURONATE
SODIUM+TELMESTEINE+VITIS
VINIFERA+PIROCTONE
OLAMINE+BISABOLOL

Protocol: B2C109575
Population: Intent-to-Treat

Page 17 of 20

Table 6.19
Summary of Non-Asthma Concomitant Medications Taken During Treatment

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------PHENPROCOUMON
0
0
0
1 (1%)
0
0
POTASSIUM NOS
0
0
1 (<1%)
0
0
0

9
3
1
1
1
1
2
0
0
0
0
0
0

(9%)
(3%)
(<1%)
(<1%)
(<1%)
(<1%)
(2%)

SENSORY ORGANS
Any medication
DICLOFENAC
TRIAMCINOLONE ACETONIDE
DICLOFENAC SODIUM
HYDROCORTISONE
CIPROFLOXACIN
EPINEPHRINE
KETOROLAC TROMETAMOL
OLOPATADINE HYDROCHLORIDE
PROCAINE HYDROCHLORIDE
TRIAMCINOLONE
XYLOMETAZOLINE HYDROCHLORIDE

7 (7%)
1 (<1%)
2 (2%)
1 (<1%)
0
0
1 (<1%)
0
0
0
0
0

12
1
1
1
1
1
0
0
1
1
2
1

(12%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(2%)
(<1%)

10
4
2
1
2
1
0
0
0
1
1
0
1

(10%)
(4%)
(2%)
(<1%)
(2%)
(<1%)

8
1
1
1
1
0
1
1
1
1
0
0

(8%)
(<1%)
(<1%)
(<1%)
(<1%)

(<1%)
(<1%)
(<1%)

(<1%)
(<1%)
(<1%)
(<1%)

8
5
0
2
0
0
0
0
1
0
0
0
0

(8%)
(5%)

6
2
2
0
0
0
0
1
0
0
0
1

(6%)
(2%)
(2%)

(2%)

(1%)

(1%)

(1%)

3 (3%)
1 (<1%)
1 (<1%)
0
0
1 (<1%)
0
0
0
0
0
0
0

7 (7%)
4 (4%)
2 (2%)
1 (<1%)
1 (<1%)
0
0
0
0
0
0
0
0

3 (3%)
1 (<1%)
0
0
1 (<1%)
0
0
0
0
0
0
0

4 (4%)
1 (<1%)
1 (<1%)
0
0
1 (<1%)
0
0
0
0
0
0

Note: A medication may be included in more than one ATC Level category and appear more than once.

YM2008/00019/00
B2C109575

9 (9%)
4 (4%)
1 (<1%)
2 (2%)
0
0
0
1 (<1%)
0
0
0
1 (<1%)
0

CONFIDENTIAL

203

SYSTEMIC HORMONAL PREPARATIONS,


EXCL. SEX HORMONES AND INSULINS
Any medication
LEVOTHYROXINE SODIUM
BUDESONIDE
TRIAMCINOLONE ACETONIDE
LEVOTHYROXINE
HYDROCORTISONE
TRIAMCINOLONE
BETAMETHASONE DIPROPIONATE
DEXAMETHASONE
LIOTHYRONINE
LIOTHYRONINE SODIUM
POTASSIUM IODIDE
THYROID

Protocol: B2C109575
Population: Intent-to-Treat

Page 18 of 20

Table 6.19
Summary of Non-Asthma Concomitant Medications Taken During Treatment

204

4 (4%)
3 (3%)
0
0
0
1 (<1%)
0
0
0
0
0
0

2 (2%)
1 (<1%)
0
1 (<1%)
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0

ANTINEOPLASTIC AND IMMUNOMODULATING


AGENTS
Any medication
IMMUNOTHERAPY{NOS}
ESTRADIOL
ESTROGENS CONJUGATED

3 (3%)
1 (<1%)
0
0

4 (4%)
2 (2%)
1 (<1%)
0

2
2
0
0

(2%)
(2%)

4
0
0
0
0
0
1
0
1
0
1
1

(4%)

2
0
1
1

(2%)

(1%)
(1%)
(1%)
(1%)

(1%)
(1%)

2 (2%)
1 (<1%)
0
0
0
0
0
0
0
1 (<1%)
0
0

4 (4%)
0
2 (2%)
1 (<1%)
1 (<1%)
0
0
1 (<1%)
0
0
0
0

2
0
0
2

3 (3%)
2 (2%)
1 (<1%)
0

(2%)
(2%)

Note: A medication may be included in more than one ATC Level category and appear more than once.

YM2008/00019/00
B2C109575

ANTIINFECTIVES FOR SYSTEMIC USE


Any medication
AZITHROMYCIN
AMOXICILLIN
CIPROFLOXACIN
ACYCLOVIR
CEFALEXIN
FLUCONAZOLE
LEVOFLOXACIN
METRONIDAZOLE
MOXIFLOXACIN
RIFAMPICIN
SULFAMETHOXAZOLE+TRIMETHOPRIM

CONFIDENTIAL

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------ACYCLOVIR
0
0
0
0
0
1 (<1%)
CLONIDINE HYDROCHLORIDE
1 (<1%)
0
0
0
0
0
DEXAMETHASONE
0
0
0
1 (1%)
0
0
DEXAMETHASONE+CIPROFLOXACIN
0
0
0
0
1 (<1%)
0
HEPARIN SODIUM
0
1 (<1%)
0
0
0
0
HYALURONIC ACID
0
0
1 (<1%)
0
0
0
INDOMETACIN
0
1 (<1%)
0
0
0
0
LIDOCAINE
0
1 (<1%)
0
0
0
0
PIROXICAM
0
0
1 (<1%)
0
0
0
POTASSIUM IODIDE
1 (<1%)
0
0
0
0
0
TETRYZOLINE HYDROCHLORIDE
0
1 (<1%)
0
0
0
0

Protocol: B2C109575
Population: Intent-to-Treat

Page 19 of 20

Table 6.19
Summary of Non-Asthma Concomitant Medications Taken During Treatment

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------MEDROXYPROGESTERONE ACETATE
2 (2%)
1 (<1%)
0
0
0
0
ESTRADIOL VALERATE
0
0
0
0
1 (<1%)
0
3 (3%)
1 (<1%)
0
1 (<1%)
0
0

1 (<1%)
0
1 (<1%)
1 (<1%)
0
0

3
1
0
0
1
1

0
0

0
1 (<1%)

0
0

0
0

0
0
0

0
0
0

0
0
0

1
1
0

1 (<1%)
0
0
0
1 (<1%)
1 (<1%)

0
0
0
0
0
0

0
0
0
0
0
0

0
0
0
0
0
0

(3%)
(1%)
(1%)
(1%)

(1%)
(1%)

2 (2%)
0
1 (<1%)
0
0
0

3 (3%)
1 (<1%)
0
0
0
0

0
0

1 (<1%)
0

0
0
1 (<1%)

0
0
0

0
0
1 (<1%)
1 (<1%)
0
0

0
1 (<1%)
0
0
0
0

Note: A medication may be included in more than one ATC Level category and appear more than once.

YM2008/00019/00
B2C109575

4 (4%)
0
1 (<1%)
0
0
0

CONFIDENTIAL

205

VARIOUS
Any medication
ALLERGENS (NOS)
LINUM USITATISSIMUM OIL
CHONDROITIN+GLUCOSAMINE
ALLIUM SATIVUM
ALOE
BARBADENSIS+GINSENG+CAMPHOR+LEVOM
ENTHOL+HAMAMELIS
VIRGINIANA+ANGELICA+LAVENDAR OIL
AMBIGUOUS MEDICATION
ATROPA BELLADONNA+MERCURIC
CHLORIDE+EUPHRASIA OFFICINALIS
CHONDROITIN SULFATE SODIUM
CINNAMOMUM VERUM
DOCOSAHEXANOIC
ACID+EICOSAPENTAENOIC
ACID+ALPHA-LINOLENIC ACID+MOROTIC
ACID+HENEICOSAPENTAENIC
ACID+CLUPANODONIC
ACID+EICOSATETRAENOIC ACID
GLUCOSE
IOVERSOL
LINUM USITATISSIMUM
MEDICATION UNKNOWN
POTASSIUM IODIDE
VITIS VINIFERA

Protocol: B2C109575
Population: Intent-to-Treat

Page 20 of 20

Table 6.19
Summary of Non-Asthma Concomitant Medications Taken During Treatment

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------ANTIPARASITIC PRODUCTS,
INSECTICIDES AND REPELLENTS
Any medication
1 (<1%)
0
0
1 (1%)
0
1 (<1%)
HYDROXYCHLOROQUINE SULFATE
1 (<1%)
0
0
0
0
0
METRONIDAZOLE
0
0
0
1 (1%)
0
0
QUININE
0
0
0
0
0
1 (<1%)

CONFIDENTIAL

206

YM2008/00019/00
B2C109575

Note: A medication may be included in more than one ATC Level category and appear more than once.

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 16

Table 6.20
Summary of Non-Asthma Concomitant Medications Taken Post Treatment

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Any medication
68 (67%)
58 (57%)
51 (50%)
67 (67%)
58 (57%)
54 (53%)
(27%)
(8%)
(4%)
(2%)
(2%)
(3%)
(2%)
(<1%)
(<1%)
(4%)
(2%)
(<1%)
(2%)
(<1%)
(<1%)

(<1%)
(<1%)

22
5
4
2
2
0
1
1
0
1
0
1
0
1
1
2
1
0
1
0
0
1
0
1
1
0
0
0
0

(22%)
(5%)
(4%)
(2%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)

20
5
2
1
3
2
0
2
0
1
0
2
1
1
0
0
3
0
1
1
0
1
0
0
0
0
0
1
0

(20%)
(5%)
(2%)
(<1%)
(3%)
(2%)
(2%)
(<1%)
(2%)
(<1%)
(<1%)
(3%)
(<1%)
(<1%)
(<1%)

(<1%)

30 (30%)
7 (7%)
3 (3%)
1 (1%)
2 (2%)
1 (1%)
3 (3%)
0
1 (1%)
1 (1%)
0
2 (2%)
4 (4%)
2 (2%)
1 (1%)
0
0
0
0
0
0
0
1 (1%)
0
0
1 (1%)
0
0
1 (1%)

27
5
6
2
0
2
1
1
4
2
2
1
1
0
1
1
0
0
1
0
0
0
0
0
0
0
1
0
1

(27%)
(5%)
(6%)
(2%)
(2%)
(<1%)
(<1%)
(4%)
(2%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)

(<1%)
(<1%)

Note: A medication may be included in more than one ATC Level category and appear more than once.

26
3
7
1
0
1
1
2
1
2
1
1
1
1
2
1
1
1
0
0
1
0
1
1
1
1
0
0
0

(25%)
(3%)
(7%)
(<1%)
(<1%)
(<1%)
(2%)
(<1%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)

YM2008/00019/00
B2C109575

28
8
4
2
2
3
2
1
1
0
4
0
0
2
0
1
0
2
0
1
1
0
0
0
0
0
1
1
0

CONFIDENTIAL

207

ALIMENTARY TRACT AND METABOLISM


Any medication
VITAMINS NOS
ACETYLSALICYLIC ACID
BECLOMETASONE DIPROPIONATE
CALCIUM CARBONATE
OMEPRAZOLE
ESOMEPRAZOLE MAGNESIUM
BUDESONIDE
LANSOPRAZOLE
METFORMIN
MINERALS NOS+VITAMINS NOS
RANITIDINE HYDROCHLORIDE
RHINOCORT (NOS)
TRIAMCINOLONE ACETONIDE
ASCORBIC ACID
CALCIUM
VITAMIN D NOS
DOCUSATE SODIUM
HYDROCORTISONE
EPINEPHRINE
FAMOTIDINE
GLIBENCLAMIDE
GLIMEPIRIDE
INSULIN ASPART
INSULIN GLARGINE
METFORMIN HYDROCHLORIDE
PANTOPRAZOLE SODIUM
RABEPRAZOLE SODIUM
TOCOPHEROL

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 16

Table 6.20
Summary of Non-Asthma Concomitant Medications Taken Post Treatment

YM2008/00019/00
B2C109575

Note: A medication may be included in more than one ATC Level category and appear more than once.

CONFIDENTIAL

208

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------TRIAMCINOLONE
0
2 (2%)
0
0
0
0
BETAMETHASONE DIPROPIONATE
1 (<1%)
0
0
0
0
0
BISMUTH SUBSALICYLATE
1 (<1%)
0
0
0
0
0
CALCIUM CARBONATE+COLECALCIFEROL
0
0
0
1 (1%)
0
0
CALCIUM D3 (NOS)
1 (<1%)
0
0
0
0
0
CALCIUM+MAGNESIUM
0
0
1 (<1%)
0
0
0
CAROTENOIDS
0
0
1 (<1%)
0
0
0
CIMETIDINE
1 (<1%)
0
0
0
0
0
CINNAMOMUM VERUM
0
0
0
1 (1%)
0
0
DEXAMETHASONE
0
0
0
1 (1%)
0
0
ERGOCALCIFEROL+CALCIUM
0
0
0
1 (1%)
0
0
ESOMEPRAZOLE
0
1 (<1%)
0
0
0
0
GAVISCON NOS
0
0
0
1 (1%)
0
0
HYOSCINE BUTYLBROMIDE
0
0
1 (<1%)
0
0
0
INSULIN DETEMIR
0
1 (<1%)
0
0
0
0
INSULIN HUMAN INJECTION, ISOPHANE
0
0
1 (<1%)
0
0
0
INSULIN LISPRO
0
0
1 (<1%)
0
0
0
INSULIN NOS
1 (<1%)
0
0
0
0
0
LINUM USITATISSIMUM
0
0
0
0
1 (<1%)
0
MESALAZINE
0
0
0
1 (1%)
0
0
METFORMIN
0
0
0
0
0
1 (<1%)
HYDROCHLORIDE+GLIBENCLAMIDE
METOCLOPRAMIDE HYDROCHLORIDE
0
0
0
0
1 (<1%)
0
PANTOPRAZOLE
0
0
0
0
0
1 (<1%)
PHLOROGLUCINOL+TRIMETHYLPHLOROGLU
1 (<1%)
0
0
0
0
0
CINOL
POTASSIUM NOS
0
0
1 (<1%)
0
0
0
PROMETHAZINE
0
0
1 (<1%)
0
0
0
RANITIDINE
0
0
0
1 (1%)
0
0
REPAGLINIDE
0
0
0
1 (1%)
0
0
RIFAXIMIN
0
0
0
1 (1%)
0
0
SENNA
1 (<1%)
0
0
0
0
0

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 16

Table 6.20
Summary of Non-Asthma Concomitant Medications Taken Post Treatment

29
5
5
2
2
1
1
2
0
2
1
0

(28%)
(5%)
(5%)
(2%)
(2%)
(<1%)
(<1%)
(2%)

(2%)

(2%)
(<1%)

27
4
6
2
2
1
1
1
0
1
3
1

(27%)
(4%)
(6%)
(2%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)
(3%)
(<1%)

21
11
1
3
1
2
2
2
1
1
1
1

(2%)

(21%)
(11%)
(<1%)
(3%)
(<1%)
(2%)
(2%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)

29 (29%)
6 (6%)
4 (4%)
6 (6%)
1 (1%)
0
0
1 (1%)
4 (4%)
2 (2%)
1 (1%)
2 (2%)
0

18
4
3
0
2
1
1
0
1
0
0
1

(18%)
(4%)
(3%)

(<1%)

26
3
4
2
1
3
2
1
1
1
0
1

1 (<1%)

(2%)
(<1%)
(<1%)
(<1%)

Note: A medication may be included in more than one ATC Level category and appear more than once.

(25%)
(3%)
(4%)
(2%)
(<1%)
(3%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)

YM2008/00019/00
B2C109575

RESPIRATORY SYSTEM
Any medication
FLUTICASONE PROPIONATE
MOMETASONE FUROATE
LORATADINE
BECLOMETASONE DIPROPIONATE
BENADRYL (NOS)
BUDESONIDE
PHENIRAMINE
RHINOCORT (NOS)
TRIAMCINOLONE ACETONIDE
FLUTICASONE FUROATE
PSEUDOEPHEDRINE
HYDROCHLORIDE+FEXOFENADINE
HYDROCHLORIDE
AZELASTINE HYDROCHLORIDE

CONFIDENTIAL

209

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------SITAGLIPTIN
0
1 (<1%)
0
0
0
0
SODIUM
0
0
1 (<1%)
0
0
0
BICARBONATE+THIAMINE+CALCIUM
CARBONATE+AMYLASE+SCOPOLIA
CARNIOLICA+SYZYGIUM
AROMATICUM+FOENICULUM VULGARE OIL
THIAMINE
0
0
0
0
0
1 (<1%)
MONONITRATE+CYANOCOBALAMIN+PYRIDO
XINE
HYDROCHLORIDE+NICOTINAMIDE+TOCOPH
ERYL ACETATE+RIBOFLAVIN+CHOLINE
ALFOSCERATE
VITAMIN B NOS
0
1 (<1%)
0
0
0
0
VITAMIN B SUBSTANCES NOS
0
0
1 (<1%)
0
0
0
ZINC
0
1 (<1%)
0
0
0
0

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 16

Table 6.20
Summary of Non-Asthma Concomitant Medications Taken Post Treatment

YM2008/00019/00
B2C109575

Note: A medication may be included in more than one ATC Level category and appear more than once.

CONFIDENTIAL

210

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------FEXOFENADINE HYDROCHLORIDE
2 (2%)
1 (<1%)
0
0
1 (<1%)
1 (<1%)
PSEUDOEPHEDRINE HYDROCHLORIDE
0
0
2 (2%)
0
0
3 (3%)
BROMHEXINE
1 (<1%)
0
1 (<1%)
1 (1%)
0
1 (<1%)
CETIRIZINE HYDROCHLORIDE
1 (<1%)
1 (<1%)
0
0
1 (<1%)
1 (<1%)
COUGH COLD PREPARATIONS NOS
0
2 (2%)
0
1 (1%)
0
1 (<1%)
DIPHENHYDRAMINE
1 (<1%)
1 (<1%)
1 (<1%)
1 (1%)
0
0
HYDROCHLORIDE+PARACETAMOL
CHLORPHENAMINE MALEATE
0
1 (<1%)
1 (<1%)
0
1 (<1%)
0
DESLORATADINE
2 (2%)
0
0
0
1 (<1%)
0
CHLORPHENAMINE
0
1 (<1%)
0
0
1 (<1%)
0
EPINEPHRINE
1 (<1%)
0
1 (<1%)
0
0
0
GUAIFENESIN
0
0
1 (<1%)
0
0
1 (<1%)
GUAIFENESIN+PSEUDOEPHEDRINE
0
1 (<1%)
0
0
0
1 (<1%)
HYDROCHLORIDE
HYOSCINE
0
0
0
2 (2%)
0
0
METHONITRATE+CHLORPHENAMINE
MALEATE+PHENYLEPHRINE
HYDROCHLORIDE
PARACETAMOL+CHLORPHENAMINE
0
0
0
2 (2%)
0
0
MALEATE+PSEUDOEPHEDRINE
HYDROCHLORIDE
PSEUDOEPHEDRINE
1 (<1%)
1 (<1%)
0
0
0
0
SULFATE+LORATADINE
PSEUDOEPHEDRINE
0
0
0
0
0
2 (2%)
HYDROCHLORIDE+TRIPROLIDINE
HYDROCHLORIDE
TRIAMCINOLONE
0
2 (2%)
0
0
0
0
TYLENOL SINUS (NOS)
0
0
0
1 (1%)
0
1 (<1%)
BETAMETHASONE DIPROPIONATE
1 (<1%)
0
0
0
0
0
CETIRIZINE
0
0
0
0
1 (<1%)
0
DEXAMETHASONE
0
0
0
1 (1%)
0
0
DIPHENHYDRAMINE
0
0
0
1 (1%)
0
0

Protocol: B2C109575
Population: Intent-to-Treat

Page 5 of 16

Table 6.20
Summary of Non-Asthma Concomitant Medications Taken Post Treatment

26 (25%)
9 (9%)
9 (9%)
4 (4%)

22 (22%)
9 (9%)
7 (7%)
4 (4%)

19 (19%)
9 (9%)
8 (8%)
2 (2%)

26 (26%)
6 (6%)
6 (6%)
3 (3%)

23 (23%)
11 (11%)
4 (4%)
6 (6%)

Note: A medication may be included in more than one ATC Level category and appear more than once.

21 (21%)
8 (8%)
2 (2%)
7 (7%)

YM2008/00019/00
B2C109575

NERVOUS SYSTEM
Any medication
PARACETAMOL
IBUPROFEN
ACETYLSALICYLIC ACID

CONFIDENTIAL

211

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------EBASTINE
1 (<1%)
0
0
0
0
0
FLUNISOLIDE
0
0
0
0
1 (<1%)
0
FLUTICASONE
0
1 (<1%)
0
0
0
0
GUAIFENESIN+DEXTROMETHORPHAN
1 (<1%)
0
0
0
0
0
HYDROBROMIDE+PSEUDOEPHEDRINE
HYDROCHLORIDE
GUAIFENESIN+HYDROCODONE
0
0
1 (<1%)
0
0
0
BITARTRATE
HYDROCODONE
0
0
0
0
1 (<1%)
0
HYOSCINE
0
0
0
0
1 (<1%)
0
METHONITRATE+CHLORPHENAMINE
MALEATE+PSEUDOEPHEDRINE
HYDROCHLORIDE
MONTELUKAST SODIUM
1 (<1%)
0
0
0
0
0
PARACETAMOL+CHLORPHENAMINE+PHENYL
0
0
0
0
1 (<1%)
0
EPHRINE HYDROCHLORIDE
PARACETAMOL+DEXTROMETHORPHAN
0
0
0
0
0
1 (<1%)
HYDROBROMIDE+PSEUDOEPHEDRINE
HYDROCHLORIDE+DOXYLAMINE
SUCCINATE
POTASSIUM IODIDE
1 (<1%)
0
0
0
0
0
PROMETHAZINE
0
0
1 (<1%)
0
0
0
PSEUDOEPHEDRINE SULFATE+AZATADINE
0
0
0
0
0
1 (<1%)
MALEATE
PSEUDOEPHEDRINE+NAPROXEN
0
1 (<1%)
0
0
0
0
XYLOMETAZOLINE HYDROCHLORIDE
0
1 (<1%)
0
0
0
0

Protocol: B2C109575
Population: Intent-to-Treat

Page 6 of 16

Table 6.20
Summary of Non-Asthma Concomitant Medications Taken Post Treatment

YM2008/00019/00
B2C109575

Note: A medication may be included in more than one ATC Level category and appear more than once.

CONFIDENTIAL

212

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------ACETYLSALICYLIC
0
1 (<1%)
0
3 (3%)
0
0
ACID+PARACETAMOL+CAFFEINE
ALPRAZOLAM
0
1 (<1%)
1 (<1%)
1 (1%)
1 (<1%)
0
CLONAZEPAM
2 (2%)
0
0
1 (1%)
0
1 (<1%)
DIPHENHYDRAMINE
1 (<1%)
1 (<1%)
1 (<1%)
1 (1%)
0
0
HYDROCHLORIDE+PARACETAMOL
ESCITALOPRAM OXALATE
1 (<1%)
1 (<1%)
0
2 (2%)
0
0
FLUOXETINE HYDROCHLORIDE
1 (<1%)
0
0
3 (3%)
0
0
SERTRALINE HYDROCHLORIDE
0
1 (<1%)
1 (<1%)
1 (1%)
0
1 (<1%)
BUPROPION HYDROCHLORIDE
1 (<1%)
1 (<1%)
0
0
0
1 (<1%)
CITALOPRAM HYDROBROMIDE
0
1 (<1%)
1 (<1%)
0
1 (<1%)
0
EXCEDRIN (NOS)
0
0
0
0
0
3 (3%)
HYDROXYZINE
0
1 (<1%)
0
0
1 (<1%)
1 (<1%)
METAMIZOLE SODIUM
0
1 (<1%)
1 (<1%)
0
1 (<1%)
0
SUMATRIPTAN
1 (<1%)
0
1 (<1%)
1 (1%)
0
0
ACETYLSALICYLIC
0
0
0
1 (1%)
1 (<1%)
0
ACID+CAFFEINE+CINNAMEDRINE
HYDROCHLORIDE
AMFETAMINE SULFATE+AMFETAMINE
0
1 (<1%)
0
0
0
1 (<1%)
ASPARTATE+DEXAMFETAMINE
SULFATE+DEXTROAMPHETAMINE
SACCHARATE
KETOROLAC TROMETAMOL
0
0
1 (<1%)
1 (1%)
0
0
MODAFINIL
1 (<1%)
0
0
0
0
1 (<1%)
PARACETAMOL+HYDROCODONE
0
1 (<1%)
1 (<1%)
0
0
0
BITARTRATE
PREGABALIN
1 (<1%)
0
0
1 (1%)
0
0
RIZATRIPTAN BENZOATE
0
0
1 (<1%)
0
0
1 (<1%)
TRAZODONE
0
1 (<1%)
0
1 (1%)
0
0
ACETYLSALICYLIC
0
0
0
1 (1%)
0
0
ACID+CAFFEINE+SALICYLAMIDE
CAFFEINE
1 (<1%)
0
0
0
0
0

Protocol: B2C109575
Population: Intent-to-Treat

Page 7 of 16

Table 6.20
Summary of Non-Asthma Concomitant Medications Taken Post Treatment

23 (23%)

21 (21%)

21 (21%)

19 (19%)

20 (20%)

Note: A medication may be included in more than one ATC Level category and appear more than once.

15 (15%)

YM2008/00019/00
B2C109575

CARDIOVASCULAR SYSTEM
Any medication

CONFIDENTIAL

213

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------CLONIDINE HYDROCHLORIDE
1 (<1%)
0
0
0
0
0
CYCLOBENZAPRINE HYDROCHLORIDE
0
0
0
0
1 (<1%)
0
DEXTROPROPOXYPHENE
1 (<1%)
0
0
0
0
0
HYDROCHLORIDE+PARACETAMOL
DEXTROPROPOXYPHENE
0
0
1 (<1%)
0
0
0
NAPSILATE+PARACETAMOL
ERGOTAMINE TARTRATE
0
0
0
0
0
1 (<1%)
ERGOTAMINE TARTRATE+CAFFEINE
0
0
0
0
0
1 (<1%)
ERGOTAMINE TARTRATE+METAMIZOLE
0
0
0
0
1 (<1%)
0
SODIUM+CAFFEINE+CHLORPHENAMINE
MALEATE
GABAPENTIN
0
0
0
0
1 (<1%)
0
HYDROCODONE
0
0
0
0
1 (<1%)
0
METHADONE
0
1 (<1%)
0
0
0
0
METHYLPHENIDATE HYDROCHLORIDE
0
0
0
1 (1%)
0
0
MIDAZOLAM MALEATE
0
0
0
0
0
1 (<1%)
MORPHINE
0
1 (<1%)
0
0
0
0
NARATRIPTAN HYDROCHLORIDE
1 (<1%)
0
0
0
0
0
OXYCODONE
0
1 (<1%)
0
0
0
0
PARACETAMOL+CAFFEINE+BUTALBITAL
0
0
0
0
1 (<1%)
0
PAROXETINE HYDROCHLORIDE
0
0
1 (<1%)
0
0
0
PROMETHAZINE
0
0
1 (<1%)
0
0
0
SERTRALINE
1 (<1%)
0
0
0
0
0
TOPIRAMATE
0
0
0
1 (1%)
0
0
VENLAFAXINE HYDROCHLORIDE
0
0
0
0
1 (<1%)
0
ZOLMITRIPTAN
1 (<1%)
0
0
0
0
0
ZOLPIDEM
0
0
1 (<1%)
0
0
0
ZOLPIDEM TARTRATE
0
0
0
1 (1%)
0
0
ZOPICLONE
0
0
0
1 (1%)
0
0

Protocol: B2C109575
Population: Intent-to-Treat

Page 8 of 16

Table 6.20
Summary of Non-Asthma Concomitant Medications Taken Post Treatment

YM2008/00019/00
B2C109575

Note: A medication may be included in more than one ATC Level category and appear more than once.

CONFIDENTIAL

214

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------ENALAPRIL
2 (2%)
0
2 (2%)
3 (3%)
3 (3%)
1 (<1%)
HYDROCHLOROTHIAZIDE
2 (2%)
4 (4%)
1 (<1%)
1 (1%)
2 (2%)
1 (<1%)
AMLODIPINE BESILATE
1 (<1%)
2 (2%)
1 (<1%)
3 (3%)
1 (<1%)
2 (2%)
SIMVASTATIN
1 (<1%)
2 (2%)
0
0
2 (2%)
2 (2%)
VERAPAMIL
3 (3%)
1 (<1%)
0
1 (1%)
2 (2%)
0
AMLODIPINE
1 (<1%)
1 (<1%)
0
0
4 (4%)
0
VERAPAMIL HYDROCHLORIDE
1 (<1%)
0
1 (<1%)
3 (3%)
1 (<1%)
0
ENALAPRIL MALEATE
1 (<1%)
1 (<1%)
1 (<1%)
0
1 (<1%)
1 (<1%)
LISINOPRIL
0
0
2 (2%)
1 (1%)
1 (<1%)
1 (<1%)
PERINDOPRIL
0
1 (<1%)
0
0
4 (4%)
0
ATORVASTATIN CALCIUM
1 (<1%)
0
0
1 (1%)
0
2 (2%)
HYDROCHLOROTHIAZIDE+LOSARTAN
0
1 (<1%)
1 (<1%)
1 (1%)
0
1 (<1%)
POTASSIUM
INDAPAMIDE
0
0
1 (<1%)
1 (1%)
0
2 (2%)
IRBESARTAN
0
2 (2%)
1 (<1%)
1 (1%)
0
0
LOSARTAN POTASSIUM
1 (<1%)
1 (<1%)
1 (<1%)
1 (1%)
0
0
VALSARTAN
1 (<1%)
1 (<1%)
1 (<1%)
1 (1%)
0
0
FISH OIL
0
0
2 (2%)
0
0
1 (<1%)
FOSINOPRIL SODIUM
1 (<1%)
1 (<1%)
0
0
0
1 (<1%)
HYDROCORTISONE
0
1 (<1%)
1 (<1%)
0
1 (<1%)
0
LOSARTAN
1 (<1%)
0
0
0
2 (2%)
0
RAMIPRIL
1 (<1%)
2 (2%)
0
0
0
0
TELMISARTAN
0
1 (<1%)
1 (<1%)
0
0
1 (<1%)
CANDESARTAN CILEXETIL
0
1 (<1%)
0
0
1 (<1%)
0
DIOSMIN
1 (<1%)
0
0
0
1 (<1%)
0
EPINEPHRINE
1 (<1%)
0
1 (<1%)
0
0
0
FELODIPINE
1 (<1%)
1 (<1%)
0
0
0
0
HYDROCHLOROTHIAZIDE+VALSARTAN
0
0
1 (<1%)
0
0
1 (<1%)
MOXONIDINE
1 (<1%)
0
0
0
1 (<1%)
0
OLMESARTAN
0
0
0
1 (1%)
0
1 (<1%)
ATORVASTATIN
1 (<1%)
0
0
0
0
0
BETAMETHASONE DIPROPIONATE
1 (<1%)
0
0
0
0
0

Protocol: B2C109575
Population: Intent-to-Treat

Page 9 of 16

Table 6.20
Summary of Non-Asthma Concomitant Medications Taken Post Treatment

YM2008/00019/00
B2C109575

Note: A medication may be included in more than one ATC Level category and appear more than once.

CONFIDENTIAL

215

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------CAPTOPRIL
1 (<1%)
0
0
0
0
0
CIPROFIBRATE
0
0
0
1 (1%)
0
0
CLONIDINE HYDROCHLORIDE
1 (<1%)
0
0
0
0
0
DEXAMETHASONE
0
0
0
1 (1%)
0
0
DILTIAZEM
0
0
0
1 (1%)
0
0
DIOSMIN+HESPERIDIN
0
1 (<1%)
0
0
0
0
DOXAZOSIN
1 (<1%)
0
0
0
0
0
FENOFIBRATE
0
0
1 (<1%)
0
0
0
HYDROCHLOROTHIAZIDE+AMILORIDE
0
0
1 (<1%)
0
0
0
HYDROCHLORIDE
HYDROCHLOROTHIAZIDE+CANDESARTAN
0
0
1 (<1%)
0
0
0
CILEXETIL
HYDROCHLOROTHIAZIDE+ENALAPRIL
1 (<1%)
0
0
0
0
0
HYDROCHLOROTHIAZIDE+RAMIPRIL
0
0
0
0
1 (<1%)
0
INDOMETACIN
0
1 (<1%)
0
0
0
0
ISOSORBIDE MONONITRATE
0
0
0
0
0
1 (<1%)
LOVASTATIN
0
0
0
0
1 (<1%)
0
MOEXIPRIL
0
0
1 (<1%)
0
0
0
NICOTINIC ACID
0
0
0
0
0
1 (<1%)
OMEGA-3 MARINE TRIGLYCERIDES
0
0
0
0
0
1 (<1%)
PENTOSAN POLYSULFATE SODIUM
0
0
0
1 (1%)
0
0
QUINAPRIL HYDROCHLORIDE
0
1 (<1%)
0
0
0
0
ROSUVASTATIN CALCIUM
0
0
0
0
1 (<1%)
0
SIMVASTATIN+EZETIMIBE
0
0
1 (<1%)
0
0
0
SPIRONOLACTONE
1 (<1%)
0
0
0
0
0
SPIRONOLACTONE+ALTIZIDE
1 (<1%)
0
0
0
0
0
TOCOPHEROL+FISH OIL
0
1 (<1%)
0
0
0
0
TORASEMIDE
0
0
0
0
1 (<1%)
0
TRIAMTERENE+HYDROCHLOROTHIAZIDE
0
0
0
0
1 (<1%)
0
TRIMETAZIDINE HYDROCHLORIDE
1 (<1%)
0
0
0
0
0
UBIDECARENONE
0
0
1 (<1%)
0
0
0

Protocol: B2C109575
Population: Intent-to-Treat

Page 10 of 16

Table 6.20
Summary of Non-Asthma Concomitant Medications Taken Post Treatment

24 (24%)

14 (14%)

14 (14%)

17 (17%)

14 (14%)

Note: A medication may be included in more than one ATC Level category and appear more than once.

14 (14%)

YM2008/00019/00
B2C109575

GENITO URINARY SYSTEM AND SEX


HORMONES
Any medication

CONFIDENTIAL

216

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------DERMATOLOGICALS
Any medication
17 (17%)
18 (18%)
20 (20%)
22 (22%)
13 (13%)
16 (16%)
FLUTICASONE PROPIONATE
5 (5%)
4 (4%)
11 (11%)
6 (6%)
4 (4%)
3 (3%)
MOMETASONE FUROATE
5 (5%)
6 (6%)
1 (<1%)
4 (4%)
3 (3%)
4 (4%)
BECLOMETASONE DIPROPIONATE
2 (2%)
2 (2%)
1 (<1%)
1 (1%)
2 (2%)
1 (<1%)
BENADRYL (NOS)
1 (<1%)
1 (<1%)
2 (2%)
0
1 (<1%)
3 (3%)
BUDESONIDE
1 (<1%)
1 (<1%)
2 (2%)
0
1 (<1%)
2 (2%)
RHINOCORT (NOS)
0
0
1 (<1%)
4 (4%)
1 (<1%)
1 (<1%)
TRIAMCINOLONE ACETONIDE
2 (2%)
1 (<1%)
1 (<1%)
2 (2%)
0
1 (<1%)
HYDROCORTISONE
0
1 (<1%)
1 (<1%)
0
1 (<1%)
0
CLINDAMYCIN
0
0
1 (<1%)
0
1 (<1%)
0
ETHINYLOESTRADIOL+CYPROTERONE
1 (<1%)
0
0
0
0
1 (<1%)
ACETATE
TOCOPHEROL
0
0
0
1 (1%)
1 (<1%)
0
TRIAMCINOLONE
0
2 (2%)
0
0
0
0
ACYCLOVIR
0
0
1 (<1%)
0
0
0
BETAMETHASONE DIPROPIONATE
1 (<1%)
0
0
0
0
0
BETAMETHASONE+CALCIPOTRIOL
0
0
0
1 (1%)
0
0
CLINDAMYCIN PHOSPHATE+TRETINOIN
0
0
0
1 (1%)
0
0
CLINDAMYCIN+BENZOYL PEROXIDE
0
0
0
1 (1%)
0
0
DESOXIMETASONE
0
0
0
1 (1%)
0
0
DEXAMETHASONE
0
0
0
1 (1%)
0
0
DIPHENHYDRAMINE
0
0
0
1 (1%)
0
0
FLUTICASONE
0
1 (<1%)
0
0
0
0
HYALURONIC ACID
0
0
1 (<1%)
0
0
0
PROMETHAZINE
0
0
1 (<1%)
0
0
0
RIFAXIMIN
0
0
0
1 (1%)
0
0
TERBINAFINE
0
0
0
1 (1%)
0
0

Protocol: B2C109575
Population: Intent-to-Treat

Page 11 of 16

Table 6.20
Summary of Non-Asthma Concomitant Medications Taken Post Treatment

YM2008/00019/00
B2C109575

Note: A medication may be included in more than one ATC Level category and appear more than once.

CONFIDENTIAL

217

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------IBUPROFEN
9 (9%)
7 (7%)
8 (8%)
6 (6%)
4 (4%)
2 (2%)
ETHINYLOESTRADIOL+LEVONORGESTREL
3 (3%)
2 (2%)
1 (<1%)
0
1 (<1%)
4 (4%)
ETHINYLOESTRADIOL+DROSPIRENONE
3 (3%)
0
1 (<1%)
2 (2%)
2 (2%)
1 (<1%)
ETHINYLOESTRADIOL+NORGESTIMATE
4 (4%)
0
0
0
0
2 (2%)
NAPROXEN SODIUM
1 (<1%)
1 (<1%)
0
2 (2%)
1 (<1%)
0
ESTRADIOL
0
1 (<1%)
0
1 (1%)
0
1 (<1%)
ESTROGENS CONJUGATED
0
0
0
1 (1%)
2 (2%)
0
ETHINYLOESTRADIOL+DESOGESTREL
1 (<1%)
0
0
1 (1%)
0
1 (<1%)
ETHINYLOESTRADIOL+NORETHISTERONE
1 (<1%)
0
0
0
1 (<1%)
1 (<1%)
ACETATE
MEDROXYPROGESTERONE ACETATE
2 (2%)
1 (<1%)
0
0
0
0
NAPROXEN
0
2 (2%)
1 (<1%)
0
0
0
ACETYLSALICYLIC
0
0
0
1 (1%)
1 (<1%)
0
ACID+CAFFEINE+CINNAMEDRINE
HYDROCHLORIDE
CLINDAMYCIN
0
0
1 (<1%)
0
1 (<1%)
0
ETHINYLOESTRADIOL+CYPROTERONE
1 (<1%)
0
0
0
0
1 (<1%)
ACETATE
ETHINYLOESTRADIOL+GESTODENE
0
0
0
0
2 (2%)
0
ETHINYLOESTRADIOL+NORETHISTERONE
0
0
2 (2%)
0
0
0
CYPROTERONE ACETATE
0
1 (<1%)
0
0
0
0
DESOGESTREL
0
0
0
1 (1%)
0
0
ESTRADIOL VALERATE
0
0
0
0
1 (<1%)
0
ESTRADIOL+DYDROGESTERONE
0
1 (<1%)
0
0
0
0
ESTRADIOL
1 (<1%)
0
0
0
0
0
VALERATE+MEDROXYPROGESTERONE
ACETATE
ESTROGEN NOS
0
0
1 (<1%)
0
0
0
ESTROGENS
1 (<1%)
0
0
0
0
0
CONJUGATED+MEDROXYPROGESTERONE
ACETATE
ETHINYLOESTRADIOL+ETONOGESTREL
0
0
0
0
0
1 (<1%)

Protocol: B2C109575
Population: Intent-to-Treat

Page 12 of 16

Table 6.20
Summary of Non-Asthma Concomitant Medications Taken Post Treatment

218

17
9
4
0
1
2
1
0
0
0
0
0
0
0
0
1
0
0
1
0

(17%)
(9%)
(4%)
(<1%)
(2%)
(<1%)

(<1%)
(<1%)

16
7
4
1
1
1
1
2
0
1
0
0
0
0
1
0
0
0
0
1

(16%)
(7%)
(4%)
(<1%)
(<1%)
(<1%)
(<1%)
(2%)
(<1%)

(<1%)

(<1%)

14
8
2
1
0
0
1
1
0
1
1
1
0
0
0
0
0
1
0
0

(14%)
(8%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)

(<1%)

15 (15%)
6 (6%)
3 (3%)
2 (2%)
2 (2%)
0
0
0
0
0
0
1 (1%)
1 (1%)
1 (1%)
0
0
0
0
0
0

14
4
6
0
1
0
0
0
1
0
1
0
0
0
0
0
1
0
0
0

(14%)
(4%)
(6%)
(<1%)

(<1%)
(<1%)

(<1%)

Note: A medication may be included in more than one ATC Level category and appear more than once.

11
2
7
1
0
1
0
0
1
0
0
0
0
0
0
0
0
0
0
0

(11%)
(2%)
(7%)
(<1%)
(<1%)
(<1%)

YM2008/00019/00
B2C109575

MUSCULO-SKELETAL SYSTEM
Any medication
IBUPROFEN
ACETYLSALICYLIC ACID
DICLOFENAC
NAPROXEN SODIUM
ALENDRONATE SODIUM
DICLOFENAC SODIUM
NAPROXEN
ALLOPURINOL
CHONDROITIN+GLUCOSAMINE
KETOPROFEN
KETOROLAC TROMETAMOL
CELECOXIB
CHONDROITIN SULFATE SODIUM
COLCHICUM AUTUMNALE
COLECALCIFEROL+ALENDRONIC ACID
CYCLOBENZAPRINE HYDROCHLORIDE
HYALURONIC ACID
HYDROXYCHLOROQUINE SULFATE
INDOMETACIN

CONFIDENTIAL

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------ETHINYLOESTRADIOL+FERROUS
0
0
0
1 (1%)
0
0
FUMARATE+NORETHISTERONE ACETATE
LEVONORGESTREL
0
0
1 (<1%)
0
0
0
METHYLTESTOSTERONE
0
0
0
0
1 (<1%)
0
NORETHISTERONE ACETATE+ESTRADIOL
0
0
0
1 (1%)
0
0
PROGESTERONE
0
0
1 (<1%)
0
0
0
SERENOA REPENS
0
0
0
0
0
1 (<1%)
TAMSULOSIN
0
0
0
1 (1%)
0
0
TAMSULOSIN HYDROCHLORIDE
0
0
0
1 (1%)
0
0
TESTOSTERONE
0
0
1 (<1%)
0
0
0

Protocol: B2C109575
Population: Intent-to-Treat

Page 13 of 16

Table 6.20
Summary of Non-Asthma Concomitant Medications Taken Post Treatment

219

9 (9%)
4 (4%)
1 (<1%)
2 (2%)
0
0
0
1 (<1%)
0
0
0
1 (<1%)
0

9
3
1
1
1
1
2
0
0
0
0
0
0

BLOOD AND BLOOD FORMING ORGANS


Any medication
ACETYLSALICYLIC ACID
FOLIC ACID
CYANOCOBALAMIN
EPINEPHRINE

6 (6%)
4 (4%)
0
0
1 (<1%)

5 (5%)
4 (4%)
1 (<1%)
1 (<1%)
0

(9%)
(3%)
(<1%)
(<1%)
(<1%)
(<1%)
(2%)

10
4
2
1
2
1
0
0
0
1
1
0
1

(10%)
(4%)
(2%)
(<1%)
(2%)
(<1%)

(8%)
(5%)

(<1%)

8
5
0
2
0
0
0
0
1
0
0
0
0

5 (5%)
2 (2%)
1 (<1%)
1 (<1%)
1 (<1%)

8
3
1
0
0

(8%)
(3%)
(1%)

(<1%)
(<1%)

(2%)

(1%)

3 (3%)
1 (<1%)
1 (<1%)
0
0
1 (<1%)
0
0
0
0
0
0
0

7 (7%)
4 (4%)
2 (2%)
1 (<1%)
1 (<1%)
0
0
0
0
0
0
0
0

8
6
0
0
0

8
7
0
0
0

(8%)
(6%)

Note: A medication may be included in more than one ATC Level category and appear more than once.

(8%)
(7%)

YM2008/00019/00
B2C109575

SYSTEMIC HORMONAL PREPARATIONS,


EXCL. SEX HORMONES AND INSULINS
Any medication
LEVOTHYROXINE SODIUM
BUDESONIDE
TRIAMCINOLONE ACETONIDE
LEVOTHYROXINE
HYDROCORTISONE
TRIAMCINOLONE
BETAMETHASONE DIPROPIONATE
DEXAMETHASONE
LIOTHYRONINE
LIOTHYRONINE SODIUM
POTASSIUM IODIDE
THYROID

CONFIDENTIAL

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------MELOXICAM
0
0
0
0
1 (<1%)
0
METHYL
0
0
1 (<1%)
0
0
0
SALICYLATE+LEVOMENTHOL+EUCALYPTUS
GLOBULUS OIL
NABUMETONE
0
0
0
0
1 (<1%)
0
PIROXICAM
0
0
1 (<1%)
0
0
0
PSEUDOEPHEDRINE+NAPROXEN
0
1 (<1%)
0
0
0
0
RISEDRONATE SODIUM
0
0
0
0
1 (<1%)
0
TROLAMINE SALICYLATE
0
0
0
1 (1%)
0
0

Protocol: B2C109575
Population: Intent-to-Treat

Page 14 of 16

Table 6.20
Summary of Non-Asthma Concomitant Medications Taken Post Treatment

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------FERROUS SULPHATE
0
0
0
1 (1%)
0
1 (<1%)
CALCIUM CHLORIDE
0
0
0
0
1 (<1%)
0
CLOPIDOGREL BISULFATE
0
0
0
1 (1%)
0
0
FERROUS GLYCINE SULFATE
1 (<1%)
0
0
0
0
0
IRON
0
0
0
0
1 (<1%)
0
PENTOSAN POLYSULFATE SODIUM
0
0
0
1 (1%)
0
0
PHENPROCOUMON
0
0
0
1 (1%)
0
0
POTASSIUM NOS
0
0
1 (<1%)
0
0
0

ANTINEOPLASTIC AND IMMUNOMODULATING


AGENTS
Any medication

(6%)
(2%)
(<1%)
(<1%)

(<1%)

(<1%)

(3%)

9
1
1
1
1
0
0
1
2
0
0
0
0
0
1
0
0
1

(9%)
(<1%)
(<1%)
(<1%)
(<1%)

(8%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)

(<1%)

8
1
1
1
1
1
1
1
0
1
0
0
0
1
0
1
0
0

(4%)

(2%)

(<1%)
(2%)

(<1%)

(<1%)

(<1%)
(<1%)

5
2
2
0
0
0
1
0
0
0
0
1
0
0
0
0
0
0

(5%)
(2%)
(2%)

(2%)

(1%)

(1%)

2 (2%)
0
0
0
1 (<1%)
0
0
0
0
0
0
0
1 (<1%)
0
0
0
0
0

2 (2%)
1 (<1%)
1 (<1%)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0

(2%)

Note: A medication may be included in more than one ATC Level category and appear more than once.

(3%)

YM2008/00019/00
B2C109575

6
2
0
1
0
1
0
0
0
0
1
0
0
0
0
0
1
0

CONFIDENTIAL

220

SENSORY ORGANS
Any medication
TRIAMCINOLONE ACETONIDE
DICLOFENAC
DICLOFENAC SODIUM
HYDROCORTISONE
EPINEPHRINE
KETOROLAC TROMETAMOL
OLOPATADINE HYDROCHLORIDE
TRIAMCINOLONE
ACYCLOVIR
CLONIDINE HYDROCHLORIDE
DEXAMETHASONE
DEXAMETHASONE+CIPROFLOXACIN
HYALURONIC ACID
INDOMETACIN
PIROXICAM
POTASSIUM IODIDE
XYLOMETAZOLINE HYDROCHLORIDE

Protocol: B2C109575
Population: Intent-to-Treat

Page 15 of 16

Table 6.20
Summary of Non-Asthma Concomitant Medications Taken Post Treatment

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------IMMUNOTHERAPY{NOS}
1 (<1%)
2 (2%)
2 (2%)
0
0
2 (2%)
ESTRADIOL
0
1 (<1%)
0
1 (1%)
0
1 (<1%)
ESTROGENS CONJUGATED
0
0
0
1 (1%)
2 (2%)
0
MEDROXYPROGESTERONE ACETATE
2 (2%)
1 (<1%)
0
0
0
0
ESTRADIOL VALERATE
0
0
0
0
1 (<1%)
0
2 (2%)
1 (<1%)
0
1 (<1%)
0
0

1 (<1%)
0
1 (<1%)
1 (<1%)
0
0

3
1
0
0
1
1

0
0
0
0

0
0
0
0

0
0
0
0

0
1
1
0

0
0
0
1 (<1%)
1 (<1%)

0
0
0
0
0

0
0
0
0
0

0
0
0
0
0

(3%)
(1%)
(1%)
(1%)

(1%)
(1%)

2 (2%)
0
1 (<1%)
0
0
0

3 (3%)
1 (<1%)
0
0
0
0

0
0
0
1 (<1%)

1 (<1%)
0
0
0

0
1 (<1%)
1 (<1%)
0
0

1 (<1%)
0
0
0
0

ANTIINFECTIVES FOR SYSTEMIC USE


Note: A medication may be included in more than one ATC Level category and appear more than once.

YM2008/00019/00
B2C109575

3 (3%)
0
1 (<1%)
0
0
0

CONFIDENTIAL

221

VARIOUS
Any medication
ALLERGENS (NOS)
LINUM USITATISSIMUM OIL
CHONDROITIN+GLUCOSAMINE
ALLIUM SATIVUM
ALOE
BARBADENSIS+GINSENG+CAMPHOR+LEVOM
ENTHOL+HAMAMELIS
VIRGINIANA+ANGELICA+LAVENDAR OIL
AMBIGUOUS MEDICATION
CHONDROITIN SULFATE SODIUM
CINNAMOMUM VERUM
DOCOSAHEXANOIC
ACID+EICOSAPENTAENOIC
ACID+ALPHA-LINOLENIC ACID+MOROTIC
ACID+HENEICOSAPENTAENIC
ACID+CLUPANODONIC
ACID+EICOSATETRAENOIC ACID
IOVERSOL
LINUM USITATISSIMUM
MEDICATION UNKNOWN
POTASSIUM IODIDE
VITIS VINIFERA

Protocol: B2C109575
Population: Intent-to-Treat

Page 16 of 16

Table 6.20
Summary of Non-Asthma Concomitant Medications Taken Post Treatment

222

ANTIPARASITIC PRODUCTS,
INSECTICIDES AND REPELLENTS
Any medication
HYDROXYCHLOROQUINE SULFATE

1 (<1%)
1 (<1%)

0
0

0
0

0
0

0
0

YM2008/00019/00
B2C109575

Note: A medication may be included in more than one ATC Level category and appear more than once.

0
0

CONFIDENTIAL

ATC Level 1
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Ingredient
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Any medication
2 (2%)
1 (<1%)
3 (3%)
2 (2%)
2 (2%)
1 (<1%)
AMOXICILLIN
1 (<1%)
0
1 (<1%)
0
0
0
TRIHYDRATE+CLAVULANATE POTASSIUM
CLINDAMYCIN
0
0
1 (<1%)
0
1 (<1%)
0
ACYCLOVIR
0
0
1 (<1%)
0
0
0
AMOXICILLIN TRIHYDRATE
0
0
0
0
1 (<1%)
0
AZITHROMYCIN
0
1 (<1%)
0
0
0
0
LEVOFLOXACIN
0
0
0
0
0
1 (<1%)
PHENOXYMETHYLPENICILLIN POTASSIUM
1 (<1%)
0
0
0
0
0
RIFAMPICIN
0
0
0
1 (1%)
0
0
SULFAMETHOXAZOLE+TRIMETHOPRIM
0
0
0
1 (1%)
0
0

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 2
Table 6.21
Summary of Screening Lung Function Test Results

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Screening
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Pre-bronchodilator
n
102
101
101
100
101
102
FEV1 (L)
Mean
2.211
2.257
2.243
2.255
2.127
2.165
SD
0.6740
0.8031
0.6494
0.6315
0.6067
0.6143
Median
2.209
2.148
2.223
2.172
2.079
2.113
Min.
0.83
1.04
1.06
1.03
0.83
0.86
Max.
4.48
4.54
3.63
4.02
3.76
4.37
102
66.9
11.97
68.1
41
90

101
65.8
13.48
66.2
40
90

101
66.5
10.75
66.6
42
88

100
67.6
11.79
67.8
41
90

101
65.3
12.08
66.0
42
89

102
65.9
12.29
66.5
40
89

Post-bronchodilator
FEV1 (L)

n
Mean
SD
Median
Min.
Max.

102
2.767
0.8004
2.676
1.18
5.26

101
2.775
0.9468
2.654
1.26
5.17

101
2.806
0.7814
2.789
1.45
4.59

100
2.792
0.7369
2.693
1.32
4.81

101
2.668
0.7027
2.555
1.32
4.23

102
2.702
0.7095
2.675
1.07
5.05

Percent Reversibility
FEV1 (%)

n
Mean
SD
Median
Min.
Max.

102
26.6
15.37
21.2
7
86

101
24.2
13.45
20.4
2
76

101
26.3
15.39
22.4
6
100

100
25.2
16.20
20.1
12
125

101
27.4
20.74
20.0
12
123

102
26.4
15.45
22.1
-12
102

YM2008/00019/00
B2C109575

n
Mean
SD
Median
Min.
Max.

CONFIDENTIAL

223

Percent Predicted
FEV1 (%)

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 2
Table 6.21
Summary of Screening Lung Function Test Results

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Screening
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Absolute Reversibility n
102
101
101
100
101
102
FEV1 (mL)
Mean
555.5
517.8
562.7
537.0
540.2
537.0
SD
300.26
271.20
291.05
280.18
339.07
253.50
Median
442.0
432.0
513.0
464.0
452.0
477.5
Min.
164
29
148
201
200
-229
Max.
1697
1317
1564
1501
2207
1427

CONFIDENTIAL

224

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Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Table 6.22
Summary of Treatment Compliance (%)

Novel Dry Powder


Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Inhaler (%)
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------n
102
101
101
100
100
101
Mean
107.0
99.3
98.9
99.5
99.0
99.6
SD
54.72
4.83
5.58
4.03
5.59
4.08
Median
100.0
100.0
100.0
100.0
100.0
100.0
Min.
79
83
81
83
75
83
Max.
633
115
125
111
112
107
102
1 (<1%)
77 (75%)
24 (24%)

101
0
75 (74%)
26 (26%)

101
0
82 (81%)
19 (19%)

100
0
79 (79%)
21 (21%)

100
3 (3%)
79 (79%)
18 (18%)

101
0
77 (76%)
24 (24%)

225

CONFIDENTIAL

n
<80%
>=80% to =<100%
>100%

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 6.23
Summary of Percent Predicted FEV1 Strata: As Randomised and Actual

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
--------------------------------------------------------------------------------------------------------As Randomised Stratum
Stratum 1: >=40% - <=65%
44 (43%)
44 (44%)
44 (44%)
44 (44%)
45 (45%)
44 (43%)
265 (44%)
Stratum 2: >65% - <=90%
58 (57%)
57 (56%)
57 (56%)
56 (56%)
56 (55%)
58 (57%)
342 (56%)
Actual Stratum
Stratum 1: >=40% - <=65%
Stratum 2: >65% - <=90%

44 (43%)
58 (57%)

46 (46%)
55 (54%)

43 (43%)
58 (57%)

42 (42%)
58 (58%)

47 (47%)
54 (53%)

46 (45%)
56 (55%)

268 (44%)
339 (56%)

CONFIDENTIAL

226

YM2008/00019/00
B2C109575

Note: Actual stratum is determined using Day 1 Pre-dose Percent Predicted FEV1.

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 6.24
Summary of Percent Predicted FEV1 (%) Day 1 Pre-Dose by Actual Stratum

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
-----------------------------------------------------------------------------------------------------Stratum 1: >=40% - <=65% n
44
46
43
42
47
46
268
Mean
55.9
54.2
57.8
56.2
55.2
56.1
55.9
SD
6.70
7.78
5.20
7.04
7.15
6.29
6.78
Median 56.6
54.4
59.1
58.9
56.7
57.1
57.1
Min.
41
34
45
40
40
42
34
Max.
65
64
65
65
65
65
65
Stratum 2: >65% - <=90%

58
75.8
6.96
74.5
65
90

55
77.1
6.97
77.3
66
90

58
76.8
7.01
76.2
66
90

58
78.3
7.13
78.5
66
90

54
75.5
7.64
74.9
65
91

339
76.6
7.05
76.6
65
91

YM2008/00019/00
B2C109575

Note: Actual stratum is determined using Day 1 Pre-dose Percent Predicted FEV1.

56
76.0
6.50
76.8
65
87

CONFIDENTIAL

227

n
Mean
SD
Median
Min.
Max.

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Table 6.103
Summary of Background Steroid Dose During Treatment

BDP Equivalent Placebo


3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Daily Dose
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------n
94
89
84
91
92
92
Mean
814.4
698.3
747.6
736.3
736.4
709.8
SD
537.50
405.53
467.68
473.29
411.78
517.24
Median
800.0
500.0
550.0
500.0
800.0
500.0
Min.
100
200
100
100
200
100
Max.
2000
2000
2000
2000
2000
2000

CONFIDENTIAL

228

YM2008/00019/00
B2C109575

Note: This is the BDP (Beclometasone Dipropionate) equivalent

CONFIDENTIAL

YM2008/00019/00
B2C109575

Efficacy Data Source Figures and Tables


Page

Figure 7.1 Adjusted Treatment Differences of Change from Baseline in Trough


FEV1 (L) (LOCF) at Day 28 Intent-to-Treat . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 7.2 Adjusted Means of Change from Baseline in Trough FEV1 (L) (LOCF)
at Day 28 Intent-to-Treat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 7.3 Box Plot of Change from Baseline in Trough FEV1 (L) (LOCF) at Day
28 Intent-to-Treat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 7.4 Empirical Distribution Function for Change from Baseline in Trough
FEV1 (L) (LOCF) at Day 28 Intent-to-Treat . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 7.5 Adjusted Treatment Differences of Change from Baseline in Trough
FEV1 (L) (LOCF) at Day 28 Per Protocol . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 7.6 Adjusted Means of Change from Baseline in Trough FEV1 (L) (LOCF)
at Day 28 Per Protocol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 7.7 Box Plot of Change from Baseline in Trough FEV1 (L) (LOCF) at Day
28 Per Protocol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 7.8 Empirical Distribution Function for Change from Baseline in Trough
FEV1 (L) (LOCF) at Day 28 Per-Protocol . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 7.9 Repeated Measures Analysis of Change from Baseline in Trough FEV1
(L) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 7.10 Repeated Measures Analysis of Change from Baseline in Trough
FEV1 (L) - Differences from Placebo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 7.11 Adjusted Treatment Differences of Change from Baseline in Trough
FEV1 (L) (LOCF) at Day 28 by %Predicted FEV1 Stratum . . . . . . . . . . . . . . . . .
Figure 7.12 Adjusted Means of Change from Baseline in Trough FEV1 (L) (LOCF)
at Day 28 by %Predicted FEV1 Stratum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 7.13 Adjusted Treatment Differences of Weighted Mean 24 hour Serial
FEV1 (L) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 7.14 Adjusted Treatment Differences from Sensitivity Analysis of Weighted
Mean 24 hour Serial FEV1 (L) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 7.15 Plot of Mean Clinic FEV1 (L) Over Time . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 7.16 Plot of Absolute Change from Baseline in Serial FEV1 (L) 0-4 hours . . .
Figure 7.17 Plot of Percentage Change from Baseline in Serial FEV1 (L) 0-4 hours
Figure 7.18 Repeated Measures Adjusted Mean Change from Baseline in FEV1
(L) Over Time Day 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 7.19 Repeated Measures Adjusted Mean Change from Baseline in FEV1
(L) Over Time Day 28 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 7.20 Repeated Measures Adjusted Treatment Differences from Placebo in
Change from Baseline FEV1 (L) Over Time - Day 1 . . . . . . . . . . . . . . . . . . . . . .
Figure 7.21 Repeated Measures Adjusted Treatment Differences from Placebo in
Change from Baseline FEV1 (L) Over Time - Day 28 . . . . . . . . . . . . . . . . . . . . .

229

234
235
236
237
238
239
240
241
242
243
244
245
246
248
250
252
254
256
257
258
259

CONFIDENTIAL

YM2008/00019/00
B2C109575

Figure 7.22 Adjusted Treatment Differences of post-salbutamol/albuterol FEV1 (L)


Day 28 - Day 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 7.23 Adjusted Treatment Differences of post-salbutamol/albuterol FEV1 (L)
Day 1 - Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 7.24 Adjusted Treatment Differences of post-salbutamol/albuterol FEV1 (L)
Day 28 - Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 7.25 Adjusted Treatment Differences of Peak Post-Dose FEV1 (L) (0-4hrs)
Day 28 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 7.26 Mean Change from Baseline in PM PEF (L/min) . . . . . . . . . . . . . . . . . .
Figure 7.27 Mean Change from Baseline in AM PEF (L/min) . . . . . . . . . . . . . . . . . .
Figure 7.109 Proportion of Subjects Obtaining >= 200mL and >= 12% Increase
from Baseline FEV1 (L). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 7.111 Adjusted Treatment Differences of Change from Baseline in
Percentage of Symptom Free 24 Hour Periods . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 7.112 Adjusted Treatment Differences of Change from Baseline in
Percentage of Rescue Free 24 Hour Periods . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 7.113 Adjusted Treatment Differences of Change from Baseline in PM PEF
(L/min), Days 1-28 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 7.114 Adjusted Treatment Differences of Change from Baseline in AM PEF
(L/min), Days 1-28 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.1 Summary of Trough FEV1 (L) (LOCF) Intent-to-Treat (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.2 Linear Trend Test of Change from Baseline in Trough FEV1 (mL/mcg)
(LOCF) Intent-to-Treat (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . .
Table 7.3 Linear Trend Test of Change from Baseline in Trough FEV1 (mL/mcg)
(LOCF) Excluding Placebo Intent-to-Treat (Intent-to-Treat Population) . . . . . . .
Table 7.4 Statistical Analysis of Change from Baseline in Trough FEV1 (L) (LOCF)
Intent-to-Treat (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.5 Summary of Trough FEV1 (L) (LOCF) Per Protocol (Per Protocol
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.6 Linear Trend Test of Change from Baseline in Trough FEV1 (mL/mcg)
(LOCF) Per Protocol (Per Protocol Population) . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.7 Statistical Analysis of Change from Baseline in Trough FEV1 (L) (LOCF)
Per Protocol (Per Protocol Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.8 Linear Trend Test of Change from Baseline in Trough FEV1 (mL/mcg)
(Repeated Measures) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . .
Table 7.9 Statistical Analysis of Change from Baseline in Trough FEV1 (L)
(Repeated Measures) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . .
Table 7.10 Summary of Pre-Dose and Trough FEV1 (L) (No Imputation)
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.11 Summary of Change from Baseline in Trough FEV1 (L) (LOCF) at Day
28 by %Predicted FEV1 Stratum (Intent-to-Treat Population) . . . . . . . . . . . . . .

230

260
261
262
263
264
265
266
268
269
270
271
272
273
274
275
276
277
278
279
280
284
290

CONFIDENTIAL

YM2008/00019/00
B2C109575

Table 7.12 Slope Estimate of Change from Baseline in Trough FEV1 (mL/mcg)
(LOCF) at Day 28 by %Predicted FEV1 Stratum (Intent-to-Treat Population) . .
Table 7.13 Statistical Analysis of Change from Baseline in Trough FEV1 (L)
(LOCF) at Day 28 by %Predicted FEV1 Stratum (Intent-to-Treat Population) . .
Table 7.14 Summary of Raw Serial FEV1 (L) (Intent-to-Treat Population) . . . . . . . .
Table 7.15 Summary of Absolute Change from Baseline in Serial FEV1 (L)
(0-4hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.16 Summary of Percentage Change from Baseline in Serial FEV1 (%%)
(0-4hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.17 Repeated Measures Analysis of Serial FEV1 (L) Day 1 (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.18 Repeated Measures Analysis of Serial FEV1 (L) Day 28
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.19 Summary of Weighted Mean Change from Baseline in 24 hour Serial
Clinic FEV1 (L) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.20 Statistical Analysis of Weighted Mean Change from Baseline in 24
Hour Serial Clinic FEV1 (L) All Subjects, including 6-12 hour time points
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.21 Sensitivity Analysis of Weighted Mean Change from Baseline in 24
Hour Serial Clinic FEV1 (L) All Subjects excluding 6-12 hour time points
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.22 Sensitivity Analysis of Weighted Mean Change from Baseline in 24
Hour Serial Clinic FEV1 (L) Subset of Subjects who had the 6-12 hour time
points measured. All time points included (Intent-to-Treat Population) . . . . . . . .
Table 7.23 Sensitivity Analysis of Weighted Mean Change from Baseline in 24
Hour Serial Clinic FEV1 (L) Subset of Subjects who had 6-12 hour time points
measured, excluding 6-12 hour time points (Intent-to-Treat Population) . . . . . .
Table 7.24 Sensitivity Analysis of Weighted Mean Change from Baseline in 24
Hour Serial Clinic FEV1 (L) Observations without rescue medication
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.25 Summary of Post-salbutamol/albuterol FEV1 (L) (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.26 Summary of Post-salbutamol/albuterol FEV1 (L) Differences
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.27 Statistical Analysis of difference in post-salbutamol/albuterol FEV1 (L)
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.28 Summary of Maximum Increase from Baseline in FEV1 (L) (0-4 hrs)
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.29 Statistical Analysis of Maximum Increase from Baseline in FEV1 (L)
(0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.30 Summary of Weighted Mean Change from Baseline in FEV1 (L)
(0-4hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

231

292
293
294
300
303
306
319
333

334

335

336

337

338
339
340
341
342
343
344

CONFIDENTIAL

YM2008/00019/00
B2C109575

Table 7.31 Statistical Analysis of Weighted Mean Change from Baseline in FEV1
(L) (0-4hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.32 Summary of the Proportion of Subjects Obtaining >= 200mL and >=
12% Increase from Baseline FEV1 (L) (0-4hrs) (Intent-to-Treat Population) . .
Table 7.33 Summary of the Cumulative Proportion of Subjects Obtaining >=200mL
and >=12% increase from Baseline FEV1 (L) (0-4hrs) (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.34 Summary of the Proportion of Subjects Obtaining >= 15% Increase
from Baseline FEV1 (L) (0-4hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . .
Table 7.35 Summary of the Cumulative Proportion of Subjects Obtaining >=15%
increase from Baseline FEV1 (L) (0-4hrs) (Intent-to-Treat Population) . . . . . . .
Table 7.36 Summary of Peak Post-Dose FEV1 (L) (0-4hrs) (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.37 Statistical Analysis of Peak Post-Dose FEV1 (L) (0-4hrs)
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.38 Summary of Ratio of Peak Post-Dose FEV1 (L) to Trough FEV1 (L)
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.39 Change from Baseline in PM PEF (L/min) (Intent-to-Treat Population) . .
Table 7.40 Statistical Analysis of Change from Baseline in PM PEF (L/min)
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.41 Change from Baseline in AM PEF (L/min) (Intent-to-Treat Population) . .
Table 7.42 Statistical Analysis of Change from Baseline in AM PEF (L/min)
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.43 Change from Baseline in Percentage of Symptom Free 24 Hour
Periods (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.44 Statistical Analysis of Change from Baseline in Percentage of
Symptom Free 24 Hour Periods (Intent-to-Treat Population) . . . . . . . . . . . . . . .
Table 7.45 Change from Baseline in Percentage of Rescue Free 24 Hour Periods
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.46 Statistical Analysis of Change from Baseline in Percentage of Rescue
Free 24 Hour Periods (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . .
Table 7.47 Change from Baseline in Percentage of Symptom Free Days
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.48 Statistical Analysis of Change from Baseline in Percentage of
Symptom Free Days (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.49 Change from Baseline in Percentage of Symptom Free Nights
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.50 Statistical Analysis of Change from Baseline in Percentage of
Symptom Free Nights (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . .
Table 7.51 Change from Baseline in Percentage of Rescue Free Days
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

232

345
346

347
348
349
350
351
352
353
362
363
372
373
374
375
376
377
378
379
380
381

CONFIDENTIAL

YM2008/00019/00
B2C109575

Table 7.52 Statistical Analysis of Change from Baseline in Percentage of Rescue


Free Days (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.53 Change from Baseline in Percentage of Rescue Free Nights
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.54 Statistical Analysis of Change from Baseline in Percentage of Rescue
Free Nights (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.55 Statistical Analysis of Withdrawals Due to Lack of Efficacy
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 7.105 Summary of the Proportion of Subjects Obtaining >= 200mL and >=
12% Increase from Baseline FEV1 (L) (0-24hrs) (Intent-to-Treat Population) . .

233

382
383
384
385
386

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Figure 7.1
Adjusted Treatment Differences of Change from Baseline in Trough FEV1 (L) (LOCF) at Day 28
Intent-to-Treat

50mcg

CONFIDENTIAL

234

Treatment

25mcg

12.5mcg

6.25mcg

-0.2

-0.1

0.0

0.1

0.2

0.3

Difference From Placebo and 95% Confidence Interval

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age, stratum and treatment

0.4

YM2008/00019/00
B2C109575

3mcg

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Figure 7.2
Adjusted Means of Change from Baseline in Trough FEV1 (L) (LOCF) at Day 28
Intent-to-Treat

0.4

CONFIDENTIAL

235

LS Mean Change from Baseline in Trough FEV1 (L)

0.3

0.2

0.1

Placebo 3mcg 6.25mcg

12.5mcg

25mcg
Treatment

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age, stratum and treatment.
Regression line is based on the adjusted means of the Placebo and treatment groups.

50mcg

YM2008/00019/00
B2C109575

0.0

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Figure 7.3
Box Plot of Change from Baseline in Trough FEV1 (L) (LOCF) at Day 28
Intent-to-Treat

This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect
patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For
further information please see the Patient Level Data section of the GSK Clincal Study Register.

CONFIDENTIAL

236

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Figure 7.4
Empirical Distribution Function for Change from Baseline in Trough FEV1 (L) (LOCF) at Day 28
Intent-to-Treat
1.0

CONFIDENTIAL

237

Cumulative Probability

0.8

0.6

0.4

0.0
-0.8

-0.6

-0.4

-0.2

0.0

0.2

0.4

0.6

Change from Baseline in Trough FEV1 (L)

0.8

1.0

1.2

1.4

YM2008/00019/00
B2C109575

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg

0.2

Protocol: B2C109575
Population: Per Protocol

Page 1 of 1
Figure 7.5
Adjusted Treatment Differences of Change from Baseline in Trough FEV1 (L) (LOCF) at Day 28
Per Protocol

50mcg

CONFIDENTIAL

238

Treatment

25mcg

12.5mcg

6.25mcg

-0.2

-0.1

0.0

0.1

0.2

0.3

Difference From Placebo and 95% Confidence Interval

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age, stratum and treatment

0.4

YM2008/00019/00
B2C109575

3mcg

Protocol: B2C109575
Population: Per Protocol

Page 1 of 1
Figure 7.6
Adjusted Means of Change from Baseline in Trough FEV1 (L) (LOCF) at Day 28
Per Protocol

0.4

CONFIDENTIAL

239

LS Mean Change from Baseline in Trough FEV1 (L)

0.3

0.2

0.1

Placebo 3mcg 6.25mcg

12.5mcg

25mcg
Treatment

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age, stratum and treatment.
Regression line is based on the adjusted means of the Placebo and treatment groups.

50mcg

YM2008/00019/00
B2C109575

0.0

Protocol: B2C109575
Population: Per Protocol

Page 1 of 1
Figure 7.7
Box Plot of Change from Baseline in Trough FEV1 (L) (LOCF) at Day 28
Per Protocol

This section contained data from each individual patient, rather than in aggregate. They have been excluded to
protect patient privacy. Anonymized data from each patient may be made available subject to an approved research
proposal. For further information please see the Patient Level Data section of the GSK Clincal Study Register.

CONFIDENTIAL

240

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Per Protocol

Page 1 of 1
Figure 7.8
Empirical Distribution Function for Change from Baseline in Trough FEV1 (L) (LOCF) at Day 28
Per-Protocol

1.0

CONFIDENTIAL

241

Cumulative Probability

0.8

0.6

0.4

0.0
-0.8

-0.6

-0.4

-0.2

0.0

0.2

0.4

0.6

Change from Baseline in Trough FEV1 (L)

0.8

1.0

1.2

1.4

YM2008/00019/00
B2C109575

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg

0.2

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Figure 7.9
Repeated Measures Analysis of Change from Baseline in Trough FEV1 (L)

0.35

0.30

0.20

0.25

0.15

14

28

29

0.10

CONFIDENTIAL

242

LS Mean (95% CI) Change from Baseline

0.40

0.05
0.0

Day of Study

Placebo
3mcg

6.25mcg
12.5mcg

25mcg
50mcg

Note: Analysis adjusted for baseline (pre-dose on day 1), country, sex, age, stratum, treatment, visit, visit by treatment interaction
and visit by baseline interaction

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Figure 7.10
Repeated Measures Analysis of Change from Baseline in Trough FEV1 (L) - Differences from Placebo
0.25

0.15

0.10
0.05

0.0

CONFIDENTIAL

243

Difference from Placebo (95% CI)

0.20

-0.05
-0.10
14

28
Day of Study

3mcg
6.25mcg

12.5mcg
25mcg

50mcg

Note: Analysis adjusted for baseline (pre-dose on day 1), country, sex, age, stratum, treatment, visit, visit by treatment interaction
and visit by baseline interaction

29

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Figure 7.11
Adjusted Treatment Differences of Change from Baseline in Trough FEV1 (L) (LOCF) at Day 28
by %Predicted FEV1 Stratum

0.4

0.2

CONFIDENTIAL

244

Mean Difference from Placebo and 95% Confidence Interval

0.3

0.1

0.0

-0.1

3mcg

6.25mcg
Stratum

12.5mcg
>=40% - <=65%

25mcg

50mcg

>65% - <=90%

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age, stratum, treatment
and treatment by stratum interaction

YM2008/00019/00
B2C109575

-0.2

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Figure 7.12
Adjusted Means of Change from Baseline in Trough FEV1 (L) (LOCF) at Day 28
by %Predicted FEV1 Stratum

0.3

CONFIDENTIAL

245

LS Mean Change from Baseline in Trough FEV1 (L)

0.4

0.2

0.1

Placebo 3mcg 6.25mcg

12.5mcg

25mcg

50mcg

Treatment
Stratum

>=40% - <=65%

>65% - <=90%

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age, stratum, treatment,
and treatment by stratum interaction.

YM2008/00019/00
B2C109575

0.0

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 2
Figure 7.13
Adjusted Treatment Differences of Weighted Mean 24 hour Serial FEV1 (L)
DAY=1

50mcg

CONFIDENTIAL

246

Treatment

25mcg

12.5mcg

6.25mcg

-0.2

-0.1

0.0

0.1

0.2

0.3

Difference From Placebo and 95% Confidence Interval

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age, stratum and treatment

0.4

YM2008/00019/00
B2C109575

3mcg

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 2
Figure 7.13
Adjusted Treatment Differences of Weighted Mean 24 hour Serial FEV1 (L)
DAY=28

50mcg

CONFIDENTIAL

247

Treatment

25mcg

12.5mcg

6.25mcg

-0.2

-0.1

0.0

0.1

0.2

0.3

Difference From Placebo and 95% Confidence Interval

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age, stratum and treatment

0.4

YM2008/00019/00
B2C109575

3mcg

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 2
Figure 7.14
Adjusted Treatment Differences from Sensitivity Analysis of Weighted Mean 24 hour Serial FEV1 (L)
Day=1

0.4

0.2

CONFIDENTIAL

248

Mean Difference from Placebo and 95% Confidence Interval

0.3

0.1

0.0

-0.1

Analysis 1
3mcg

Analysis 2
6.25mcg

Analysis 3
12.5mcg

Analysis 4
25mcg

50mcg

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age, stratum and treatment
Analysis 1: All Subjects. The 6-12 hr time points are included.
Analysis 2: All Subjects. The 6-12 hr time points are excluded.
Analysis 3: Subset of subjects who had the 6-12 hr time points measured. The 6-12 hr time points are included.
Analysis 4: Subset of subjects who had the 6-12 hr time points measured. The 6-12 hr time points are excluded.

YM2008/00019/00
B2C109575

-0.2

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 2
Figure 7.14
Adjusted Treatment Differences from Sensitivity Analysis of Weighted Mean 24 hour Serial FEV1 (L)
Day=28

0.4

0.2

CONFIDENTIAL

249

Mean Difference from Placebo and 95% Confidence Interval

0.3

0.1

0.0

-0.1

Analysis 1
3mcg

Analysis 2
6.25mcg

Analysis 3
12.5mcg

Analysis 4
25mcg

50mcg

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age, stratum and treatment
Analysis 1: All Subjects. The 6-12 hr time points are included.
Analysis 2: All Subjects. The 6-12 hr time points are excluded.
Analysis 3: Subset of subjects who had the 6-12 hr time points measured. The 6-12 hr time points are included.
Analysis 4: Subset of subjects who had the 6-12 hr time points measured. The 6-12 hr time points are excluded.

YM2008/00019/00
B2C109575

-0.2

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 2
Figure 7.15
Plot of Mean Clinic FEV1 (L) Over Time
Day 1

3.0

2.6

2.4

2.2

CONFIDENTIAL

250

Mean (95% CI) FEV1 (L)

2.8

2.0
2

10

12

14

16

18

20

22

Time (hours)

Placebo
3mcg

6.25mcg
12.5mcg

25mcg
50mcg

Note: Serial FEV1 measurements taken at the following timepoints; Pre-dose, 15mins, 30mins, 1hr, 2hrs, 3hrs, 4hrs, 6hrs, 12hrs,
16hrs, 20hrs, 22hrs, 23hrs, 24hrs

24

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 2
Figure 7.15
Plot of Mean Clinic FEV1 (L) Over Time
Day 28

3.0

2.6

2.4

20

22

2.2

CONFIDENTIAL

251

Mean (95% CI) FEV1 (L)

2.8

2.0
6

10

12

14

16

18

Time (hours)

Placebo
3mcg

6.25mcg
12.5mcg

25mcg
50mcg

Note: Serial FEV1 measurements taken at the following timepoints; Pre-dose, 15mins, 30mins, 1hr, 2hrs, 3hrs, 4hrs, 6hrs, 12hrs,
16hrs, 20hrs, 22hrs, 23hrs, 24hrs

24

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 2
Figure 7.16
Plot of Absolute Change from Baseline in Serial FEV1 (L) 0-4 hours
Day 1

0.4

0.3

0.2

0.1

CONFIDENTIAL

252

Mean (95% CI) Absolute Change in FEV1 (L)

0.5

0.0
1

Time (hours)

Placebo
3mcg

6.25mcg
12.5mcg

25mcg
50mcg

Note: Serial FEV1 measurements taken at the following timepoints; Pre-dose, 15mins, 30mins, 1hr, 2hrs, 3hrs and 4hrs

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 2
Figure 7.16
Plot of Absolute Change from Baseline in Serial FEV1 (L) 0-4 hours
Day 28

0.4

0.3

0.2

CONFIDENTIAL

253

Mean (95% CI) Absolute Change in FEV1 (L)

0.5

0.1

0.0
3

Time (hours)

Placebo
3mcg

6.25mcg
12.5mcg

25mcg
50mcg

Note: Serial FEV1 measurements taken at the following timepoints; Pre-dose, 15mins, 30mins, 1hr, 2hrs, 3hrs and 4hrs

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 2
Figure 7.17
Plot of Percentage Change from Baseline in Serial FEV1 (L) 0-4 hours
Day 1

20

15

10

CONFIDENTIAL

254

Mean (95% CI) Percentage Change in FEV1

25

Time (hours)

Placebo
3mcg

6.25mcg
12.5mcg

25mcg
50mcg

Note: Serial FEV1 measurements taken at the following timepoints; Pre-dose, 15mins, 30mins, 1hr, 2hrs, 3hrs and 4hrs

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 2
Figure 7.17
Plot of Percentage Change from Baseline in Serial FEV1 (L) 0-4 hours
Day 28

20

10

15

CONFIDENTIAL

255

Mean (95% CI) Percentage Change in FEV1

25

0
1

Time (hours)

Placebo
3mcg

6.25mcg
12.5mcg

25mcg
50mcg

Note: Serial FEV1 measurements taken at the following timepoints; Pre-dose, 15mins, 30mins, 1hr, 2hrs, 3hrs and 4hrs

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Figure 7.18
Repeated Measures Adjusted Mean Change from Baseline in FEV1 (L) Over Time
Day 1

0.4

0.3

0.2

0.1

CONFIDENTIAL

256

LS Mean (95% CI) Change from Baseline

0.5

0.0
2

10

12

14

16

18

20

22

24

Time (hours)

Placebo
3mcg

6.25mcg
12.5mcg

25mcg
50mcg

Note: Analysis adjusted for baseline (pre-dose on day 1), country, sex, age, stratum, treatment, time (nominal), time by treatment interaction
and time by baseline interaction

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Figure 7.19
Repeated Measures Adjusted Mean Change from Baseline in FEV1 (L) Over Time
Day 28

0.4

0.3

0.2

0.1

CONFIDENTIAL

257

LS Mean (95% CI) Change from Baseline

0.5

0.0
2

10

12

14

16

18

20

22

24

Time (hours)

Placebo
3mcg

6.25mcg
12.5mcg

25mcg
50mcg

Note: Analysis adjusted for baseline (pre-dose on day 1), country, sex, age, stratum, treatment, time (nominal), time by treatment interaction
and time by baseline interaction

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Figure 7.20
Repeated Measures Adjusted Treatment Differences from Placebo in Change from Baseline FEV1 (L)
Over Time - Day 1

0.3

0.2

0.1

0.0

CONFIDENTIAL

258

Difference from Placebo (95% CI)

0.4

-0.1
2

10

12

14

16

18

20

22

24

Time (hours)

3mcg
6.25mcg

12.5mcg
25mcg

50mcg

Note: Analysis adjusted for baseline (pre-dose on day 1), country, sex, age, stratum, treatment, time (nominal), time by treatment interaction
and time by baseline interaction

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Figure 7.21
Repeated Measures Adjusted Treatment Differences from Placebo in Change from Baseline FEV1 (L)
Over Time - Day 28

0.3

0.2

0.1

20

22

0.0

CONFIDENTIAL

259

Difference from Placebo (95% CI)

0.4

-0.1
2

10

12

14

16

18

24

Time (hours)

3mcg
6.25mcg

12.5mcg
25mcg

50mcg

Note: Analysis adjusted for baseline (pre-dose on day 1), country, sex, age, stratum, treatment, time (nominal), time by treatment interaction
and time by baseline interaction

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Figure 7.22
Adjusted Treatment Differences of post-salbutamol/albuterol FEV1 (L)
Day 28 - Day 1

50mcg

CONFIDENTIAL

260

Treatment

25mcg

12.5mcg

6.25mcg

-0.2

-0.1

0.0

0.1

Difference From Placebo and 95% Confidence Interval

Note: Analysis performed using ANCOVA with covariates of baseline (pre-salbutamol measurement at Screening), country, sex, age,
stratum and treatment

0.2

YM2008/00019/00
B2C109575

3mcg

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Figure 7.23
Adjusted Treatment Differences of post-salbutamol/albuterol FEV1 (L)
Day 1 - Screening

50mcg

CONFIDENTIAL

261

Treatment

25mcg

12.5mcg

6.25mcg

-0.2

-0.1

0.0

0.1

Difference From Placebo and 95% Confidence Interval

Note: Analysis performed using ANCOVA with covariates of baseline (pre-salbutamol measurement at Screening), country, sex, age,
stratum and treatment

0.2

YM2008/00019/00
B2C109575

3mcg

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Figure 7.24
Adjusted Treatment Differences of post-salbutamol/albuterol FEV1 (L)
Day 28 - Screening

50mcg

CONFIDENTIAL

262

Treatment

25mcg

12.5mcg

6.25mcg

-0.2

-0.1

0.0

0.1

0.2

Difference From Placebo and 95% Confidence Interval

Note: Analysis performed using ANCOVA with covariates of baseline (pre-salbutamol measurement at Screening), country, sex, age, stratum and treatment

YM2008/00019/00
B2C109575

3mcg

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Figure 7.25
Adjusted Treatment Differences of Peak Post-Dose FEV1 (L) (0-4hrs)
Day 28

50mcg

CONFIDENTIAL

263

Treatment

25mcg

12.5mcg

6.25mcg

-0.2

-0.1

0.0

0.1

0.2

0.3

Difference From Placebo and 95% Confidence Interval

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age, stratum and treatment

0.4

YM2008/00019/00
B2C109575

3mcg

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Figure 7.26
Mean Change from Baseline in PM PEF (L/min)

60

40

30

10

20

CONFIDENTIAL

264

Mean Change in PM PEF (L/min)

50

-10
7

14

21

Day

Placebo
3mcg

Treatment
6.25mcg
12.5mcg

25mcg
50mcg

28

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Figure 7.27
Mean Change from Baseline in AM PEF (L/min)

60

40

30

10

20

CONFIDENTIAL

265

Mean Change in AM PEF (L/min)

50

-10
7

14

21

Day

Placebo
3mcg

Treatment
6.25mcg
12.5mcg

25mcg
50mcg

28

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 2
Figure 7.109
Proportion of Subjects Obtaining >= 200mL and >= 12% Increase from Baseline FEV1 (L)
Day 1

70

50

40

30

20

10

12

14

16

Time (hours)

Placebo
3mcg

6.25mcg
12.5mcg

25mcg
50mcg

18

20

22

24

YM2008/00019/00
B2C109575

CONFIDENTIAL

266

Percentage of Subjects

60

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 2
Figure 7.109
Proportion of Subjects Obtaining >= 200mL and >= 12% Increase from Baseline FEV1 (L)
Day 28

70

50

30

40

CONFIDENTIAL

267

Percentage of Subjects

60

20

10

12

14

16

Time (hours)

Placebo
3mcg

6.25mcg
12.5mcg

25mcg
50mcg

18

20

22

24

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Figure 7.111
Adjusted Treatment Differences of Change from Baseline in Percentage of Symptom Free 24 Hour Periods

50mcg

CONFIDENTIAL

268

Treatment

25mcg

12.5mcg

6.25mcg

-5

10

15

20

25

Difference From Placebo and 95% Confidence Interval

30

35

40

YM2008/00019/00
B2C109575

3mcg

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Figure 7.112
Adjusted Treatment Differences of Change from Baseline in Percentage of Rescue Free 24 Hour Periods

50mcg

CONFIDENTIAL

269

Treatment

25mcg

12.5mcg

6.25mcg

-5

10

15

20

25

Difference From Placebo and 95% Confidence Interval

30

35

40

YM2008/00019/00
B2C109575

3mcg

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Figure 7.113
Adjusted Treatment Differences of Change from Baseline in PM PEF (L/min), Days 1-28

50mcg

CONFIDENTIAL

270

Treatment

25mcg

12.5mcg

6.25mcg

10

20

30

40

Difference From Placebo and 95% Confidence Interval

50

60

YM2008/00019/00
B2C109575

3mcg

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Figure 7.114
Adjusted Treatment Differences of Change from Baseline in AM PEF (L/min), Days 1-28

50mcg

CONFIDENTIAL

271

Treatment

25mcg

12.5mcg

6.25mcg

10

20

30

40

Difference From Placebo and 95% Confidence Interval

50

60

YM2008/00019/00
B2C109575

3mcg

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Table 7.1
Summary of Trough FEV1 (L) (LOCF)
Intent-to-Treat

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------Trough FEV1 (L)
n
95
98
99
97
99
100
Mean
2.340
2.489
2.540
2.571
2.432
2.503
SD
0.7796
0.9238
0.7789
0.7867
0.7016
0.6678
Median
2.276
2.368
2.442
2.419
2.340
2.430
Min.
1.03
0.66
1.07
1.13
1.07
1.20
Max.
4.53
5.02
4.50
4.84
4.03
4.98

272

95

98

99

97

99

Mean
SD
Median
Min.
Max.

0.163
0.4100
0.066
-0.77
1.79

0.197
0.3994
0.119
-0.70
1.45

0.217
0.3693
0.183
-0.91
1.80

0.268
0.3871
0.201
-0.52
1.71

0.282
0.3295
0.278
-0.77
1.32

100
0.305
0.3106
0.248
-0.23
1.23

CONFIDENTIAL

Change from Baseline


in Trough FEV1 (L)

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.2
Linear Trend Test of Change from Baseline in Trough FEV1 (mL/mcg) (LOCF)
Intent-to-Treat
Day 28
----------------------------------------------------------------Linear Trend Test, p-value
0.003
Estimate of Slope
95% C.I.

2.545 mL/mcg
(0.893, 4.196)

CONFIDENTIAL

273

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and dose. Where dose is the dose in mcg of GW642444M for the 444 groups and 0 for placebo.

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.3
Linear Trend Test of Change from Baseline in Trough FEV1 (mL/mcg) (LOCF) Excluding Placebo
Intent-to-Treat
Day 28
----------------------------------------------------------------Linear Trend Test, p-value
0.037
Estimate of Slope
95% C.I.

1.924 mL/mcg
(0.120, 3.728)

CONFIDENTIAL

274

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and dose. Where dose is the dose in mcg of GW642444M for the 444 groups (Placebo is not included).

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.4
Statistical Analysis of Change from Baseline in Trough FEV1 (L) (LOCF)
Intent-to-Treat

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
95
98
99
97
99
100
LS Mean
2.388
2.452
2.458
2.518
2.509
2.550
LS Mean Change
0.147(0.036)
0.212(0.036)
0.217(0.035)
0.278(0.036)
0.269(0.035)
0.309(0.035)
(SE)
0.064
0.069
0.130
(-0.036,0.164) (-0.029,0.168) (0.030,0.230)
0.208
0.169
0.011

0.121
(0.023,0.220)
0.016

0.162
(0.062,0.261)
0.001

275

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.
p-value

Protocol: B2C109575
Population: Per Protocol

Page 1 of 1
Table 7.5
Summary of Trough FEV1 (L) (LOCF)
Per Protocol

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=98)
(N=97)
(N=98)
(N=98)
(N=93)
(N=99)
-------------------------------------------------------------------------------------------Trough FEV1 (L)
n
89
92
94
93
92
96
Mean
2.330
2.527
2.565
2.559
2.457
2.478
SD
0.8029
0.9228
0.7730
0.7753
0.6990
0.6418
Median
2.238
2.403
2.448
2.411
2.350
2.381
Min.
0.92
0.66
1.25
1.13
1.19
1.20
Max.
4.60
5.02
4.50
4.84
4.03
4.98

276

89

92

94

93

92

96

Mean
SD
Median
Min.
Max.

0.172
0.3948
0.084
-0.77
1.79

0.183
0.4186
0.116
-0.70
1.45

0.235
0.3597
0.187
-0.68
1.80

0.262
0.3884
0.209
-0.69
1.71

0.312
0.3028
0.298
-0.29
1.32

0.290
0.2970
0.244
-0.23
1.23

CONFIDENTIAL

Change from Baseline


in Trough FEV1 (L)

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Per Protocol

Page 1 of 1

Table 7.6
Linear Trend Test of Change from Baseline in Trough FEV1 (mL/mcg) (LOCF)
Per Protocol
Day 28
----------------------------------------------------------------Linear Trend Test, p-value
0.009
Estimate of Slope
95% C.I.

2.212 mL/mcg
(0.557, 3.867)

CONFIDENTIAL

277

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and dose. Where dose is the dose in mcg of GW642444M for the 444 groups and 0 for placebo.

Protocol: B2C109575
Population: Per Protocol

Page 1 of 1

Table 7.7
Statistical Analysis of Change from Baseline in Trough FEV1 (L) (LOCF)
Per Protocol

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=98)
(N=97)
(N=98)
(N=98)
(N=93)
(N=99)
-----------------------------------------------------------------------------------------------------------n
89
92
94
93
92
96
LS Mean
2.402
2.447
2.478
2.519
2.536
2.537
LS Mean Change
0.157(0.037)
0.203(0.036)
0.233(0.035)
0.275(0.035)
0.292(0.036)
0.293(0.035)
(SE)
0.046
0.076
0.118
(-0.056,0.148) (-0.024,0.176) (0.017,0.218)
0.375
0.134
0.022

0.135
(0.035,0.234)
0.008

0.135
(0.035,0.235)
0.008

278

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.
p-value

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.8
Linear Trend Test of Change from Baseline in Trough FEV1 (mL/mcg) (Repeated Measures)
Day 28
----------------------------------------------------------------Linear Trend Test, p-value
0.004
Estimate of Slope
95% C.I.

2.352 mL/mcg
(0.748, 3.957)

CONFIDENTIAL

279

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, dose, visit, visit by baseline interaction and visit by dose interaction
Where dose is the dose in mcg of GW642444M for the 444 groups and 0 for placebo.

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 4

Table 7.9
Statistical Analysis of Change from Baseline in Trough FEV1 (L) (Repeated Measures)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7: pre-dose
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
95
98
99
97
99
100
LS Mean
2.383
2.450
2.433
2.465
2.455
2.498
LS Mean Change
0.142(0.034)
0.210(0.033)
0.192(0.033)
0.225(0.033)
0.214(0.033)
0.258(0.033)
(SE)
0.068
0.050
0.082
0.072
0.116
(-0.026,0.162) (-0.043,0.143) (-0.011,0.176) (-0.020,0.165) (0.022,0.209)
0.158
0.292
0.085
0.126
0.015

280

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, visit, treatment, visit by baseline and visit by treatment interactions

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.
p-value

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 4

Table 7.9
Statistical Analysis of Change from Baseline in Trough FEV1 (L) (Repeated Measures)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14: pre-dose
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
95
98
99
97
99
100
LS Mean
2.391
2.452
2.417
2.456
2.463
2.499
LS Mean Change
0.150(0.036)
0.212(0.035)
0.177(0.035)
0.216(0.035)
0.222(0.035)
0.258(0.035)
(SE)
0.061
0.026
0.065
0.072
0.108
(-0.038,0.161) (-0.072,0.124) (-0.034,0.164) (-0.026,0.169) (0.010,0.206)
0.224
0.600
0.196
0.150
0.032

281

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, visit, treatment, visit by baseline and visit by treatment interactions

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.
p-value

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 4

Table 7.9
Statistical Analysis of Change from Baseline in Trough FEV1 (L) (Repeated Measures)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28: pre-dose
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
95
98
99
97
99
100
LS Mean
2.395
2.411
2.412
2.452
2.461
2.522
LS Mean Change
0.154(0.035)
0.171(0.035)
0.172(0.035)
0.212(0.035)
0.221(0.035)
0.282(0.034)
(SE)
0.017
0.018
0.058
0.067
0.128
(-0.082,0.116) (-0.080,0.115) (-0.041,0.156) (-0.030,0.164) (0.030,0.225)
0.741
0.724
0.251
0.178
0.010

282

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, visit, treatment, visit by baseline and visit by treatment interactions

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.
p-value

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 4

Table 7.9
Statistical Analysis of Change from Baseline in Trough FEV1 (L) (Repeated Measures)

Day 28: 23-24


Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
95
98
99
97
99
100
LS Mean
2.397
2.470
2.461
2.521
2.524
2.549
LS Mean Change
0.156(0.035)
0.230(0.035)
0.221(0.034)
0.280(0.035)
0.283(0.034)
0.309(0.034)
(SE)
0.073
0.064
0.124
(-0.025,0.172) (-0.032,0.161) (0.026,0.221)
0.142
0.191
0.013

0.127
(0.031,0.223)
0.010

0.152
(0.056,0.249)
0.002

283

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, visit, treatment, visit by baseline and visit by treatment interactions

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.
p-value

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 6

Table 7.10
Summary of Pre-Dose and Trough FEV1 (L) (No Imputation)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1: pre-dose
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
--------------------------------------------------------------------------------------------------------FEV1 (L)
n
102
101
101
100
101
102
Mean
2.220
2.284
2.310
2.303
2.150
2.199
SD
0.6826
0.7898
0.6385
0.6632
0.6154
0.5953
Median
2.118
2.228
2.351
2.269
2.095
2.173
Min.
0.93
0.79
1.16
0.91
1.01
1.12
Max.
4.47
3.99
3.64
4.12
3.84
4.08

CONFIDENTIAL

284

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 6

Table 7.10
Summary of Pre-Dose and Trough FEV1 (L) (No Imputation)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1: 23-24 hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
--------------------------------------------------------------------------------------------------------FEV1 (L)
n
101
101
101
99
100
101
Mean
2.398
2.523
2.517
2.557
2.464
2.513
SD
0.7885
0.9285
0.7657
0.7754
0.7154
0.6408
Median
2.276
2.415
2.528
2.484
2.342
2.509
Min.
1.06
0.83
1.17
1.07
1.03
1.27
Max.
4.58
4.90
4.27
5.00
4.23
4.57
Change from Baseline in FEV1 (L)

101
0.186
0.3811
0.117
-0.39
1.74

101
0.238
0.3608
0.148
-0.44
1.56

101
0.208
0.3070
0.192
-0.55
1.27

99
0.257
0.3593
0.173
-0.22
1.98

100
0.319
0.3453
0.246
-0.33
1.97

101
0.314
0.2564
0.275
-0.60
1.13

CONFIDENTIAL

285

n
Mean
SD
Median
Min.
Max.

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 6

Table 7.10
Summary of Pre-Dose and Trough FEV1 (L) (No Imputation)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7: pre-dose
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
--------------------------------------------------------------------------------------------------------FEV1 (L)
n
95
98
99
97
99
100
Mean
2.332
2.489
2.517
2.520
2.375
2.452
SD
0.7569
0.9000
0.7875
0.7947
0.6751
0.6786
Median
2.273
2.365
2.495
2.426
2.239
2.455
Min.
0.98
0.86
0.93
0.82
1.10
1.20
Max.
4.80
4.74
4.65
5.12
4.03
5.10
Change from Baseline in FEV1 (L)

95
0.155
0.3675
0.049
-0.43
1.66

98
0.197
0.3563
0.128
-0.39
1.53

99
0.194
0.3432
0.117
-0.68
1.18

97
0.216
0.3753
0.151
-0.73
1.73

99
0.225
0.3128
0.189
-0.77
1.13

100
0.254
0.3009
0.202
-0.39
1.10

CONFIDENTIAL

286

n
Mean
SD
Median
Min.
Max.

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 6

Table 7.10
Summary of Pre-Dose and Trough FEV1 (L) (No Imputation)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14: pre-dose
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
--------------------------------------------------------------------------------------------------------FEV1 (L)
n
93
92
95
92
95
98
Mean
2.347
2.562
2.523
2.500
2.400
2.461
SD
0.7816
0.8677
0.7736
0.7822
0.7065
0.6569
Median
2.274
2.399
2.465
2.428
2.262
2.391
Min.
1.00
0.66
1.07
0.87
1.11
1.36
Max.
4.89
4.82
4.44
5.05
3.99
5.20
Change from Baseline in FEV1 (L)

93
0.171
0.3794
0.078
-0.46
1.84

92
0.208
0.3722
0.176
-0.70
1.30

95
0.183
0.3675
0.100
-0.91
1.44

92
0.199
0.3464
0.153
-0.40
1.77

95
0.256
0.3045
0.193
-0.29
1.60

98
0.252
0.3154
0.203
-0.31
1.27

CONFIDENTIAL

287

n
Mean
SD
Median
Min.
Max.

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 5 of 6

Table 7.10
Summary of Pre-Dose and Trough FEV1 (L) (No Imputation)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28: pre-dose
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
--------------------------------------------------------------------------------------------------------FEV1 (L)
n
89
86
91
89
94
98
Mean
2.347
2.571
2.563
2.483
2.399
2.485
SD
0.8012
0.8443
0.7555
0.7727
0.6911
0.6755
Median
2.289
2.444
2.541
2.349
2.315
2.470
Min.
0.92
1.27
1.14
1.02
1.16
1.29
Max.
5.07
4.82
4.33
4.90
4.08
4.95
Change from Baseline in FEV1 (L)

89
0.174
0.3840
0.084
-0.60
1.68

86
0.191
0.3676
0.109
-0.63
1.38

91
0.195
0.3309
0.129
-0.39
1.51

89
0.194
0.3241
0.154
-0.69
1.72

94
0.258
0.3176
0.226
-0.43
1.70

98
0.276
0.3229
0.225
-0.28
1.46

CONFIDENTIAL

288

n
Mean
SD
Median
Min.
Max.

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 6 of 6

Table 7.10
Summary of Pre-Dose and Trough FEV1 (L) (No Imputation)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28: 23-24 hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
--------------------------------------------------------------------------------------------------------FEV1 (L)
n
87
84
91
88
93
97
Mean
2.365
2.637
2.611
2.556
2.469
2.516
SD
0.7837
0.8704
0.7609
0.7635
0.7051
0.6630
Median
2.286
2.511
2.495
2.415
2.385
2.450
Min.
1.03
1.22
1.25
1.13
1.07
1.42
Max.
4.53
5.02
4.50
4.84
4.03
4.98
Change from Baseline in FEV1 (L)

87
0.186
0.4057
0.084
-0.77
1.79

84
0.254
0.3668
0.147
-0.41
1.45

91
0.243
0.3466
0.186
-0.34
1.80

88
0.269
0.3438
0.205
-0.36
1.71

93
0.318
0.2915
0.297
-0.18
1.32

97
0.302
0.3119
0.245
-0.23
1.23

CONFIDENTIAL

289

n
Mean
SD
Median
Min.
Max.

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 2

Table 7.11
Summary of Change from Baseline in Trough FEV1 (L) (LOCF) at Day 28 by %Predicted FEV1 Stratum

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Stratum 1: >=40% - <=65%
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
------------------------------------------------------------------------------------------------Trough FEV1 (L)
n
43
44
41
40
46
45
Mean
1.974
1.897
2.121
2.151
2.165
2.200
SD
0.6917
0.6543
0.6599
0.6369
0.6689
0.5461
Median
1.758
1.811
1.924
2.038
2.022
2.107
Min.
1.03
0.66
1.07
1.13
1.07
1.20
Max.
4.16
3.76
4.50
4.09
3.76
3.45

290

43

44

41

40

46

45

Mean
SD
Median
Min.
Max.

0.233
0.4549
0.106
-0.52
1.79

0.159
0.3899
0.152
-0.70
1.45

0.265
0.3790
0.221
-0.91
1.80

0.311
0.4419
0.214
-0.50
1.71

0.322
0.3264
0.302
-0.77
1.32

0.373
0.3183
0.329
-0.19
1.23

CONFIDENTIAL

Change from Baseline in


Trough FEV1 (L)

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 2

Table 7.11
Summary of Change from Baseline in Trough FEV1 (L) (LOCF) at Day 28 by %Predicted FEV1 Stratum

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Stratum 2: >65% - <=90%
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
------------------------------------------------------------------------------------------------Trough FEV1 (L)
n
52
54
58
57
53
55
Mean
2.642
2.972
2.836
2.867
2.663
2.751
SD
0.7210
0.8287
0.7224
0.7505
0.6504
0.6598
Median
2.472
2.837
2.801
2.786
2.612
2.731
Min.
1.26
1.23
1.60
1.65
1.39
1.75
Max.
4.53
5.02
4.35
4.84
4.03
4.98

291

52

54

58

57

53

55

Mean
SD
Median
Min.
Max.

0.105
0.3631
0.042
-0.77
1.20

0.228
0.4080
0.111
-0.57
1.18

0.183
0.3617
0.157
-0.68
0.93

0.238
0.3444
0.199
-0.52
1.71

0.248
0.3315
0.228
-0.60
1.21

0.249
0.2955
0.222
-0.23
1.16

CONFIDENTIAL

Change from Baseline in


Trough FEV1 (L)

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.12
Slope Estimate of Change from Baseline in Trough FEV1 (mL/mcg) (LOCF) at Day 28
by %Predicted FEV1 Stratum
Stratum
------------------------------------------------------------------1: >=40% - <=65%
Estimate of Slope
2.833 mL/mcg
95% C.I.
(0.136, 5.529)
2: >65% - <=90%

Estimate of Slope
95% C.I.

2.222 mL/mcg
(0.085, 4.359)

CONFIDENTIAL

292

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
and dose. Where dose is the dose in mcg of GW642444M for the 444 groups and 0 for placebo.

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.13
Statistical Analysis of Change from Baseline in Trough FEV1 (L) (LOCF) at Day 28
by %Predicted FEV1 Stratum

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Stratum 1: >=40% <=65%
n
43
44
41
40
46
45
LS Mean
2.450
2.402
2.487
2.559
2.522
2.590
LS Mean Change
0.210(0.057)
0.161(0.056)
0.247(0.057)
0.319(0.057)
0.281(0.054)
0.349(0.055)
(SE)

293

Stratum 2: >65% <=90%


n
LS Mean
LS Mean Change
(SE)
Column vs Placebo
Difference
95% C.I.

-0.049
0.037
0.109
0.072
0.139
(-0.198,0.100) (-0.113,0.188) (-0.044,0.262) (-0.075,0.218) (-0.009,0.287)

52
2.338
0.098(0.049)

54
2.495
0.254(0.051)

0.156
(0.022,0.291)

58
2.435
0.194(0.048)

57
2.488
0.247(0.049)

0.097
0.149
(-0.035,0.228) (0.018,0.281)

53
2.499
0.259(0.049)

0.161
(0.027,0.295)

55
2.517
0.276(0.049)

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.

0.178
(0.045,0.312)

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age, ,
stratum, treatment and treatment by stratum interaction

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 6
Table 7.14
Summary of Raw Serial FEV1 (L)

Day 28

89
86
85
87
87
86
86
59
59
87
87
87
86
86

2.347
2.326
2.337
2.328
2.331
2.330
2.315
2.434
2.334
2.366
2.375
2.371
2.377
2.361

0.8012
0.7668
0.7873
0.7645
0.7684
0.7774
0.7882
0.7966
0.7574
0.7351
0.7756
0.7584
0.7798
0.7989

2.289
2.266
2.278
2.243
2.239
2.196
2.213
2.382
2.264
2.261
2.276
2.273
2.316
2.260

0.92
0.90
0.85
0.96
0.96
0.89
0.83
1.11
1.00
1.06
1.01
1.03
1.07
0.97

5.07
4.69
4.74
4.63
4.68
4.53
4.52
4.85
4.37
4.32
4.63
4.43
4.46
4.60

YM2008/00019/00
B2C109575

Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours
6 hours
12 hours
16 hours
20 hours
22 hours
23 hours
24 hours

CONFIDENTIAL

294

Planned
Treatment
N Visit
Relative time
n
Mean
SD
Median
Min.
Max.
--------------------------------------------------------------------------------------------Placebo
102
Day 1
Pre-dose
102
2.220
0.6826
2.118
0.93
4.47
15 mins
102
2.310
0.7626
2.203
0.84
4.88
30 mins
99
2.318
0.7810
2.227
0.89
5.11
1 hour
101
2.346
0.7843
2.218
0.87
5.12
2 hours
100
2.351
0.7991
2.273
0.77
5.00
3 hours
101
2.339
0.7660
2.266
0.76
4.97
4 hours
100
2.320
0.7778
2.269
0.70
4.87
6 hours
66
2.412
0.7851
2.353
1.05
4.65
12 hours
66
2.360
0.7995
2.246
0.72
4.78
16 hours
101
2.412
0.8069
2.317
0.83
4.69
20 hours
100
2.423
0.7862
2.314
0.89
4.62
22 hours
101
2.388
0.7908
2.290
1.05
4.71
23 hours
99
2.414
0.7996
2.345
1.08
4.63
24 hours
98
2.375
0.7937
2.219
1.05
4.53

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 6
Table 7.14
Summary of Raw Serial FEV1 (L)

Day 28

86
84
85
85
84
82
84
56
56
84
84
84
84
83

2.571
2.616
2.627
2.654
2.657
2.664
2.636
2.690
2.629
2.693
2.675
2.678
2.653
2.615

0.8443
0.8418
0.8198
0.8553
0.8389
0.8644
0.8556
0.8682
0.8710
0.8673
0.8584
0.8745
0.8658
0.8842

2.444
2.581
2.546
2.485
2.526
2.522
2.477
2.550
2.469
2.522
2.569
2.510
2.474
2.478

1.27
1.32
1.31
1.26
1.30
1.29
1.26
1.24
1.23
1.22
1.15
1.21
1.24
1.19

4.82
4.85
4.87
5.02
5.03
5.05
5.06
5.07
4.96
4.99
5.02
4.96
4.98
5.06

YM2008/00019/00
B2C109575

Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours
6 hours
12 hours
16 hours
20 hours
22 hours
23 hours
24 hours

CONFIDENTIAL

295

Planned
Treatment
N Visit
Relative time
n
Mean
SD
Median
Min.
Max.
--------------------------------------------------------------------------------------------3mcg
101
Day 1
Pre-dose
101
2.284
0.7898
2.228
0.79
3.99
15 mins
97
2.430
0.8621
2.345
0.74
4.51
30 mins
97
2.465
0.8856
2.351
0.73
4.79
1 hour
101
2.466
0.9038
2.258
0.84
4.70
2 hours
101
2.485
0.9342
2.337
0.80
4.72
3 hours
100
2.501
0.9412
2.379
0.92
4.80
4 hours
101
2.486
0.9357
2.374
0.92
4.79
6 hours
67
2.523
0.9637
2.425
0.93
4.90
12 hours
66
2.511
0.9619
2.353
0.91
4.78
16 hours
100
2.518
0.9087
2.402
0.89
4.88
20 hours
99
2.555
0.9347
2.394
0.83
4.91
22 hours
99
2.530
0.9418
2.390
0.80
4.98
23 hours
101
2.516
0.9322
2.422
0.88
4.86
24 hours
98
2.499
0.9137
2.373
0.79
4.95

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 6
Table 7.14
Summary of Raw Serial FEV1 (L)

Day 28

91
90
90
91
91
91
91
61
61
90
91
90
90
91

2.563
2.588
2.592
2.622
2.625
2.645
2.621
2.752
2.688
2.637
2.656
2.628
2.619
2.606

0.7555
0.7577
0.7575
0.7726
0.7738
0.7748
0.7713
0.7770
0.7467
0.7682
0.7676
0.7749
0.7621
0.7667

2.541
2.520
2.512
2.659
2.658
2.598
2.620
2.731
2.635
2.578
2.601
2.564
2.536
2.440

1.14
1.18
1.15
1.16
1.24
1.22
1.19
1.28
1.13
1.24
1.12
1.15
1.28
1.23

4.33
4.37
4.28
4.37
4.38
4.41
4.34
4.21
4.25
4.45
4.61
4.60
4.57
4.44

YM2008/00019/00
B2C109575

Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours
6 hours
12 hours
16 hours
20 hours
22 hours
23 hours
24 hours

CONFIDENTIAL

296

Planned
Treatment
N Visit
Relative time
n
Mean
SD
Median
Min.
Max.
--------------------------------------------------------------------------------------------6.25mcg
101
Day 1
Pre-dose
101
2.310
0.6385
2.351
1.16
3.64
15 mins
99
2.410
0.7211
2.392
1.11
4.03
30 mins
100
2.455
0.7318
2.399
1.16
4.09
1 hour
101
2.483
0.7388
2.433
1.18
4.31
2 hours
101
2.510
0.7369
2.538
1.22
4.39
3 hours
99
2.507
0.7649
2.483
1.14
4.44
4 hours
101
2.511
0.7526
2.485
1.19
4.32
6 hours
69
2.649
0.7653
2.673
1.24
4.32
12 hours
70
2.567
0.8007
2.516
0.85
4.46
16 hours
101
2.572
0.7601
2.596
1.23
4.43
20 hours
101
2.541
0.7536
2.544
1.14
4.29
22 hours
101
2.528
0.7625
2.499
1.15
4.29
23 hours
101
2.506
0.7681
2.485
1.17
4.47
24 hours
101
2.528
0.7694
2.519
1.15
4.17

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 6
Table 7.14
Summary of Raw Serial FEV1 (L)

Day 28

89
87
88
88
88
88
88
64
64
88
87
85
87
87

2.483
2.530
2.536
2.558
2.568
2.591
2.576
2.617
2.520
2.582
2.581
2.528
2.563
2.546

0.7727
0.7837
0.7935
0.8028
0.8039
0.7934
0.7983
0.7958
0.8031
0.7560
0.7691
0.7380
0.7646
0.7661

2.349
2.424
2.427
2.435
2.434
2.440
2.454
2.525
2.436
2.489
2.468
2.427
2.434
2.440

1.02
1.14
1.07
1.16
1.16
1.15
1.15
1.02
1.01
1.16
1.07
1.12
1.11
1.14

4.90
5.00
5.04
5.10
5.02
4.92
4.86
4.78
4.80
5.00
4.90
4.94
4.88
4.81

YM2008/00019/00
B2C109575

Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours
6 hours
12 hours
16 hours
20 hours
22 hours
23 hours
24 hours

CONFIDENTIAL

297

Planned
Treatment
N Visit
Relative time
n
Mean
SD
Median
Min.
Max.
--------------------------------------------------------------------------------------------12.5mcg
100
Day 1
Pre-dose
100
2.303
0.6632
2.269
0.91
4.12
15 mins
99
2.481
0.8050
2.388
1.03
4.84
30 mins
99
2.535
0.8160
2.414
1.04
4.93
1 hour
99
2.569
0.7981
2.436
1.02
4.94
2 hours
98
2.589
0.8139
2.499
1.08
4.99
3 hours
99
2.603
0.8068
2.477
1.00
5.07
4 hours
99
2.589
0.8009
2.490
1.00
5.18
6 hours
71
2.615
0.7589
2.553
1.36
4.75
12 hours
70
2.549
0.7824
2.481
1.29
4.96
16 hours
99
2.572
0.8067
2.508
1.09
5.07
20 hours
99
2.570
0.7923
2.493
1.03
4.94
22 hours
96
2.559
0.7584
2.487
1.03
4.93
23 hours
98
2.568
0.7923
2.512
1.08
5.03
24 hours
97
2.543
0.7741
2.473
1.06
4.97

Protocol: B2C109575
Population: Intent-to-Treat

Page 5 of 6
Table 7.14
Summary of Raw Serial FEV1 (L)

Day 28

94
93
93
93
93
92
93
56
56
93
93
93
93
93

2.399
2.457
2.487
2.511
2.513
2.511
2.503
2.500
2.406
2.476
2.504
2.492
2.465
2.474

0.6911
0.6931
0.7063
0.7102
0.6942
0.7085
0.6899
0.7085
0.6966
0.6796
0.6993
0.7151
0.7030
0.7110

2.315
2.334
2.358
2.396
2.370
2.359
2.380
2.308
2.323
2.270
2.401
2.460
2.358
2.412

1.16
1.16
1.12
1.24
1.23
1.24
1.22
1.18
1.13
1.34
1.15
1.02
0.99
1.15

4.08
4.05
4.15
4.10
4.10
4.07
4.10
4.08
4.07
4.08
4.23
4.01
4.06
4.03

YM2008/00019/00
B2C109575

Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours
6 hours
12 hours
16 hours
20 hours
22 hours
23 hours
24 hours

CONFIDENTIAL

298

Planned
Treatment
N Visit
Relative time
n
Mean
SD
Median
Min.
Max.
--------------------------------------------------------------------------------------------25mcg
101
Day 1
Pre-dose
101
2.150
0.6154
2.095
1.01
3.84
15 mins
98
2.410
0.7122
2.238
1.06
4.08
30 mins
98
2.451
0.7128
2.388
1.08
4.08
1 hour
101
2.462
0.7138
2.384
1.07
4.16
2 hours
101
2.490
0.7246
2.363
0.97
4.30
3 hours
98
2.532
0.7401
2.352
1.04
4.33
4 hours
100
2.505
0.7321
2.378
0.99
4.30
6 hours
62
2.512
0.7679
2.336
1.01
4.29
12 hours
62
2.432
0.7847
2.228
1.06
4.07
16 hours
101
2.512
0.7218
2.334
1.20
4.55
20 hours
101
2.491
0.7256
2.318
1.09
4.35
22 hours
100
2.471
0.7071
2.304
1.02
4.16
23 hours
99
2.472
0.7128
2.353
1.07
4.10
24 hours
98
2.467
0.7314
2.345
1.00
4.36

Protocol: B2C109575
Population: Intent-to-Treat

Page 6 of 6
Table 7.14
Summary of Raw Serial FEV1 (L)

Day 28

98
94
97
97
97
98
98
57
58
97
97
94
97
96

2.485
2.519
2.530
2.568
2.577
2.569
2.553
2.518
2.494
2.539
2.557
2.521
2.523
2.505

0.6755
0.6897
0.6533
0.6757
0.6811
0.6728
0.6702
0.6731
0.7353
0.6764
0.6611
0.6558
0.6812
0.6574

2.470
2.507
2.498
2.539
2.570
2.579
2.537
2.472
2.420
2.484
2.512
2.413
2.426
2.409

1.29
1.34
1.24
1.32
1.35
1.43
1.35
1.32
1.15
1.23
1.23
1.32
1.32
1.41

4.95
4.98
4.82
4.84
5.03
4.91
4.88
4.87
4.99
5.17
4.74
4.93
5.07
4.90

YM2008/00019/00
B2C109575

Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours
6 hours
12 hours
16 hours
20 hours
22 hours
23 hours
24 hours

CONFIDENTIAL

299

Planned
Treatment
N Visit
Relative time
n
Mean
SD
Median
Min.
Max.
--------------------------------------------------------------------------------------------50mcg
102
Day 1
Pre-dose
102
2.199
0.5953
2.173
1.12
4.08
15 mins
98
2.428
0.6583
2.340
1.10
4.98
30 mins
97
2.491
0.6586
2.431
1.17
4.91
1 hour
101
2.527
0.6604
2.486
1.28
5.03
2 hours
100
2.561
0.7003
2.466
1.20
5.22
3 hours
100
2.570
0.6776
2.553
1.27
5.05
4 hours
99
2.562
0.6844
2.548
1.28
5.18
6 hours
59
2.549
0.7025
2.545
1.20
4.64
12 hours
60
2.529
0.7509
2.512
1.04
4.76
16 hours
101
2.561
0.6948
2.546
1.14
5.18
20 hours
99
2.551
0.6897
2.511
1.05
5.07
22 hours
100
2.511
0.6829
2.477
1.19
5.14
23 hours
100
2.523
0.6682
2.486
1.31
4.94
24 hours
99
2.497
0.6298
2.464
1.19
4.24

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 3

Table 7.15
Summary of Absolute Change from Baseline in Serial FEV1 (L) (0-4hrs)

Planned
Treatment
N Visit
Relative time
n
Mean
SD
Median
Min.
Max.
--------------------------------------------------------------------------------------------Placebo
102
Day 1
15 mins
102
0.090
0.3169
0.009
-0.47
1.65
30 mins
99
0.090
0.3521
-0.001
-0.94
1.59
1 hour
101
0.118
0.3423
0.013
-0.43
1.63
2 hours
100
0.130
0.3490
0.042
-0.52
1.62
3 hours
101
0.112
0.3458
0.025
-0.44
1.72
4 hours
100
0.099
0.3743
0.018
-1.02
1.66

101

Day 1

15 mins
30 mins
1 hour
2 hours
3 hours
4 hours

Day 28

Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours

0.174
0.138
0.146
0.149
0.152
0.166
0.133

0.3840
0.3737
0.3797
0.3728
0.3865
0.3872
0.3693

0.084
0.042
0.094
0.078
0.031
0.085
0.075

-0.60
-0.55
-0.67
-0.71
-0.74
-0.92
-0.79

1.68
1.71
1.74
1.57
1.62
1.79
1.66

97
97
101
101
100
101

0.121
0.152
0.182
0.201
0.221
0.201

0.2668
0.2930
0.3126
0.3448
0.3515
0.3380

0.069
0.074
0.084
0.099
0.115
0.110

-0.31
-0.23
-0.27
-0.42
-0.39
-0.28

1.15
1.16
1.42
1.43
1.49
1.34

86
84
85
85
84
82
84

0.191
0.226
0.237
0.263
0.275
0.267
0.254

0.3676
0.3304
0.3302
0.3555
0.3515
0.3494
0.3408

0.109
0.127
0.147
0.162
0.178
0.179
0.170

-0.63
-0.44
-0.43
-0.27
-0.47
-0.38
-0.41

1.38
1.40
1.33
1.48
1.48
1.52
1.52

CONFIDENTIAL

3mcg

89
86
85
87
87
86
86

YM2008/00019/00
B2C109575

Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours

300

Day 28

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 3

Table 7.15
Summary of Absolute Change from Baseline in Serial FEV1 (L) (0-4hrs)

Planned
Treatment
N Visit
Relative time
n
Mean
SD
Median
Min.
Max.
--------------------------------------------------------------------------------------------6.25mcg
101
Day 1
15 mins
99
0.098
0.2312
0.078
-0.40
1.18
30 mins
100
0.148
0.2673
0.117
-0.40
1.39
1 hour
101
0.174
0.2772
0.117
-0.36
1.36
2 hours
101
0.200
0.2885
0.137
-0.25
1.43
3 hours
99
0.210
0.3070
0.167
-0.48
1.40
4 hours
101
0.201
0.2912
0.157
-0.47
1.30
0.195
0.221
0.226
0.254
0.257
0.278
0.253

0.3309
0.3288
0.3320
0.3422
0.3464
0.3408
0.3367

0.129
0.155
0.166
0.191
0.198
0.205
0.226

-0.39
-0.36
-0.33
-0.35
-0.31
-0.25
-0.45

1.51
1.33
1.49
1.44
1.68
1.67
1.64

12.5mcg

100

Day 1

15 mins
30 mins
1 hour
2 hours
3 hours
4 hours

99
99
99
98
99
99

0.179
0.234
0.270
0.292
0.304
0.290

0.3562
0.3641
0.3335
0.3620
0.3398
0.3498

0.123
0.180
0.211
0.228
0.232
0.236

-0.46
-0.27
-0.31
-0.21
-0.15
-0.26

1.92
1.95
1.95
2.05
1.97
2.00

Day 28

Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours

89
87
88
88
88
88
88

0.194
0.238
0.250
0.272
0.281
0.305
0.290

0.3241
0.3260
0.3311
0.3336
0.3345
0.3263
0.3251

0.154
0.198
0.219
0.248
0.215
0.251
0.235

-0.69
-0.39
-0.34
-0.24
-0.26
-0.28
-0.36

1.72
1.61
1.57
1.61
1.65
1.60
1.53

CONFIDENTIAL

91
90
90
91
91
91
91

YM2008/00019/00
B2C109575

Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours

301

Day 28

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 3

Table 7.15
Summary of Absolute Change from Baseline in Serial FEV1 (L) (0-4hrs)

Planned
Treatment
N Visit
Relative time
n
Mean
SD
Median
Min.
Max.
--------------------------------------------------------------------------------------------25mcg
101
Day 1
15 mins
98
0.253
0.3088
0.180
-0.32
1.89
30 mins
98
0.293
0.3241
0.231
-0.48
1.89
1 hour
101
0.312
0.3231
0.257
-0.32
1.95
2 hours
101
0.340
0.3397
0.277
-0.26
2.12
3 hours
98
0.392
0.3527
0.313
-0.19
2.05
4 hours
100
0.355
0.3423
0.312
-0.22
2.01

102

Day 1

15 mins
30 mins
1 hour
2 hours
3 hours
4 hours

Day 28

Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours

0.258
0.306
0.337
0.360
0.362
0.368
0.353

0.3176
0.3057
0.3123
0.3266
0.2992
0.3053
0.2957

0.226
0.253
0.278
0.324
0.328
0.347
0.342

-0.43
-0.39
-0.28
-0.23
-0.17
-0.28
-0.46

1.70
1.66
1.77
1.68
1.45
1.48
1.33

98
97
101
100
100
99

0.233
0.293
0.331
0.368
0.374
0.367

0.2177
0.2067
0.2250
0.2651
0.2563
0.2730

0.213
0.272
0.292
0.317
0.324
0.331

-0.56
-0.17
-0.29
-0.20
-0.30
-0.26

0.90
0.88
0.95
1.51
1.22
1.33

98
94
97
97
97
98
98

0.276
0.315
0.319
0.361
0.366
0.360
0.343

0.3229
0.3299
0.3271
0.3365
0.3499
0.3395
0.3365

0.225
0.256
0.259
0.319
0.281
0.304
0.290

-0.28
-0.48
-0.41
-0.32
-0.34
-0.47
-0.45

1.46
1.57
1.50
1.52
1.49
1.46
1.56

CONFIDENTIAL

50mcg

94
93
93
93
93
92
93

YM2008/00019/00
B2C109575

Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours

302

Day 28

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 3

Table 7.16
Summary of Percentage Change from Baseline in Serial FEV1 (%) (0-4hrs)

Planned
Treatment
N Visit
Relative time
n
Mean
SD
Median
Min.
Max.
--------------------------------------------------------------------------------------------Placebo
102
Day 1
15 mins
102
4.17
15.118
0.36
-26.5
79.6
30 mins
99
4.22
15.706
-0.06
-28.4
79.0
1 hour
101
5.39
15.813
0.73
-19.6
75.6
2 hours
100
5.70
16.243
1.73
-23.8
80.5
3 hours
101
5.20
15.703
1.23
-25.2
75.1
4 hours
100
4.77
16.965
0.77
-30.8
82.4

101

Day 1

15 mins
30 mins
1 hour
2 hours
3 hours
4 hours

Day 28

Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours

8.46
6.94
7.13
7.68
7.78
8.16
6.29

18.127
17.669
17.401
17.403
18.283
17.838
16.938

3.43
2.92
4.05
3.58
2.90
3.49
3.03

-23.6
-19.3
-22.2
-25.3
-25.5
-31.8
-27.3

79.5
70.9
76.0
76.1
80.6
82.2
77.1

97
97
101
101
100
101

5.43
6.52
8.01
8.56
9.56
8.49

11.936
12.578
13.195
14.584
14.829
14.010

3.38
3.67
4.42
5.03
5.71
5.60

-15.3
-9.3
-10.1
-13.6
-21.1
-14.8

48.3
46.5
60.8
65.8
66.8
57.6

86
84
85
85
84
82
84

9.20
10.66
11.38
12.13
13.08
12.25
11.77

16.611
14.742
15.324
16.201
16.755
16.435
15.826

5.42
5.97
6.97
7.76
7.38
8.88
8.59

-32.8
-14.9
-13.7
-12.2
-21.1
-17.0
-18.3

59.7
60.3
59.0
72.6
65.6
72.8
65.7

CONFIDENTIAL

3mcg

89
86
85
87
87
86
86

YM2008/00019/00
B2C109575

Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours

303

Day 28

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 3

Table 7.16
Summary of Percentage Change from Baseline in Serial FEV1 (%) (0-4hrs)

Planned
Treatment
N Visit
Relative time
n
Mean
SD
Median
Min.
Max.
--------------------------------------------------------------------------------------------6.25mcg
101
Day 1
15 mins
99
3.92
9.764
3.49
-19.9
43.7
30 mins
100
6.36
11.142
5.35
-14.1
51.4
1 hour
101
7.46
11.410
5.71
-12.9
50.2
2 hours
101
8.75
12.055
6.97
-10.6
53.1
3 hours
99
9.01
13.022
8.50
-29.5
52.0
4 hours
101
8.65
12.002
7.72
-16.1
48.1
8.37
9.53
9.82
10.85
11.00
11.84
10.77

13.663
13.450
13.765
13.967
14.377
14.082
13.813

5.46
7.21
6.79
10.06
8.02
9.13
9.69

-17.2
-12.9
-15.3
-18.4
-16.4
-10.4
-18.0

55.8
49.2
55.1
53.3
62.3
61.9
60.6

12.5mcg

100

Day 1

15 mins
30 mins
1 hour
2 hours
3 hours
4 hours

99
99
99
98
99
99

7.62
10.03
11.82
12.89
13.26
12.87

14.270
14.776
13.778
15.295
13.596
14.277

5.41
7.73
9.64
9.72
10.26
9.54

-18.0
-15.0
-14.6
-11.1
-7.0
-9.2

80.7
77.6
78.3
86.5
77.0
77.8

Day 28

Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours

89
87
88
88
88
88
88

8.64
10.71
11.10
12.03
12.48
13.75
12.95

13.464
14.253
14.474
14.691
14.721
14.868
14.483

6.33
8.41
10.11
9.85
9.71
11.04
10.67

-24.9
-14.3
-14.9
-15.4
-13.2
-14.2
-13.6

57.5
65.3
66.8
71.4
70.6
68.3
76.5

CONFIDENTIAL

91
90
90
91
91
91
91

YM2008/00019/00
B2C109575

Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours

304

Day 28

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 3

Table 7.16
Summary of Percentage Change from Baseline in Serial FEV1 (%) (0-4hrs)

Planned
Treatment
N Visit
Relative time
n
Mean
SD
Median
Min.
Max.
--------------------------------------------------------------------------------------------25mcg
101
Day 1
15 mins
98
12.33
15.169
9.21
-13.9
103.6
30 mins
98
14.27
15.835
11.47
-21.0
104.0
1 hour
101
15.38
16.112
12.62
-14.0
107.2
2 hours
101
16.74
17.250
14.61
-11.7
116.2
3 hours
98
19.25
17.456
16.31
-7.8
112.3
4 hours
100
17.44
17.104
15.02
-10.3
110.5

102

Day 1

15 mins
30 mins
1 hour
2 hours
3 hours
4 hours

Day 28

Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours

13.26
15.50
16.92
18.15
18.28
18.48
17.88

14.961
14.842
15.168
16.057
15.204
14.858
15.019

10.51
12.74
14.57
15.26
14.71
17.21
16.64

-15.7
-14.3
-10.1
-9.6
-6.0
-10.1
-18.7

71.4
69.8
74.3
70.6
60.8
62.3
56.9

98
97
101
100
100
99

11.10
13.95
16.04
17.65
18.17
17.89

9.882
9.972
11.448
12.459
12.951
13.378

10.29
13.28
14.04
14.87
16.35
16.99

-16.7
-8.3
-14.7
-10.7
-14.8
-13.3

39.2
43.9
50.3
65.7
67.1
66.6

98
94
97
97
97
98
98

13.70
15.62
16.09
17.93
18.19
17.95
17.18

15.458
15.946
16.123
16.541
17.167
17.237
17.197

11.15
13.14
12.87
15.53
14.55
14.25
13.43

-13.6
-24.2
-12.4
-13.4
-11.9
-22.7
-21.9

71.5
67.9
63.4
72.4
75.3
75.2
83.9

CONFIDENTIAL

50mcg

94
93
93
93
93
92
93

YM2008/00019/00
B2C109575

Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours

305

Day 28

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 13
Table 7.17
Repeated Measures Analysis of Serial FEV1 (L)
Day 1

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
15 Mins
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
LS Mean
2.323
2.377
2.342
2.424
2.496
2.474
LS Mean Change
0.079(0.027)
0.133(0.027)
0.098(0.027)
0.180(0.027)
0.252(0.027)
0.230(0.027)
(SE)
0.054
0.019
0.101
(-0.022,0.130) (-0.056,0.094) (0.025,0.176)

0.173
(0.098,0.248)

0.150
(0.075,0.226)

306

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 13
Table 7.17
Repeated Measures Analysis of Serial FEV1 (L)
Day 1

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
30 Mins
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
LS Mean
2.324
2.407
2.389
2.481
2.530
2.535
LS Mean Change
0.080(0.029)
0.163(0.029)
0.145(0.029)
0.237(0.029)
0.286(0.029)
0.291(0.029)
(SE)
0.083
(0.003,0.163)

0.065
0.157
(-0.015,0.144) (0.078,0.237)

0.206
(0.127,0.286)

0.211
(0.131,0.291)

307

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 13
Table 7.17
Repeated Measures Analysis of Serial FEV1 (L)
Day 1

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
1 Hour
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
LS Mean
2.352
2.441
2.415
2.527
2.553
2.576
LS Mean Change
0.108(0.029)
0.197(0.029)
0.171(0.029)
0.283(0.029)
0.309(0.029)
0.332(0.029)
(SE)
0.089
(0.009,0.169)

0.063
0.176
(-0.016,0.143) (0.096,0.255)

0.201
(0.122,0.280)

0.224
(0.145,0.304)

308

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 13
Table 7.17
Repeated Measures Analysis of Serial FEV1 (L)
Day 1

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
2 Hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
LS Mean
2.362
2.459
2.440
2.552
2.582
2.614
LS Mean Change
0.118(0.031)
0.215(0.031)
0.196(0.031)
0.308(0.031)
0.338(0.031)
0.370(0.031)
(SE)
0.097
(0.011,0.182)

0.078
0.189
(-0.007,0.163) (0.104,0.275)

0.219
(0.135,0.304)

0.251
(0.166,0.337)

309

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.

Protocol: B2C109575
Population: Intent-to-Treat

Page 5 of 13
Table 7.17
Repeated Measures Analysis of Serial FEV1 (L)
Day 1

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
3 Hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
LS Mean
2.345
2.478
2.448
2.560
2.626
2.619
LS Mean Change
0.101(0.031)
0.234(0.031)
0.203(0.031)
0.316(0.031)
0.382(0.031)
0.375(0.031)
(SE)
0.133
(0.047,0.218)

0.102
(0.017,0.187)

0.215
(0.130,0.300)

0.280
(0.196,0.365)

0.274
(0.188,0.359)

310

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.

Protocol: B2C109575
Population: Intent-to-Treat

Page 6 of 13
Table 7.17
Repeated Measures Analysis of Serial FEV1 (L)
Day 1

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
4 Hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
LS Mean
2.332
2.460
2.442
2.547
2.599
2.611
LS Mean Change
0.088(0.031)
0.216(0.031)
0.198(0.031)
0.303(0.031)
0.355(0.031)
0.367(0.031)
(SE)
0.127
(0.041,0.214)

0.109
(0.023,0.196)

0.215
(0.128,0.301)

0.266
(0.181,0.352)

0.278
(0.192,0.365)

311

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.

Protocol: B2C109575
Population: Intent-to-Treat

Page 7 of 13
Table 7.17
Repeated Measures Analysis of Serial FEV1 (L)
Day 1

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
6 Hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
LS Mean
2.365
2.473
2.484
2.537
2.596
2.609
LS Mean Change
0.121(0.032)
0.229(0.033)
0.240(0.032)
0.292(0.032)
0.352(0.033)
0.365(0.033)
(SE)
0.108
(0.017,0.198)

0.119
(0.029,0.209)

0.172
(0.082,0.261)

0.231
(0.141,0.321)

0.244
(0.153,0.335)

312

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.

Protocol: B2C109575
Population: Intent-to-Treat

Page 8 of 13
Table 7.17
Repeated Measures Analysis of Serial FEV1 (L)
Day 1

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
12 Hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
LS Mean
2.334
2.447
2.414
2.466
2.526
2.597
LS Mean Change
0.090(0.037)
0.202(0.037)
0.170(0.036)
0.222(0.037)
0.282(0.037)
0.353(0.037)
(SE)
0.112
(0.010,0.215)

0.080
0.132
(-0.021,0.181) (0.030,0.233)

0.192
(0.089,0.294)

0.263
(0.161,0.366)

313

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.

Protocol: B2C109575
Population: Intent-to-Treat

Page 9 of 13
Table 7.17
Repeated Measures Analysis of Serial FEV1 (L)
Day 1

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
16 Hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
LS Mean
2.430
2.504
2.504
2.529
2.602
2.605
LS Mean Change
0.186(0.033)
0.260(0.033)
0.260(0.033)
0.285(0.033)
0.358(0.033)
0.361(0.033)
(SE)
0.074
0.074
0.099
(-0.018,0.166) (-0.017,0.165) (0.008,0.191)

0.172
(0.081,0.263)

0.175
(0.084,0.267)

314

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.

Protocol: B2C109575
Population: Intent-to-Treat

Page 10 of 13
Table 7.17
Repeated Measures Analysis of Serial FEV1 (L)
Day 1

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
20 Hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
LS Mean
2.444
2.526
2.472
2.528
2.581
2.585
LS Mean Change
0.200(0.033)
0.282(0.033)
0.228(0.033)
0.284(0.033)
0.337(0.033)
0.341(0.033)
(SE)
0.083
0.029
0.084
0.138
(-0.009,0.174) (-0.062,0.120) (-0.007,0.175) (0.047,0.229)

0.141
(0.050,0.232)

315

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.

Protocol: B2C109575
Population: Intent-to-Treat

Page 11 of 13
Table 7.17
Repeated Measures Analysis of Serial FEV1 (L)
Day 1

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
22 Hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
LS Mean
2.410
2.514
2.460
2.543
2.564
2.549
LS Mean Change
0.166(0.032)
0.270(0.032)
0.215(0.032)
0.299(0.032)
0.320(0.032)
0.305(0.032)
(SE)
0.104
(0.016,0.193)

0.050
0.133
(-0.038,0.138) (0.045,0.222)

0.155
(0.067,0.242)

0.139
(0.051,0.228)

316

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.

Protocol: B2C109575
Population: Intent-to-Treat

Page 12 of 13
Table 7.17
Repeated Measures Analysis of Serial FEV1 (L)
Day 1

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
23 Hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
LS Mean
2.426
2.491
2.438
2.523
2.557
2.571
LS Mean Change
0.182(0.032)
0.247(0.032)
0.194(0.032)
0.279(0.032)
0.313(0.032)
0.327(0.032)
(SE)
0.065
0.013
0.097
(-0.024,0.155) (-0.076,0.102) (0.008,0.187)

0.131
(0.042,0.221)

0.145
(0.056,0.235)

317

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.

Protocol: B2C109575
Population: Intent-to-Treat

Page 13 of 13
Table 7.17
Repeated Measures Analysis of Serial FEV1 (L)
Day 1

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
24 Hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
LS Mean
2.407
2.506
2.461
2.507
2.553
2.541
LS Mean Change
0.162(0.032)
0.262(0.033)
0.217(0.032)
0.263(0.033)
0.309(0.032)
0.297(0.032)
(SE)
0.099
(0.009,0.190)

0.055
0.100
(-0.035,0.145) (0.010,0.190)

0.147
(0.057,0.236)

0.135
(0.045,0.225)

318

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 14
Table 7.18
Repeated Measures Analysis of Serial FEV1 (L)
Day 28

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Pre-Dose
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
89
87
91
89
94
98
LS Mean
2.416
2.466
2.447
2.469
2.504
2.535
LS Mean Change
0.158(0.035)
0.208(0.035)
0.189(0.034)
0.211(0.034)
0.246(0.034)
0.277(0.033)
(SE)
0.050
0.031
0.053
0.088
0.119
(-0.047,0.147) (-0.064,0.127) (-0.043,0.149) (-0.006,0.182) (0.025,0.213)

319

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 14
Table 7.18
Repeated Measures Analysis of Serial FEV1 (L)
Day 28

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
15 Mins
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
89
87
91
89
94
98
LS Mean
2.366
2.497
2.469
2.509
2.553
2.569
LS Mean Change
0.108(0.034)
0.238(0.034)
0.210(0.033)
0.251(0.033)
0.295(0.033)
0.311(0.032)
(SE)
0.131
(0.036,0.225)

0.103
(0.010,0.195)

0.143
(0.050,0.236)

0.187
(0.096,0.279)

0.203
(0.112,0.294)

320

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 14
Table 7.18
Repeated Measures Analysis of Serial FEV1 (L)
Day 28

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
30 Mins
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
89
87
91
89
94
98
LS Mean
2.374
2.510
2.478
2.518
2.583
2.573
LS Mean Change
0.116(0.034)
0.252(0.034)
0.220(0.033)
0.260(0.034)
0.325(0.033)
0.315(0.032)
(SE)
0.135
(0.041,0.230)

0.104
(0.011,0.197)

0.143
(0.050,0.237)

0.209
(0.117,0.301)

0.199
(0.107,0.290)

321

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 14
Table 7.18
Repeated Measures Analysis of Serial FEV1 (L)
Day 28

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
1 Hour
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
89
87
91
89
94
98
LS Mean
2.379
2.534
2.505
2.539
2.609
2.619
LS Mean Change
0.121(0.034)
0.276(0.035)
0.247(0.034)
0.281(0.034)
0.350(0.033)
0.361(0.033)
(SE)
0.155
(0.058,0.252)

0.126
(0.031,0.221)

0.160
(0.064,0.256)

0.229
(0.135,0.323)

0.240
(0.146,0.333)

322

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.

Protocol: B2C109575
Population: Intent-to-Treat

Page 5 of 14
Table 7.18
Repeated Measures Analysis of Serial FEV1 (L)
Day 28

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
2 Hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
89
87
91
89
94
98
LS Mean
2.381
2.541
2.509
2.549
2.609
2.618
LS Mean Change
0.123(0.034)
0.283(0.035)
0.251(0.034)
0.291(0.034)
0.351(0.033)
0.360(0.033)
(SE)
0.160
(0.063,0.256)

0.128
(0.033,0.223)

0.168
(0.073,0.264)

0.228
(0.134,0.322)

0.237
(0.144,0.331)

323

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.

Protocol: B2C109575
Population: Intent-to-Treat

Page 6 of 14
Table 7.18
Repeated Measures Analysis of Serial FEV1 (L)
Day 28

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
3 Hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
89
87
91
89
94
98
LS Mean
2.397
2.533
2.528
2.573
2.617
2.619
LS Mean Change
0.139(0.034)
0.274(0.035)
0.270(0.034)
0.314(0.034)
0.358(0.033)
0.361(0.032)
(SE)
0.136
(0.040,0.232)

0.131
(0.037,0.225)

0.176
(0.081,0.271)

0.220
(0.127,0.313)

0.223
(0.130,0.315)

324

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.

Protocol: B2C109575
Population: Intent-to-Treat

Page 7 of 14
Table 7.18
Repeated Measures Analysis of Serial FEV1 (L)
Day 28

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
4 Hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
89
87
91
89
94
98
LS Mean
2.365
2.519
2.504
2.558
2.601
2.603
LS Mean Change
0.107(0.034)
0.260(0.034)
0.246(0.033)
0.300(0.033)
0.343(0.033)
0.344(0.032)
(SE)
0.154
(0.059,0.248)

0.139
(0.047,0.231)

0.193
(0.100,0.286)

0.236
(0.145,0.328)

0.238
(0.147,0.329)

325

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.

Protocol: B2C109575
Population: Intent-to-Treat

Page 8 of 14
Table 7.18
Repeated Measures Analysis of Serial FEV1 (L)
Day 28

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
6 Hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
89
87
91
89
94
98
LS Mean
2.418
2.554
2.516
2.538
2.592
2.574
LS Mean Change
0.160(0.035)
0.296(0.036)
0.257(0.035)
0.280(0.035)
0.333(0.035)
0.315(0.034)
(SE)
0.136
(0.037,0.235)

0.098
(0.001,0.194)

0.120
(0.023,0.217)

0.174
(0.077,0.270)

0.155
(0.059,0.252)

326

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.

Protocol: B2C109575
Population: Intent-to-Treat

Page 9 of 14
Table 7.18
Repeated Measures Analysis of Serial FEV1 (L)
Day 28

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
12 Hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
89
87
91
89
94
98
LS Mean
2.320
2.500
2.458
2.472
2.487
2.551
LS Mean Change
0.061(0.038)
0.242(0.039)
0.200(0.038)
0.214(0.038)
0.229(0.038)
0.293(0.037)
(SE)
0.181
(0.072,0.289)

0.138
(0.032,0.244)

0.152
(0.046,0.258)

0.167
(0.061,0.273)

0.231
(0.126,0.337)

327

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.

Protocol: B2C109575
Population: Intent-to-Treat

Page 10 of 14
Table 7.18
Repeated Measures Analysis of Serial FEV1 (L)
Day 28

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
16 Hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
89
87
91
89
94
98
LS Mean
2.415
2.581
2.529
2.564
2.570
2.583
LS Mean Change
0.157(0.035)
0.323(0.036)
0.271(0.035)
0.306(0.035)
0.312(0.034)
0.325(0.034)
(SE)
0.166
(0.066,0.266)

0.114
(0.016,0.211)

0.149
(0.051,0.248)

0.154
(0.058,0.251)

0.168
(0.072,0.264)

328

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.

Protocol: B2C109575
Population: Intent-to-Treat

Page 11 of 14
Table 7.18
Repeated Measures Analysis of Serial FEV1 (L)
Day 28

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
20 Hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
89
87
91
89
94
98
LS Mean
2.425
2.561
2.542
2.573
2.599
2.602
LS Mean Change
0.167(0.035)
0.303(0.036)
0.284(0.035)
0.315(0.035)
0.341(0.034)
0.344(0.033)
(SE)
0.136
(0.037,0.235)

0.117
(0.020,0.214)

0.148
(0.050,0.246)

0.174
(0.078,0.270)

0.177
(0.081,0.273)

329

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.

Protocol: B2C109575
Population: Intent-to-Treat

Page 12 of 14
Table 7.18
Repeated Measures Analysis of Serial FEV1 (L)
Day 28

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
22 Hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
89
87
91
89
94
98
LS Mean
2.422
2.563
2.515
2.539
2.588
2.542
LS Mean Change
0.164(0.035)
0.305(0.035)
0.257(0.034)
0.281(0.035)
0.330(0.034)
0.284(0.033)
(SE)
0.141
(0.043,0.238)

0.093
0.117
(-0.003,0.188) (0.021,0.213)

0.166
(0.072,0.260)

0.120
(0.026,0.214)

330

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.

Protocol: B2C109575
Population: Intent-to-Treat

Page 13 of 14
Table 7.18
Repeated Measures Analysis of Serial FEV1 (L)
Day 28

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
23 Hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
89
87
91
89
94
98
LS Mean
2.428
2.538
2.501
2.539
2.560
2.568
LS Mean Change
0.170(0.035)
0.280(0.036)
0.243(0.034)
0.280(0.035)
0.302(0.034)
0.310(0.033)
(SE)
0.110
(0.012,0.209)

0.074
0.111
(-0.023,0.170) (0.013,0.208)

0.132
(0.037,0.228)

0.140
(0.045,0.236)

331

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.

Protocol: B2C109575
Population: Intent-to-Treat

Page 14 of 14
Table 7.18
Repeated Measures Analysis of Serial FEV1 (L)
Day 28

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
24 Hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
89
87
91
89
94
98
LS Mean
2.403
2.506
2.490
2.538
2.570
2.555
LS Mean Change
0.144(0.035)
0.248(0.036)
0.232(0.034)
0.280(0.035)
0.312(0.034)
0.297(0.033)
(SE)
0.103
(0.005,0.201)

0.088
0.135
(-0.009,0.184) (0.038,0.232)

0.168
(0.072,0.263)

0.152
(0.058,0.247)

332

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum, treatment, time (nominal), time by treatment and time by baseline interactions
n = Number of subjects with data at one or more time points.

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.19
Summary of Weighted Mean Change from Baseline in 24 hour Serial Clinic FEV1 (L)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 1
n
101
100
101
99
100
100
Mean
0.150
0.219
0.217
0.264
0.338
0.352
SD
0.3384
0.3321
0.2779
0.3354
0.3254
0.2546
Median
0.045
0.119
0.191
0.202
0.296
0.302
Min.
-0.24
-0.28
-0.28
-0.18
-0.39
-0.18
Max.
1.68
1.41
1.32
1.98
1.97
1.28
Day 28

87
0.166
0.3661
0.100
-0.58
1.76

83
0.281
0.3444
0.162
-0.39
1.56

91
0.258
0.3175
0.219
-0.33
1.60

88
0.272
0.3093
0.218
-0.28
1.53

93
0.327
0.2756
0.344
-0.25
1.20

97
0.324
0.3231
0.242
-0.32
1.51

CONFIDENTIAL

333

n
Mean
SD
Median
Min.
Max.

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.20
Statistical Analysis of Weighted Mean Change from Baseline in 24 Hour Serial Clinic FEV1 (L)
All Subjects, including 6-12 hour time points

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Day 1
n
LS Mean Change
(SE)

101
100
101
0.137(0.029)
0.239(0.029)
0.215(0.029)

0.102
(0.020,0.183)
0.015

0.078
0.130
(-0.003,0.158) (0.049,0.211)
0.059
0.002

0.193
(0.112,0.273)
<0.001

0.215
(0.134,0.296)
<0.001

334

Day 28
n
LS Mean Change
(SE)
Column vs Placebo
Difference
95% C.I.
p-value

87
0.149(0.032)

83
0.300(0.033)

0.151
(0.059,0.242)
0.001

91
0.253(0.031)

0.103
(0.014,0.192)
0.023

88
0.292(0.032)

0.142
(0.052,0.232)
0.002

93
0.315(0.031)

0.165
(0.077,0.253)
<0.001

97
0.321(0.031)

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.
p-value

99
100
100
0.267(0.029)
0.330(0.029)
0.352(0.029)

0.172
(0.084,0.260)
<0.001

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on Day 1), country, sex, age,
stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.21
Sensitivity Analysis of Weighted Mean Change from Baseline in 24 Hour Serial Clinic FEV1 (L)
All Subjects excluding 6-12 hour time points

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Day 1
n
LS Mean Change
(SE)

101
100
101
0.144(0.029)
0.244(0.029)
0.220(0.029)

0.099
(0.017,0.181)
0.018

0.076
0.135
(-0.006,0.157) (0.053,0.216)
0.068
0.001

0.199
(0.118,0.280)
<0.001

0.207
(0.126,0.289)
<0.001

335

Day 28
n
LS Mean Change
(SE)
Column vs Placebo
Difference
95% C.I.
p-value

87
0.153(0.033)

83
0.305(0.033)

0.152
(0.060,0.244)
0.001

91
0.259(0.032)

0.106
(0.017,0.195)
0.020

88
0.309(0.032)

0.155
(0.065,0.246)
<0.001

93
0.328(0.031)

0.175
(0.086,0.263)
<0.001

97
0.330(0.031)

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.
p-value

99
100
100
0.279(0.029)
0.343(0.029)
0.352(0.029)

0.177
(0.088,0.265)
<0.001

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on Day 1), country, sex, age,
stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.22
Sensitivity Analysis of Weighted Mean Change from Baseline in 24 Hour Serial Clinic FEV1 (L)
Subset of Subjects who had the 6-12 hour time points measured. All time points included

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Day 1
n
LS Mean Change
(SE)

68
0.121(0.037)

0.159
(0.056,0.263)
0.003

70
0.226(0.036)

0.104
(0.002,0.206)
0.045

71
0.259(0.036)

0.138
(0.036,0.239)
0.008

63
0.366(0.038)

0.245
(0.140,0.350)
<0.001

60
0.350(0.039)

0.229
(0.122,0.336)
<0.001

336

Day 28
n
LS Mean Change
(SE)
Column vs Placebo
Difference
95% C.I.
p-value

60
0.135(0.040)

56
0.340(0.042)

0.205
(0.090,0.320)
<0.001

61
0.276(0.040)

0.140
(0.028,0.252)
0.014

65
0.274(0.039)

0.138
(0.028,0.249)
0.014

57
0.366(0.042)

0.231
(0.116,0.345)
<0.001

58
0.327(0.041)

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.
p-value

67
0.281(0.037)

0.191
(0.077,0.306)
0.001

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on Day 1), country, sex, age,
stratum and treatment
Note: Subjects are included if they have either a 6hr or 12hr assessment on day 1 or day 28

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.23
Sensitivity Analysis of Weighted Mean Change from Baseline in 24 Hour Serial Clinic FEV1 (L)
Subset of Subjects who had 6-12 hour time points measured, excluding 6-12 hour time points

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Day 1
n
LS Mean Change
(SE)

68
0.132(0.037)

0.157
(0.052,0.261)
0.004

70
0.233(0.037)

71
0.276(0.036)

0.100
0.143
(-0.003,0.203) (0.041,0.246)
0.056
0.006

63
0.386(0.039)

0.253
(0.148,0.359)
<0.001

60
0.349(0.040)

0.217
(0.109,0.324)
<0.001

337

Day 28
n
LS Mean Change
(SE)
Column vs Placebo
Difference
95% C.I.
p-value

60
0.141(0.041)

56
0.348(0.042)

0.207
(0.091,0.323)
<0.001

61
0.285(0.040)

0.143
(0.031,0.256)
0.013

65
0.297(0.039)

0.156
(0.045,0.267)
0.006

57
0.389(0.042)

0.248
(0.133,0.363)
<0.001

58
0.339(0.041)

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.
p-value

67
0.289(0.038)

0.198
(0.083,0.313)
<0.001

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on Day 1), country, sex, age,
stratum and treatment
Note: Subjects are included if they have either a 6hr or 12hr assessment on day 1 or day 28

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.24
Sensitivity Analysis of Weighted Mean Change from Baseline in 24 Hour Serial Clinic FEV1 (L)
Observations without rescue medication

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Day 1
n
LS Mean Change
(SE)

89
0.134(0.032)

0.113
(0.027,0.200)
0.010

95
0.224(0.030)

0.090
(0.004,0.176)
0.040

94
0.269(0.031)

0.135
(0.049,0.222)
0.002

97
0.333(0.030)

0.199
(0.114,0.285)
<0.001

95
0.359(0.031)

0.226
(0.139,0.312)
<0.001

338

Day 28
n
LS Mean Change
(SE)
Column vs Placebo
Difference
95% C.I.
p-value

77
0.150(0.035)

79
0.306(0.035)

0.157
(0.060,0.253)
0.002

88
0.252(0.032)

0.103
(0.009,0.196)
0.031

87
0.288(0.033)

0.138
(0.044,0.233)
0.004

92
0.319(0.032)

0.169
(0.077,0.262)
<0.001

96
0.323(0.031)

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.
p-value

96
0.247(0.030)

0.174
(0.082,0.266)
<0.001

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on Day 1), country, sex, age,
stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Table 7.25
Summary of Post-salbutamol/albuterol FEV1 (L)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Screening
n
102
101
101
100
101
102
Mean
2.767
2.775
2.806
2.792
2.668
2.702
SD
0.8004
0.9468
0.7814
0.7369
0.7027
0.7095
Median
2.676
2.654
2.789
2.693
2.555
2.675
Min.
1.18
1.26
1.45
1.32
1.32
1.07
Max.
5.26
5.17
4.59
4.81
4.23
5.05
n
Mean
SD
Median
Min.
Max.

97
2.713
0.8589
2.661
1.15
5.30

97
2.754
0.9460
2.610
0.87
5.25

98
2.731
0.8000
2.718
1.33
4.66

99
2.744
0.8027
2.639
1.15
5.03

96
2.640
0.7476
2.498
1.27
4.34

98
2.658
0.7010
2.643
1.34
5.21

Day 28

n
Mean
SD
Median
Min.
Max.

84
2.640
0.8338
2.610
1.16
5.16

80
2.813
0.9109
2.660
1.27
5.18

89
2.804
0.7983
2.709
1.40
4.73

86
2.690
0.7978
2.543
1.23
5.08

88
2.577
0.7293
2.464
1.11
4.14

93
2.625
0.6895
2.539
1.43
4.96

CONFIDENTIAL

339

Day 1

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.26
Summary of Post-salbutamol/albuterol FEV1 (L) Differences

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------Day 28 - Day 1
n
83
80
87
86
86
92
Mean
-0.035
-0.040
-0.015
-0.019
-0.056
-0.050
SD
0.1784
0.2213
0.2005
0.1858
0.2401
0.2229
Median
-0.029
-0.026
-0.029
-0.018
-0.047
-0.058
Min.
-0.46
-0.78
-0.45
-0.61
-1.37
-0.48
Max.
0.37
0.71
0.61
0.51
0.56
0.91
n
Mean
SD
Median
Min.
Max.

97
-0.028
0.2788
-0.038
-0.99
0.74

97
-0.013
0.3406
0.016
-0.96
1.28

98
-0.062
0.2928
-0.074
-0.94
0.76

99
-0.033
0.2963
-0.050
-0.97
1.37

96
-0.009
0.2505
0.005
-1.05
0.84

98
-0.054
0.2548
-0.030
-1.13
0.47

Day 28 - Screening

n
Mean
SD
Median
Min.
Max.

84
-0.053
0.3026
-0.062
-1.20
0.80

80
-0.048
0.3558
-0.045
-1.44
1.11

89
-0.057
0.2780
-0.064
-0.59
1.33

86
-0.062
0.3111
-0.091
-0.94
1.50

88
-0.068
0.2635
-0.034
-1.33
0.48

93
-0.104
0.2509
-0.072
-0.80
0.68

CONFIDENTIAL

340

Day 1 - Screening

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.27
Statistical Analysis of difference in post-salbutamol/albuterol FEV1 (L)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 28 - Day 1
n
83
80
87
86
86
92
LS Mean (SE)
-0.039(0.023) -0.035(0.024) -0.012(0.023) -0.017(0.023) -0.062(0.023) -0.049(0.022)
Column vs Placebo
Difference
95% C.I.
p-value

97
-0.040(0.028)

Column vs Placebo
Difference
95% C.I.
p-value
Day 28 Screening
n
LS Mean (SE)

98
-0.061(0.028)

99
-0.029(0.028)

96
-0.020(0.028)

98
-0.060(0.028)

0.047
-0.021
0.011
0.020
-0.020
(-0.032,0.126) (-0.099,0.057) (-0.067,0.089) (-0.058,0.098) (-0.099,0.058)
0.241
0.598
0.791
0.619
0.613

84
-0.076(0.031)

80
-0.022(0.031)

89
-0.055(0.030)

86
-0.048(0.030)

88
-0.086(0.030)

93
-0.104(0.029)

0.055
0.021
0.029
-0.009
-0.027
(-0.032,0.141) (-0.062,0.105) (-0.056,0.114) (-0.093,0.075) (-0.111,0.056)
0.217
0.615
0.507
0.826
0.519

Note: Analysis performed using ANCOVA with covariates of baseline (pre-salbutamol measurement at Screening),
country, sex, age, stratum and treatment
Analysis is of the differences in absolute FEV1 measurements taken post-salbutamol/albuterol

YM2008/00019/00
B2C109575

Column vs Placebo
Difference
95% C.I.
p-value

97
0.008(0.028)

CONFIDENTIAL

341

Day 1 - Screening
n
LS Mean (SE)

0.004
0.027
0.022
-0.023
-0.010
(-0.062,0.069) (-0.037,0.091) (-0.042,0.087) (-0.087,0.041) (-0.074,0.054)
0.916
0.410
0.498
0.482
0.756

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.28
Summary of Maximum Increase from Baseline in FEV1 (L) (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 1
n
102
101
101
100
101
101
Mean
0.243
0.290
0.295
0.387
0.442
0.457
SD
0.3324
0.3279
0.2789
0.3658
0.3425
0.2580
Median
0.137
0.180
0.238
0.309
0.372
0.406
Min.
-0.23
-0.15
-0.12
-0.06
-0.10
-0.06
Max.
1.72
1.49
1.43
2.05
2.12
1.51
Day 28

87
0.268
0.3722
0.191
-0.47
1.79

85
0.348
0.3480
0.241
-0.27
1.52

91
0.342
0.3328
0.295
-0.24
1.68

88
0.373
0.3339
0.327
-0.19
1.65

93
0.440
0.3106
0.437
-0.17
1.77

98
0.442
0.3420
0.370
-0.28
1.57

CONFIDENTIAL

342

n
Mean
SD
Median
Min.
Max.

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.29
Statistical Analysis of Maximum Increase from Baseline in FEV1 (L) (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Day 1
n
LS Mean Change
(SE)

102
101
101
100
101
101
0.230(0.029)
0.309(0.029)
0.291(0.029)
0.385(0.029)
0.439(0.029)
0.459(0.029)

0.079
0.061
0.155
(-0.003,0.161) (-0.020,0.142) (0.073,0.236)
0.059
0.142
<0.001

0.209
(0.128,0.290)
<0.001

0.228
(0.146,0.310)
<0.001

343

Day 28
n
LS Mean Change
(SE)
Column vs Placebo
Difference
95% C.I.
p-value

87
0.253(0.034)

85
0.366(0.034)

0.113
(0.019,0.208)
0.019

91
0.333(0.033)

88
0.390(0.033)

0.079
0.137
(-0.013,0.172) (0.044,0.230)
0.091
0.004

93
0.430(0.032)

0.176
(0.085,0.268)
<0.001

98
0.442(0.032)

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.
p-value

0.189
(0.098,0.280)
<0.001

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.30
Summary of Weighted Mean Change from Baseline in FEV1 (L) (0-4hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 1
n
101
101
101
99
100
101
Mean
0.108
0.184
0.178
0.265
0.325
0.331
SD
0.3190
0.3078
0.2605
0.3229
0.3131
0.2161
Median
0.023
0.089
0.148
0.200
0.270
0.294
Min.
-0.40
-0.23
-0.23
-0.15
-0.20
-0.21
Max.
1.58
1.32
1.33
1.87
1.95
0.97
Day 28

87
0.152
0.3659
0.104
-0.72
1.67

83
0.264
0.3364
0.164
-0.37
1.47

91
0.254
0.3326
0.183
-0.28
1.58

88
0.278
0.3205
0.235
-0.25
1.60

93
0.352
0.2989
0.314
-0.25
1.54

98
0.348
0.3283
0.286
-0.24
1.50

CONFIDENTIAL

344

n
Mean
SD
Median
Min.
Max.

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.31
Statistical Analysis of Weighted Mean Change from Baseline in FEV1 (L) (0-4hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Day 1
n
LS Mean Change
(SE)

101
101
101
0.095(0.027)
0.202(0.027)
0.176(0.027)

0.107
(0.031,0.183)
0.006

0.081
(0.005,0.156)
0.037

0.173
(0.097,0.249)
<0.001

0.226
(0.151,0.302)
<0.001

0.236
(0.160,0.312)
<0.001

345

Day 28
n
LS Mean Change
(SE)
Column vs Placebo
Difference
95% C.I.
p-value

87
0.136(0.033)

83
0.281(0.034)

0.145
(0.051,0.238)
0.003

91
0.246(0.032)

0.110
(0.019,0.201)
0.018

88
0.296(0.033)

0.160
(0.068,0.252)
<0.001

93
0.341(0.032)

0.205
(0.115,0.295)
<0.001

98
0.349(0.031)

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.
p-value

99
100
101
0.268(0.027)
0.321(0.027)
0.331(0.027)

0.213
(0.123,0.302)
<0.001

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on Day 1), country, sex, age,
stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.32
Summary of the Proportion of Subjects Obtaining >= 200mL and >= 12%
Increase from Baseline FEV1 (L) (0-4hrs)

Planned
Relative Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Time
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 1
15 mins
16 / 102 (16%) 16 / 97 (16%) 16 / 99 (16%) 18 / 99 (18%) 35 / 98 (36%) 34 / 98 (35%)
30 mins
23 / 99 (23%) 20 / 97 (21%) 25 / 100 (25%) 25 / 99 (25%) 45 / 98 (46%) 49 / 97 (51%)
1 hour
21 / 101 (21%) 24 / 101 (24%) 27 / 101 (27%) 33 / 99 (33%) 51 / 101 (50%) 62 / 101 (61%)
2 hours
24 / 100 (24%) 23 / 101 (23%) 32 / 101 (32%) 37 / 98 (38%) 56 / 101 (55%) 60 / 100 (60%)
3 hours
25 / 101 (25%) 26 / 100 (26%) 33 / 99 (33%) 42 / 99 (42%) 58 / 98 (59%) 58 / 100 (58%)
4 hours
22 / 100 (22%) 22 / 101 (22%) 28 / 101 (28%) 45 / 99 (45%) 58 / 100 (58%) 58 / 99 (59%)

346

Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours

30
27
23
25
26
28
24

/
/
/
/
/
/
/

89
86
85
87
87
86
86

(34%)
(31%)
(27%)
(29%)
(30%)
(33%)
(28%)

26
26
31
32
33
32
29

/
/
/
/
/
/
/

86
84
85
85
84
82
84

(30%)
(31%)
(36%)
(38%)
(39%)
(39%)
(35%)

32
30
32
35
34
37
33

/
/
/
/
/
/
/

91
90
90
91
91
91
91

(35%)
(33%)
(36%)
(38%)
(37%)
(41%)
(36%)

29
32
36
36
36
40
37

/
/
/
/
/
/
/

89
87
88
88
88
88
88

(33%)
(37%)
(41%)
(41%)
(41%)
(45%)
(42%)

43
46
54
53
53
55
55

/
/
/
/
/
/
/

94
93
93
93
93
92
93

(46%)
(49%)
(58%)
(57%)
(57%)
(60%)
(59%)

45
48
51
60
55
54
51

/
/
/
/
/
/
/

98
94
97
97
97
98
98

(46%)
(51%)
(53%)
(62%)
(57%)
(55%)
(52%)

CONFIDENTIAL

Day 28

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.33
Summary of the Cumulative Proportion of Subjects Obtaining >=200mL and >=12% increase from
Baseline FEV1 (L) (0-4hrs)

Planned
Relative Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Time
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 1
15 mins
16 / 102 (16%) 16 / 97 (16%) 16 / 99 (16%) 18 / 99 (18%) 35 / 98 (36%) 34 / 98 (35%)
30 mins
24 / 102 (24%) 21 / 98 (21%) 25 / 101 (25%) 28 / 100 (28%) 48 / 100 (48%) 52 / 100 (52%)
1 hour
25 / 102 (25%) 27 / 101 (27%) 31 / 101 (31%) 38 / 100 (38%) 56 / 101 (55%) 69 / 101 (68%)
2 hours
29 / 102 (28%) 29 / 101 (29%) 37 / 101 (37%) 48 / 100 (48%) 61 / 101 (60%) 72 / 101 (71%)
3 hours
32 / 102 (31%) 32 / 101 (32%) 43 / 101 (43%) 54 / 100 (54%) 66 / 101 (65%) 76 / 101 (75%)
4 hours
35 / 102 (34%) 33 / 101 (33%) 45 / 101 (45%) 60 / 100 (60%) 70 / 101 (69%) 77 / 101 (76%)

347

Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours

30
30
30
33
34
36
37

/
/
/
/
/
/
/

89
89
89
89
89
89
89

(34%)
(34%)
(34%)
(37%)
(38%)
(40%)
(42%)

26
30
35
37
40
42
45

/
/
/
/
/
/
/

86
86
87
87
87
87
87

(30%)
(35%)
(40%)
(43%)
(46%)
(48%)
(52%)

32
33
35
39
40
43
44

/
/
/
/
/
/
/

91
91
91
91
91
91
91

(35%)
(36%)
(38%)
(43%)
(44%)
(47%)
(48%)

29
39
43
44
46
48
50

/
/
/
/
/
/
/

89
89
89
89
89
89
89

(33%)
(44%)
(48%)
(49%)
(52%)
(54%)
(56%)

43
48
57
61
62
65
65

/
/
/
/
/
/
/

94
94
94
94
94
94
94

(46%)
(51%)
(61%)
(65%)
(66%)
(69%)
(69%)

45
51
54
62
63
64
64

/
/
/
/
/
/
/

98
98
98
98
98
98
98

(46%)
(52%)
(55%)
(63%)
(64%)
(65%)
(65%)

CONFIDENTIAL

Day 28

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.34
Summary of the Proportion of Subjects Obtaining >= 15% Increase from Baseline FEV1 (L) (0-4hrs)

Planned
Relative Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Time
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 1
15 mins
12 / 102 (12%) 11 / 97 (11%) 12 / 99 (12%) 14 / 99 (14%) 32 / 98 (33%) 28 / 98 (29%)
30 mins
17 / 99 (17%) 15 / 97 (15%) 17 / 100 (17%) 16 / 99 (16%) 40 / 98 (41%) 39 / 97 (40%)
1 hour
18 / 101 (18%) 20 / 101 (20%) 19 / 101 (19%) 23 / 99 (23%) 43 / 101 (43%) 46 / 101 (46%)
2 hours
20 / 100 (20%) 21 / 101 (21%) 23 / 101 (23%) 27 / 98 (28%) 46 / 101 (46%) 50 / 100 (50%)
3 hours
19 / 101 (19%) 23 / 100 (23%) 22 / 99 (22%) 30 / 99 (30%) 52 / 98 (53%) 51 / 100 (51%)
4 hours
21 / 100 (21%) 18 / 101 (18%) 24 / 101 (24%) 31 / 99 (31%) 50 / 100 (50%) 53 / 99 (54%)

348

Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours

26
23
21
22
23
23
19

/
/
/
/
/
/
/

89
86
85
87
87
86
86

(29%)
(27%)
(25%)
(25%)
(26%)
(27%)
(22%)

23
22
24
28
29
28
22

/
/
/
/
/
/
/

86
84
85
85
84
82
84

(27%)
(26%)
(28%)
(33%)
(35%)
(34%)
(26%)

24
26
28
30
30
33
30

/
/
/
/
/
/
/

91
90
90
91
91
91
91

(26%)
(29%)
(31%)
(33%)
(33%)
(36%)
(33%)

18
26
29
29
29
31
33

/
/
/
/
/
/
/

89
87
88
88
88
88
88

(20%)
(30%)
(33%)
(33%)
(33%)
(35%)
(38%)

36
39
46
47
44
51
50

/
/
/
/
/
/
/

94
93
93
93
93
92
93

(38%)
(42%)
(49%)
(51%)
(47%)
(55%)
(54%)

36
44
45
50
46
49
45

/
/
/
/
/
/
/

98
94
97
97
97
98
98

(37%)
(47%)
(46%)
(52%)
(47%)
(50%)
(46%)

CONFIDENTIAL

Day 28

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.35
Summary of the Cumulative Proportion of Subjects Obtaining
Baseline FEV1 (L) (0-4hrs)

>=15% increase from

Planned
Relative Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Time
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 1
15 mins
12 / 102 (12%) 11 / 97 (11%) 12 / 99 (12%) 14 / 99 (14%) 32 / 98 (33%) 28 / 98 (29%)
30 mins
19 / 102 (19%) 15 / 98 (15%) 18 / 101 (18%) 18 / 100 (18%) 41 / 100 (41%) 42 / 100 (42%)
1 hour
21 / 102 (21%) 21 / 101 (21%) 22 / 101 (22%) 26 / 100 (26%) 48 / 101 (48%) 51 / 101 (50%)
2 hours
23 / 102 (23%) 25 / 101 (25%) 26 / 101 (26%) 33 / 100 (33%) 54 / 101 (53%) 57 / 101 (56%)
3 hours
24 / 102 (24%) 29 / 101 (29%) 30 / 101 (30%) 38 / 100 (38%) 60 / 101 (59%) 61 / 101 (60%)
4 hours
28 / 102 (27%) 29 / 101 (29%) 33 / 101 (33%) 43 / 100 (43%) 63 / 101 (62%) 64 / 101 (63%)

349

Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours

26
27
27
29
30
30
30

/
/
/
/
/
/
/

89
89
89
89
89
89
89

(29%)
(30%)
(30%)
(33%)
(34%)
(34%)
(34%)

23
25
27
31
34
35
35

/
/
/
/
/
/
/

86
86
87
87
87
87
87

(27%)
(29%)
(31%)
(36%)
(39%)
(40%)
(40%)

24
27
28
31
33
35
36

/
/
/
/
/
/
/

91
91
91
91
91
91
91

(26%)
(30%)
(31%)
(34%)
(36%)
(38%)
(40%)

18
28
35
35
38
41
42

/
/
/
/
/
/
/

89
89
89
89
89
89
89

(20%)
(31%)
(39%)
(39%)
(43%)
(46%)
(47%)

36
41
49
51
53
58
59

/
/
/
/
/
/
/

94
94
94
94
94
94
94

(38%)
(44%)
(52%)
(54%)
(56%)
(62%)
(63%)

36
48
52
56
57
57
57

/
/
/
/
/
/
/

98
98
98
98
98
98
98

(37%)
(49%)
(53%)
(57%)
(58%)
(58%)
(58%)

CONFIDENTIAL

Day 28

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Table 7.36
Summary of Peak Post-Dose FEV1 (L) (0-4hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 28
n
86
85
91
88
93
97
Mean
2.458
2.739
2.709
2.660
2.591
2.660
SD
0.7916
0.8562
0.7743
0.8045
0.7088
0.6808
Median
2.410
2.591
2.672
2.537
2.456
2.679
Min.
1.03
1.36
1.31
1.16
1.24
1.48
Max.
4.74
5.06
4.41
5.10
4.15
5.03

CONFIDENTIAL

350

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.37
Statistical Analysis of Peak Post-Dose FEV1 (L) (0-4hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
86
85
91
88
93
97
LS Mean (SE)
2.517(0.034)
2.629(0.034)
2.596(0.032)
2.655(0.033)
2.694(0.032)
2.715(0.032)
Column vs Placebo
Difference
95% C.I.
p-value

0.112
(0.018,0.206)
0.020

0.079
0.138
(-0.013,0.171) (0.045,0.231)
0.093
0.004

0.177
(0.085,0.268)
<0.001

0.198
(0.107,0.289)
<0.001

CONFIDENTIAL

351

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on Day 1), country, sex, age,
stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.38
Summary of Ratio of Peak Post-Dose FEV1 (L) to Trough FEV1 (L)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------Ratio
n
86
84
91
88
93
96
Mean
1.042
1.045
1.040
1.043
1.056
1.060
SD
0.0912
0.0682
0.0533
0.0843
0.0718
0.0607
Median
1.031
1.036
1.028
1.032
1.048
1.050
Min.
0.78
0.81
0.97
0.63
0.92
0.96
Max.
1.36
1.35
1.25
1.32
1.34
1.24

CONFIDENTIAL

352

YM2008/00019/00
B2C109575

Note: Trough FEV1 as used in the ratio is the mean of the FEV1 values obtained 23 and 24 hours after dosing
on Day 28 (i.e., no imputation was used)

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 9
Table 7.39
Change from Baseline in PM PEF (L/min)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Baseline
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------PM PEF (L/min)
n
102
101
101
100
101
102
Mean
362.3
393.4
400.2
382.7
375.8
355.0
SD
114.30
135.27
113.55
116.33
117.76
106.58
Median
342.7
396.6
387.8
373.5
362.5
341.5
Min.
102
100
168
105
76
148
Max.
638
681
695
636
681
656

CONFIDENTIAL

353

YM2008/00019/00
B2C109575

Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Note: Endpoint is defined as the last 7 days on study medication ending with the treatment stop date

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 9
Table 7.39
Change from Baseline in PM PEF (L/min)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Week 1
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------PM PEF (L/min)
n
99
99
101
98
101
102
Mean
365.5
409.2
425.7
413.3
409.7
396.8
SD
113.20
136.33
115.03
117.64
120.26
112.86
Median
343.3
405.3
408.0
399.1
395.8
391.8
Min.
141
105
180
175
103
185
Max.
646
680
748
682
709
725

354

n
Mean
SD
Median
Min.
Max.

99
4.4
36.51
5.9
-109
193

99
16.4
36.56
15.4
-85
121

101
25.5
34.87
18.3
-43
127

98
30.7
34.68
29.0
-54
152

101
33.9
36.34
28.0
-47
187

102
41.8
38.17
38.6
-38
196

YM2008/00019/00
B2C109575

Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Note: Endpoint is defined as the last 7 days on study medication ending with the treatment stop date

CONFIDENTIAL

Change From Baseline


in PM PEF (L/min)

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 9
Table 7.39
Change from Baseline in PM PEF (L/min)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Week 2
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------PM PEF (L/min)
n
93
92
97
95
97
98
Mean
365.2
418.8
424.3
413.9
407.7
400.5
SD
110.07
124.84
117.97
115.87
120.47
112.08
Median
339.7
414.7
407.8
398.9
385.5
391.0
Min.
150
134
183
154
117
191
Max.
619
669
719
700
718
707

355

n
Mean
SD
Median
Min.
Max.

93
4.1
38.88
5.1
-153
162

92
13.4
42.85
10.8
-71
175

97
22.6
37.05
17.0
-56
132

95
30.1
44.20
20.4
-47
159

97
32.1
39.43
27.7
-57
206

98
40.6
47.27
29.4
-44
245

YM2008/00019/00
B2C109575

Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Note: Endpoint is defined as the last 7 days on study medication ending with the treatment stop date

CONFIDENTIAL

Change From Baseline


in PM PEF (L/min)

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 9
Table 7.39
Change from Baseline in PM PEF (L/min)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Week 3
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------PM PEF (L/min)
n
90
85
91
92
94
97
Mean
363.6
428.4
432.7
411.8
409.0
398.0
SD
113.75
123.66
115.33
112.96
120.28
114.21
Median
339.8
424.6
403.1
399.3
391.8
383.4
Min.
142
119
191
155
128
191
Max.
657
685
712
671
705
704

356

n
Mean
SD
Median
Min.
Max.

90
3.2
39.31
-2.1
-95
199

85
15.2
43.26
6.9
-61
197

91
24.4
38.52
17.6
-43
151

92
28.3
49.91
19.1
-57
204

94
35.3
43.86
27.4
-52
266

97
38.9
47.44
31.0
-43
242

YM2008/00019/00
B2C109575

Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Note: Endpoint is defined as the last 7 days on study medication ending with the treatment stop date

CONFIDENTIAL

Change From Baseline


in PM PEF (L/min)

Protocol: B2C109575
Population: Intent-to-Treat

Page 5 of 9
Table 7.39
Change from Baseline in PM PEF (L/min)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Week 4
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------PM PEF (L/min)
n
85
84
88
89
93
98
Mean
366.7
419.6
428.7
413.3
406.5
397.7
SD
111.54
127.31
116.29
108.67
119.39
116.91
Median
348.0
408.8
405.7
402.1
396.7
382.5
Min.
131
110
177
171
135
184
Max.
593
676
701
696
695
722

357

n
Mean
SD
Median
Min.
Max.

85
5.6
41.32
3.6
-66
201

84
11.3
46.48
4.9
-77
185

88
22.0
42.67
21.0
-98
164

89
29.1
48.89
20.2
-67
187

93
35.2
44.41
30.6
-66
249

98
38.2
52.76
30.9
-50
263

YM2008/00019/00
B2C109575

Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Note: Endpoint is defined as the last 7 days on study medication ending with the treatment stop date

CONFIDENTIAL

Change From Baseline


in PM PEF (L/min)

Protocol: B2C109575
Population: Intent-to-Treat

Page 6 of 9
Table 7.39
Change from Baseline in PM PEF (L/min)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Days 1-14
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------PM PEF (L/min)
n
99
99
101
98
101
102
Mean
364.7
406.7
423.7
412.1
408.9
396.6
SD
111.57
134.34
115.53
116.02
118.87
112.60
Median
343.6
408.1
405.3
397.6
390.5
393.2
Min.
146
106
182
164
110
185
Max.
634
674
725
680
714
715

358

n
Mean
SD
Median
Min.
Max.

99
3.6
36.09
5.1
-119
177

99
13.9
37.86
11.5
-85
123

101
23.6
34.13
21.6
-45
129

98
29.4
38.04
22.2
-54
135

101
33.2
36.38
28.2
-52
197

102
41.7
41.38
34.1
-41
223

YM2008/00019/00
B2C109575

Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Note: Endpoint is defined as the last 7 days on study medication ending with the treatment stop date

CONFIDENTIAL

Change From Baseline


in PM PEF (L/min)

Protocol: B2C109575
Population: Intent-to-Treat

Page 7 of 9
Table 7.39
Change from Baseline in PM PEF (L/min)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Days 1-28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------PM PEF (L/min)
n
99
99
101
98
101
102
Mean
363.2
404.9
422.9
411.6
409.2
395.8
SD
111.05
134.26
114.74
113.62
117.05
113.69
Median
339.5
405.3
405.9
401.6
390.7
385.7
Min.
146
106
183
163
124
185
Max.
623
678
718
677
707
713

359

n
Mean
SD
Median
Min.
Max.

99
2.1
37.13
2.4
-119
188

99
12.0
38.22
8.6
-85
158

101
22.8
34.82
19.2
-59
138

98
29.0
41.85
20.4
-54
149

101
33.4
38.28
29.0
-42
222

102
40.8
44.16
33.9
-32
225

YM2008/00019/00
B2C109575

Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Note: Endpoint is defined as the last 7 days on study medication ending with the treatment stop date

CONFIDENTIAL

Change From Baseline


in PM PEF (L/min)

Protocol: B2C109575
Population: Intent-to-Treat

Page 8 of 9
Table 7.39
Change from Baseline in PM PEF (L/min)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Endpoint
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------PM PEF (L/min)
n
98
99
101
98
101
102
Mean
360.9
400.5
421.3
412.9
408.0
392.9
SD
109.99
135.97
116.52
110.92
117.49
117.74
Median
339.9
399.4
401.0
404.1
392.1
377.5
Min.
131
103
177
171
135
184
Max.
583
673
723
696
696
722

360

n
Mean
SD
Median
Min.
Max.

98
0.3
44.08
1.3
-154
201

99
7.6
43.46
5.0
-85
185

101
21.2
41.22
16.4
-98
161

98
30.3
51.48
21.1
-68
204

101
32.2
46.20
27.4
-66
273

102
37.9
52.57
30.5
-52
263

YM2008/00019/00
B2C109575

Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Note: Endpoint is defined as the last 7 days on study medication ending with the treatment stop date

CONFIDENTIAL

Change From Baseline


in PM PEF (L/min)

Protocol: B2C109575
Population: Intent-to-Treat

Page 9 of 9
Table 7.39
Change from Baseline in PM PEF (L/min)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Follow-up
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------PM PEF (L/min)
n
64
78
69
80
78
83
Mean
372.4
424.2
419.1
409.0
385.8
392.0
SD
110.94
119.16
114.15
115.41
121.46
119.66
Median
346.7
413.2
387.0
388.0
373.4
380.3
Min.
149
161
171
173
126
192
Max.
625
674
731
758
708
690

361

n
Mean
SD
Median
Min.
Max.

64
14.5
52.26
9.8
-90
221

78
8.2
48.78
5.6
-96
167

69
18.1
42.04
21.6
-88
104

80
24.7
53.83
16.5
-69
209

78
19.1
42.38
15.5
-82
186

83
29.8
56.27
22.4
-72
236

YM2008/00019/00
B2C109575

Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Note: Endpoint is defined as the last 7 days on study medication ending with the treatment stop date

CONFIDENTIAL

Change From Baseline


in PM PEF (L/min)

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.40
Statistical Analysis of Change from Baseline in PM PEF (L/min)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Days 1-28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------------n
99
99
101
98
101
102
LS Mean
378.3
391.9
402.4
406.7
411.8
416.2
LS Mean Change (SE)
0.4 (3.87)
14.0 (3.87)
24.5 (3.82)
28.9 (3.87)
34.0 (3.81)
38.4 (3.82)
Column vs Placebo
LS Mean Difference
95% C.I.
p-value

13.6
(2.8, 24.4)
0.014

24.1
(13.5, 34.8)
<0.001

28.5
(17.7, 39.3)
<0.001

33.6
(22.9, 44.2)
<0.001

38.0
(27.3, 48.7)
<0.001

CONFIDENTIAL

362

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline, country, sex, age, stratum and treatment
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 9
Table 7.41
Change from Baseline in AM PEF (L/min)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Baseline
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------AM PEF (L/min)
n
102
101
101
100
101
102
Mean
345.6
377.4
387.5
366.3
360.7
340.1
SD
113.65
128.51
114.40
113.51
116.68
107.46
Median 330.1
371.8
379.9
355.4
353.2
321.5
Min.
104
106
158
105
88
131
Max.
617
691
659
625
638
662

CONFIDENTIAL

363

YM2008/00019/00
B2C109575

Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Note: Endpoint is defined as the last 7 days on study medication ending with the treatment stop date

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 9
Table 7.41
Change from Baseline in AM PEF (L/min)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Week 1
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------AM PEF (L/min)
n
98
99
101
97
101
101
Mean
349.5
393.7
414.3
400.9
397.0
384.8
SD
113.10
128.07
115.92
117.11
119.35
110.44
Median 332.4
395.5
401.7
385.7
389.0
372.3
Min.
111
91
170
163
101
188
Max.
647
685
685
658
659
681

364

n
Mean
SD
Median
Min.
Max.

98
4.5
31.84
1.6
-58
141

99
16.7
36.90
15.1
-105
108

101
26.7
29.62
24.5
-38
120

97
34.4
35.94
34.6
-65
146

101
36.2
36.28
34.7
-79
168

101
47.1
35.10
44.5
-40
174

YM2008/00019/00
B2C109575

Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Note: Endpoint is defined as the last 7 days on study medication ending with the treatment stop date

CONFIDENTIAL

Change From Baseline


in AM PEF (L/min)

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 9
Table 7.41
Change from Baseline in AM PEF (L/min)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Week 2
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------AM PEF (L/min)
n
93
93
97
94
97
98
Mean
346.5
404.1
412.6
403.5
397.9
390.6
SD
111.68
120.83
119.46
117.26
120.17
111.82
Median 323.9
401.0
399.1
394.0
377.0
381.7
Min.
122
146
175
157
104
165
Max.
664
677
698
659
686
687

365

n
Mean
SD
Median
Min.
Max.

93
2.4
37.16
2.7
-76
155

93
17.4
44.01
13.6
-97
209

97
23.0
34.57
18.3
-81
124

94
35.8
42.28
31.9
-75
144

97
35.9
41.05
32.4
-78
206

98
46.1
43.51
43.0
-71
192

YM2008/00019/00
B2C109575

Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Note: Endpoint is defined as the last 7 days on study medication ending with the treatment stop date

CONFIDENTIAL

Change From Baseline


in AM PEF (L/min)

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 9
Table 7.41
Change from Baseline in AM PEF (L/min)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Week 3
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------AM PEF (L/min)
n
90
86
91
92
94
98
Mean
349.7
415.2
421.4
403.0
400.0
390.9
SD
113.11
119.80
115.96
113.57
118.80
116.57
Median 325.8
413.9
405.4
395.8
378.4
375.0
Min.
123
152
169
167
129
175
Max.
630
689
684
673
689
677

366

n
Mean
SD
Median
Min.
Max.

90
5.3
40.40
0.9
-76
175

86
22.7
45.38
12.4
-77
230

91
25.3
36.58
19.3
-45
133

92
35.8
48.89
27.0
-53
232

94
40.0
40.79
36.6
-48
224

98
46.8
46.88
44.4
-62
184

YM2008/00019/00
B2C109575

Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Note: Endpoint is defined as the last 7 days on study medication ending with the treatment stop date

CONFIDENTIAL

Change From Baseline


in AM PEF (L/min)

Protocol: B2C109575
Population: Intent-to-Treat

Page 5 of 9
Table 7.41
Change from Baseline in AM PEF (L/min)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Week 4
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------AM PEF (L/min)
n
87
84
90
89
93
98
Mean
348.0
408.9
420.2
401.0
399.5
389.3
SD
108.67
122.65
117.28
109.80
119.59
115.28
Median 338.1
393.7
399.1
382.8
388.8
377.2
Min.
121
101
170
154
120
164
Max.
624
670
673
672
703
665

367

n
Mean
SD
Median
Min.
Max.

87
3.2
42.02
0.6
-95
191

84
18.8
48.62
13.6
-76
211

90
23.0
35.60
13.0
-39
120

89
33.5
45.83
30.5
-106
193

93
41.7
47.25
38.0
-52
297

98
45.2
45.94
40.1
-39
186

YM2008/00019/00
B2C109575

Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Note: Endpoint is defined as the last 7 days on study medication ending with the treatment stop date

CONFIDENTIAL

Change From Baseline


in AM PEF (L/min)

Protocol: B2C109575
Population: Intent-to-Treat

Page 6 of 9
Table 7.41
Change from Baseline in AM PEF (L/min)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Days 1-14
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------AM PEF (L/min)
n
98
99
101
98
101
102
Mean
348.8
393.4
412.5
400.6
396.9
386.9
SD
112.00
126.91
116.41
115.58
118.47
111.64
Median 327.0
393.0
401.7
389.0
384.9
381.1
Min.
117
88
173
164
111
185
Max.
656
681
683
656
672
685

368

n
Mean
SD
Median
Min.
Max.

98
3.8
32.61
1.0
-50
149

99
16.4
38.05
12.6
-101
138

101
24.9
30.30
17.7
-34
117

98
34.3
37.20
32.6
-65
133

101
36.2
36.93
32.4
-76
189

102
46.8
36.42
44.8
-55
157

YM2008/00019/00
B2C109575

Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Note: Endpoint is defined as the last 7 days on study medication ending with the treatment stop date

CONFIDENTIAL

Change From Baseline


in AM PEF (L/min)

Protocol: B2C109575
Population: Intent-to-Treat

Page 7 of 9
Table 7.41
Change from Baseline in AM PEF (L/min)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Days 1-28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------AM PEF (L/min)
n
98
99
101
98
101
102
Mean
348.7
393.6
412.3
400.7
398.5
386.5
SD
110.82
127.00
115.43
114.11
116.54
112.92
Median 328.1
390.0
401.5
391.9
376.9
378.0
Min.
120
88
171
163
126
177
Max.
641
680
678
657
682
672

369

n
Mean
SD
Median
Min.
Max.

98
3.7
34.81
-0.2
-58
167

99
16.5
39.57
9.0
-89
172

101
24.7
31.68
19.3
-34
120

98
34.5
41.31
28.7
-65
149

101
37.8
38.19
34.7
-76
217

102
46.4
39.07
42.7
-53
171

YM2008/00019/00
B2C109575

Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Note: Endpoint is defined as the last 7 days on study medication ending with the treatment stop date

CONFIDENTIAL

Change From Baseline


in AM PEF (L/min)

Protocol: B2C109575
Population: Intent-to-Treat

Page 8 of 9
Table 7.41
Change from Baseline in AM PEF (L/min)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Endpoint
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------AM PEF (L/min)
n
98
99
101
98
101
102
Mean
345.9
392.8
411.9
401.6
399.6
384.9
SD
108.15
128.77
116.70
113.47
116.90
114.75
Median 333.6
390.3
393.2
382.9
396.4
378.9
Min.
121
88
170
154
120
164
Max.
624
675
676
673
696
665

370

n
Mean
SD
Median
Min.
Max.

98
0.8
40.83
0.6
-77
191

99
15.8
46.68
10.5
-76
211

101
24.4
37.66
12.7
-34
119

98
35.3
52.84
30.9
-127
232

101
38.9
46.05
36.5
-73
268

102
44.8
45.66
40.0
-43
191

YM2008/00019/00
B2C109575

Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Note: Endpoint is defined as the last 7 days on study medication ending with the treatment stop date

CONFIDENTIAL

Change From Baseline


in AM PEF (L/min)

Protocol: B2C109575
Population: Intent-to-Treat

Page 9 of 9
Table 7.41
Change from Baseline in AM PEF (L/min)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Follow-up
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------AM PEF (L/min)
n
65
79
71
81
78
84
Mean
346.7
405.1
403.9
395.9
377.5
380.1
SD
106.80
115.11
111.21
110.68
115.81
116.66
Median 321.3
397.0
385.2
385.8
373.9
360.7
Min.
113
161
161
135
103
185
Max.
583
660
662
651
678
662

371

n
Mean
SD
Median
Min.
Max.

65
13.0
42.76
9.0
-82
151

79
9.7
46.53
6.4
-89
182

71
15.7
43.19
15.0
-115
141

81
30.6
46.67
28.4
-66
197

78
26.8
37.67
26.3
-54
155

84
34.6
49.25
28.2
-102
187

YM2008/00019/00
B2C109575

Note: Baseline is defined as the last 7 days prior to the randomisation of the subject
Note: Endpoint is defined as the last 7 days on study medication ending with the treatment stop date

CONFIDENTIAL

Change From Baseline


in AM PEF (L/min)

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.42
Statistical Analysis of Change from Baseline in AM PEF (L/min)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Days 1-28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------------n
98
99
101
98
101
102
LS Mean
364.7
381.4
389.5
397.0
400.9
406.7
LS Mean Change (SE)
1.9 (3.69)
18.7 (3.67)
26.8 (3.63)
34.2 (3.68)
38.1 (3.61)
44.0 (3.63)
Column vs Placebo
LS Mean Difference
95% C.I.
p-value

16.8
(6.5, 27.1)
0.001

24.9
(14.7, 35.1)
<0.001

32.3
(22.1, 42.6)
<0.001

36.2
(26.1, 46.4)
<0.001

42.1
(31.9, 52.2)
<0.001

CONFIDENTIAL

372

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline, country, sex, age, stratum and treatment
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.43
Change from Baseline in Percentage of Symptom Free 24 Hour Periods

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Days 1-28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------Baseline
n
102
101
101
100
101
102
Mean
10.2
10.5
10.8
10.5
11.6
8.5
SD
18.29
20.21
22.55
21.64
21.36
16.13
Median
0.0
0.0
0.0
0.0
0.0
0.0
Min.
0
0
0
0
0
0
Max.
100
100
100
100
100
71
n
Mean
SD
Median
Min.
Max.

98
24.6
28.79
11.6
0
100

99
31.9
33.67
19.0
0
100

101
33.3
35.15
22.2
0
100

98
38.6
37.37
34.5
0
100

101
48.2
38.87
50.0
0
100

102
41.6
37.23
34.1
0
100

Change from Baseline

n
Mean
SD
Median
Min.
Max.

98
14.6
25.97
3.8
-35
93

99
21.4
31.27
7.4
-31
100

101
22.5
31.71
11.7
-71
100

98
27.8
35.21
16.5
-43
100

101
36.5
36.33
33.3
-21
100

102
33.1
34.72
27.2
-40
100

YM2008/00019/00
B2C109575

Note: Baseline is defined as the last 7 days prior to the randomisation of the subject

CONFIDENTIAL

373

Symptom Free
24 Hour Periods (%)

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.44
Statistical Analysis of Change from Baseline in Percentage of Symptom Free 24 Hour Periods

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Days 1-28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
98
99
101
98
101
102
LS Mean Change (SE) 14.2 (3.27)
22.6 (3.25)
23.6 (3.21)
26.8 (3.26)
36.4 (3.21)
32.3 (3.21)
Column vs Placebo
LS Mean Difference
95% C.I.
p-value

8.4
(-0.7, 17.5)
0.069

9.4
(0.4, 18.4)
0.040

12.7
(3.6, 21.8)
0.006

22.2
(13.3, 31.2)
<0.001

18.1
(9.1, 27.2)
<0.001

CONFIDENTIAL

374

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline, country, sex, age, stratum and treatment
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.45
Change from Baseline in Percentage of Rescue Free 24 Hour Periods

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Days 1-28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------Baseline
n
102
101
101
100
101
102
Mean
14.8
15.3
12.1
10.4
12.7
13.3
SD
24.77
25.76
22.04
21.63
21.11
23.28
Median
0.0
0.0
0.0
0.0
0.0
0.0
Min.
0
0
0
0
0
0
Max.
100
100
100
100
100
100
n
Mean
SD
Median
Min.
Max.

99
29.2
31.43
18.5
0
100

99
38.7
37.51
34.6
0
100

101
38.9
36.45
30.4
0
100

98
42.7
39.42
35.7
0
100

101
56.5
36.07
69.2
0
100

102
47.4
38.30
51.9
0
100

Change from Baseline

n
Mean
SD
Median
Min.
Max.

99
15.3
27.69
3.8
-43
96

99
23.1
35.07
7.4
-56
100

101
26.7
32.13
15.4
-29
100

98
32.1
36.18
22.6
-43
100

101
43.7
37.16
45.8
-32
100

102
34.1
36.43
30.7
-48
100

YM2008/00019/00
B2C109575

Note: Baseline is defined as the last 7 days prior to the randomisation of the subject

CONFIDENTIAL

375

Rescue Free
24 Hour Periods (%)

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.46
Statistical Analysis of Change from Baseline in Percentage of Rescue Free 24 Hour Periods

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Days 1-28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
99
99
101
98
101
102
LS Mean Change (SE) 15.0 (3.33) 25.8 (3.33)
27.3 (3.28)
29.6 (3.34)
43.4 (3.28)
34.0 (3.28)
Column vs Placebo
LS Mean Difference
95% C.I.
p-value

10.8
(1.5, 20.1)
0.023

12.3
(3.1, 21.5)
0.009

14.7
(5.4, 24.0)
0.002

28.4
(19.3, 37.6)
<0.001

19.0
(9.8, 28.3)
<0.001

CONFIDENTIAL

376

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline, country, sex, age, stratum and treatment
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.47
Change from Baseline in Percentage of Symptom Free Days

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------Baseline
n
102
101
101
100
101
102
Mean
16.3
16.5
15.9
16.8
19.5
14.9
SD
22.45
25.56
26.77
26.07
26.09
22.57
Median
0.0
0.0
0.0
0.0
0.0
0.0
Min.
0
0
0
0
0
0
Max.
100
100
100
100
100
100
n
Mean
SD
Median
Min.
Max.

99
32.5
32.40
19.2
0
100

99
38.1
35.40
30.8
0
100

101
42.3
36.82
35.7
0
100

98
44.9
38.17
43.2
0
100

101
55.1
38.83
65.0
0
100

102
50.3
37.48
55.6
0
100

Change from Baseline

n
Mean
SD
Median
Min.
Max.

99
16.0
28.60
4.2
-38
96

99
21.5
32.33
10.7
-46
100

101
26.4
33.58
17.9
-64
100

98
27.9
33.72
21.2
-43
100

101
35.6
34.30
29.6
-14
100

102
35.4
34.62
29.4
-29
100

YM2008/00019/00
B2C109575

Note: Baseline is defined as the last 7 days prior to the randomisation of the subject

CONFIDENTIAL

377

Days 1-28

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.48
Statistical Analysis of Change from Baseline in Percentage of Symptom Free Days

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Days 1-28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
99
99
101
98
101
102
LS Mean Change (SE) 15.8 (3.24)
22.5 (3.24)
26.9 (3.20)
27.1 (3.25)
36.1 (3.20)
34.4 (3.19)
Column vs Placebo
LS Mean Difference
95% C.I.
p-value

6.7
(-2.3, 15.8)
0.146

11.1
(2.2, 20.0)
0.015

11.4
(2.3, 20.4)
0.014

20.3
(11.4, 29.2)
<0.001

18.6
(9.6, 27.6)
<0.001

CONFIDENTIAL

378

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline, country, sex, age, stratum and treatment
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.49
Change from Baseline in Percentage of Symptom Free Nights

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------Baseline
n
102
101
101
100
101
102
Mean
42.5
35.9
40.9
40.5
40.6
34.0
SD
39.35
37.02
38.75
42.21
37.58
36.96
Median
31.0
28.6
33.3
16.7
40.0
15.5
Min.
0
0
0
0
0
0
Max.
100
100
100
100
100
100
n
Mean
SD
Median
Min.
Max.

98
53.8
36.49
59.0
0
100

99
54.2
38.28
65.4
0
100

101
59.0
39.50
71.4
0
100

98
64.2
38.78
83.6
0
100

101
70.7
35.51
89.3
0
100

102
59.4
38.45
68.5
0
100

Change from Baseline

n
Mean
SD
Median
Min.
Max.

98
12.7
27.58
0.0
-43
100

99
18.6
36.33
6.4
-100
100

101
18.1
33.04
4.8
-96
96

98
22.9
34.63
4.3
-53
100

101
30.1
35.89
24.7
-43
100

102
25.4
33.81
17.3
-39
100

YM2008/00019/00
B2C109575

Note: Baseline is defined as the last 7 days prior to the randomisation of the subject

CONFIDENTIAL

379

Days 1-28

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.50
Statistical Analysis of Change from Baseline in Percentage of Symptom Free Nights

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Days 1-28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
98
99
101
98
101
102
LS Mean Change (SE) 13.2 (3.04)
18.2 (3.02)
19.7 (2.98)
23.1 (3.03)
30.3 (2.98)
23.2 (2.98)
Column vs Placebo
LS Mean Difference
95% C.I.
p-value

5.0
(-3.5, 13.4)
0.249

6.5
(-1.9, 14.8)
0.128

9.9
(1.4, 18.3)
0.022

17.1
(8.8, 25.4)
<0.001

10.0
(1.6, 18.4)
0.020

CONFIDENTIAL

380

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline, country, sex, age, stratum and treatment
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Table 7.51
Change from Baseline in Percentage of Rescue Free Days

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------Baseline
n
102
101
101
100
101
102
Mean
22.0
23.5
19.5
19.0
22.7
21.2
SD
27.73
30.37
26.10
27.85
27.52
26.64
Median
14.3
14.3
14.3
14.3
14.3
14.3
Min.
0
0
0
0
0
0
Max.
100
100
100
100
100
100
n
Mean
SD
Median
Min.
Max.

99
37.2
33.52
33.3
0
100

99
44.7
38.20
40.0
0
100

101
49.2
36.78
48.0
0
100

98
47.8
39.69
41.0
0
100

101
63.1
35.08
75.0
0
100

102
56.0
37.09
69.1
0
100

Change from Baseline

n
Mean
SD
Median
Min.
Max.

99
15.9
29.02
4.8
-39
100

99
20.7
35.49
6.9
-50
100

101
29.8
34.46
21.1
-43
100

98
28.5
36.03
17.2
-52
100

101
40.4
36.83
40.0
-47
100

102
34.8
35.84
26.8
-50
100

YM2008/00019/00
B2C109575

Note: Baseline is defined as the last 7 days prior to the randomisation of the subject

CONFIDENTIAL

381

Days 1-28

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.52
Statistical Analysis of Change from Baseline in Percentage of Rescue Free Days

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Days 1-28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
99
99
101
98
101
102
LS Mean Change (SE) 15.3 (3.29)
23.4 (3.29)
29.6 (3.25)
26.2 (3.30)
41.0 (3.24)
34.5 (3.24)
Column vs Placebo
LS Mean Difference
95% C.I.
p-value

8.0
(-1.2, 17.2)
0.087

14.2
(5.2, 23.3)
0.002

10.9
(1.7, 20.0)
0.020

25.6
(16.6, 34.7)
<0.001

19.2
(10.1, 28.3)
<0.001

CONFIDENTIAL

382

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline, country, sex, age, stratum and treatment
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.53
Change from Baseline in Percentage of Rescue Free Nights

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------Baseline
n
102
101
101
100
101
102
Mean
45.5
39.6
38.6
36.9
38.2
36.8
SD
39.14
38.89
37.66
41.37
35.34
37.74
Median
42.9
28.6
28.6
14.3
33.3
28.6
Min.
0
0
0
0
0
0
Max.
100
100
100
100
100
100
n
Mean
SD
Median
Min.
Max.

98
54.7
36.62
63.0
0
100

99
57.7
38.71
67.9
0
100

101
60.7
37.10
71.4
0
100

98
63.3
39.10
84.9
0
100

101
75.5
32.54
92.0
0
100

102
65.5
36.65
84.8
0
100

Change from Baseline

n
Mean
SD
Median
Min.
Max.

98
10.6
31.49
3.8
-92
100

99
18.3
36.84
10.3
-100
100

101
22.1
34.93
10.7
-68
100

98
25.6
33.22
7.7
-44
96

101
37.2
35.85
32.1
-37
100

102
28.7
35.15
22.3
-40
100

YM2008/00019/00
B2C109575

Note: Baseline is defined as the last 7 days prior to the randomisation of the subject

CONFIDENTIAL

383

Days 1-28

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.54
Statistical Analysis of Change from Baseline in Percentage of Rescue Free Nights

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Days 1-28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
98
99
101
98
101
102
LS Mean Change (SE) 12.6 (3.05)
19.2 (3.03)
22.6 (2.99)
24.0 (3.04)
36.7 (2.98)
27.5 (2.98)
Column vs Placebo
LS Mean Difference
95% C.I.
p-value

6.7
(-1.8, 15.1)
0.123

10.0
(1.6, 18.4)
0.020

11.4
(3.0, 19.9)
0.008

24.1
(15.7, 32.5)
<0.001

14.9
(6.5, 23.3)
<0.001

CONFIDENTIAL

384

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline, country, sex, age, stratum and treatment
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.55
Statistical Analysis of Withdrawals Due to Lack of Efficacy

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------No. of subjects whose primary
9
(9%)
12 (12%)
3
(3%)
5
(5%)
4
(4%)
0
reason for withdrawal was lack
of efficacy
Column vs Placebo
p-value

0.499

0.134

0.407

0.251

0.003

CONFIDENTIAL

385

YM2008/00019/00
B2C109575

Note: Based on Fishers Exact Test

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.105
Summary of the Proportion of Subjects Obtaining >= 200mL and >= 12%
Increase from Baseline FEV1 (L) (0-24hrs)

Day 28

30
27
23
25
26
28
24
15
15
30
33
29
27
26

/
/
/
/
/
/
/
/
/
/
/
/
/
/

89
86
85
87
87
86
86
59
59
87
87
87
86
86

(34%)
(31%)
(27%)
(29%)
(30%)
(33%)
(28%)
(25%)
(25%)
(34%)
(38%)
(33%)
(31%)
(30%)

26
26
31
32
33
32
29
24
21
39
31
36
28
26

/
/
/
/
/
/
/
/
/
/
/
/
/
/

86
84
85
85
84
82
84
56
56
84
84
84
84
83

(30%)
(31%)
(36%)
(38%)
(39%)
(39%)
(35%)
(43%)
(38%)
(46%)
(37%)
(43%)
(33%)
(31%)

32
30
32
35
34
37
33
25
22
35
38
36
33
35

/
/
/
/
/
/
/
/
/
/
/
/
/
/

91
90
90
91
91
91
91
61
61
90
91
90
90
91

(35%)
(33%)
(36%)
(38%)
(37%)
(41%)
(36%)
(41%)
(36%)
(39%)
(42%)
(40%)
(37%)
(38%)

29
32
36
36
36
40
37
25
21
35
39
31
35
33

/
/
/
/
/
/
/
/
/
/
/
/
/
/

89
87
88
88
88
88
88
64
64
88
87
85
87
87

(33%)
(37%)
(41%)
(41%)
(41%)
(45%)
(42%)
(39%)
(33%)
(40%)
(45%)
(36%)
(40%)
(38%)

43
46
54
53
53
55
55
40
33
53
59
53
52
54

/
/
/
/
/
/
/
/
/
/
/
/
/
/

94
93
93
93
93
92
93
56
56
93
93
93
93
93

(46%)
(49%)
(58%)
(57%)
(57%)
(60%)
(59%)
(71%)
(59%)
(57%)
(63%)
(57%)
(56%)
(58%)

45
48
51
60
55
54
51
31
27
51
53
48
48
50

/
/
/
/
/
/
/
/
/
/
/
/
/
/

98
94
97
97
97
98
98
57
58
97
97
94
97
96

(46%)
(51%)
(53%)
(62%)
(57%)
(55%)
(52%)
(54%)
(47%)
(53%)
(55%)
(51%)
(49%)
(52%)

YM2008/00019/00
B2C109575

Pre-dose
15 mins
30 mins
1 hour
2 hours
3 hours
4 hours
6 hours
12 hours
16 hours
20 hours
22 hours
23 hours
24 hours

CONFIDENTIAL

386

Planned
Relative Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Time
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 1
15 mins
16 / 102 (16%) 16 / 97 (16%) 16 / 99 (16%) 18 / 99 (18%) 35 / 98 (36%) 34 / 98 (35%)
30 mins
23 / 99 (23%) 20 / 97 (21%) 25 / 100 (25%) 25 / 99 (25%) 45 / 98 (46%) 49 / 97 (51%)
1 hour
21 / 101 (21%) 24 / 101 (24%) 27 / 101 (27%) 33 / 99 (33%) 51 / 101 (50%) 62 / 101 (61%)
2 hours
24 / 100 (24%) 23 / 101 (23%) 32 / 101 (32%) 37 / 98 (38%) 56 / 101 (55%) 60 / 100 (60%)
3 hours
25 / 101 (25%) 26 / 100 (26%) 33 / 99 (33%) 42 / 99 (42%) 58 / 98 (59%) 58 / 100 (58%)
4 hours
22 / 100 (22%) 22 / 101 (22%) 28 / 101 (28%) 45 / 99 (45%) 58 / 100 (58%) 58 / 99 (59%)
6 hours
17 / 66 (26%) 17 / 67 (25%) 30 / 69 (43%) 29 / 71 (41%) 39 / 62 (63%) 40 / 59 (68%)
12 hours 16 / 66 (24%) 20 / 66 (30%) 22 / 70 (31%) 23 / 70 (33%) 32 / 62 (52%) 37 / 60 (62%)
16 hours 31 / 101 (31%) 33 / 100 (33%) 42 / 101 (42%) 36 / 99 (36%) 58 / 101 (57%) 57 / 101 (56%)
20 hours 35 / 100 (35%) 39 / 99 (39%) 40 / 101 (40%) 32 / 99 (32%) 58 / 101 (57%) 56 / 99 (57%)
22 hours 31 / 101 (31%) 30 / 99 (30%) 36 / 101 (36%) 34 / 96 (35%) 52 / 100 (52%) 53 / 100 (53%)
23 hours 30 / 99 (30%) 35 / 101 (35%) 34 / 101 (34%) 33 / 98 (34%) 50 / 99 (51%) 51 / 100 (51%)
24 hours 28 / 98 (29%) 32 / 98 (33%) 34 / 101 (34%) 33 / 97 (34%) 48 / 98 (49%) 52 / 99 (53%)

CONFIDENTIAL

YM2008/00019/00
B2C109575

Safety Data Source Figures and Tables


Page

Figure 8.1 Trellis Display of Maximum Post-Baseline LFT Values Versus Baseline
LFT Values . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 8.2 Box-Plot of Maximum Post Baseline Liver Function Tests . . . . . . . . . . . .
Figure 8.3 Trough FEV1 (L) (LOCF) Versus Change from Baseline in Weighted
Mean Pulse Rate at Day 28 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 8.4 Empirical Distribution Function for Maximum Change (0-4 hours) in QTc
(F) Interval (msec) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 8.5 Empirical Distribution Function for Maximum Change (0-4 hours) in QTc
(B) Interval (msec) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 8.6 Mean (95% CI) Change From Baseline in QTc (F) interval by Time and
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 8.7 Mean (95% CI) Change From Baseline in QTc (B) interval by Time and
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 8.8 Adjusted Treatment Differences (95% CI) of Change from Baseline in
Post-Dose Serial QTc(F) (msec) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 8.9 Adjusted Treatment Differences (95% CI) of Change from Baseline in
Post-Dose Serial QTc(B) (msec) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 8.10 Serial QTc(F) (msec) versus Heart Rate (beats/min) . . . . . . . . . . . . . . .
Figure 8.11 Serial QTc(B) (msec) versus Heart Rate (beats/min) . . . . . . . . . . . . . . .
Figure 8.12 Minimum Post-Baseline Potassium Values Versus Baseline Potassium
Values . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 8.13 Box Plot of Minimum Post-Baseline Potassium Values . . . . . . . . . . . . .
Figure 8.14 Maximum Post-Baseline Glucose Values Versus Baseline Glucose
Values . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 8.15 Box Plot of Maximum Post-Baseline Glucose Values. . . . . . . . . . . . . . .
Figure 8.16 Mean Fasting Potassium by Time and Treatment . . . . . . . . . . . . . . . . .
Figure 8.17 Mean Fasting Glucose by Time and Treatment . . . . . . . . . . . . . . . . . . .
Figure 8.18 Box Plot of Maximum Increase from Baseline in Pulse Rate
(beats/min) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 8.101 Potassium Profiles for Subjects with Values >7 (MMOL/L). . . . . . . . . .
Table 8.1 Summary of Exposure (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . .
Table 8.2 Summary of On-Treatment Adverse Events (Intent-to-Treat Population) .
Table 8.3 Summary of Post-Treatment Adverse Events (Intent-to-Treat Population)
Table 8.4 Summary of Most Frequent On-Treatment Adverse Events
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.5 Summary of Drug-Related Adverse Events (Intent-to-Treat Population) . .
Table 8.6 Summary of Adverse Events Leading to Permanent Discontinuation of
Study drug or Withdrawal from the Study (Intent-to-Treat Population) . . . . . . .

387

392
393
394
395
399
403
407
411
415
419
439
459
460
461
462
463
464
465
466
475
476
483
485
486
489

CONFIDENTIAL

YM2008/00019/00
B2C109575

Table 8.7 Summary of Pre-Treatment Serious Adverse Events (Intent-to-Treat


Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.8 Summary of On-Treatment Serious Adverse Events (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.9 Summary of Post-Treatment Serious Adverse Events (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.10 Relationship of Adverse Event System Organ Class, Preferred Term
and Verbatim Text (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.11 Summary of Chemistry Data (Intent-to-Treat Population) . . . . . . . . . . . .
Table 8.12 Summary of Chemistry Data Outside the Normal Range
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.13 Summary of Chemistry Changes from Baseline Relative to the Normal
Range (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.14 Summary of Haematology Data (Intent-to-Treat Population) . . . . . . . . . .
Table 8.15 Summary of Haematology Data Outside the Normal Range
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.16 Summary of Haematology Changes from Baseline Relative to the
Normal Range (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.17 Summary of Urine Dipstick Results (Intent-to-Treat Population) . . . . . . .
Table 8.18 Summary of Vital Signs (Intent-to-Treat Population) . . . . . . . . . . . . . . . .
Table 8.19 Summary of Change from Baseline in Vital Signs (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.20 Summary of Maximum Increase from Baseline in Systolic Blood
Pressure (mmHg) (0-4hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . .
Table 8.21 Summary of Maximum Increase from Pre-Dose in Systolic Blood
Pressure (mmHg) (0-4hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . .
Table 8.22 Statistical Analysis of Maximum Increase from Baseline in Systolic
Blood Pressure (mmHg) (0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . .
Table 8.23 Summary of Maximum Decrease from Baseline in Diastolic Blood
Pressure (mmHg) (0-4hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . .
Table 8.24 Summary of Maximum Decrease from Pre-Dose in Diastolic Blood
Pressure (mmHg) (0-4hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . .
Table 8.25 Statistical Analysis of Maximum Decrease from Baseline in Diastolic
Blood Pressure (mmHg) (0-4hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . .
Table 8.26 Summary of Maximum Increase from Baseline in Pulse Rate
(beats/min) (0-4hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.27 Summary of Maximum Increase from Pre-Dose in Pulse Rate
(beats/min) (0-4hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.28 Statistical Analysis of Maximum Increase from Baseline in Pulse Rate
(beats/min) (0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.29 Summary of Weighted Mean Change from Baseline in Systolic Blood
Pressure (mmHg) (0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . .

388

490
491
492
493
502
521
540
550
563
576
584
588
606
624
625
626
630
631
632
636
637
638
642

CONFIDENTIAL

YM2008/00019/00
B2C109575

Table 8.30 Summary of Weighted Mean Change from Pre-Dose in Systolic Blood
Pressure (mmHg) (0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . .
Table 8.31 Statistical Analysis of Weighted Mean Change from Baseline in
Systolic Blood Pressure (mmHg) (0-4 hrs) (Intent-to-Treat Population) . . . . . .
Table 8.32 Summary of Weighted Mean Change from Baseline in Diastolic Blood
Pressure (mmHg) (0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . .
Table 8.33 Summary of Weighted Mean Change from Pre-Dose in Diastolic Blood
Pressure (mmHg) (0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . .
Table 8.34 Statistical Analysis of Weighted Mean Change from Baseline in
Diastolic Blood Pressure (mmHg) (0-4 hrs) (Intent-to-Treat Population) . . . . . .
Table 8.35 Summary of Weighted Mean Change from Baseline in Pulse Rate
(beats/min) (0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.36 Summary of Weighted Mean Change from Pre-Dose in Pulse Rate
(beats/min) (0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.37 Statistical Analysis of Weighted Mean Change from Baseline in Pulse
Rate (beats/min) (0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . .
Table 8.38 Summary of ECG Values (Intent-to-Treat Population) . . . . . . . . . . . . . . .
Table 8.39 Summary of ECG Findings (Intent-to-Treat Population) . . . . . . . . . . . . .
Table 8.40 Summary of Maximum Post-Dose QTc(F) Interval (msec)
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.41 Summary of Maximum Post-Dose QTc(B) Interval (msec)
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.42 Summary of Maximum Change From Baseline (0-4 hours) in QTc(F)
Interval (msec) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.43 Summary of Maximum Change From Baseline (0-4 hours) in QTc(B)
Interval (msec) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.44 Summary of Weighted Mean Change From Baseline (0-4 hours) in
QTc(F) Interval (msec) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . .
Table 8.45 Summary of Weighted Mean Change From Pre-Dose (0-4 hours) in
QTc(F) Interval (msec) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . .
Table 8.46 Summary of Weighted Mean Change From Baseline (0-4 hours) in
QTc(B) Interval (msec) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . .
Table 8.47 Summary of Weighted Mean Change From Pre-Dose (0-4 hours) in
QTc(B) Interval (msec) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . .
Table 8.48 Statistical Analysis of Change from Baseline in Post-Dose Serial
QTc(F) (msec) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.49 Statistical Analysis of Change from Baseline in Post-Dose Serial
QTc(B) (msec) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.50 Statistical Analysis of Change from Baseline in Maximum Value (0-4
hrs) QTc(F) (msec) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.51 Statistical Analysis of Change from Baseline in Maximum Value (0-4
hrs) QTc(B) (msec) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . .

389

643
644
648
649
650
654
655
656
660
696
717
718
719
721
723
724
725
726
727
743
759
763

CONFIDENTIAL

YM2008/00019/00
B2C109575

Table 8.52 Statistical Analysis of Weighted Mean Change from Baseline (0-4 hrs)
QTc(F) (msec) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.53 Statistical Analysis of Weighted Mean Change from Baseline (0-4 hrs)
QTc(B) (msec) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.54 Summary of Fasting Potassium and Glucose (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.55 Summary of Non-Fasting Potassium (Intent-to-Treat Population) . . . . . .
Table 8.56 Summary of Fasting Potassium and Glucose Changes from Baseline
Relative to the Normal Range (Intent-to-Treat Population) . . . . . . . . . . . . . . . . .
Table 8.57 Summary of Non-Fasting Potassium Changes from Baseline Relative
to the Normal Range (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.58 Summary of Maximum Decrease from Baseline in Fasting Potassium
(0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.59 Summary of Maximum Decrease from Pre-Dose in Fasting Potassium
(0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.60 Summary of Maximum Decrease from Baseline in Non-Fasting
Potassium (0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.61 Summary of Maximum Decrease from Pre-Dose in Non-Fasting
Potassium (0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.62 Summary of Maximum Increase from Baseline in Glucose (0-4 hrs)
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.63 Summary of Maximum Increase from Pre-Dose in Glucose (0-4 hrs)
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.64 Summary of Weighted Mean Change from Baseline in Fasting
Potassium (0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.65 Summary of Weighted Mean Change from Pre-Dose in Fasting
Potassium (0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.66 Summary of Weighted Mean Change from Baseline in Non-Fasting
Potassium (0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.67 Summary of Weighted Mean Change from Pre-Dose in Non-Fasting
Potassium (0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.68 Summary of Weighted Mean Change from Baseline in Glucose (0-4
hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.69 Summary of Weighted Mean Change from Pre-Dose in Glucose (0-4
hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.70 Statistical Analysis of Maximum Decrease from Baseline in Fasting
Potassium (0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.71 Statistical Analysis of Maximum Decrease from Baseline in
Non-Fasting Potassium (0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . .
Table 8.72 Statistical Analysis of Maximum Increase from Baseline in Glucose (0-4
hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

390

767
771
775
781
784
790
793
794
795
796
797
798
799
800
801
802
803
804
805
807
809

CONFIDENTIAL

YM2008/00019/00
B2C109575

Table 8.73 Statistical Analysis of Weighted Mean Change from Baseline in Fasting
Potassium (0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.74 Statistical Analysis of Weighted Mean Change from Baseline in
Non-Fasting Potassium (0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . .
Table 8.75 Statistical Analysis of Weighted Mean Change from Baseline in
Glucose (0-4 hrs) (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8.76 Summary of Subjects with Asthma Exacerbations (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

391

811
813
815
817

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Figure 8.1
Trellis Display of Maximum Post-Baseline LFT Values Versus Baseline LFT Values

ALT
3.0

2.5
2.0
1.5
1.0
0.5
0.0

Alk. Phos.

Total Bili.

0.0

1.0

2.0

0.0

1.0

2.0

0.0

1.0

CONFIDENTIAL

392

Maximum (/ULN)

AST

2.0

0.0

1.0

2.0

Baseline (/ULN)
Placebo

3mcg

6.25mcg

12.5mcg

25mcg

50mcg

Note: Clinical Concern Levels: AST, ALT, Alk Phos : 2xULN, Total Bili : 1.5xULN
Note: Shows each subjects maximum value against their baseline value, each divided by the upper limit of normal

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Figure 8.2
Box-Plot of Maximum Post Baseline Liver Function Tests

This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy.
Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see
the Patient Level Data section of the GSK Clincal Study Register.

CONFIDENTIAL

393

YM2008/00019/00
B2C109575

Note: Graph includes subjects who were below ULN at baseline. Shows each subjects maximum value divided by the upper limit of normal
Clinical concern levels: AST, ALT, Alk. Phos: 2xULN, Total Bili: 1.5xULN

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Figure 8.3
Trough FEV1 (L) (LOCF) Versus Change from Baseline in Weighted Mean Pulse Rate at Day 28

0.4

0.3

CONFIDENTIAL

394

FEV1 (L) Change from Baseline Difference From Placebo and 95% CI

0.5

0.2

0.1

0.0

-6

-3

Pulse Rate (beats/min) Weighted Mean Change from Baseline (0-4 hrs) Difference From Placebo and 95% CI
Treatment

3mcg

6.25mcg

12.5mcg

Note: Analyses performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum, and treatment

25mcg

50mcg

YM2008/00019/00
B2C109575

-0.1

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 4
Figure 8.4
Empirical Distribution Function for Maximum Change (0-4 hours) in QTc (F) Interval (msec)
Day: 1

1.0

CONFIDENTIAL

395

Cumulative Probability

0.8

0.6

0.4

0.0
-50

50
Change in QTc (msec)

Note: Normal (Increase <= 30 msec), High (Increase >30 - 60 msec), Concern (Increase > 60 msec)

100

YM2008/00019/00
B2C109575

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg

0.2

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 4
Figure 8.4
Empirical Distribution Function for Maximum Change (0-4 hours) in QTc (F) Interval (msec)
Day: 7

1.0

CONFIDENTIAL

396

Cumulative Probability

0.8

0.6

0.4

0.0
-50

50
Change in QTc (msec)

Note: Normal (Increase <= 30 msec), High (Increase >30 - 60 msec), Concern (Increase > 60 msec)

100

YM2008/00019/00
B2C109575

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg

0.2

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 4
Figure 8.4
Empirical Distribution Function for Maximum Change (0-4 hours) in QTc (F) Interval (msec)
Day: 14

1.0

CONFIDENTIAL

397

Cumulative Probability

0.8

0.6

0.4

0.0
-50

50
Change in QTc (msec)

Note: Normal (Increase <= 30 msec), High (Increase >30 - 60 msec), Concern (Increase > 60 msec)

100

YM2008/00019/00
B2C109575

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg

0.2

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 4
Figure 8.4
Empirical Distribution Function for Maximum Change (0-4 hours) in QTc (F) Interval (msec)
Day: 28

1.0

CONFIDENTIAL

398

Cumulative Probability

0.8

0.6

0.4

0.0
-50

50
Change in QTc (msec)

Note: Normal (Increase <= 30 msec), High (Increase >30 - 60 msec), Concern (Increase > 60 msec)

100

YM2008/00019/00
B2C109575

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg

0.2

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 4
Figure 8.5
Empirical Distribution Function for Maximum Change (0-4 hours) in QTc (B) Interval (msec)
Day: 1

1.0

CONFIDENTIAL

399

Cumulative Probability

0.8

0.6

0.4

0.0
-50

50
Change in QTc (msec)

Note: Normal (Increase <= 30 msec), High (Increase >30 - 60 msec), Concern (Increase > 60 msec)

100

YM2008/00019/00
B2C109575

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg

0.2

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 4
Figure 8.5
Empirical Distribution Function for Maximum Change (0-4 hours) in QTc (B) Interval (msec)
Day: 7

1.0

CONFIDENTIAL

400

Cumulative Probability

0.8

0.6

0.4

0.0
-50

50
Change in QTc (msec)

Note: Normal (Increase <= 30 msec), High (Increase >30 - 60 msec), Concern (Increase > 60 msec)

100

YM2008/00019/00
B2C109575

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg

0.2

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 4
Figure 8.5
Empirical Distribution Function for Maximum Change (0-4 hours) in QTc (B) Interval (msec)
Day: 14

1.0

CONFIDENTIAL

401

Cumulative Probability

0.8

0.6

0.4

0.0
-50

50
Change in QTc (msec)

Note: Normal (Increase <= 30 msec), High (Increase >30 - 60 msec), Concern (Increase > 60 msec)

100

YM2008/00019/00
B2C109575

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg

0.2

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 4
Figure 8.5
Empirical Distribution Function for Maximum Change (0-4 hours) in QTc (B) Interval (msec)
Day: 28

1.0

CONFIDENTIAL

402

Cumulative Probability

0.8

0.6

0.4

0.0
-50

50
Change in QTc (msec)

Note: Normal (Increase <= 30 msec), High (Increase >30 - 60 msec), Concern (Increase > 60 msec)

100

YM2008/00019/00
B2C109575

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg

0.2

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 4
Figure 8.6
Mean (95% CI) Change From Baseline in QTc (F) interval by Time and Treatment

2 hours

4 hours

CONFIDENTIAL

403

Mean Change in QTc (msec)

Day: 1

-5

1 hour

Time (hours)

Placebo
3mcg

6.25mcg
12.5mcg

25mcg
50mcg

YM2008/00019/00
B2C109575

Pre-dose 10 mins

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 4
Figure 8.6
Mean (95% CI) Change From Baseline in QTc (F) interval by Time and Treatment

CONFIDENTIAL

404

Mean Change in QTc (msec)

Day: 7

-5

1 hour

2 hours

4 hours

Time (hours)

Placebo
3mcg

6.25mcg
12.5mcg

25mcg
50mcg

YM2008/00019/00
B2C109575

Pre-dose 10 mins

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 4
Figure 8.6
Mean (95% CI) Change From Baseline in QTc (F) interval by Time and Treatment

CONFIDENTIAL

405

Mean Change in QTc (msec)

Day: 14

-5

1 hour

2 hours

4 hours

Time (hours)

Placebo
3mcg

6.25mcg
12.5mcg

25mcg
50mcg

YM2008/00019/00
B2C109575

Pre-dose 10 mins

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 4
Figure 8.6
Mean (95% CI) Change From Baseline in QTc (F) interval by Time and Treatment

CONFIDENTIAL

406

Mean Change in QTc (msec)

Day: 28

-5

1 hour

2 hours

4 hours

Time (hours)

Placebo
3mcg

6.25mcg
12.5mcg

25mcg
50mcg

YM2008/00019/00
B2C109575

Pre-dose 10 mins

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 4
Figure 8.7
Mean (95% CI) Change From Baseline in QTc (B) interval by Time and Treatment
Day: 1

15

-5

2 hours

4 hours

CONFIDENTIAL

407

Mean Change in QTc (msec)

10

-10

1 hour

Time (hours)

Placebo
3mcg

6.25mcg
12.5mcg

25mcg
50mcg

YM2008/00019/00
B2C109575

Pre-dose 10 mins

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 4
Figure 8.7
Mean (95% CI) Change From Baseline in QTc (B) interval by Time and Treatment
Day: 7

15

-5

CONFIDENTIAL

408

Mean Change in QTc (msec)

10

-10

1 hour

2 hours

4 hours

Time (hours)

Placebo
3mcg

6.25mcg
12.5mcg

25mcg
50mcg

YM2008/00019/00
B2C109575

Pre-dose 10 mins

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 4
Figure 8.7
Mean (95% CI) Change From Baseline in QTc (B) interval by Time and Treatment
Day: 14

15

CONFIDENTIAL

409

Mean Change in QTc (msec)

10

-5

-10

1 hour

2 hours

4 hours

Time (hours)

Placebo
3mcg

6.25mcg
12.5mcg

25mcg
50mcg

YM2008/00019/00
B2C109575

Pre-dose 10 mins

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 4
Figure 8.7
Mean (95% CI) Change From Baseline in QTc (B) interval by Time and Treatment
Day: 28

15

-5

CONFIDENTIAL

410

Mean Change in QTc (msec)

10

-10

1 hour

2 hours

4 hours

Time (hours)

Placebo
3mcg

6.25mcg
12.5mcg

25mcg
50mcg

YM2008/00019/00
B2C109575

Pre-dose 10 mins

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 4

Figure 8.8
Adjusted Treatment Differences (95% CI) of Change from Baseline in Post-Dose Serial QTc(F) (msec)
Day: 1
10

-5

CONFIDENTIAL

411

QTc (msec)

-10
0

3mcg
6.25mcg

Treatment (vs. Placebo)


12.5mcg
25mcg

50mcg

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

YM2008/00019/00
B2C109575

Time (hours)

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 4

Figure 8.8
Adjusted Treatment Differences (95% CI) of Change from Baseline in Post-Dose Serial QTc(F) (msec)
Day: 7
10

-5

CONFIDENTIAL

412

QTc (msec)

-10
0

3mcg
6.25mcg

Treatment (vs. Placebo)


12.5mcg
25mcg

50mcg

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

YM2008/00019/00
B2C109575

Time (hours)

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 4

Figure 8.8
Adjusted Treatment Differences (95% CI) of Change from Baseline in Post-Dose Serial QTc(F) (msec)
Day: 14
10

-5

CONFIDENTIAL

413

QTc (msec)

-10
0

3mcg
6.25mcg

Treatment (vs. Placebo)


12.5mcg
25mcg

50mcg

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

YM2008/00019/00
B2C109575

Time (hours)

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 4

Figure 8.8
Adjusted Treatment Differences (95% CI) of Change from Baseline in Post-Dose Serial QTc(F) (msec)
Day: 28
10

-5

CONFIDENTIAL

414

QTc (msec)

-10
0

3mcg
6.25mcg

Treatment (vs. Placebo)


12.5mcg
25mcg

50mcg

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

YM2008/00019/00
B2C109575

Time (hours)

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 4

Figure 8.9
Adjusted Treatment Differences (95% CI) of Change from Baseline in Post-Dose Serial QTc(B) (msec)
Day: 1

15

-5

CONFIDENTIAL

415

QTc (msec)

10

-10

3mcg
6.25mcg

Treatment (vs. Placebo)


12.5mcg
25mcg

50mcg

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

YM2008/00019/00
B2C109575

Time (hours)

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 4

Figure 8.9
Adjusted Treatment Differences (95% CI) of Change from Baseline in Post-Dose Serial QTc(B) (msec)
Day: 7

15

-5

CONFIDENTIAL

416

QTc (msec)

10

-10

3mcg
6.25mcg

Treatment (vs. Placebo)


12.5mcg
25mcg

50mcg

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

YM2008/00019/00
B2C109575

Time (hours)

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 4

Figure 8.9
Adjusted Treatment Differences (95% CI) of Change from Baseline in Post-Dose Serial QTc(B) (msec)
Day: 14

15

-5

CONFIDENTIAL

417

QTc (msec)

10

-10

3mcg
6.25mcg

Treatment (vs. Placebo)


12.5mcg
25mcg

50mcg

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

YM2008/00019/00
B2C109575

Time (hours)

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 4

Figure 8.9
Adjusted Treatment Differences (95% CI) of Change from Baseline in Post-Dose Serial QTc(B) (msec)
Day: 28

15

-5

CONFIDENTIAL

418

QTc (msec)

10

-10

3mcg
6.25mcg

Treatment (vs. Placebo)


12.5mcg
25mcg

50mcg

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

YM2008/00019/00
B2C109575

Time (hours)

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 20
Figure 8.10
Serial QTc(F) (msec) versus Heart Rate (beats/min)
Day 1, Pre-dose

400

350

60

80

100

Heart Rate (beats/min)

Placebo

Note: Heart rate is from ECG.

3mcg

6.25mcg

12.5mcg

25mcg

50mcg

YM2008/00019/00
B2C109575

40

CONFIDENTIAL

419

QTc(F) (msec)

450

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 20
Figure 8.10
Serial QTc(F) (msec) versus Heart Rate (beats/min)
Day 1, 10 mins

QTc(F) (msec)

420

400

350

60

80

100

Heart Rate (beats/min)


Placebo

Note: Heart rate is from ECG.

3mcg

6.25mcg

12.5mcg

25mcg

50mcg

YM2008/00019/00
B2C109575

40

CONFIDENTIAL

450

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 20
Figure 8.10
Serial QTc(F) (msec) versus Heart Rate (beats/min)
Day 1, 1 hour

400

350

CONFIDENTIAL

421

QTc(F) (msec)

450

60

80

100

Heart Rate (beats/min)

Placebo

Note: Heart rate is from ECG.

3mcg

6.25mcg

12.5mcg

25mcg

50mcg

YM2008/00019/00
B2C109575

40

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 20
Figure 8.10
Serial QTc(F) (msec) versus Heart Rate (beats/min)
Day 1, 2 hours

400

350

60

80

100

Heart Rate (beats/min)

Placebo

Note: Heart rate is from ECG.

3mcg

6.25mcg

12.5mcg

25mcg

50mcg

YM2008/00019/00
B2C109575

40

CONFIDENTIAL

QTc(F) (msec)

450

422

Protocol: B2C109575
Population: Intent-to-Treat

Page 5 of 20
Figure 8.10
Serial QTc(F) (msec) versus Heart Rate (beats/min)
Day 1, 4 hours

400

350

60

80

100

Heart Rate (beats/min)

Placebo

Note: Heart rate is from ECG.

3mcg

6.25mcg

12.5mcg

25mcg

50mcg

YM2008/00019/00
B2C109575

40

CONFIDENTIAL

423

QTc(F) (msec)

450

Protocol: B2C109575
Population: Intent-to-Treat

Page 6 of 20
Figure 8.10
Serial QTc(F) (msec) versus Heart Rate (beats/min)
Day 7, Pre-dose

400

350

60

80

100

Heart Rate (beats/min)

Placebo

Note: Heart rate is from ECG.

3mcg

6.25mcg

12.5mcg

25mcg

50mcg

YM2008/00019/00
B2C109575

40

CONFIDENTIAL

424

QTc(F) (msec)

450

Protocol: B2C109575
Population: Intent-to-Treat

Page 7 of 20
Figure 8.10
Serial QTc(F) (msec) versus Heart Rate (beats/min)
Day 7, 10 mins

400

350

60

80

100

Heart Rate (beats/min)

Placebo

Note: Heart rate is from ECG.

3mcg

6.25mcg

12.5mcg

25mcg

50mcg

YM2008/00019/00
B2C109575

40

CONFIDENTIAL

425

QTc(F) (msec)

450

Protocol: B2C109575
Population: Intent-to-Treat

Page 8 of 20
Figure 8.10
Serial QTc(F) (msec) versus Heart Rate (beats/min)
Day 7, 1 hour

400

350

60

80

100

Heart Rate (beats/min)

Placebo

Note: Heart rate is from ECG.

3mcg

6.25mcg

12.5mcg

25mcg

50mcg

YM2008/00019/00
B2C109575

40

CONFIDENTIAL

426

QTc(F) (msec)

450

Protocol: B2C109575
Population: Intent-to-Treat

Page 9 of 20
Figure 8.10
Serial QTc(F) (msec) versus Heart Rate (beats/min)
Day 7, 2 hours

450

400

350

CONFIDENTIAL

427

QTc(F) (msec)

60

80

100

Heart Rate (beats/min)

Placebo

Note: Heart rate is from ECG.

3mcg

6.25mcg

12.5mcg

25mcg

50mcg

YM2008/00019/00
B2C109575

40

Protocol: B2C109575
Population: Intent-to-Treat

Page 10 of 20
Figure 8.10
Serial QTc(F) (msec) versus Heart Rate (beats/min)
Day 7, 4 hours

450

QTc(F) (msec)

400

350

CONFIDENTIAL

428

60

80

100

Heart Rate (beats/min)

Placebo

Note: Heart rate is from ECG.

3mcg

6.25mcg

12.5mcg

25mcg

50mcg

YM2008/00019/00
B2C109575

40

Protocol: B2C109575
Population: Intent-to-Treat

Page 11 of 20
Figure 8.10
Serial QTc(F) (msec) versus Heart Rate (beats/min)
Day 14, Pre-dose

450

400

350

CONFIDENTIAL

429

QTc(F) (msec)

40

60

80

100

Heart Rate (beats/min)

Placebo

Note: Heart rate is from ECG.

3mcg

6.25mcg

12.5mcg

25mcg

50mcg

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 12 of 20
Figure 8.10
Serial QTc(F) (msec) versus Heart Rate (beats/min)
Day 14, 10 mins

400

350

CONFIDENTIAL

430

QTc(F) (msec)

450

60

80

100

Heart Rate (beats/min)

Placebo

Note: Heart rate is from ECG.

3mcg

6.25mcg

12.5mcg

25mcg

50mcg

YM2008/00019/00
B2C109575

40

Protocol: B2C109575
Population: Intent-to-Treat

Page 13 of 20
Figure 8.10
Serial QTc(F) (msec) versus Heart Rate (beats/min)
Day 14, 1 hour

400

350

CONFIDENTIAL

431

QTc(F) (msec)

450

60

80

100

Heart Rate (beats/min)

Placebo

Note: Heart rate is from ECG.

3mcg

6.25mcg

12.5mcg

25mcg

50mcg

YM2008/00019/00
B2C109575

40

Protocol: B2C109575
Population: Intent-to-Treat

Page 14 of 20
Figure 8.10
Serial QTc(F) (msec) versus Heart Rate (beats/min)
Day 14, 2 hours

450

400

350

60

80

100

Heart Rate (beats/min)

Placebo

Note: Heart rate is from ECG.

3mcg

6.25mcg

12.5mcg

25mcg

50mcg

YM2008/00019/00
B2C109575

40

CONFIDENTIAL

432

QTc(F) (msec)

Protocol: B2C109575
Population: Intent-to-Treat

Page 15 of 20
Figure 8.10
Serial QTc(F) (msec) versus Heart Rate (beats/min)

450

400

350

CONFIDENTIAL

433

QTc(F) (msec)

Day 14, 4 hours

60

80

100

Heart Rate (beats/min)

Placebo

Note: Heart rate is from ECG.

3mcg

6.25mcg

12.5mcg

25mcg

50mcg

YM2008/00019/00
B2C109575

40

Protocol: B2C109575
Population: Intent-to-Treat

Page 16 of 20
Figure 8.10
Serial QTc(F) (msec) versus Heart Rate (beats/min)
Day 28, Pre-dose

400

350

60

80

100

Heart Rate (beats/min)


Placebo

Note: Heart rate is from ECG.

3mcg

6.25mcg

12.5mcg

25mcg

50mcg

YM2008/00019/00
B2C109575

40

CONFIDENTIAL

434

QTc(F) (msec)

450

Protocol: B2C109575
Population: Intent-to-Treat

Page 17 of 20
Figure 8.10
Serial QTc(F) (msec) versus Heart Rate (beats/min)
Day 28, 10 mins

400

350

60

80

100

Heart Rate (beats/min)

Placebo

Note: Heart rate is from ECG.

3mcg

6.25mcg

12.5mcg

25mcg

50mcg

YM2008/00019/00
B2C109575

40

CONFIDENTIAL

435

QTc(F) (msec)

450

Protocol: B2C109575
Population: Intent-to-Treat

Page 18 of 20
Figure 8.10
Serial QTc(F) (msec) versus Heart Rate (beats/min)
Day 28, 1 hour

450

400

350

60

80

100

Heart Rate (beats/min)

Placebo

Note: Heart rate is from ECG.

3mcg

6.25mcg

12.5mcg

25mcg

50mcg

YM2008/00019/00
B2C109575

40

CONFIDENTIAL

436

QTc(F) (msec)

Protocol: B2C109575
Population: Intent-to-Treat

Page 19 of 20
Figure 8.10
Serial QTc(F) (msec) versus Heart Rate (beats/min)
Day 28, 2 hours

450

400

350

60

80

100

Heart Rate (beats/min)

Placebo

Note: Heart rate is from ECG.

3mcg

6.25mcg

12.5mcg

25mcg

50mcg

YM2008/00019/00
B2C109575

40

CONFIDENTIAL

437

QTc(F) (msec)

Protocol: B2C109575
Population: Intent-to-Treat

Page 20 of 20
Figure 8.10
Serial QTc(F) (msec) versus Heart Rate (beats/min)
Day 28, 4 hours

400

350

CONFIDENTIAL

438

QTc(F) (msec)

450

60

80

100

Heart Rate (beats/min)

Placebo

Note: Heart rate is from ECG.

3mcg

6.25mcg

12.5mcg

25mcg

50mcg

YM2008/00019/00
B2C109575

40

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 20
Figure 8.11
Serial QTc(B) (msec) versus Heart Rate (beats/min)
Day 1, Pre-dose

500

439

QTc(B) (msec)

450

400

350

CONFIDENTIAL

60

80

100

Heart Rate (beats/min)

Placebo

Note: Heart rate is from ECG.

3mcg

6.25mcg

12.5mcg

25mcg

50mcg

YM2008/00019/00
B2C109575

40

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 20
Figure 8.11
Serial QTc(B) (msec) versus Heart Rate (beats/min)
Day 1, 10 mins

500

440

QTc(B) (msec)

450

400

350

60

80

100

Heart Rate (beats/min)

Placebo

Note: Heart rate is from ECG.

3mcg

6.25mcg

12.5mcg

25mcg

50mcg

YM2008/00019/00
B2C109575

40

CONFIDENTIAL

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 20
Figure 8.11
Serial QTc(B) (msec) versus Heart Rate (beats/min)
Day 1, 1 hour

500

400

350

60

80

100

Heart Rate (beats/min)

Placebo

Note: Heart rate is from ECG.

3mcg

6.25mcg

12.5mcg

25mcg

50mcg

YM2008/00019/00
B2C109575

40

CONFIDENTIAL

441

QTc(B) (msec)

450

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 20
Figure 8.11
Serial QTc(B) (msec) versus Heart Rate (beats/min)
Day 1, 2 hours

500

442

QTc(B) (msec)

450

400

350

CONFIDENTIAL

60

80

100

Heart Rate (beats/min)

Placebo

Note: Heart rate is from ECG.

3mcg

6.25mcg

12.5mcg

25mcg

50mcg

YM2008/00019/00
B2C109575

40

Protocol: B2C109575
Population: Intent-to-Treat

Page 5 of 20
Figure 8.11
Serial QTc(B) (msec) versus Heart Rate (beats/min)
Day 1, 4 hours

500

400

350

60

80

100

Heart Rate (beats/min)

Placebo

Note: Heart rate is from ECG.

3mcg

6.25mcg

12.5mcg

25mcg

50mcg

YM2008/00019/00
B2C109575

40

CONFIDENTIAL

443

QTc(B) (msec)

450

Protocol: B2C109575
Population: Intent-to-Treat

Page 6 of 20
Figure 8.11
Serial QTc(B) (msec) versus Heart Rate (beats/min)
Day 7, Pre-dose

500

400

350

60

80

100

Heart Rate (beats/min)

Note: Heart rate is from ECG.

3mcg

6.25mcg

12.5mcg

25mcg

50mcg

YM2008/00019/00
B2C109575

40

Placebo

CONFIDENTIAL

444

QTc(B) (msec)

450

Protocol: B2C109575
Population: Intent-to-Treat

Page 7 of 20
Figure 8.11
Serial QTc(B) (msec) versus Heart Rate (beats/min)
Day 7, 10 mins

500

450

400

350

80

100

Note: Heart rate is from ECG.

3mcg

6.25mcg

12.5mcg

25mcg

50mcg

YM2008/00019/00
B2C109575

60
Heart Rate (beats/min)

Placebo

40

CONFIDENTIAL

445

QTc(B) (msec)

Protocol: B2C109575
Population: Intent-to-Treat

Page 8 of 20
Figure 8.11
Serial QTc(B) (msec) versus Heart Rate (beats/min)
Day 7, 1 hour

500

400

350

CONFIDENTIAL

446

QTc(B) (msec)

450

60

80

100

Heart Rate (beats/min)

Placebo

Note: Heart rate is from ECG.

3mcg

6.25mcg

12.5mcg

25mcg

50mcg

YM2008/00019/00
B2C109575

40

Protocol: B2C109575
Population: Intent-to-Treat

Page 9 of 20
Figure 8.11
Serial QTc(B) (msec) versus Heart Rate (beats/min)
Day 7, 2 hours

500

450

447

400

350

60

80

100

Heart Rate (beats/min)

Placebo

Note: Heart rate is from ECG.

3mcg

6.25mcg

12.5mcg

25mcg

50mcg

YM2008/00019/00
B2C109575

40

CONFIDENTIAL

QTc(B) (msec)

Protocol: B2C109575
Population: Intent-to-Treat

Page 10 of 20
Figure 8.11
Serial QTc(B) (msec) versus Heart Rate (beats/min)
Day 7, 4 hours

500

450

400

350

60

80

Placebo

Note: Heart rate is from ECG.

3mcg

6.25mcg

12.5mcg

25mcg

100

Heart Rate (beats/min)

50mcg

YM2008/00019/00
B2C109575

40

CONFIDENTIAL

448

QTc(B) (msec)

Protocol: B2C109575
Population: Intent-to-Treat

Page 11 of 20
Figure 8.11
Serial QTc(B) (msec) versus Heart Rate (beats/min)
Day 14, Pre-dose

500

400

350

60

80

100

Heart Rate (beats/min)

Note: Heart rate is from ECG.

3mcg

6.25mcg

12.5mcg

25mcg

50mcg

YM2008/00019/00
B2C109575

40

Placebo

CONFIDENTIAL

QTc(B) (msec)

450

449

Protocol: B2C109575
Population: Intent-to-Treat

Page 12 of 20
Figure 8.11
Serial QTc(B) (msec) versus Heart Rate (beats/min)
Day 14, 10 mins

500

450

QTc(B) (msec)

450

400

350

CONFIDENTIAL

60

80

100

Heart Rate (beats/min)

Placebo

Note: Heart rate is from ECG.

3mcg

6.25mcg

12.5mcg

25mcg

50mcg

YM2008/00019/00
B2C109575

40

Protocol: B2C109575
Population: Intent-to-Treat

Page 13 of 20
Figure 8.11
Serial QTc(B) (msec) versus Heart Rate (beats/min)
Day 14, 1 hour

500

450

400

350

Note: Heart rate is from ECG.

3mcg

80

100

6.25mcg

12.5mcg

25mcg

50mcg

YM2008/00019/00
B2C109575

60
Heart Rate (beats/min)

Placebo

40

CONFIDENTIAL

451

QTc(B) (msec)

Protocol: B2C109575
Population: Intent-to-Treat

Page 14 of 20
Figure 8.11
Serial QTc(B) (msec) versus Heart Rate (beats/min)
Day 14, 2 hours

500

400

350

60

80

100

Heart Rate (beats/min)

Placebo

Note: Heart rate is from ECG.

3mcg

6.25mcg

12.5mcg

25mcg

50mcg

YM2008/00019/00
B2C109575

40

CONFIDENTIAL

452

QTc(B) (msec)

450

Protocol: B2C109575
Population: Intent-to-Treat

Page 15 of 20
Figure 8.11
Serial QTc(B) (msec) versus Heart Rate (beats/min)
Day 14, 4 hours

500

400

350

80

100

Note: Heart rate is from ECG.

3mcg

6.25mcg

12.5mcg

25mcg

50mcg

YM2008/00019/00
B2C109575

60
Heart Rate (beats/min)

Placebo

40

CONFIDENTIAL

453

QTc(B) (msec)

450

Protocol: B2C109575
Population: Intent-to-Treat

Page 16 of 20
Figure 8.11
Serial QTc(B) (msec) versus Heart Rate (beats/min)
Day 28, Pre-dose

500

400

350

40

60

80

100

Heart Rate (beats/min)

Placebo

Note: Heart rate is from ECG.

3mcg

6.25mcg

12.5mcg

25mcg

50mcg

YM2008/00019/00
B2C109575

CONFIDENTIAL

454

QTc(B) (msec)

450

Protocol: B2C109575
Population: Intent-to-Treat

Page 17 of 20
Figure 8.11
Serial QTc(B) (msec) versus Heart Rate (beats/min)
Day 28, 10 mins

500

400

350

80

100

Placebo

Note: Heart rate is from ECG.

3mcg

6.25mcg

12.5mcg

25mcg

50mcg

YM2008/00019/00
B2C109575

60
Heart Rate (beats/min)

40

CONFIDENTIAL

455

QTc(B) (msec)

450

Protocol: B2C109575
Population: Intent-to-Treat

Page 18 of 20
Figure 8.11
Serial QTc(B) (msec) versus Heart Rate (beats/min)
Day 28, 1 hour

500

400

350

60

80

100

Heart Rate (beats/min)

Placebo

Note: Heart rate is from ECG.

3mcg

6.25mcg

12.5mcg

25mcg

50mcg

YM2008/00019/00
B2C109575

40

CONFIDENTIAL

456

QTc(B) (msec)

450

Protocol: B2C109575
Population: Intent-to-Treat

Page 19 of 20
Figure 8.11
Serial QTc(B) (msec) versus Heart Rate (beats/min)
Day 28, 2 hours

500

400

350

60

80

100

Heart Rate (beats/min)

Placebo

Note: Heart rate is from ECG.

3mcg

6.25mcg

12.5mcg

25mcg

50mcg

YM2008/00019/00
B2C109575

40

CONFIDENTIAL

457

QTc(B) (msec)

450

Protocol: B2C109575
Population: Intent-to-Treat

Page 20 of 20
Figure 8.11
Serial QTc(B) (msec) versus Heart Rate (beats/min)
Day 28, 4 hours

500

458

QTc(B) (msec)

450

400

350

60

80

100

Heart Rate (beats/min)

Placebo

Note: Heart rate is from ECG.

3mcg

6.25mcg

12.5mcg

25mcg

50mcg

YM2008/00019/00
B2C109575

40

CONFIDENTIAL

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Figure 8.12
Minimum Post-Baseline Potassium Values Versus Baseline Potassium Values

2.8
2.6
2.4
2.2
2.0

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg

Minimum (/LLN)

459

Treatment

CONFIDENTIAL

1.8
1.6
1.4
1.2
1.0
0.8
0.6

0.2
0.0
0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

Baseline (/LLN)

Note: Shows each subjects minimum value against their baseline value, each divided by the lower limit of normal
Note: Clinical concern level is 0.9xLLN
Note: Includes fasting and non-fasting samples.
Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.

2.2

2.4

2.6

2.8

YM2008/00019/00
B2C109575

0.4

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Figure 8.13
Box Plot of Minimum Post-Baseline Potassium Values

This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect
patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For
further information please see the Patient Level Data section of the GSK Clincal Study Register.

CONFIDENTIAL

460

YM2008/00019/00
B2C109575

Note: Shows each subjects minimum value divided by the lower limit of normal
Note: Clinical concern level is 0.9xLLN
Note: Graph only shows subjects who were above LLN at baseline
Note: Includes fasting and non-fasting samples.
Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Figure 8.14
Maximum Post-Baseline Glucose Values Versus Baseline Glucose Values

4.0

3.5

3.0

CONFIDENTIAL

461

Treatment
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg

Maximum (/ULN)

2.5

2.0

1.5

1.0

0.0
0.0

0.5

1.0

1.5

2.0

2.5

3.0

Baseline (/ULN)

Note: Shows each subjects maximum value against their baseline value, each divided by the upper limit of normal
Note: Clinical concern level is 1.5xULN
Note: Includes fasting and non-fasting samples.
Note: Glucose values below 1.1 were set to 0.55.

3.5

4.0

YM2008/00019/00
B2C109575

0.5

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Figure 8.15
Box Plot of Maximum Post-Baseline Glucose Values

This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect
patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For
further information please see the Patient Level Data section of the GSK Clincal Study Register.

CONFIDENTIAL

462

YM2008/00019/00
B2C109575

Note: Shows each subjects maximum value divided by the upper limit of normal
Note: Clinical concern level is 1.5xULN
Note: Graph only shows subjects who were below ULN at baseline
Note: Includes fasting and non-fasting samples.
Note: Glucose values below 1.1 were set to 0.55.

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Figure 8.16
Mean Fasting Potassium by Time and Treatment
Day: 1

Day: 28

4.35

4.25

4.30

4.20

Time (hours)

Placebo
3mcg

6.25mcg
12.5mcg

Note: Includes fasting and non-fasting samples.


Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.

25mcg
50mcg

YM2008/00019/00
B2C109575

CONFIDENTIAL

463

Mean Potassium (MMOL/L)

4.40

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Figure 8.17
Mean Fasting Glucose by Time and Treatment
Day: 1

Day: 28

5.4

5.3

5.1

5.2

CONFIDENTIAL

464

Mean Glucose (MMOL/L)

5.0

4.9

Time (hours)

Placebo
3mcg

Note: Includes fasting and non-fasting samples.


Note: Glucose values below 1.1 were set to 0.55.

6.25mcg
12.5mcg

25mcg
50mcg

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Figure 8.18
Box Plot of Maximum Increase from Baseline in Pulse Rate (beats/min)

This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect
patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal.
For further information please see the Patient Level Data section of the GSK Clincal Study Register.

CONFIDENTIAL

465

YM2008/00019/00
B2C109575

Note: Plot includes data from scheduled and unscheduled visits.

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 9
Figure 8.101
Potassium Profiles for Subjects with Values >7 (MMOL/L)

This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data
from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of
the GSK Clincal Study Register.

CONFIDENTIAL

466

YM2008/00019/00
B2C109575

Note: Std. lab is the potassium value from the standard lab dataset

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Table 8.1
Summary of Exposure

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------------Exposure (Days) [1]
n
102
101
101
100
101
102
Mean
25.5
25.7
26.6
26.8
27.0
27.6
SD
7.06
7.03
5.92
5.96
5.17
4.08
Median
29.0
29.0
29.0
29.0
29.0
29.0
Min.
1
1
4
1
5
6
Max.
31
31
35
36
32
31
Range of exposure

102
8 (8%)
4 (4%)
38 (37%)
52 (51%)

101
5 (5%)
8 (8%)
30 (30%)
58 (57%)

101
4 (4%)
4 (4%)
33 (33%)
60 (59%)

100
2 (2%)
6 (6%)
27 (27%)
65 (65%)

101
3 (3%)
2 (2%)
39 (39%)
57 (56%)

102
1 (<1%)
3 (3%)
35 (34%)
63 (62%)

475

YM2008/00019/00
B2C109575

[1] Calculated as ((date of last dose - date of first dose) + 1)


Note: For subjects who withdraw prior to Day 7 and do not have a date of last dose, the date of withdrawal
will be used as the last dose date

CONFIDENTIAL

n
<=7 days
8-14 days
15-28 days
>=29 days

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 7
Table 8.2
Summary of On-Treatment Adverse Events

System Organ Class


Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Preferred Term
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------ANY EVENT
37 (36%)
37 (37%)
34 (34%)
25 (25%)
23 (23%)
31 (30%)
14
12
1
0
0
1
1
1
1
0
0
0

(14%)
(12%)
(<1%)

12 (12%)
2 (2%)

8
2

4 (4%)
2 (2%)
2 (2%)
0
1 (<1%)
0
0
0
0
0
0
0
0

(9%)
(9%)
(1%)
(1%)

(<1%)
(<1%)

9
9
1
1
0
0
0
0
0
0
0
0

8 (8%)
7 (7%)
0
1 (<1%)
0
0
0
0
0
0
0
0

10 (10%)
8 (8%)
3 (3%)
1 (<1%)
0
0
0
0
0
0
0
0

(8%)
(2%)

7 (7%)
1 (<1%)

7
3

(7%)
(3%)

3
2

12 (12%)
2 (2%)

2 (2%)
1 (<1%)
2 (2%)
0
1 (<1%)
0
0
0
0
0
0
0
1 (<1%)

2 (2%)
1 (<1%)
0
0
0
1 (<1%)
1 (<1%)
0
0
0
0
0
0

0
0
0
1
0
0
0
0
1
1
0
0
0

(<1%)
(<1%)
(<1%)
(<1%)

11
7
1
0
2
0
0
0
0
0
1
1

(11%)
(7%)
(<1%)
(2%)

(1%)

(1%)
(1%)

(3%)
(2%)

0
0
0
0
0
1 (<1%)
0
0
0
0
0
0
0

2
1
1
2
0
0
0
1
0
0
1
1
0

(2%)
(<1%)
(<1%)
(2%)

(<1%)
(<1%)
(<1%)

YM2008/00019/00
B2C109575

Infections and infestations


Any event
Upper respiratory tract
infection
Nasopharyngitis
Pharyngitis
Sinusitis
Influenza
Gastroenteritis
Otitis media
Acute sinusitis
Eye infection
Gastrointestinal infection
Genital infection
Hepatitis E
Infectious mononucleosis
Oral candidiasis

9 (9%)
8 (8%)
2 (2%)
1 (<1%)
0
0
0
0
0
1 (<1%)
0
0

CONFIDENTIAL

476

Nervous system disorders


Any event
Headache
Dizziness
Migraine
Tremor
Intercostal neuralgia
Paraesthesia
Psychomotor hyperactivity
Restless legs syndrome
Sensory disturbance
Sinus headache
Syncope vasovagal

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 7
Table 8.2
Summary of On-Treatment Adverse Events

System Organ Class


Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Preferred Term
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------Rhinitis
0
0
0
0
0
1 (<1%)
Urinary tract infection
0
1 (<1%)
0
0
0
0
Varicella
0
0
0
0
0
1 (<1%)
Viral infection
0
0
1 (<1%)
0
0
0
Viral upper respiratory
1 (<1%)
0
0
0
0
0
tract infection
Vulvovaginal mycotic
0
0
0
1 (1%)
0
0
infection
(6%)

(<1%)
(<1%)
(<1%)

5
1
1
0
1
1
1
2
1
0
0
0
0
0

0
0
0
1 (<1%)

0
0
0
0

(<1%)
(<1%)
(2%)

(3%)

(5%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(2%)
(<1%)

(5%)

7
1
1
1
0
0
1
0
1
1
0
0
0
0

(7%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)

4
0
1
0
1
1
0
0
0
0
0
0
0
0

1 (<1%)
0
1 (<1%)
0

0
1
0
0

(4%)

(4%)
(1%)
(1%)
(1%)

(1%)

(2%)

3 (3%)
2 (2%)
1 (<1%)
1 (<1%)
0
0
0
0
0
0
0
0
0
0

7
2
1
1
1
0
1
1
0
0
1
0
0
0

0
0
0
0

0
0
0
0

(6%)

(7%)
(2%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)
(<1%)

(4%)

YM2008/00019/00
B2C109575

Musculoskeletal and connective


tissue disorders
Any event

6
0
0
1
1
2
0
0
0
0
0
1
1
1

CONFIDENTIAL

477

Gastrointestinal disorders
Any event
Nausea
Toothache
Abdominal pain upper
Diarrhoea
Dyspepsia
Flatulence
Vomiting
Dry mouth
Abdominal discomfort
Abdominal pain
Colitis
Enteritis
Gastrooesophageal reflux
disease
Hypoaesthesia oral
Mouth ulceration
Peptic ulcer
Stomach discomfort

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 7
Table 8.2
Summary of On-Treatment Adverse Events

478

Investigations
Any event
Blood creatine phosphokinase
increased

6 (6%)
0
0
3 (3%)
1 (<1%)
2 (2%)
0
0
0
0
0
1 (<1%)
0
0

4
2
1
0
1
0
0
1
0
0
0
0
1
0

(4%)
(2%)
(<1%)

1 (<1%)
0

3
2

(3%)
(2%)

(<1%)
(<1%)

(<1%)

1 (<1%)
0
0
0
0
0
0
0
0
0
1 (<1%)
0
0
0

3
1
1
0
0
0
1
0
1
1
0
0
0
1

(3%)
(1%)
(1%)

5 (5%)
1 (<1%)

2
0

(2%)

(1%)
(1%)
(1%)

(1%)

4
0
1
0
1
0
1
1
0
0
0
0
0
0

(4%)
(<1%)
(<1%)
(<1%)
(<1%)

2 (2%)
1 (<1%)

2 (2%)
1 (<1%)
1 (<1%)
0
0
0
0
0
0
0
0
0
0
0
4
0

(4%)

YM2008/00019/00
B2C109575

Respiratory, thoracic and


mediastinal disorders
Any event
Cough
Nasal congestion
Dyspnoea
Pharyngolaryngeal pain
Dysphonia
Epistaxis
Rhinitis allergic
Dry throat
Productive cough
Respiratory disorder
Rhinorrhoea
Sinus congestion
Sinus disorder

CONFIDENTIAL

System Organ Class


Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Preferred Term
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------Arthralgia
2 (2%)
1 (<1%)
1 (<1%)
0
2 (2%)
0
Back pain
0
3 (3%)
0
1 (1%)
1 (<1%)
0
Muscle spasms
0
0
2 (2%)
0
0
3 (3%)
Myalgia
0
0
1 (<1%)
1 (1%)
2 (2%)
0
Neck pain
1 (<1%)
0
0
0
2 (2%)
0
Pain in extremity
0
1 (<1%)
0
0
0
1 (<1%)
Flank pain
0
0
0
0
0
1 (<1%)
Intervertebral disc
0
0
0
1 (1%)
0
0
protrusion
Temporomandibular joint
0
0
0
0
0
1 (<1%)
syndrome

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 7
Table 8.2
Summary of On-Treatment Adverse Events

General disorders and


administration site conditions

4
1
1
1
1
0
0
0
0

(4%)
(<1%)
(<1%)
(<1%)
(<1%)

2 (2%)
1 (<1%)
1 (<1%)
0
0
0
0
0
0

2 (2%)
1 (<1%)
0
0
0
0
0
0
1 (<1%)

1
0
0
0
0
0
1
0
0

(1%)

(1%)

2 (2%)
0
0
0
0
1 (<1%)
0
1 (<1%)
0

0
0
0
0
0
0
0
0
0

YM2008/00019/00
B2C109575

Injury, poisoning and


procedural complications
Any event
Contusion
Hand fracture
Back injury
Chest injury
Excoriation
Face injury
Procedural pain
Skin laceration

CONFIDENTIAL

479

System Organ Class


Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Preferred Term
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------Blood pressure increased
0
0
1 (<1%)
1 (1%)
1 (<1%)
0
Blood potassium increased
1 (<1%)
0
0
0
0
1 (<1%)
Alanine aminotransferase
0
0
0
0
0
1 (<1%)
increased
Aspartate aminotransferase
0
0
0
0
0
1 (<1%)
increased
Blood glucose increased
0
0
0
0
0
1 (<1%)
Electrocardiogram PR
0
0
1 (<1%)
0
0
0
prolongation
Electrocardiogram QT
0
1 (<1%)
0
0
0
0
prolonged
Electrocardiogram ST-T
0
0
0
0
0
1 (<1%)
change
Electrocardiogram ST-T
0
0
1 (<1%)
0
0
0
segment abnormal
Electrocardiogram T wave
0
0
1 (<1%)
0
0
0
amplitude decreased
Liver function test abnormal
0
0
0
1 (1%)
0
0

Protocol: B2C109575
Population: Intent-to-Treat

Page 5 of 7
Table 8.2
Summary of On-Treatment Adverse Events

System Organ Class


Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Preferred Term
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------Any event
1 (<1%)
4 (4%)
1 (<1%)
0
2 (2%)
2 (2%)
Pyrexia
1 (<1%)
2 (2%)
0
0
1 (<1%)
0
Chest pain
0
0
1 (<1%)
0
0
0
Fatigue
0
0
0
0
1 (<1%)
0
Feeling jittery
0
1 (<1%)
0
0
0
0
Non-cardiac chest pain
0
1 (<1%)
0
0
0
0
Oedema peripheral
0
0
0
0
0
1 (<1%)
Vessel puncture site pain
0
0
0
0
0
1 (<1%)
2
2
0

0
1 (<1%)
0
0

Psychiatric disorders
Any event
Insomnia
Anxiety
Middle insomnia
Nervousness
Restlessness
Skin and subcutaneous tissue
disorders
Any event
Dermatitis contact
Pruritus
Rash

(2%)
(2%)

2 (2%)
1 (<1%)
0

2
0
1

(2%)

0
0
0
0

0
0
0
1 (<1%)

1
0
0
0

(1%)

3 (3%)
1 (<1%)
1 (<1%)
1 (<1%)
0
0

2 (2%)
1 (<1%)
1 (<1%)
0
0
0

0
0
0
0
0
0

1 (<1%)
0
0
1 (<1%)

1 (<1%)
0
0
1 (<1%)

5
2
2
0

(5%)
(2%)
(2%)

1 (<1%)
0
0

0
0
0

0
0
1 (<1%)
0

0
0
0
0

0
0
0
0
0
0

1 (<1%)
0
0
0
1 (<1%)
0

2 (2%)
1 (<1%)
0
0
0
1 (<1%)

0
0
0
0

0
0
0
0

1 (<1%)
1 (<1%)
0
0

(1%)

YM2008/00019/00
B2C109575

2 (2%)
1 (<1%)
0

CONFIDENTIAL

480

Cardiac disorders
Any event
Palpitations
Atrioventricular block
second degree
Bradycardia
Ventricular arrhythmia
Ventricular extrasystoles
Wandering pacemaker

Protocol: B2C109575
Population: Intent-to-Treat

Page 6 of 7
Table 8.2
Summary of On-Treatment Adverse Events

System Organ Class


Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Preferred Term
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------Pruritus generalised
0
0
1 (<1%)
0
0
0
1 (<1%)
1 (<1%)
0

0
0
0

0
0
0

1 (<1%)
0
1 (<1%)

1 (<1%)
1 (<1%)
0

Immune system disorders


Any event
Hypersensitivity

0
0

2
2

0
0

0
0

1 (<1%)
1 (<1%)

0
0

Vascular disorders
Any event
Hypertension

1 (<1%)
1 (<1%)

1 (<1%)
1 (<1%)

1 (<1%)
1 (<1%)

0
0

0
0

0
0

Eye disorders
Any event
Conjunctivitis
Conjunctivitis allergic

0
0
0

2 (2%)
1 (<1%)
1 (<1%)

0
0
0

0
0
0

0
0
0

0
0
0

Metabolism and nutrition


disorders
Any event
Dehydration
Glucose tolerance impaired

0
0
0

0
0
0

0
0
0

1
0
1

(1%)

0
0
0

1 (<1%)
1 (<1%)
0

Reproductive system and breast


disorders
Any event
Dysmenorrhoea
Premenstrual syndrome

0
0
0

1 (<1%)
1 (<1%)
0

0
0
0

1
0
1

(1%)

0
0
0

0
0
0

(2%)
(2%)

(1%)

(1%)

YM2008/00019/00
B2C109575

0
0
0

CONFIDENTIAL

481

Ear and labyrinth disorders


Any event
Vertigo
Ear pain

Protocol: B2C109575
Population: Intent-to-Treat

Page 7 of 7
Table 8.2
Summary of On-Treatment Adverse Events

System Organ Class


Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Preferred Term
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------Blood and lymphatic system
disorders
Any event
0
0
1 (<1%)
0
0
0
Lymphadenopathy
0
0
1 (<1%)
0
0
0
1 (<1%)
1 (<1%)

0
0

0
0

0
0

0
0

0
0

Surgical and medical


procedures
Any event
Phlebectomy

0
0

1 (<1%)
1 (<1%)

0
0

0
0

0
0

0
0

CONFIDENTIAL

482

Renal and urinary disorders


Any event
Proteinuria

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 2
Table 8.3
Summary of Post-Treatment Adverse Events

System Organ Class


Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Preferred Term
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------ANY EVENT
6 (6%)
4 (4%)
5 (5%)
0
5 (5%)
2 (2%)

483

2 (2%)
0
1 (<1%)
1 (<1%)

4 (4%)
1 (<1%)
0
1 (<1%)

0
0
0
0

2 (2%)
1 (<1%)
0
0

1 (<1%)
0
1 (<1%)
0

0
0
0

0
0
0

1 (<1%)
0
1 (<1%)

0
0
0

0
1 (<1%)
0

0
0
0

Nervous system disorders


Any event
Headache
Dizziness
Migraine

3 (3%)
2 (2%)
0
1 (<1%)

1 (<1%)
0
1 (<1%)
0

1 (<1%)
1 (<1%)
0
0

0
0
0
0

2
2
0
0

1 (<1%)
1 (<1%)
0
0

Respiratory, thoracic and


mediastinal disorders
Any event
Pharyngolaryngeal pain
Epistaxis

0
0
0

1 (<1%)
1 (<1%)
0

1 (<1%)
1 (<1%)
0

0
0
0

1 (<1%)
0
1 (<1%)

0
0
0

Gastrointestinal disorders
Any event
Nausea
Toothache

0
0
0

0
0
0

1 (<1%)
0
1 (<1%)

0
0
0

1 (<1%)
1 (<1%)
0

0
0
0

Immune system disorders


Any event
Hypersensitivity
Seasonal allergy

2 (2%)
1 (<1%)
1 (<1%)

0
0
0

0
0
0

0
0
0

0
0
0

0
0
0

(2%)
(2%)

YM2008/00019/00
B2C109575

0
0
0
0

CONFIDENTIAL

Infections and infestations


Any event
Bronchitis
Nasopharyngitis
Upper respiratory tract
infection
Oral herpes
Pharyngitis
Tooth infection

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 2
Table 8.3
Summary of Post-Treatment Adverse Events

System Organ Class


Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Preferred Term
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
------------------------------------------------------------------------------------------------

1 (<1%)
1 (<1%)

0
0

0
0

0
0

0
0

0
0

General disorders and


administration site conditions
Any event
Pyrexia

0
0

1 (<1%)
1 (<1%)

0
0

0
0

0
0

0
0

Injury, poisoning and


procedural complications
Any event
Soft tissue injury

1 (<1%)
1 (<1%)

0
0

0
0

0
0

0
0

0
0

Musculoskeletal and connective


tissue disorders
Any event
Bursitis

0
0

0
0

0
0

0
0

1 (<1%)
1 (<1%)

0
0

CONFIDENTIAL

484

Blood and lymphatic system


disorders
Any event
Anaemia

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Table 8.4
Summary of Most Frequent On-Treatment Adverse Events

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Preferred Term
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------Any event
37 (36%)
37 (37%)
34 (34%)
25 (25%)
23 (23%)
31 (30%)
8
2

(8%)
(2%)

12 (12%)
2 (2%)

7 (7%)
1 (<1%)

9
3

4
2
0
0
3

(4%)
(2%)

2 (2%)
1 (<1%)
3 (3%)
0
0

2 (2%)
1 (<1%)
0
2 (2%)
0

0
1
1
0
0

(3%)

(9%)
(3%)
(1%)
(1%)

7
2

(7%)
(2%)

8
2

(8%)
(2%)

0
0
1 (<1%)
0
0

2
3
0
3
0

(2%)
(3%)

485

YM2008/00019/00
B2C109575

Note: Adverse events summarised at an incidence of 3% or greater in any treatment group

(3%)

CONFIDENTIAL

Headache
Upper respiratory tract
infection
Nasopharyngitis
Dizziness
Back pain
Muscle spasms
Dyspnoea

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 3
Table 8.5
Summary of Drug-Related Adverse Events

System Organ Class


Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Preferred Term
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------ANY EVENT
7 (7%)
8 (8%)
8 (8%)
5 (5%)
4 (4%)
7 (7%)

486

Investigations
Any event
Blood creatine phosphokinase
increased
Blood potassium increased
Blood pressure increased
Electrocardiogram PR
prolongation
Electrocardiogram QT
prolonged
Electrocardiogram T wave
amplitude decreased
Liver function test abnormal

Gastrointestinal disorders

2
1
1
1
1
0

(2%)
(<1%)
(<1%)
(<1%)
(<1%)

3 (3%)
2 (2%)
0
0
0
1 (<1%)

2
2
0
0
0
0

(2%)
(2%)

2
2
0
0
0
0

1 (<1%)
0

2 (2%)
1 (<1%)

3 (3%)
1 (<1%)

2
0

(2%)

1 (<1%)
0

1 (<1%)
0

1 (<1%)
0
0

0
0
0

0
0
1 (<1%)

0
1
0

0
1 (<1%)
0

1 (<1%)
0
0

1 (<1%)

1 (<1%)

(1%)

2 (2%)
1 (<1%)
0

2
2
0

1 (<1%)
1 (<1%)
0

1
0
1

(1%)

1 (<1%)
0
0

0
0
0

1 (<1%)
0

0
0

0
0

0
0

0
1 (<1%)

0
0

(2%)
(2%)

(1%)

(1%)

(2%)
(2%)

2
0
2
0
0
0

(2%)
(2%)

YM2008/00019/00
B2C109575

Cardiac disorders
Any event
Palpitations
Atrioventricular block
second degree
Ventricular arrhythmia
Ventricular extrasystoles

0
0
0
0
0
0

CONFIDENTIAL

Nervous system disorders


Any event
Headache
Dizziness
Psychomotor hyperactivity
Restless legs syndrome
Tremor

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 3
Table 8.5
Summary of Drug-Related Adverse Events

System Organ Class


Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Preferred Term
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------Any event
1 (<1%)
2 (2%)
2 (2%)
0
1 (<1%)
0
Dry mouth
0
1 (<1%)
1 (<1%)
0
0
0
Nausea
0
0
1 (<1%)
0
1 (<1%)
0
Abdominal pain upper
1 (<1%)
0
0
0
0
0
Dyspepsia
0
1 (<1%)
0
0
0
0

2 (2%)
0
1 (<1%)
1 (<1%)
0

0
0
0
0
0

0
0
0
0
0

1 (<1%)
1 (<1%)
0
0
0

1 (<1%)
0
0
0
1 (<1%)

Psychiatric disorders
Any event
Insomnia
Middle insomnia
Restlessness

1 (<1%)
0
1 (<1%)
0

1 (<1%)
1 (<1%)
0
0

0
0
0
0

0
0
0
0

0
0
0
0

2 (2%)
1 (<1%)
0
1 (<1%)

Infections and infestations


Any event
Influenza
Pharyngitis
Viral infection

0
0
0
0

1 (<1%)
0
1 (<1%)
0

1 (<1%)
0
0
1 (<1%)

0
0
0
0

0
0
0
0

1 (<1%)
1 (<1%)
0
0

Respiratory, thoracic and


mediastinal disorders
Any event
Dysphonia
Pharyngolaryngeal pain

1 (<1%)
1 (<1%)
0

0
0
0

1 (<1%)
0
1 (<1%)

0
0
0

0
0
0

0
0
0

Immune system disorders

YM2008/00019/00
B2C109575

0
0
0
0
0

CONFIDENTIAL

487

General disorders and


administration site conditions
Any event
Fatigue
Feeling jittery
Non-cardiac chest pain
Vessel puncture site pain

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 3
Table 8.5
Summary of Drug-Related Adverse Events

System Organ Class


Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Preferred Term
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------Any event
0
1 (<1%)
0
0
0
0
Hypersensitivity
0
1 (<1%)
0
0
0
0

0
0

0
0

0
0

1
1

Musculoskeletal and connective


tissue disorders
Any event
Flank pain
Muscle spasms
Pain in extremity

0
0
0
0

0
0
0
0

0
0
0
0

Renal and urinary disorders


Any event
Proteinuria

1 (<1%)
1 (<1%)

0
0

0
0

(1%)
(1%)

0
0

0
0

0
0
0
0

0
0
0
0

1
1
1
1

0
0

0
0

0
0

(<1%)
(<1%)
(<1%)
(<1%)

CONFIDENTIAL

488

Metabolism and nutrition


disorders
Any event
Glucose tolerance impaired

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 8.6
Summary of Adverse Events Leading to Permanent Discontinuation of Study drug or
Withdrawal from the Study

System Organ Class


Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Preferred Term
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------ANY EVENT
1 (<1%)
1 (<1%)
2 (2%)
1 (1%)
1 (<1%)
0
Cardiac disorders
Any event
Atrioventricular block
second degree
Ventricular arrhythmia

0
0

1
1

1 (<1%)

0
0
0

1 (<1%)
1 (<1%)
0

0
0

(1%)
(1%)

0
0
0

0
0
0

1 (<1%)
0
1 (<1%)

0
0
0

0
0

2 (2%)
1 (<1%)

0
0

0
0

0
0

1 (<1%)

Immune system disorders


Any event
Hypersensitivity

0
0

0
0

0
0

0
0

1 (<1%)
1 (<1%)

0
0

Nervous system disorders


Any event
Psychomotor hyperactivity

0
0

1 (<1%)
1 (<1%)

0
0

0
0

0
0

0
0

Psychiatric disorders
Any event
Insomnia

0
0

1 (<1%)
1 (<1%)

0
0

0
0

0
0

0
0

YM2008/00019/00
B2C109575

0
0

Investigations
Any event
Electrocardiogram PR
prolongation
Electrocardiogram T wave
amplitude decreased

0
0

CONFIDENTIAL

489

0
0

General disorders and


administration site conditions
Any event
Feeling jittery
Pyrexia

1 (<1%)
0

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Table 8.7
Summary of Pre-Treatment Serious Adverse Events

No data to report

CONFIDENTIAL

490

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Table 8.8
Summary of On-Treatment Serious Adverse Events

No data to report

CONFIDENTIAL

491

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Table 8.9
Summary of Post-Treatment Serious Adverse Events

No data to report

CONFIDENTIAL

492

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 9

Table 8.10
Relationship of Adverse Event System Organ Class, Preferred Term and Verbatim Text

System Organ Class


Preferred Term
Verbatim Text
-----------------------------------------------------------------------------------------Blood and lymphatic system
Anaemia
anemia
disorders
Lymphadenopathy
swollen glands
Cardiac disorders

Atrioventricular block second


degree
Bradycardia
Palpitations

2nd degree AV block

Ear pain
Vertigo

Left ear pain


Vertigo

Eye disorders

Conjunctivitis
Conjunctivitis allergic

Conjunctivitis
Allergic Conjunctivitis Flare
up

Gastrointestinal disorders

Abdominal discomfort
Abdominal pain
Abdominal pain upper

abdominal discomfort
abdominal pain
Stomach Ache
epigastric soreness
stomach pain
COLITIS
Diarrhoea
diarrhea
diarrhoe
Dry Mouth
dry mouth
Dyspepsia
Indigestion
heartburn

Colitis
Diarrhoea
Dry mouth
Dyspepsia

YM2008/00019/00
B2C109575

Ear and labyrinth disorders

CONFIDENTIAL

493

Ventricular arrhythmia
Ventricular extrasystoles
Wandering pacemaker

Episodic Bradycardia
cardiac palpitations
palpitations
Ventricular Dysrhythmia
Ventricular ectopy
wandering atrial pacemaker

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 9

Table 8.10
Relationship of Adverse Event System Organ Class, Preferred Term and Verbatim Text

General disorders and


administration site
conditions

Unexplained chest pain

Fatigue
Feeling jittery
Non-cardiac chest pain
Oedema peripheral
Pyrexia

tiredness
Jittery
non cardiac chest pain
Oedema of legs
Fever
fever
high fever
Right and Left arm pain (due
to blood draws)

Vessel puncture site pain


Immune system disorders

Hypersensitivity

Allergy

YM2008/00019/00
B2C109575

Chest pain

CONFIDENTIAL

494

System Organ Class


Preferred Term
Verbatim Text
-----------------------------------------------------------------------------------------Gastrointestinal disorders
Enteritis
enteritis
Flatulence
Flatulence
Intermittant gasiness
meteorismus
Gastrooesophageal reflux
gastro oesophageal reflux
disease
disease (increased in
intensity
Hypoaesthesia oral
tongue numness
Mouth ulceration
Oral ulcer
Nausea
Nausea
nausea
Peptic ulcer
Peptic ulcer
Stomach discomfort
Stomach Upset
Toothache
Tooth pain
teethache
toothache
toothpain
Vomiting
Vomiting

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 9

Table 8.10
Relationship of Adverse Event System Organ Class, Preferred Term and Verbatim Text

System Organ Class


Preferred Term
Verbatim Text
-----------------------------------------------------------------------------------------Immune system disorders
Hypersensitivity
Localized right upper arm
swelling [Allergic reaction to
llergy shot]
increase in allergy symptoms
Seasonal allergy
seasonal allergy
Infections and infestations

Acute sinusitis
Bronchitis

495

Gastrointestinal infection
Genital infection
Hepatitis E
Infectious mononucleosis
Influenza
Nasopharyngitis

Pharyngitis
Rhinitis
Sinusitis

YM2008/00019/00
B2C109575

Oral candidiasis
Oral herpes
Otitis media

CONFIDENTIAL

Candidiasis
Eye infection
Gastroenteritis

Acute Sinusitis
Acute Bronchitis
Bronchitis
Thrush
eye-infection
Gasterointeritis
Gastroenteritis
gastro intestinal infection
Gynecological Infection
Hepatitis E
Mononucleosis
Influenza
fLU
flu
Cold
Cold Symptoms
Common cold
Common cold
common cold
oral candidiasis
herpes labialis
Left Otitis Media
Otitis Media Right Ear
Acute pharingitis
Pharyngitis
pharyngitis
rhinitis
Sinus Infection

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 9

Table 8.10
Relationship of Adverse Event System Organ Class, Preferred Term and Verbatim Text

Injury, poisoning and


procedural complications

upper back injury

Chest injury

BLUNT TRAUMA TO ANTERIOR RIGHT


CHEST
Left leg contusion
Thoracic contusion
chest contusion
Skin abrasion
Facial injury
Broken Right Hand
broken middle finger on left
hand

Contusion
Excoriation
Face injury
Hand fracture

YM2008/00019/00
B2C109575

Back injury

CONFIDENTIAL

496

System Organ Class


Preferred Term
Verbatim Text
-----------------------------------------------------------------------------------------Infections and infestations Sinusitis
Sinusitis
acute rhinosinusitis
Tooth infection
toothinfection
Upper respiratory tract
URI
infection
Upper RESPIRATORY TRACT
INFECTION
Upper Respiratory Infection
Upper Respiratory Tract
Infection
Upper respiratory Infection
Upper respiratory tract
infection
upper respiratory infection
Urinary tract infection
lower urinary tract infection
urinary tract infection
Varicella
chicken - pox
Viral infection
viral syndrome
Viral upper respiratory tract Upper respiratory tract
infection
infection, viral
Vulvovaginal mycotic infection vaginal mycosis

Protocol: B2C109575
Population: Intent-to-Treat

Page 5 of 9

Table 8.10
Relationship of Adverse Event System Organ Class, Preferred Term and Verbatim Text

System Organ Class


Preferred Term
Verbatim Text
-----------------------------------------------------------------------------------------Injury, poisoning and
Procedural pain
pain from root canal
procedural complications
Skin laceration
Laceration of head requiring
stiches
Pain associated with head
laceration
Soft tissue injury
Soft tissue injury left leg
Investigations

Blood glucose increased


Blood potassium increased
Blood pressure increased

ALAT(SGPT) elevation
ASAT(SGOT) elevation
CPK serum level elevated
Elevated CPK Levels
Elevated creatinine kinase
elevated total CPK
Elevated glucose on labs
Elevated Potassium
elevated potassium
Elevated blood pressure
Increased blood pressure
Worsening of Elevated blood
pressure
Prolonged PR Interval [245 ms]

Electrocardiogram ST-T segment Moderate ECG segment ST-T


abnormal
abnormalities

YM2008/00019/00
B2C109575

Electrocardiogram PR
prolongation
Electrocardiogram QT prolonged QT prolongation
Electrocardiogram ST-T change ECG ST-T wave abnormalities on
but
we received the result on

CONFIDENTIAL

497

Alanine aminotransferase
increased
Aspartate aminotransferase
increased
Blood creatine phosphokinase
increased

Protocol: B2C109575
Population: Intent-to-Treat

Page 6 of 9

Table 8.10
Relationship of Adverse Event System Organ Class, Preferred Term and Verbatim Text

System Organ Class


Preferred Term
Verbatim Text
-----------------------------------------------------------------------------------------Investigations
Electrocardiogram T wave
T-wave flattening
amplitude decreased
Liver function test abnormal
abnormal LFT's
Dehydration

Dehydration

Glucose tolerance impaired

Impaired glucose tolerance

Musculoskeletal and
connective tissue disorders

Arthralgia

498

YM2008/00019/00
B2C109575

Arthralgia metacarpal
phalangeal joint
Arthralgia of right shoulder
Right knee pain
elbow joint pain
joint pain
pain of right hip
Back pain
Backache
Lower back ache
back pain
backache
lower back pain
Bursitis
left shoulder bursitis
(observation)
Flank pain
left flank pain
Intervertebral disc protrusion slipped disk
Muscle spasms
Leg Cramps
calf cramping
cramps
foot cramping
hand cramping
leg cramping
muscle spasm left trapezius
Myalgia
Muscle Aches
Muscle pain lower back right
side

CONFIDENTIAL

Metabolism and nutrition


disorders

Protocol: B2C109575
Population: Intent-to-Treat

Page 7 of 9

Table 8.10
Relationship of Adverse Event System Organ Class, Preferred Term and Verbatim Text

Nervous system disorders

Dizziness

499
Headache

Paraesthesia
Psychomotor hyperactivity
Restless legs syndrome

YM2008/00019/00
B2C109575

Intercostal neuralgia
Migraine

Dizziness
Lightheadedness
dizziness
lightheaded
Head ache
Headache
Headaches
headach
headache
headache intermittend
hedache exacervation
worsening headache
worsening of headaches
Intercostal neuralgia
Headache Migraine
Migraine
episode of migraine
migraine
migraine headache
Parestheasia in limbs
Hyperactivity "wired"
restless legs

CONFIDENTIAL

System Organ Class


Preferred Term
Verbatim Text
-----------------------------------------------------------------------------------------Musculoskeletal and
Myalgia
muscle pain
connective tissue disorders
muscle pain at both arms
muscle soreness
recurrent mucle pain
Neck pain
Neck pain
neck pain
Pain in extremity
Pain left index finger
calf pain
Temporomandibular joint
Temporomandibular Joint
syndrome
Syndrome

Protocol: B2C109575
Population: Intent-to-Treat

Page 8 of 9

Table 8.10
Relationship of Adverse Event System Organ Class, Preferred Term and Verbatim Text

System Organ Class


Preferred Term
Verbatim Text
-----------------------------------------------------------------------------------------Nervous system disorders
Sensory disturbance
nervous feeling in throat
Sinus headache
Sinus Headache
Syncope vasovagal
Vagal response
Tremor
shaking
temor muscles
Psychiatric disorders

Anxiety

Renal and urinary disorders

Proteinuria

PROTEINURIA

Reproductive system and


breast disorders

Dysmenorrhoea

Menstrual Cramps

Premenstrual syndrome

Pre-menstrual syndrome

Respiratory, thoracic and


mediastinal disorders

Cough

Cough

Insomnia

500

Epistaxis
Nasal congestion

cough
dry troat by night
hoarseness
dyspnea
increased dyspnoe
increased dyspnoea
Nose Bleed
Nose bleed
bleeding nose
Nasal congestion
nasal congestion
worsening nasal congestion

YM2008/00019/00
B2C109575

Dry throat
Dysphonia
Dyspnoea

CONFIDENTIAL

Middle insomnia
Nervousness
Restlessness

Anxiety
anxiety
Insomnia
sleeplessness
nighttime awakenings
nervousness
Intermittant Restlessness

Protocol: B2C109575
Population: Intent-to-Treat

Page 9 of 9

Table 8.10
Relationship of Adverse Event System Organ Class, Preferred Term and Verbatim Text

501

Skin and subcutaneous tissue Dermatitis contact


disorders
Pruritus
Pruritus generalised
Rash

Allergic contact dermatitis


left cubital fossa
Contact Dermatitis
contact dermatitis
Itching right wrist and arm
itch
Body itching.
Exanthema
Rash on forearms of both hands

Phlebectomy

phlebectomie right thigh

Vascular disorders

Hypertension

Arterial hypertension
Worsening of hypertension
arterial hypertension

YM2008/00019/00
B2C109575

Surgical and medical


procedures

CONFIDENTIAL

System Organ Class


Preferred Term
Verbatim Text
-----------------------------------------------------------------------------------------Respiratory, thoracic and
Pharyngolaryngeal pain
Sore Throat
mediastinal disorders
sore throat
throat pain
Productive cough
a lot of sputum by night
Respiratory disorder
Chest Hyperinflation
Rhinitis allergic
Allergic Rhinitis Flare Up
exacerbation of allergic
rhinitis
Rhinorrhoea
rhinorrhea
Sinus congestion
Sinus congestion
Sinus disorder
sinus problems

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 19
Table 8.11
Summary of Chemistry Data

Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
-------------------------------------------------------------------------------------------------------Alanine Amino
Placebo
102 Screening
102
23.0
16.05
20.0
6
137
Transferase (IU/L)
Day 14
91
20.6
10.54
17.0
8
59
Day 28
87
19.4
11.52
17.0
6
83
101

Screening
Day 14
Day 28

101
88
85

20.8
18.9
19.2

13.63
8.55
10.54

18.0
17.0
17.0

6
6
6

115
57
77

6.25mcg

101

Screening
Day 14
Day 28

100
91
89

21.0
19.7
20.3

9.76
8.25
8.10

19.0
18.0
19.0

4
6
7

64
40
49

12.5mcg

100

Screening
Day 14
Day 28

99
90
89

24.1
22.5
22.9

17.04
13.86
15.09

18.0
18.0
18.0

5
8
7

91
83
97

25mcg

101

Screening
Day 14
Day 28

101
93
92

20.2
18.7
20.5

15.31
10.16
11.20

16.0
17.0
16.0

5
6
7

131
56
63

50mcg

102

Screening
Day 14
Day 28

101
93
96

21.2
22.2
21.2

13.48
18.34
12.52

17.0
17.0
19.0

5
4
3

103
150
70

CONFIDENTIAL

502

3mcg

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 19
Table 8.11
Summary of Chemistry Data

Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
-------------------------------------------------------------------------------------------------------Albumin (G/L)
Placebo
102 Screening
102
45.3
3.21
45.0
37
53
Day 14
91
43.6
3.28
44.0
36
52
Day 28
87
43.9
3.21
44.0
34
52
Screening
Day 14
Day 28

101
88
85

45.0
43.8
43.6

4.06
3.73
3.74

45.0
44.0
44.0

23
25
27

54
53
51

6.25mcg

101

Screening
Day 14
Day 28

100
91
89

45.4
44.0
44.3

3.18
3.27
3.24

45.0
44.0
44.0

38
36
37

53
51
51

12.5mcg

100

Screening
Day 14
Day 28

99
90
89

45.6
44.1
43.9

2.92
2.94
2.93

45.0
44.0
44.0

37
36
35

52
53
50

25mcg

101

Screening
Day 14
Day 28

101
93
92

45.1
43.7
43.9

2.96
2.51
2.85

45.0
44.0
44.0

37
37
33

52
49
52

50mcg

102

Screening
Day 14
Day 28

101
93
96

45.4
43.5
44.0

2.89
2.92
2.98

45.0
43.0
44.0

37
35
36

55
50
54

CONFIDENTIAL

101

503

3mcg

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 19
Table 8.11
Summary of Chemistry Data

Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
-------------------------------------------------------------------------------------------------------Alkaline Phosphatase
Placebo
102 Screening
102
82.6
57.21
71.5
32
432
(IU/L)
Day 14
91
75.7
47.58
64.0
28
460
Day 28
87
74.8
47.11
67.0
33
447
101

Screening
Day 14
Day 28

101
88
85

74.4
72.1
71.5

27.38
24.03
22.88

69.0
68.0
67.0

24
25
23

177
166
146

6.25mcg

101

Screening
Day 14
Day 28

100
91
89

75.5
72.9
72.4

24.88
24.46
22.59

70.0
66.0
68.0

36
32
38

158
147
138

12.5mcg

100

Screening
Day 14
Day 28

99
90
89

86.3
81.0
77.4

50.84
46.65
38.10

73.0
67.5
70.0

26
27
22

367
363
303

25mcg

101

Screening
Day 14
Day 28

101
93
92

80.9
79.0
80.5

47.28
48.44
49.83

73.0
70.0
71.0

30
35
36

377
376
386

50mcg

102

Screening
Day 14
Day 28

101
93
96

80.3
78.6
78.2

33.68
36.67
33.96

74.0
71.0
72.0

37
32
29

314
308
317

CONFIDENTIAL

504

3mcg

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 19
Table 8.11
Summary of Chemistry Data

Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
-------------------------------------------------------------------------------------------------------Aspartate Amino
Placebo
102 Screening
102
21.8
8.65
20.0
9
87
Transferase (IU/L)
Day 14
91
20.2
5.71
19.0
8
44
Day 28
86
19.9
6.04
18.5
7
38
101

Screening
Day 14
Day 28

101
88
85

21.1
20.8
20.3

8.14
11.66
7.02

19.0
18.0
19.0

10
11
10

70
106
46

6.25mcg

101

Screening
Day 14
Day 28

100
90
88

20.8
21.0
21.3

5.81
7.56
6.10

19.0
19.0
20.0

11
12
10

40
71
39

12.5mcg

100

Screening
Day 14
Day 28

99
88
87

23.0
22.4
22.6

9.81
8.67
9.46

19.0
21.0
20.0

11
12
10

63
62
71

25mcg

101

Screening
Day 14
Day 28

101
91
92

21.8
21.0
21.8

10.06
6.03
7.34

20.0
21.0
20.0

10
11
10

105
43
54

50mcg

102

Screening
Day 14
Day 28

101
90
95

22.3
22.9
23.0

8.36
10.38
10.79

20.0
20.0
21.0

11
12
11

61
74
88

CONFIDENTIAL

505

3mcg

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 5 of 19
Table 8.11
Summary of Chemistry Data

Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
-------------------------------------------------------------------------------------------------------Calcium (MMOL/L)
Placebo
102 Screening
102
2.366
0.0862
2.370
2.13
2.56
Day 14
91
2.313
0.0870
2.330
2.05
2.52
Day 28
86
2.304
0.1138
2.320
1.72
2.50
Screening
Day 14
Day 28

101
88
85

2.343
2.313
2.300

0.1027
0.1019
0.1107

2.340
2.320
2.300

2.04
2.00
2.04

2.58
2.54
2.54

6.25mcg

101

Screening
Day 14
Day 28

100
90
88

2.350
2.311
2.305

0.1080
0.1120
0.1110

2.350
2.320
2.310

2.10
2.03
1.89

2.59
2.54
2.56

12.5mcg

100

Screening
Day 14
Day 28

99
88
87

2.375
2.338
2.316

0.1129
0.1184
0.1219

2.360
2.340
2.320

2.14
2.08
1.84

2.96
2.91
2.71

25mcg

101

Screening
Day 14
Day 28

101
91
92

2.353
2.308
2.327

0.0937
0.0929
0.1073

2.350
2.320
2.340

2.09
2.03
1.98

2.54
2.52
2.64

50mcg

102

Screening
Day 14
Day 28

101
90
95

2.353
2.321
2.301

0.1067
0.1089
0.1192

2.350
2.320
2.310

2.03
2.04
1.92

2.56
2.54
2.54

CONFIDENTIAL

101

506

3mcg

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 6 of 19
Table 8.11
Summary of Chemistry Data

Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
-------------------------------------------------------------------------------------------------------Chloride (MMOL/L)
Placebo
102 Screening
102 104.2
2.16
104.0
97
110
Day 14
91 104.9
2.23
105.0
99
109
Day 28
87 105.0
2.26
105.0
98
111
Screening
Day 14
Day 28

101
88
85

103.9
104.7
104.8

2.25
2.35
2.34

104.0
105.0
105.0

98
98
97

109
109
109

6.25mcg

101

Screening
Day 14
Day 28

100
91
89

104.0
105.0
104.7

2.06
2.09
2.25

104.0
105.0
104.0

98
99
97

109
110
110

12.5mcg

100

Screening
Day 14
Day 28

99
90
89

104.3
104.9
104.9

2.15
2.43
2.17

104.0
105.0
105.0

99
93
98

111
110
109

25mcg

101

Screening
Day 14
Day 28

101
93
92

104.5
105.4
105.1

1.82
2.10
2.37

104.0
106.0
105.0

100
101
99

110
110
110

50mcg

102

Screening
Day 14
Day 28

101
93
96

104.2
105.0
105.2

2.45
2.46
2.77

104.0
105.0
105.0

99
98
97

110
110
112

CONFIDENTIAL

101

507

3mcg

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 7 of 19
Table 8.11
Summary of Chemistry Data

Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
-------------------------------------------------------------------------------------------------------Creatine Kinase (IU/L) Placebo
102 Screening
102 121.4
88.61
101.0
30
628
Day 14
91 110.4
61.16
92.0
26
371
Day 28
87 116.8
75.68
98.0
32
509
Screening
Day 14
Day 28

101
88
85

124.6
157.5
148.7

74.95
177.11
196.10

104.0
114.5
107.0

29
29
26

474
1395
1489

6.25mcg

101

Screening
Day 14
Day 28

100
91
89

137.0
151.8
140.7

108.48
106.70
89.41

112.5
123.0
121.0

33
34
36

720
579
563

12.5mcg

100

Screening
Day 14
Day 28

99
90
89

130.3
194.5
161.3

79.80
452.51
129.85

109.0
114.0
132.0

35
31
37

465
4280
762

25mcg

101

Screening
Day 14
Day 28

101
93
92

165.7
176.0
161.9

231.67
212.23
147.36

109.0
112.0
113.5

36
33
33

1988
1683
917

50mcg

102

Screening
Day 14
Day 28

101
93
96

129.1
138.4
252.2

120.45
141.68
1235.48

93.0
101.0
108.5

32
38
43

869
1194
12213

CONFIDENTIAL

101

508

3mcg

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 8 of 19
Table 8.11
Summary of Chemistry Data

Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
-------------------------------------------------------------------------------------------------------Creatinine (UMOL/L)
Placebo
102 Screening
102
82.6
13.94
80.0
52
124
Day 14
91
82.2
15.38
82.0
53
133
Day 28
87
82.1
14.59
80.0
53
129
Screening
Day 14
Day 28

101
88
85

84.5
86.5
84.5

14.64
16.36
15.83

83.0
84.0
85.0

53
56
53

133
135
124

6.25mcg

101

Screening
Day 14
Day 28

100
91
89

83.1
84.4
83.8

16.32
17.50
18.28

83.5
84.0
81.0

47
47
45

133
141
150

12.5mcg

100

Screening
Day 14
Day 28

99
90
89

81.5
82.0
81.4

15.19
16.56
14.13

80.0
80.0
80.0

53
49
53

141
133
133

25mcg

101

Screening
Day 14
Day 28

101
93
92

81.6
82.8
80.7

13.40
18.51
14.00

80.0
80.0
80.0

55
53
53

124
192
124

50mcg

102

Screening
Day 14
Day 28

101
92
96

81.3
82.6
81.4

14.33
16.56
14.89

80.0
80.0
80.0

44
53
53

113
140
130

CONFIDENTIAL

101

509

3mcg

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 9 of 19
Table 8.11
Summary of Chemistry Data

Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
-------------------------------------------------------------------------------------------------------Direct Bilirubin
Placebo
102 Screening
102
2.0
0.99
2.0
0
6
(UMOL/L)
Day 14
87
1.9
0.99
2.0
0
4
Day 28
87
1.7
0.85
2.0
0
4
101

Screening
Day 14
Day 28

101
86
85

1.9
2.0
1.7

1.05
1.14
1.02

2.0
2.0
2.0

0
0
0

6
6
4

6.25mcg

101

Screening
Day 14
Day 28

100
89
89

2.1
1.8
1.9

1.17
1.13
1.04

2.0
2.0
2.0

0
0
0

6
6
8

12.5mcg

100

Screening
Day 14
Day 28

99
89
89

2.1
1.9
1.8

1.15
1.01
1.02

2.0
2.0
2.0

0
0
0

6
5
6

25mcg

101

Screening
Day 14
Day 28

101
92
91

2.0
1.7
1.8

1.12
0.99
0.96

2.0
2.0
2.0

0
0
0

6
4
6

50mcg

102

Screening
Day 14
Day 28

101
92
96

1.9
1.8
1.8

0.98
1.13
0.88

2.0
2.0
2.0

0
0
0

4
8
4

CONFIDENTIAL

510

3mcg

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 10 of 19
Table 8.11
Summary of Chemistry Data

Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
-------------------------------------------------------------------------------------------------------Gamma Glutamyl
Placebo
102 Screening
102
29.8
27.15
21.5
8
223
Transferase (IU/L)
Day 14
91
29.4
35.08
21.0
9
300
Day 28
87
29.7
33.54
22.0
9
277
101

Screening
Day 14
Day 28

101
88
85

31.1
30.0
28.5

25.32
23.25
19.81

23.0
22.0
22.0

10
10
11

149
154
120

6.25mcg

101

Screening
Day 14
Day 28

100
91
89

31.3
28.9
29.7

24.83
23.14
22.61

23.0
21.0
23.0

7
7
9

130
119
120

12.5mcg

100

Screening
Day 14
Day 28

99
90
89

35.5
32.1
32.7

31.65
28.02
26.08

28.0
27.5
27.0

6
6
7

232
216
223

25mcg

101

Screening
Day 14
Day 28

101
93
92

28.9
27.6
29.1

21.96
19.43
20.88

21.0
20.0
20.0

8
6
7

119
88
109

50mcg

102

Screening
Day 14
Day 28

101
93
96

34.8
31.9
33.0

42.34
25.46
28.90

25.0
24.0
26.0

9
8
8

398
170
222

CONFIDENTIAL

511

3mcg

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 11 of 19
Table 8.11
Summary of Chemistry Data

Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
-------------------------------------------------------------------------------------------------------Glucose (MMOL/L)
Placebo
102 Screening
102
5.19
1.870
5.00
3.0
22.8
Day 14
91
5.14
1.538
4.80
2.9
15.9
Day 28
87
5.02
1.370
4.80
2.7
13.4
Screening
Day 14
Day 28

101
87
85

4.89
5.46
5.05

0.849
2.086
1.528

4.90
5.10
4.80

1.3
2.9
2.3

7.3
22.0
14.5

6.25mcg

101

Screening
Day 14
Day 28

100
91
88

4.94
5.11
4.86

0.696
0.761
0.757

4.90
4.90
4.70

2.7
3.4
2.0

8.0
8.5
8.2

12.5mcg

100

Screening
Day 14
Day 28

99
90
89

5.12
5.40
5.06

0.851
1.915
1.062

5.10
5.10
4.90

3.4
3.6
1.9

9.6
21.1
11.5

25mcg

101

Screening
Day 14
Day 28

101
93
92

5.16
5.07
4.96

0.792
0.950
1.191

5.10
4.90
4.80

3.3
3.0
2.7

9.9
8.3
14.0

50mcg

102

Screening
Day 14
Day 28

101
91
94

5.07
5.55
5.10

1.033
2.138
1.749

5.00
5.00
4.80

2.6
3.3
2.6

11.2
20.9
17.0

CONFIDENTIAL

101

512

3mcg

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 12 of 19
Table 8.11
Summary of Chemistry Data

Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
-------------------------------------------------------------------------------------------------------Indirect Bilirubin
Placebo
102 Screening
102
7.3
3.62
6.0
2
30
(UMOL/L)
Day 14
87
6.5
3.08
6.0
2
20
Day 28
87
6.9
2.70
6.0
3
16
101

Screening
Day 14
Day 28

101
86
85

7.5
6.9
7.0

4.14
4.04
3.68

6.0
6.0
6.0

2
1
2

30
22
24

6.25mcg

101

Screening
Day 14
Day 28

100
89
89

8.0
7.2
6.7

4.88
4.90
5.19

6.0
6.0
6.0

4
2
2

36
42
48

12.5mcg

100

Screening
Day 14
Day 28

99
89
89

8.0
7.1
7.3

4.25
3.50
4.26

7.0
6.0
6.0

2
2
2

28
21
23

25mcg

101

Screening
Day 14
Day 28

101
92
91

7.5
6.7
6.9

4.10
3.63
3.40

6.0
6.0
6.0

3
2
2

23
20
21

50mcg

102

Screening
Day 14
Day 28

101
92
96

7.1
6.1
6.3

2.83
2.66
2.80

6.0
6.0
6.0

2
0
2

18
15
17

CONFIDENTIAL

513

3mcg

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 13 of 19
Table 8.11
Summary of Chemistry Data

Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
-------------------------------------------------------------------------------------------------------Lactate Dehydrogenase
Placebo
102 Screening
102 162.4
30.40
157.5
79
243
(IU/L)
Day 14
91 159.3
32.91
153.0
78
268
Day 28
86 156.1
32.63
151.5
78
292
101

Screening
Day 14
Day 28

101
88
85

161.5
157.3
156.8

29.40
28.74
29.27

154.0
153.0
156.0

105
107
93

272
223
247

6.25mcg

101

Screening
Day 14
Day 28

100
90
88

162.1
160.0
162.5

27.79
25.25
29.01

156.0
160.5
159.0

100
108
110

230
231
258

12.5mcg

100

Screening
Day 14
Day 28

99
88
87

161.3
162.8
166.9

31.43
35.72
32.19

158.0
156.0
164.0

85
87
78

240
277
251

25mcg

101

Screening
Day 14
Day 28

101
91
92

163.1
164.3
165.4

35.51
37.95
36.56

156.0
159.0
161.0

99
106
105

280
308
291

50mcg

102

Screening
Day 14
Day 28

101
90
95

161.5
157.4
160.9

33.67
34.10
49.59

160.0
153.0
154.0

108
100
93

273
310
509

CONFIDENTIAL

514

3mcg

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 14 of 19
Table 8.11
Summary of Chemistry Data

Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
-------------------------------------------------------------------------------------------------------Potassium (MMOL/L)
Placebo
102 Screening
102
4.20
0.425
4.20
3.4
5.8
Day 14
91
4.28
0.665
4.20
3.2
8.8
Day 28
86
4.31
0.524
4.20
3.7
6.6
Screening
Day 14
Day 28

101
88
85

4.19
4.16
4.19

0.345
0.333
0.393

4.10
4.10
4.10

3.3
3.5
3.5

5.3
5.0
5.9

6.25mcg

101

Screening
Day 14
Day 28

100
90
88

4.14
4.17
4.18

0.368
0.395
0.364

4.10
4.10
4.20

3.3
3.2
3.4

5.6
5.3
5.7

12.5mcg

100

Screening
Day 14
Day 28

99
88
87

4.18
4.19
4.18

0.499
0.361
0.471

4.10
4.15
4.10

3.5
3.6
3.3

7.8
5.3
6.1

25mcg

101

Screening
Day 14
Day 28

101
91
92

4.16
4.25
4.29

0.354
0.485
0.515

4.10
4.20
4.20

3.3
3.1
3.1

5.3
6.9
6.9

50mcg

102

Screening
Day 14
Day 28

101
90
95

4.19
4.18
4.25

0.493
0.361
0.443

4.10
4.15
4.20

3.2
3.5
3.4

5.8
5.5
5.5

CONFIDENTIAL

101

515

3mcg

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 15 of 19
Table 8.11
Summary of Chemistry Data

Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
-------------------------------------------------------------------------------------------------------Sodium (MMOL/L)
Placebo
102 Screening
102 140.5
1.83
140.0
136
146
Day 14
91 140.5
2.10
140.0
136
147
Day 28
87 140.5
2.15
141.0
136
147
Screening
Day 14
Day 28

101
88
85

140.2
140.1
140.2

1.70
2.07
1.85

140.0
140.0
140.0

136
136
135

145
147
145

6.25mcg

101

Screening
Day 14
Day 28

100
91
89

140.5
140.4
140.2

2.09
2.10
2.58

140.5
140.0
140.0

136
135
133

147
146
151

12.5mcg

100

Screening
Day 14
Day 28

99
90
89

140.4
140.1
140.2

1.82
1.96
2.18

140.0
140.0
140.0

137
133
134

146
145
146

25mcg

101

Screening
Day 14
Day 28

101
93
92

140.7
140.8
140.6

1.99
1.65
1.93

141.0
141.0
141.0

136
137
136

146
145
147

50mcg

102

Screening
Day 14
Day 28

101
93
96

140.4
140.0
140.4

2.11
1.84
2.30

140.0
140.0
140.0

135
136
135

145
145
148

CONFIDENTIAL

101

516

3mcg

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 16 of 19
Table 8.11
Summary of Chemistry Data

Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
-------------------------------------------------------------------------------------------------------Total Bilirubin
Placebo
102 Screening
102
9.1
4.47
8.0
3
38
(UMOL/L)
Day 14
91
8.2
3.85
7.0
4
24
Day 28
87
8.2
3.24
7.0
4
18
101

Screening
Day 14
Day 28

101
88
85

9.2
8.7
8.5

5.14
4.86
4.32

8.0
7.0
7.0

3
2
4

38
28
28

6.25mcg

101

Screening
Day 14
Day 28

100
91
89

9.9
8.8
8.4

5.86
5.86
6.02

8.0
8.0
7.0

4
3
3

42
50
56

12.5mcg

100

Screening
Day 14
Day 28

99
90
89

9.8
8.8
8.9

5.06
4.31
4.98

8.0
7.0
7.0

4
4
3

30
26
27

25mcg

101

Screening
Day 14
Day 28

101
93
92

9.2
8.2
8.4

5.00
4.22
4.15

8.0
6.0
7.0

4
4
4

28
24
25

50mcg

102

Screening
Day 14
Day 28

101
93
96

8.8
7.7
7.8

3.58
3.19
3.38

8.0
7.0
6.5

4
4
3

22
19
21

CONFIDENTIAL

517

3mcg

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 17 of 19
Table 8.11
Summary of Chemistry Data

Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
-------------------------------------------------------------------------------------------------------Total Protein (G/L)
Placebo
102 Screening
102
73.7
3.98
74.0
64
83
Day 14
91
70.8
3.84
71.0
63
81
Day 28
87
71.4
3.92
72.0
62
78
Screening
Day 14
Day 28

101
88
85

73.2
70.5
70.3

4.44
4.21
4.79

74.0
70.0
70.0

58
62
58

82
82
85

6.25mcg

101

Screening
Day 14
Day 28

100
91
89

73.2
70.5
71.0

4.12
4.32
4.44

73.0
70.0
71.0

64
62
60

84
83
83

12.5mcg

100

Screening
Day 14
Day 28

99
90
89

73.5
70.6
70.6

3.84
4.19
4.34

74.0
71.0
71.0

62
61
60

80
80
79

25mcg

101

Screening
Day 14
Day 28

101
93
92

73.5
70.4
71.3

3.87
3.81
4.46

74.0
70.0
71.0

64
62
55

85
79
83

50mcg

102

Screening
Day 14
Day 28

101
93
96

74.3
71.0
71.8

4.40
4.44
4.37

74.0
71.0
72.0

66
59
59

85
83
89

CONFIDENTIAL

101

518

3mcg

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 18 of 19
Table 8.11
Summary of Chemistry Data

Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
-------------------------------------------------------------------------------------------------------Urea (MMOL/L)
Placebo
102 Screening
102
5.33
1.482
5.15
2.1
10.5
Day 14
91
5.40
1.504
5.30
1.7
8.8
Day 28
87
5.50
1.556
5.50
3.0
10.5
Screening
Day 14
Day 28

101
88
85

5.58
5.85
5.72

1.493
1.705
1.465

5.50
5.50
5.50

3.0
2.9
3.4

9.6
10.7
11.5

6.25mcg

101

Screening
Day 14
Day 28

100
91
89

5.63
5.51
5.58

1.421
1.525
1.556

5.50
5.50
5.50

3.0
2.0
2.5

9.5
8.9
9.5

12.5mcg

100

Screening
Day 14
Day 28

99
90
89

5.37
5.58
5.40

1.620
1.640
1.786

5.00
5.50
5.10

2.5
3.0
2.5

10.2
11.5
12.0

25mcg

101

Screening
Day 14
Day 28

101
93
92

5.46
5.56
5.56

1.570
1.521
1.451

5.40
5.50
5.50

2.5
2.5
2.5

11.0
10.2
9.6

50mcg

102

Screening
Day 14
Day 28

101
93
96

5.13
5.36
5.54

1.471
1.414
1.487

5.00
5.40
5.50

2.0
3.0
3.0

9.5
9.3
9.5

CONFIDENTIAL

101

519

3mcg

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 19 of 19
Table 8.11
Summary of Chemistry Data

Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
-------------------------------------------------------------------------------------------------------Uric acid (UMOL/L)
Placebo
102 Screening
102 334.2
79.48
333.5
124
536
Day 14
91 324.5
82.93
322.0
150
541
Day 28
87 329.3
78.70
335.0
148
490
Screening
Day 14
Day 28

101
88
85

330.5
344.8
339.7

69.05
87.87
82.67

332.0
337.5
330.0

162
150
140

470
777
582

6.25mcg

101

Screening
Day 14
Day 28

100
91
89

331.6
337.5
341.4

81.90
88.75
88.59

333.5
339.0
343.0

162
146
191

528
630
610

12.5mcg

100

Screening
Day 14
Day 28

99
90
89

329.5
327.4
323.6

76.50
78.79
77.41

330.0
320.0
330.0

150
160
170

497
520
490

25mcg

101

Screening
Day 14
Day 28

101
93
92

311.6
323.0
317.8

76.95
90.13
80.99

307.0
320.0
313.5

180
150
170

618
668
624

50mcg

102

Screening
Day 14
Day 28

101
92
96

322.5
330.4
327.4

85.13
87.13
86.37

318.0
326.5
320.0

150
140
170

530
516
520

CONFIDENTIAL

101

520

3mcg

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 19
Table 8.12
Summary of Chemistry Data Outside the Normal Range

Lab Test: Alanine Amino Transferase (IU/L)


Normal Range Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------------Screening
n
102
101
100
99
101
101
High
5
(5%)
2
(2%)
1
(1%)
11 (11%)
6
(6%)
5
(5%)
n
High

91
2

(2%)

88
1

(1%)

91
0

Day 28

n
High

87
2

(2%)

85
2

(2%)

89
1

Any Visit Post


Screening

99

521

High

99
(3%)

(1%)

101
(3%)

90
5

(6%)

93
3

(3%)

93
5

(5%)

89
5

(6%)

92
2

(2%)

96
5

(5%)

98
(2%)

(9%)

99
(5%)

(6%)

YM2008/00019/00
B2C109575

Note: Any visit post screening may also contain unscheduled visits

100

CONFIDENTIAL

Day 14

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 19
Table 8.12
Summary of Chemistry Data Outside the Normal Range

Lab Test: Albumin (G/L)


Normal Range Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------------Screening
n
102
101
100
99
101
101
High
7
(7%)
5
(5%)
7
(7%)
7
(7%)
3
(3%)
3
(3%)
Low
0
1 (<1%)
0
0
0
0
n
High
Low

91
2
0

(2%)

88
3
1

(3%)
(1%)

91
2
0

(2%)

90
1
0

Day 28

n
High
Low

87
1
0

(1%)

85
1
1

(1%)
(1%)

89
1
0

(1%)

89
0
0

92
1
0

Any Visit Post


Screening

99

98

100

High
Low

2
0

99
(2%)

3
1

101
(3%)
(1%)

3
0

(3%)

(1%)

93
0
0

1
0

93
0
0
(1%)

96
1
0

(1%)

99
(1%)

1
0

(1%)

YM2008/00019/00
B2C109575

Note: Any visit post screening may also contain unscheduled visits

1
0

(1%)

CONFIDENTIAL

522

Day 14

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 19
Table 8.12
Summary of Chemistry Data Outside the Normal Range

Lab Test: Alkaline Phosphatase (IU/L)


Normal Range Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------------Screening
n
102
101
100
99
101
101
High
0
2
(2%)
1
(1%)
4
(4%)
1 (<1%)
1 (<1%)
Low
0
0
0
0
0
0
n
High
Low

91
0
0

88
1
0

(1%)

91
4
0

(4%)

90
2
0

(2%)

93
1
0

(1%)

93
2
0

(2%)

Day 28

n
High
Low

87
0
0

85
1
0

(1%)

89
2
0

(2%)

89
1
0

(1%)

92
1
0

(1%)

96
2
0

(2%)

Any Visit Post


Screening

99

99

0
0

2
0

High
Low

101
(2%)

4
0

98
(4%)

(3%)

1
0

99
(1%)

2
0

(2%)

YM2008/00019/00
B2C109575

Note: Any visit post screening may also contain unscheduled visits

3
0

100

CONFIDENTIAL

523

Day 14

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 19
Table 8.12
Summary of Chemistry Data Outside the Normal Range

Lab Test: Aspartate Amino Transferase (IU/L)


Normal Range Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------------Screening
n
102
101
100
99
101
101
High
1 (<1%)
1 (<1%)
0
4
(4%)
1 (<1%)
5
(5%)
n
High

91
1

Day 28

n
High

Any Visit Post


Screening

524

High

88
3

(3%)

90
1

86
0

85
2

(2%)

99

99

(1%)

(1%)

(5%)

88
3

(3%)

91
1

(1%)

90
4

(4%)

88
0

87
4

(5%)

92
1

(1%)

95
7

(7%)

100

98

(1%)

(2%)

(6%)

99
(2%)

(9%)

YM2008/00019/00
B2C109575

Note: Any visit post screening may also contain unscheduled visits

100

CONFIDENTIAL

Day 14

Protocol: B2C109575
Population: Intent-to-Treat

Page 5 of 19
Table 8.12
Summary of Chemistry Data Outside the Normal Range

Lab Test: Calcium (MMOL/L)


Normal Range Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------------Screening
n
102
101
100
99
101
101
High
0
1 (<1%)
2
(2%)
3
(3%)
0
0
Low
0
1 (<1%)
1
(1%)
0
2
(2%)
1 (<1%)
Day 14

525

Any Visit Post


Screening

91
0
1

n
High
Low

86
0
4

99

High
Low

0
5

(1%)

88
0
3

(5%)

85
0
3

(3%)

90
0
6

(4%)

88
0
2

99
(5%)

0
6

(7%)

88
2
2

(2%)
(2%)

91
0
1

(2%)

87
2
3

(2%)
(3%)

92
1
4

100
(6%)

0
7

98
(7%)

(3%)

(1%)
(4%)

95
0
7

(7%)

100
(2%)
(5%)

1
4

99
(1%)
(4%)

0
8

(8%)

YM2008/00019/00
B2C109575

Note: Any visit post screening may also contain unscheduled visits

2
5

(1%)

90
0
3

CONFIDENTIAL

Day 28

n
High
Low

Protocol: B2C109575
Population: Intent-to-Treat

Page 6 of 19
Table 8.12
Summary of Chemistry Data Outside the Normal Range

Lab Test: Chloride (MMOL/L)


Normal Range Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------------Screening
n
102
101
100
99
101
101
High
3
(3%)
1 (<1%)
1
(1%)
5
(5%)
3
(3%)
5
(5%)
Low
0
0
0
0
0
0
n
High
Low

91
1
0

(1%)

88
4
0

(5%)

91
3
0

(3%)

90
4
1

Day 28

n
High
Low

87
3
0

(3%)

85
4
0

(5%)

89
6
0

(7%)

89
4
0

Any Visit Post


Screening

99

High
Low

5
0

99
(5%)

8
0

101
(8%)

8
0

(4%)
(1%)
(4%)

98
(8%)

(5%)

93
8
0

(9%)

92
6
0

(7%)

96
8
0

(8%)

100
(8%)
(1%)

10
0

99
(10%)

12
0

(12%)

YM2008/00019/00
B2C109575

Note: Any visit post screening may also contain unscheduled visits

8
1

93
5
0

CONFIDENTIAL

526

Day 14

Protocol: B2C109575
Population: Intent-to-Treat

Page 7 of 19
Table 8.12
Summary of Chemistry Data Outside the Normal Range

Lab Test: Creatine Kinase (IU/L)


Normal Range Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------------Screening
n
102
101
100
99
101
101
High
7
(7%)
9
(9%)
13 (13%)
12 (12%)
18 (18%)
10 (10%)
n
High

91
4

(4%)

88
13

(15%)

91
15

(16%)

90
17

(19%)

93
19

(20%)

93
9

(10%)

Day 28

n
High

87
8

(9%)

85
7

(8%)

89
13

(15%)

89
18

(20%)

92
18

(20%)

96
12

(13%)

Any Visit Post


Screening

99

High

11

99
(11%)

16

101
(16%)

19

98
(19%)

(24%)

26

99
(26%)

17

(17%)

YM2008/00019/00
B2C109575

Note: Any visit post screening may also contain unscheduled visits

24

100

CONFIDENTIAL

527

Day 14

Protocol: B2C109575
Population: Intent-to-Treat

Page 8 of 19
Table 8.12
Summary of Chemistry Data Outside the Normal Range

Lab Test: Creatinine (UMOL/L)


Normal Range Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------------Screening
n
102
101
100
99
101
101
High
0
1 (<1%)
1
(1%)
1
(1%)
0
0
Low
0
0
0
0
0
0
n
High
Low

91
1
0

(1%)

88
1
0

Day 28

n
High
Low

87
1
0

(1%)

Any Visit Post


Screening

99

High
Low

1
0

(1%)

91
2
0

(2%)

90
1
0

(1%)

93
2
0

85
0
0

89
2
0

(2%)

89
1
0

(1%)

99

101

1
0

(1%)

(1%)

3
0

98
(3%)

(2%)

(1%)

92
0
0

96
1
0

(1%)

100

99

3
0

(3%)

2
0

(2%)

YM2008/00019/00
B2C109575

Note: Any visit post screening may also contain unscheduled visits

2
0

92
1
0

(2%)

CONFIDENTIAL

528

Day 14

Protocol: B2C109575
Population: Intent-to-Treat

Page 9 of 19
Table 8.12
Summary of Chemistry Data Outside the Normal Range

Lab Test: Direct Bilirubin (UMOL/L)


Normal Range Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------------Screening
n
102
101
100
99
101
101
High
0
0
0
0
0
0
n
High

87
0

86
0

89
0

Day 28

n
High

87
0

85
0

89
1

Any Visit Post


Screening

99

98

100

High

(1%)

(1%)

92
0

92
1

89
0

91
0

96
0

98

99

99

(1%)

(1%)

YM2008/00019/00
B2C109575

Note: Any visit post screening may also contain unscheduled visits

89
0

CONFIDENTIAL

529

Day 14

Protocol: B2C109575
Population: Intent-to-Treat

Page 10 of 19
Table 8.12
Summary of Chemistry Data Outside the Normal Range

Lab Test: Gamma Glutamyl Transferase (IU/L)


Normal Range Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------------Screening
n
102
101
100
99
101
101
High
10 (10%)
9
(9%)
13 (13%)
10 (10%)
13 (13%)
11 (11%)
n
High

91
7

(8%)

88
8

(9%)

91
10

(11%)

90
9

(10%)

93
10

(11%)

93
11

(12%)

Day 28

n
High

87
8

(9%)

85
6

(7%)

89
12

(13%)

89
9

(10%)

92
9

(10%)

96
11

(11%)

Any Visit Post


Screening

99

High

10

99
(10%)

101
(9%)

14

98
(14%)

(13%)

13

99
(13%)

13

(13%)

YM2008/00019/00
B2C109575

Note: Any visit post screening may also contain unscheduled visits

13

100

CONFIDENTIAL

530

Day 14

Protocol: B2C109575
Population: Intent-to-Treat

Page 11 of 19
Table 8.12
Summary of Chemistry Data Outside the Normal Range

Lab Test: Glucose (MMOL/L)


Normal Range Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------------Screening
n
102
101
100
99
101
101
High
1 (<1%)
2
(2%)
1
(1%)
4
(4%)
3
(3%)
3
(3%)
Low
6
(6%)
8
(8%)
5
(5%)
3
(3%)
2
(2%)
4
(4%)
n
High
Low

91
5
4

(5%)
(4%)

87
6
2

(7%)
(2%)

91
1
1

(1%)
(1%)

90
7
2

(8%)
(2%)

93
6
6

(6%)
(6%)

91
9
3

(10%)
(3%)

Day 28

n
High
Low

87
5
6

(6%)
(7%)

85
6
5

(7%)
(6%)

88
2
2

(2%)
(2%)

89
5
3

(6%)
(3%)

92
3
3

(3%)
(3%)

94
4
5

(4%)
(5%)

Any Visit Post


Screening

99

High
Low

10
8

99
(10%)
(8%)

11
5

101
(11%)
(5%)

4
4

98
(4%)
(4%)

(10%)
(5%)

9
8

98
(9%)
(8%)

10
8

(10%)
(8%)

YM2008/00019/00
B2C109575

Note: Any visit post screening may also contain unscheduled visits

10
5

100

CONFIDENTIAL

531

Day 14

Protocol: B2C109575
Population: Intent-to-Treat

Page 12 of 19
Table 8.12
Summary of Chemistry Data Outside the Normal Range

Lab Test: Indirect Bilirubin (UMOL/L)


Normal Range Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------------Screening
n
102
101
100
99
101
101
High
1 (<1%)
1 (<1%)
2
(2%)
1
(1%)
1 (<1%)
0
n
High

87
0

86
0

Day 28

n
High

87
0

85
1

Any Visit Post


Screening

99

98

High

(1%)

89
1

(1%)

89
0

89
1

(1%)

89
1

100
(1%)

(1%)

98
(1%)

(2%)

92
0

91
0

96
0

99

99

YM2008/00019/00
B2C109575

Note: Any visit post screening may also contain unscheduled visits

92
0

CONFIDENTIAL

532

Day 14

Protocol: B2C109575
Population: Intent-to-Treat

Page 13 of 19
Table 8.12
Summary of Chemistry Data Outside the Normal Range

Lab Test: Lactate Dehydrogenase (IU/L)


Normal Range Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------------Screening
n
102
101
100
99
101
101
High
0
1 (<1%)
0
0
4
(4%)
3
(3%)
n
High

91
1

(1%)

88
0

90
0

Day 28

n
High

86
1

(1%)

85
0

88
1

Any Visit Post


Screening

99

99

100

High

(2%)

(1%)

88
3

(3%)

91
3

(3%)

90
3

(3%)

87
1

(1%)

92
3

(3%)

95
3

(3%)

98
(1%)

(4%)

99
(4%)

(5%)

YM2008/00019/00
B2C109575

Note: Any visit post screening may also contain unscheduled visits

100

CONFIDENTIAL

533

Day 14

Protocol: B2C109575
Population: Intent-to-Treat

Page 14 of 19
Table 8.12
Summary of Chemistry Data Outside the Normal Range

Lab Test: Potassium (MMOL/L)


Normal Range Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------------Screening
n
102
101
100
99
101
101
High
1 (<1%)
0
1
(1%)
1
(1%)
0
3
(3%)
Low
1 (<1%)
1 (<1%)
2
(2%)
0
2
(2%)
2
(2%)
Day 14

91
3
2

Day 28

n
High
Low

86
3
0

Any Visit Post


Screening

99

High
Low

5
2

(3%)
(2%)
(3%)

88
0
0
85
2
0

(2%)

99
(5%)
(2%)

2
0

90
0
2

(2%)

88
0
0

88
1
1

(1%)
(1%)

87
2
1

100
(2%)

1
2

(2%)
(1%)

98
(1%)
(2%)

(3%)
(1%)

90
1
0

92
3
2

(3%)
(2%)

95
3
1

100
(2%)
(1%)

4
2

(1%)

(3%)
(1%)

99
(4%)
(2%)

4
2

(4%)
(2%)

YM2008/00019/00
B2C109575

Note: Any visit post screening may also contain unscheduled visits

2
1

91
3
1

CONFIDENTIAL

534

n
High
Low

Protocol: B2C109575
Population: Intent-to-Treat

Page 15 of 19
Table 8.12
Summary of Chemistry Data Outside the Normal Range

Lab Test: Sodium (MMOL/L)


Normal Range Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------------Screening
n
102
101
100
99
101
101
High
0
0
1
(1%)
0
0
0
Low
0
0
0
0
0
0
Day 14

535

Any Visit Post


Screening

91
1
0

(1%)

88
1
0

n
High
Low

87
1
0

(1%)

85
0
0

89
1
2

99

99

101

High
Low

2
0

(2%)

1
0

(1%)

(1%)

91
0
0

1
2

90
0
1
(1%)
(2%)

89
0
1

(1%)

93
0
0

(1%)

92
1
0

98
(<1%)
(2%)

(1%)

100
(2%)

1
0

96
2
0

(2%)

99
(1%)

2
0

(2%)

YM2008/00019/00
B2C109575

Note: Any visit post screening may also contain unscheduled visits

0
2

93
0
0

CONFIDENTIAL

Day 28

n
High
Low

Protocol: B2C109575
Population: Intent-to-Treat

Page 16 of 19
Table 8.12
Summary of Chemistry Data Outside the Normal Range

Lab Test: Total Bilirubin (UMOL/L)


Normal Range Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------------Screening
n
102
101
100
99
101
101
High
1 (<1%)
3
(3%)
4
(4%)
3
(3%)
5
(5%)
0
n
High

91
1

Day 28

n
High

Any Visit Post


Screening

536

High

88
3

(3%)

91
2

(2%)

90
1

(1%)

93
1

(1%)

93
0

87
0

85
2

(2%)

89
1

(1%)

89
3

(3%)

92
1

(1%)

96
0

99

99

(1%)

(1%)

101
(3%)

98
(2%)

(5%)

99
(2%)

YM2008/00019/00
B2C109575

Note: Any visit post screening may also contain unscheduled visits

100

CONFIDENTIAL

Day 14

Protocol: B2C109575
Population: Intent-to-Treat

Page 17 of 19
Table 8.12
Summary of Chemistry Data Outside the Normal Range

Lab Test: Total Protein (G/L)


Normal Range Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------------Screening
n
102
101
100
99
101
101
High
1 (<1%)
0
0
0
0
0
Low
0
1 (<1%)
0
0
0
0
Day 14

537

Any Visit Post


Screening

91
0
0

88
0
0

91
0
0

90
0
0

93
0
0

93
0
1

(1%)

n
High
Low

87
0
0

85
0
2

89
0
0

89
0
0

92
0
1

96
1
1

(1%)
(1%)

99

99

101

98

100

0
0

0
2

0
0

0
0

0
1

High
Low

(2%)

(2%)

99
(1%)

1
2

(1%)
(2%)

YM2008/00019/00
B2C109575

Note: Any visit post screening may also contain unscheduled visits

(1%)

CONFIDENTIAL

Day 28

n
High
Low

Protocol: B2C109575
Population: Intent-to-Treat

Page 18 of 19
Table 8.12
Summary of Chemistry Data Outside the Normal Range

Lab Test: Urea (MMOL/L)


Normal Range Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------------Screening
n
102
101
100
99
101
101
High
2
(2%)
2
(2%)
1
(1%)
3
(3%)
3
(3%)
1 (<1%)
Low
1 (<1%)
0
0
0
0
2
(2%)
Day 14

91
0
1

Day 28

n
High
Low

87
4
0

Any Visit Post


Screening

99

High
Low

4
1

(1%)
(5%)

88
7
0

(8%)

91
0
1

85
1
0

(1%)

89
1
0

99
(4%)
(1%)

7
0

(1%)
(1%)

101
(7%)

1
1

90
3
0
89
3
1

(3%)

(3%)
(1%)

98
(<1%)
(<1%)

(2%)
(1%)

93
1
0

(1%)

92
1
1

(1%)
(1%)

96
1
0

(1%)

100
(4%)
(1%)

3
1

99
(3%)
(1%)

2
0

(2%)

YM2008/00019/00
B2C109575

Note: Any visit post screening may also contain unscheduled visits

4
1

93
2
1

CONFIDENTIAL

538

n
High
Low

Protocol: B2C109575
Population: Intent-to-Treat

Page 19 of 19
Table 8.12
Summary of Chemistry Data Outside the Normal Range

Lab Test: Uric acid (UMOL/L)


Normal Range Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------------Screening
n
102
101
100
99
101
101
High
2
(2%)
0
3
(3%)
2
(2%)
1 (<1%)
2
(2%)
Low
1 (<1%)
1 (<1%)
0
1
(1%)
1 (<1%)
1 (<1%)
n
High
Low

91
1
0

Day 28

n
High
Low

87
0
1

99

Any Visit Post


Screening

High
Low

2
1

(1%)

(1%)

88
3
0
85
4
1

(3%)

(5%)
(1%)

99
(2%)
(1%)

5
1

91
3
1
89
4
0

(3%)
(1%)
(4%)

101
(5%)
(1%)

6
1

90
2
2
89
1
0

(2%)
(2%)
(1%)

98
(6%)
(<1%)

(4%)

92
2
2

(2%)
(2%)

92
3
0

(3%)

96
2
2

(2%)
(2%)

100
(2%)
(2%)

5
1

99
(5%)
(1%)

4
3

(4%)
(3%)

YM2008/00019/00
B2C109575

Note: Any visit post screening may also contain unscheduled visits

2
2

93
4
0

CONFIDENTIAL

539

Day 14

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 10

Table 8.13
Summary of Chemistry Changes from Baseline Relative to the Normal Range

Visit: Day 14
Parameter/
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Alanine Amino Transferase (IU/L)
n
91
88
91
90
93
93
To Normal or No Change
89 (98%)
88 (100%)
90 (99%)
89 (99%)
92 (99%)
90 (97%)
To High
2
(2%)
0
0
0
1
(1%)
2
(2%)
Missing
0
0
1
(1%)
1
(1%)
0
1
(1%)

Alkaline Phosphatase (IU/L)


n
To Low
To Normal or No Change
To High
Missing

91
0
91 (100%)
0
0

88
0
88 (100%)
0
0

Aspartate Amino Transferase (IU/L)


n
To Normal or No Change
To High
Missing

91
90
1
0

88
85
3
0

(99%)
(1%)

(99%)
(1%)

88
0
87
1
0

(99%)
(1%)

(97%)
(3%)

91
0
90
0
1

(1%)

90
0
89
0
1

91
0
87
3
1

(96%)
(3%)
(1%)

90
0
89
0
1

90
88
1
1

(98%)
(1%)
(1%)

88
86
1
1

(99%)

(99%)
(1%)

(99%)
(1%)

(98%)
(1%)
(1%)

93
0
93 (100%)
0
0

93
0
92
0
1

93
0
93 (100%)
0
0

93
0
91
1
1

(98%)
(1%)
(1%)

91
90
1
0

90
86
3
1

(96%)
(3%)
(1%)

(99%)
(1%)

(99%)
(1%)

Note: Subjects are counted in the category that their value changes to (low, normal or high), unless there
is no change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
whose value became normal, are recorded in the "To Normal or No Change" category.

YM2008/00019/00
B2C109575

91
0
90
1
0

CONFIDENTIAL

540

Albumin (G/L)
n
To Low
To Normal or No Change
To High
Missing

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 10

Table 8.13
Summary of Chemistry Changes from Baseline Relative to the Normal Range

Visit: Day 14
Parameter/
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Calcium (MMOL/L)
n
91
88
90
88
91
90
To Low
1
(1%)
3
(3%)
6
(7%)
2
(2%)
0
3
(3%)
To Normal or No Change
90 (99%)
85 (97%)
83 (92%)
84 (95%)
91 (100%)
86 (96%)
To High
0
0
0
1
(1%)
0
0
Missing
0
0
1
(1%)
1
(1%)
0
1
(1%)

Creatine Kinase (IU/L)


n
To Normal or No Change
To High
Missing

91
89
2
0

Creatinine (UMOL/L)
n
To Low
To Normal or No Change
To High
Missing

91
0
90
1
0

(99%)
(1%)

(98%)
(2%)

(99%)
(1%)

88
0
84
4
0
88
81
7
0
88
0
87
1
0

(95%)
(5%)

(92%)
(8%)

(99%)
(1%)

91
0
87
3
1
91
84
6
1
91
0
90
0
1

(96%)
(3%)
(1%)

90
1
87
1
1

(1%)
(97%)
(1%)
(1%)

93
0
89
4
0

(92%)
(7%)
(1%)

90
80
9
1

(89%)
(10%)
(1%)

93
83
10
0

(98%)
(1%)
(1%)

93
0
91
2
0

(99%)
(1%)

90
0
88
1
1

(96%)
(4%)

(89%)
(11%)

(98%)
(2%)

93
0
87
5
1

(94%)
(5%)
(1%)

93
85
7
1

(91%)
(8%)
(1%)

93
0
90
1
2

(97%)
(1%)
(2%)

Note: Subjects are counted in the category that their value changes to (low, normal or high), unless there
is no change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
whose value became normal, are recorded in the "To Normal or No Change" category.

YM2008/00019/00
B2C109575

91
0
90
1
0

CONFIDENTIAL

541

Chloride (MMOL/L)
n
To Low
To Normal or No Change
To High
Missing

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 10

Table 8.13
Summary of Chemistry Changes from Baseline Relative to the Normal Range

Visit: Day 14
Parameter/
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Direct Bilirubin (UMOL/L)
n
87
86
89
89
92
92
To Normal or No Change
87 (100%)
86 (100%)
88 (99%)
88 (99%)
92 (100%)
90 (98%)
To High
0
0
0
0
0
1
(1%)
Missing
0
0
1
(1%)
1
(1%)
0
1
(1%)

(98%)
(2%)

88
87
1
0

Glucose (MMOL/L)
n
To Low
To Normal or No Change
To High
Missing

91
2
85
4
0

(2%)
(93%)
(4%)

88
0
81
6
1

Indirect Bilirubin (UMOL/L)


n
To Normal or No Change
To High
Missing

87
87 (100%)
0
0

(99%)
(1%)

91
89
1
1

(92%)
(7%)
(1%)

91
1
89
0
1

86
86 (100%)
0
0

89
88
0
1

(98%)
(1%)
(1%)

(1%)
(98%)
(1%)

(99%)
(1%)

90
86
3
1

(96%)
(3%)
(1%)

93
92
1
0

(99%)
(1%)

93
90
2
1

(97%)
(2%)
(1%)

90
2
81
6
1

(2%)
(90%)
(7%)
(1%)

93
6
81
6
0

(6%)
(87%)
(6%)

93
2
80
8
3

(2%)
(86%)
(9%)
(3%)

92
92 (100%)
0
0

92
91
0
1

89
88
0
1

(99%)
(1%)

(99%)
(1%)

Note: Subjects are counted in the category that their value changes to (low, normal or high), unless there
is no change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
whose value became normal, are recorded in the "To Normal or No Change" category.

YM2008/00019/00
B2C109575

91
89
2
0

CONFIDENTIAL

542

Gamma Glutamyl Transferase (IU/L)


n
To Normal or No Change
To High
Missing

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 10

Table 8.13
Summary of Chemistry Changes from Baseline Relative to the Normal Range

Visit: Day 14
Parameter/
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Lactate Dehydrogenase (IU/L)
n
91
88
90
88
91
90
To Normal or No Change
90 (99%)
88 (100%)
89 (99%)
84 (95%)
89 (98%)
87 (97%)
To High
1
(1%)
0
0
3
(3%)
2
(2%)
2
(2%)
Missing
0
0
1
(1%)
1
(1%)
0
1
(1%)

Sodium (MMOL/L)
n
To Low
To Normal or No Change
To High
Missing

91
0
90
1
0

Total Bilirubin (UMOL/L)


n
To Normal or No Change
To High
Missing

91
91 (100%)
0
0

(2%)
(96%)
(2%)

(99%)
(1%)

88
0
88 (100%)
0
0

90
2
87
0
1

88
0
87
1
0

91
0
90
0
1

(99%)
(1%)

88
88 (100%)
0
0

91
90
0
1

(2%)
(97%)
(1%)

(99%)
(1%)

(99%)
(1%)

88
0
87
0
1
90
1
88
0
1
90
88
1
1

(99%)
(1%)

91
0
88
3
0

(97%)
(3%)

90
0
88
1
1

(1%)

93
0
93 (100%)
0
0

93
0
92
0
1

(98%)
(1%)
(1%)

93
93 (100%)
0
0

93
92
0
1

(1%)
(98%)

(98%)
(1%)
(1%)

(99%)
(1%)

(99%)
(1%)

Note: Subjects are counted in the category that their value changes to (low, normal or high), unless there
is no change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
whose value became normal, are recorded in the "To Normal or No Change" category.

YM2008/00019/00
B2C109575

91
2
87
2
0

CONFIDENTIAL

543

Potassium (MMOL/L)
n
To Low
To Normal or No Change
To High
Missing

Protocol: B2C109575
Population: Intent-to-Treat

Page 5 of 10

Table 8.13
Summary of Chemistry Changes from Baseline Relative to the Normal Range

Visit: Day 14
Parameter/
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Total Protein (G/L)
n
91
88
91
90
93
93
To Low
0
0
0
0
0
1
(1%)
To Normal or No Change
91 (100%)
88 (100%)
90 (99%)
89 (99%)
93 (100%)
91 (98%)
To High
0
0
0
0
0
0
Missing
0
0
1
(1%)
1
(1%)
0
1
(1%)
91
0
91 (100%)
0
0

88
0
83
5
0

Uric acid (UMOL/L)


n
To Low
To Normal or No Change
To High
Missing

91
0
91 (100%)
0
0

88
0
85
3
0

(94%)
(6%)

(97%)
(3%)

91
1
89
0
1
91
1
87
2
1

(1%)

90
0
87
2
1

(97%)
(2%)
(1%)

93
1
91
1
0

(1%)
(96%)
(2%)
(1%)

90
2
86
1
1

(2%)
(96%)
(1%)
(1%)

93
0
90
3
0

(1%)
(98%)

(1%)
(98%)
(1%)

(97%)
(3%)

93
0
91
1
1

(98%)
(1%)
(1%)

93
2
87
2
2

(2%)
(94%)
(2%)
(2%)

YM2008/00019/00
B2C109575

Note: Subjects are counted in the category that their value changes to (low, normal or high), unless there
is no change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
whose value became normal, are recorded in the "To Normal or No Change" category.

CONFIDENTIAL

544

Urea (MMOL/L)
n
To Low
To Normal or No Change
To High
Missing

Protocol: B2C109575
Population: Intent-to-Treat

Page 6 of 10

Table 8.13
Summary of Chemistry Changes from Baseline Relative to the Normal Range

Visit: Day 28
Parameter/
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Alanine Amino Transferase (IU/L)
n
87
85
89
89
92
96
To Normal or No Change
86 (99%)
84 (99%)
87 (98%)
87 (98%)
91 (99%)
93 (97%)
To High
1
(1%)
1
(1%)
1
(1%)
1
(1%)
1
(1%)
2
(2%)
Missing
0
0
1
(1%)
1
(1%)
0
1
(1%)
85
0
85 (100%)
0
0

89
0
87
1
1

Alkaline Phosphatase (IU/L)


n
To Low
To Normal or No Change
To High
Missing

87
0
87 (100%)
0
0

85
0
85 (100%)
0
0

89
0
87
1
1

Aspartate Amino Transferase (IU/L)


n
To Normal or No Change
To High
Missing

86
86 (100%)
0
0

85
83
2
0

88
87
0
1

(98%)
(2%)

(98%)
(1%)
(1%)

89
0
88
0
1

(98%)
(1%)
(1%)

89
0
88
0
1

(99%)
(1%)

87
83
3
1

(99%)
(1%)

(99%)
(1%)

(95%)
(3%)
(1%)

92
0
92 (100%)
0
0

96
0
94
1
1

(98%)
(1%)
(1%)

92
0
92 (100%)
0
0

96
0
94
1
1

(98%)
(1%)
(1%)

92
91
1
0

95
89
5
1

(94%)
(5%)
(1%)

(99%)
(1%)

Note: Subjects are counted in the category that their value changes to (low, normal or high), unless there
is no change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
whose value became normal, are recorded in the "To Normal or No Change" category.

YM2008/00019/00
B2C109575

87
0
87 (100%)
0
0

CONFIDENTIAL

545

Albumin (G/L)
n
To Low
To Normal or No Change
To High
Missing

Protocol: B2C109575
Population: Intent-to-Treat

Page 7 of 10

Table 8.13
Summary of Chemistry Changes from Baseline Relative to the Normal Range

Visit: Day 28
Parameter/
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Calcium (MMOL/L)
n
86
85
88
87
92
95
To Low
4
(5%)
3
(4%)
2
(2%)
3
(3%)
2
(2%)
6
(6%)
To Normal or No Change
82 (95%)
82 (96%)
85 (97%)
82 (94%)
89 (97%)
88 (93%)
To High
0
0
0
1
(1%)
1
(1%)
0
Missing
0
0
1
(1%)
1
(1%)
0
1
(1%)

Creatine Kinase (IU/L)


n
To Normal or No Change
To High
Missing

87
83
4
0

Creatinine (UMOL/L)
n
To Low
To Normal or No Change
To High
Missing

87
0
86
1
0

(97%)
(3%)

(95%)
(5%)

(99%)
(1%)

85
0
81
4
0

89
0
83
5
1

(98%)
(2%)

89
84
4
1

85
0
85 (100%)
0
0

89
0
87
1
1

85
83
2
0

(95%)
(5%)

(93%)
(6%)
(1%)

89
0
84
4
1

(94%)
(4%)
(1%)

92
0
86
6
0

(94%)
(4%)
(1%)

89
80
8
1

(90%)
(9%)
(1%)

92
83
9
0

(98%)
(1%)
(1%)

89
0
88
0
1

(99%)
(1%)

96
0
90
5
1

(94%)
(5%)
(1%)

(90%)
(10%)

96
89
6
1

(93%)
(6%)
(1%)

92
0
92 (100%)
0
0

96
0
95
0
1

(93%)
(7%)

(99%)
(1%)

Note: Subjects are counted in the category that their value changes to (low, normal or high), unless there
is no change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
whose value became normal, are recorded in the "To Normal or No Change" category.

YM2008/00019/00
B2C109575

87
0
84
3
0

CONFIDENTIAL

546

Chloride (MMOL/L)
n
To Low
To Normal or No Change
To High
Missing

Protocol: B2C109575
Population: Intent-to-Treat

Page 8 of 10

Table 8.13
Summary of Chemistry Changes from Baseline Relative to the Normal Range

Visit: Day 28
Parameter/
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Direct Bilirubin (UMOL/L)
n
87
85
89
89
91
96
To Normal or No Change
87 (100%)
85 (100%)
87 (98%)
88 (99%)
91 (100%)
95 (99%)
To High
0
0
1
(1%)
0
0
0
Missing
0
0
1
(1%)
1
(1%)
0
1
(1%)

(99%)
(1%)

85
84
1
0

(99%)
(1%)

89
86
2
1

Glucose (MMOL/L)
n
To Low
To Normal or No Change
To High
Missing

87
3
80
4
0

(3%)
(92%)
(5%)

85
1
78
6
0

(1%)
(92%)
(7%)

89
0
85
2
2

Indirect Bilirubin (UMOL/L)


n
To Normal or No Change
To High
Missing

87
87 (100%)
0
0

85
84
1
0

(99%)
(1%)

89
88
0
1

(97%)
(2%)
(1%)

89
85
3
1

(96%)
(3%)
(1%)

92
89
3
0

(97%)
(3%)

96
93
2
1

(97%)
(2%)
(1%)

(96%)
(2%)
(2%)

89
3
81
4
1

(3%)
(91%)
(4%)
(1%)

92
3
87
2
0

(3%)
(95%)
(2%)

96
5
85
3
3

(5%)
(89%)
(3%)
(3%)

89
87
1
1

(98%)
(1%)
(1%)

91
91 (100%)
0
0

96
95
0
1

(99%)
(1%)

(99%)
(1%)

Note: Subjects are counted in the category that their value changes to (low, normal or high), unless there
is no change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
whose value became normal, are recorded in the "To Normal or No Change" category.

YM2008/00019/00
B2C109575

87
86
1
0

CONFIDENTIAL

547

Gamma Glutamyl Transferase (IU/L)


n
To Normal or No Change
To High
Missing

Protocol: B2C109575
Population: Intent-to-Treat

Page 9 of 10

Table 8.13
Summary of Chemistry Changes from Baseline Relative to the Normal Range

Visit: Day 28
Parameter/
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Lactate Dehydrogenase (IU/L)
n
86
85
88
87
92
95
To Normal or No Change
85 (99%)
85 (100%)
86 (98%)
85 (98%)
90 (98%)
92 (97%)
To High
1
(1%)
0
1
(1%)
1
(1%)
2
(2%)
2
(2%)
Missing
0
0
1
(1%)
1
(1%)
0
1
(1%)

Sodium (MMOL/L)
n
To Low
To Normal or No Change
To High
Missing

87
0
86
1
0

Total Bilirubin (UMOL/L)


n
To Normal or No Change
To High
Missing

87
87 (100%)
0
0

(97%)
(3%)

(99%)
(1%)

85
0
83
2
0

88
1
85
1
1

(1%)
(97%)
(1%)
(1%)

87
1
83
2
1

85
0
85 (100%)
0
0

89
2
85
1
1

(2%)
(96%)
(1%)
(1%)

89
1
87
0
1

85
85 (100%)
0
0

89
88
0
1

(98%)
(2%)

(99%)
(1%)

89
86
2
1

(1%)
(95%)
(2%)
(1%)

(1%)
(98%)
(1%)

(97%)
(2%)
(1%)

92
1
88
3
0
92
0
91
1
0

(1%)
(96%)
(3%)

(99%)
(1%)

92
92 (100%)
0
0

95
1
90
3
1

(1%)
(95%)
(3%)
(1%)

96
0
93
2
1

(97%)
(2%)
(1%)

96
95
0
1

(99%)
(1%)

Note: Subjects are counted in the category that their value changes to (low, normal or high), unless there
is no change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
whose value became normal, are recorded in the "To Normal or No Change" category.

YM2008/00019/00
B2C109575

86
0
83
3
0

CONFIDENTIAL

548

Potassium (MMOL/L)
n
To Low
To Normal or No Change
To High
Missing

Protocol: B2C109575
Population: Intent-to-Treat

Page 10 of 10

Table 8.13
Summary of Chemistry Changes from Baseline Relative to the Normal Range

Visit: Day 28
Parameter/
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Total Protein (G/L)
n
87
85
89
89
92
96
To Low
0
2
(2%)
0
0
1
(1%)
1
(1%)
To Normal or No Change
87 (100%)
83 (98%)
88 (99%)
88 (99%)
91 (99%)
93 (97%)
To High
0
0
0
0
0
1
(1%)
Missing
0
0
1
(1%)
1
(1%)
0
1
(1%)
87
0
85
2
0

Uric acid (UMOL/L)


n
To Low
To Normal or No Change
To High
Missing

87
0
87 (100%)
0
0

(98%)
(2%)

85
0
84
1
0
85
1
80
4
0

(99%)
(1%)

(1%)
(94%)
(5%)

89
0
87
1
1
89
0
86
2
1

(98%)
(1%)
(1%)

89
1
85
2
1

(97%)
(2%)
(1%)

89
0
88
0
1

(1%)
(96%)
(2%)
(1%)

(99%)
(1%)

92
1
90
1
0
92
0
90
2
0

(1%)
(98%)
(1%)

(98%)
(2%)

96
0
94
1
1

(98%)
(1%)
(1%)

96
1
92
2
1

(1%)
(96%)
(2%)
(1%)

YM2008/00019/00
B2C109575

Note: Subjects are counted in the category that their value changes to (low, normal or high), unless there
is no change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
whose value became normal, are recorded in the "To Normal or No Change" category.

CONFIDENTIAL

549

Urea (MMOL/L)
n
To Low
To Normal or No Change
To High
Missing

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 13
Table 8.14
Summary of Haematology Data

Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
---------------------------------------------------------------------------------------------------Basophils (GI/L)
Placebo
102 Screening
90
0.025
0.0197
0.020
0.00
0.10
Day 14
78
0.028
0.0220
0.020
0.00
0.11
Day 28
76
0.027
0.0284
0.020
0.00
0.20
Screening
Day 14
Day 28

85
79
80

0.021
0.022
0.026

0.0148
0.0150
0.0199

0.020
0.020
0.030

0.00
0.00
0.00

0.07
0.06
0.12

6.25mcg

101

Screening
Day 14
Day 28

86
76
80

0.023
0.024
0.025

0.0174
0.0183
0.0194

0.020
0.020
0.020

0.00
0.00
0.00

0.10
0.10
0.10

12.5mcg

100

Screening
Day 14
Day 28

83
73
76

0.025
0.023
0.023

0.0171
0.0189
0.0196

0.020
0.020
0.020

0.00
0.00
0.00

0.08
0.10
0.15

25mcg

101

Screening
Day 14
Day 28

87
78
78

0.025
0.025
0.025

0.0166
0.0202
0.0196

0.020
0.020
0.020

0.00
0.00
0.00

0.10
0.11
0.10

50mcg

102

Screening
Day 14
Day 28

81
74
81

0.024
0.022
0.024

0.0193
0.0175
0.0189

0.020
0.020
0.020

0.00
0.00
0.00

0.10
0.10
0.09

CONFIDENTIAL

101

550

3mcg

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 13
Table 8.14
Summary of Haematology Data

Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
---------------------------------------------------------------------------------------------------Eosinophils (GI/L) Placebo
102 Screening
99
0.276
0.2285
0.210
0.00
1.35
Day 14
87
0.294
0.1991
0.250
0.01
1.00
Day 28
84
0.303
0.2480
0.220
0.00
1.28
Screening
Day 14
Day 28

93
84
85

0.307
0.290
0.273

0.2378
0.2018
0.2222

0.250
0.240
0.220

0.00
0.00
0.00

1.70
1.17
1.40

6.25mcg

101

Screening
Day 14
Day 28

91
83
86

0.305
0.329
0.311

0.2242
0.2628
0.2610

0.220
0.260
0.230

0.00
0.04
0.01

0.94
1.10
1.40

12.5mcg

100

Screening
Day 14
Day 28

93
81
83

0.304
0.284
0.267

0.2490
0.2246
0.2216

0.240
0.210
0.220

0.03
0.00
0.02

1.66
1.40
1.33

25mcg

101

Screening
Day 14
Day 28

98
90
90

0.323
0.312
0.334

0.1954
0.2060
0.2358

0.285
0.245
0.280

0.00
0.04
0.00

0.98
0.98
1.06

50mcg

102

Screening
Day 14
Day 28

96
88
95

0.304
0.306
0.341

0.2504
0.3185
0.3321

0.230
0.220
0.240

0.00
0.00
0.00

2.00
2.40
2.70

CONFIDENTIAL

101

551

3mcg

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 13
Table 8.14
Summary of Haematology Data

Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
---------------------------------------------------------------------------------------------------Hematocrit (1)
Placebo
102 Screening
99
0.4237
0.03535
0.4230
0.352
0.529
Day 14
87
0.4094
0.03476
0.4140
0.325
0.480
Day 28
85
0.4085
0.03297
0.4140
0.336
0.478
Screening
Day 14
Day 28

93
84
85

0.4298
0.4114
0.4128

0.04413
0.03262
0.03292

0.4260
0.4125
0.4110

0.325
0.325
0.327

0.654
0.482
0.496

6.25mcg

101

Screening
Day 14
Day 28

91
84
86

0.4315
0.4136
0.4129

0.04201
0.04301
0.04264

0.4340
0.4200
0.4125

0.290
0.267
0.258

0.546
0.487
0.484

12.5mcg

100

Screening
Day 14
Day 28

93
81
84

0.4219
0.4042
0.4063

0.04692
0.03882
0.04340

0.4220
0.4110
0.4075

0.232
0.279
0.264

0.526
0.467
0.490

25mcg

101

Screening
Day 14
Day 28

98
90
90

0.4242
0.4046
0.4089

0.03643
0.03609
0.03670

0.4250
0.4040
0.4105

0.320
0.286
0.296

0.507
0.484
0.495

50mcg

102

Screening
Day 14
Day 28

96
89
95

0.4175
0.4044
0.4073

0.04566
0.04245
0.03791

0.4185
0.4050
0.4060

0.215
0.269
0.308

0.542
0.527
0.483

CONFIDENTIAL

101

552

3mcg

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 13
Table 8.14
Summary of Haematology Data

Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
---------------------------------------------------------------------------------------------------Hemoglobin (G/L)
Placebo
102 Screening
99 140.0
12.15
139.0
114
173
Day 14
87 134.1
12.03
134.0
103
161
Day 28
85 134.2
11.54
134.0
107
162
Screening
Day 14
Day 28

93
84
85

141.7
135.0
135.1

14.16
11.56
10.83

141.0
135.0
134.0

104
103
106

211
164
162

6.25mcg

101

Screening
Day 14
Day 28

91
84
86

141.8
136.0
135.2

14.25
15.74
15.29

144.0
138.5
137.0

92
85
80

167
164
161

12.5mcg

100

Screening
Day 14
Day 28

93
81
84

139.4
132.1
132.8

16.75
14.14
15.79

141.0
134.0
132.5

66
80
74

174
152
160

25mcg

101

Screening
Day 14
Day 28

98
90
90

139.7
132.9
133.6

12.47
12.34
12.37

141.0
133.0
134.0

96
89
91

165
163
162

50mcg

102

Screening
Day 14
Day 28

96
89
95

137.4
132.0
133.4

16.36
14.03
13.49

138.5
132.0
133.0

59
85
94

168
164
160

CONFIDENTIAL

101

553

3mcg

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 5 of 13
Table 8.14
Summary of Haematology Data

Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
---------------------------------------------------------------------------------------------------Lymphocytes (GI/L) Placebo
102 Screening
99
2.607
0.8562
2.520
0.82
6.10
Day 14
87
2.392
0.7292
2.290
1.16
4.38
Day 28
84
2.447
0.7643
2.330
1.25
5.20
Screening
Day 14
Day 28

93
84
85

2.615
2.343
2.345

0.8272
0.6532
0.6458

2.470
2.315
2.250

1.06
1.16
1.00

5.50
4.10
4.27

6.25mcg

101

Screening
Day 14
Day 28

91
83
86

2.394
2.238
2.227

0.6557
0.6371
0.6261

2.320
2.140
2.160

1.13
1.22
1.07

4.80
3.99
4.13

12.5mcg

100

Screening
Day 14
Day 28

93
81
83

2.478
2.306
2.316

0.6898
0.7392
0.8288

2.420
2.150
2.110

1.22
1.05
0.85

4.52
5.20
6.22

25mcg

101

Screening
Day 14
Day 28

98
90
90

2.637
2.390
2.334

0.8179
0.6790
0.7443

2.420
2.300
2.230

0.97
1.25
1.22

5.60
5.00
4.91

50mcg

102

Screening
Day 14
Day 28

96
88
95

2.528
2.419
2.261

0.8088
0.8334
0.6653

2.480
2.255
2.140

0.89
1.09
0.99

5.10
6.57
4.28

CONFIDENTIAL

101

554

3mcg

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 6 of 13
Table 8.14
Summary of Haematology Data

Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
---------------------------------------------------------------------------------------------------Mean Corpuscle
Placebo
102 Screening
99
29.95
1.927
30.00
21.8
33.7
Hemoglobin (PG)
Day 14
87
30.17
1.738
30.00
23.9
33.8
Day 28
85
30.17
1.911
30.20
22.6
33.8
101

Screening
Day 14
Day 28

93
84
85

30.50
30.52
30.52

1.607
1.617
1.508

30.60
30.60
30.60

25.1
25.4
25.6

34.7
35.3
33.4

6.25mcg

101

Screening
Day 14
Day 28

91
84
86

30.05
29.99
30.02

2.368
2.539
2.489

30.20
30.30
30.15

20.9
20.9
20.9

39.9
40.1
40.1

12.5mcg

100

Screening
Day 14
Day 28

93
81
84

29.98
29.67
29.68

2.218
2.243
2.243

30.10
29.80
29.80

19.2
20.2
20.2

34.0
34.0
33.8

25mcg

101

Screening
Day 14
Day 28

98
90
90

29.86
29.84
29.71

1.767
1.976
1.927

29.90
30.00
29.80

22.6
22.6
22.6

34.4
34.3
34.1

50mcg

102

Screening
Day 14
Day 28

96
89
95

29.93
29.97
29.91

2.965
2.270
2.642

30.50
30.10
30.40

16.4
20.9
18.5

34.6
33.9
34.7

CONFIDENTIAL

555

3mcg

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 7 of 13
Table 8.14
Summary of Haematology Data

Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
---------------------------------------------------------------------------------------------------Mean Corpuscle
Placebo
102 Screening
99 330.1
10.57
328.0
306
354
Hemoglobin
concentration
(G/L)
Day 14
87 327.5
9.00
327.0
306
354
Day 28
85 327.8
9.71
329.0
306
355
Screening
Day 14
Day 28

93
84
85

330.0
328.0
327.8

10.19
9.88
8.80

328.0
327.5
326.0

306
306
306

354
350
345

6.25mcg

101

Screening
Day 14
Day 28

91
84
86

328.4
328.2
326.9

10.51
9.38
10.75

328.0
329.0
327.0

306
298
303

353
348
353

12.5mcg

100

Screening
Day 14
Day 28

93
81
84

330.5
326.9
326.7

10.54
10.73
10.81

331.0
327.0
327.0

286
288
281

354
352
354

25mcg

101

Screening
Day 14
Day 28

98
90
90

329.3
328.1
326.8

9.89
10.38
9.96

330.0
329.0
325.5

299
290
290

351
352
354

50mcg

102

Screening
Day 14
Day 28

96
89
95

328.5
326.4
326.9

11.86
10.81
9.85

331.0
325.0
327.0

270
294
306

349
354
350

YM2008/00019/00
B2C109575

101

CONFIDENTIAL

556

3mcg

Protocol: B2C109575
Population: Intent-to-Treat

Page 8 of 13
Table 8.14
Summary of Haematology Data

Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
---------------------------------------------------------------------------------------------------Mean Corpuscle
Placebo
102 Screening
99
90.7
5.26
90.0
70
103
Volume (FL)
Day 14
87
92.1
4.99
92.0
76
105
Day 28
85
91.8
5.26
92.0
71
103
101

Screening
Day 14
Day 28

93
84
85

92.5
93.2
93.3

4.70
5.00
4.55

92.0
93.0
93.0

79
80
80

107
110
104

6.25mcg

101

Screening
Day 14
Day 28

91
84
85

91.4
91.3
91.8

6.23
6.75
6.60

91.0
91.0
91.0

70
69
68

122
122
121

12.5mcg

100

Screening
Day 14
Day 28

93
81
84

90.7
90.9
90.9

5.79
6.10
5.71

91.0
91.0
91.0

67
70
72

104
106
101

25mcg

101

Screening
Day 14
Day 28

98
90
90

90.7
91.0
90.9

4.79
5.54
5.60

90.0
91.0
91.0

75
74
74

103
106
108

50mcg

102

Screening
Day 14
Day 28

96
89
95

91.0
91.9
91.3

7.58
6.50
7.01

92.0
92.0
92.0

60
67
61

103
106
106

CONFIDENTIAL

557

3mcg

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 9 of 13
Table 8.14
Summary of Haematology Data

Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
---------------------------------------------------------------------------------------------------Monocytes (GI/L)
Placebo
102 Screening
99
0.395
0.1834
0.380
0.00
0.92
Day 14
87
0.364
0.1903
0.330
0.00
0.91
Day 28
84
0.367
0.1943
0.315
0.01
1.11
Screening
Day 14
Day 28

93
84
85

0.397
0.352
0.366

0.1766
0.1688
0.2185

0.390
0.315
0.340

0.05
0.00
0.01

0.93
0.84
1.62

6.25mcg

101

Screening
Day 14
Day 28

91
83
86

0.395
0.344
0.345

0.1704
0.1637
0.1840

0.390
0.320
0.305

0.01
0.06
0.04

0.87
0.78
0.95

12.5mcg

100

Screening
Day 14
Day 28

93
81
83

0.376
0.335
0.338

0.1731
0.1336
0.1487

0.360
0.320
0.300

0.00
0.00
0.08

1.16
0.62
0.79

25mcg

101

Screening
Day 14
Day 28

98
90
90

0.399
0.395
0.358

0.1852
0.2011
0.1521

0.360
0.355
0.340

0.02
0.10
0.05

0.94
1.18
0.96

50mcg

102

Screening
Day 14
Day 28

96
88
95

0.386
0.371
0.348

0.1681
0.2191
0.1587

0.370
0.350
0.330

0.02
0.01
0.02

0.84
1.46
0.76

CONFIDENTIAL

101

558

3mcg

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 10 of 13
Table 8.14
Summary of Haematology Data

Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
---------------------------------------------------------------------------------------------------Platelet count
Placebo
102 Screening
98 275.3
66.55
264.5
159
541
(GI/L)
Day 14
87 270.7
61.61
268.0
154
457
Day 28
82 278.1
71.95
270.0
95
496
101

Screening
Day 14
Day 28

93
82
84

271.6
269.2
264.7

60.97
58.80
61.58

262.0
265.5
258.0

96
144
135

437
464
467

6.25mcg

101

Screening
Day 14
Day 28

89
83
84

256.2
252.8
249.1

56.55
54.07
58.11

253.0
244.0
236.0

144
142
82

423
465
476

12.5mcg

100

Screening
Day 14
Day 28

93
79
83

264.9
269.5
267.0

51.26
60.97
58.16

263.0
268.0
259.0

139
75
145

370
400
426

25mcg

101

Screening
Day 14
Day 28

98
89
87

264.2
264.7
270.4

57.99
54.28
62.43

256.0
260.0
265.0

124
140
135

410
433
441

50mcg

102

Screening
Day 14
Day 28

93
87
93

282.6
272.0
272.0

71.22
64.48
58.61

281.0
271.0
268.0

115
140
151

501
503
471

CONFIDENTIAL

559

3mcg

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 11 of 13
Table 8.14
Summary of Haematology Data

Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
---------------------------------------------------------------------------------------------------Red Blood Cell
Placebo
102 Screening
99
4.69
0.452
4.70
3.6
6.3
count (TI/L)
Day 14
87
4.46
0.442
4.40
3.4
5.6
Day 28
85
4.47
0.449
4.50
3.5
6.2
101

Screening
Day 14
Day 28

93
84
85

4.66
4.43
4.43

0.468
0.353
0.351

4.60
4.40
4.40

3.6
3.7
3.8

7.1
5.3
5.3

6.25mcg

101

Screening
Day 14
Day 28

91
84
86

4.74
4.55
4.51

0.464
0.484
0.449

4.70
4.60
4.50

3.6
3.4
3.5

6.1
5.6
5.5

12.5mcg

100

Screening
Day 14
Day 28

93
81
84

4.65
4.46
4.47

0.474
0.424
0.443

4.70
4.50
4.50

3.4
3.4
3.6

5.6
5.2
5.4

25mcg

101

Screening
Day 14
Day 28

98
90
90

4.69
4.46
4.52

0.454
0.452
0.449

4.70
4.40
4.50

3.7
3.6
3.7

5.8
5.6
5.5

50mcg

102

Screening
Day 14
Day 28

96
89
95

4.61
4.42
4.48

0.495
0.545
0.464

4.60
4.40
4.40

3.3
3.0
3.3

6.9
6.8
6.5

CONFIDENTIAL

560

3mcg

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 12 of 13
Table 8.14
Summary of Haematology Data

Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
---------------------------------------------------------------------------------------------------Total Neutrophils
Placebo
102 Screening
99
4.871
1.8185
4.570
1.91
13.13
(GI/L)
Day 14
87
4.740
1.9558
3.970
0.80
11.53
Day 28
84
4.845
1.7052
4.680
1.65
9.92
101

Screening
Day 14
Day 28

93
84
85

4.591
4.583
4.615

1.5541
1.7221
1.5389

4.550
4.375
4.440

1.43
1.37
1.67

10.75
11.64
9.03

6.25mcg

101

Screening
Day 14
Day 28

91
83
86

4.544
4.148
4.373

1.3390
1.1722
1.2918

4.400
4.060
4.210

2.11
1.88
2.01

8.89
8.47
8.58

12.5mcg

100

Screening
Day 14
Day 28

93
81
83

4.641
4.521
4.586

1.5256
1.4377
1.6108

4.440
4.230
4.350

2.21
2.09
1.92

9.09
7.43
9.84

25mcg

101

Screening
Day 14
Day 28

98
90
90

4.597
4.569
4.546

1.4732
1.5842
1.5431

4.420
4.330
4.245

1.36
1.34
1.78

8.81
9.99
9.68

50mcg

102

Screening
Day 14
Day 28

96
88
95

4.798
4.742
4.565

1.7048
1.6168
1.6008

4.580
4.525
4.200

1.46
2.08
1.65

11.61
9.94
10.52

CONFIDENTIAL

561

3mcg

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 13 of 13
Table 8.14
Summary of Haematology Data

Lab Test
Treatment
N Visit
n
Mean
SD
Median
Min.
Max.
---------------------------------------------------------------------------------------------------White Blood Cell
Placebo
102 Screening
99
8.18
2.215
7.90
3.7
16.9
count (GI/L)
Day 14
87
7.82
2.278
7.10
2.5
15.6
Day 28
84
8.00
2.095
7.55
3.5
13.6
101

Screening
Day 14
Day 28

93
84
85

7.94
7.59
7.63

1.893
1.961
1.921

7.80
7.40
7.40

3.8
3.5
4.0

13.4
13.6
12.7

6.25mcg

101

Screening
Day 14
Day 28

91
83
86

7.66
7.09
7.29

1.704
1.447
1.644

7.50
6.80
7.20

4.6
4.4
4.5

15.1
12.2
12.9

12.5mcg

100

Screening
Day 14
Day 28

93
81
83

7.82
7.47
7.53

1.893
1.785
2.048

7.60
7.40
7.10

4.1
4.4
3.8

12.8
13.2
16.8

25mcg

101

Screening
Day 14
Day 28

98
90
90

7.98
7.69
7.60

1.896
1.982
1.954

7.85
7.40
7.45

3.9
3.8
3.9

14.6
13.5
12.6

50mcg

102

Screening
Day 14
Day 28

96
88
95

8.05
7.87
7.54

2.134
2.054
2.038

7.70
7.60
7.10

3.0
4.4
3.4

15.5
14.0
14.8

CONFIDENTIAL

562

3mcg

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 13
Table 8.15
Summary of Haematology Data Outside the Normal Range

Lab Test: Basophils (GI/L)


Normal Range Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Screening
n
90
85
86
83
87
81
High
0
0
0
0
0
0
n
High

78
0

79
0

76
0

73
0

78
0

74
0

Day 28

n
High

76
0

80
0

80
0

76
0

78
0

81
0

Any Visit Post


Screening

89

92

91

88

87

85

High

YM2008/00019/00
B2C109575

Note: Any visit post screening may also contain unscheduled visits

CONFIDENTIAL

563

Day 14

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 13
Table 8.15
Summary of Haematology Data Outside the Normal Range

Lab Test: Eosinophils (GI/L)


Normal Range Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Screening
n
99
93
91
93
98
96
High
12 (12%)
10 (11%)
13 (14%)
11 (12%)
11 (11%)
8
(8%)
Low
6
(6%)
4
(4%)
7
(8%)
2
(2%)
3
(3%)
3
(3%)
n
High
Low

87
9
3

(10%)
(3%)

84
6
4

(7%)
(5%)

83
13
3

(16%)
(4%)

81
9
5

(11%)
(6%)

90
11
1

(12%)
(1%)

88
11
5

(13%)
(6%)

Day 28

n
High
Low

84
10
4

(12%)
(5%)

85
7
5

(8%)
(6%)

86
16
7

(19%)
(8%)

83
7
4

(8%)
(5%)

90
14
4

(16%)
(4%)

95
11
4

(12%)
(4%)

Any Visit Post


Screening

98

High
Low

15
5

98
(15%)
(5%)

9
7

99
(9%)
(7%)

20
9

97
(20%)
(9%)

(15%)
(7%)

21
5

100
(21%)
(5%)

14
9

(14%)
(9%)

YM2008/00019/00
B2C109575

Note: Any visit post screening may also contain unscheduled visits

15
7

99

CONFIDENTIAL

564

Day 14

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 13
Table 8.15
Summary of Haematology Data Outside the Normal Range

Lab Test: Hematocrit (1)


Normal Range Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Screening
n
99
93
91
93
98
96
High
4
(4%)
5
(5%)
4
(4%)
6
(6%)
3
(3%)
3
(3%)
Low
1
(1%)
7
(8%)
4
(4%)
6
(6%)
3
(3%)
11 (11%)
Day 14

565

Any Visit Post


Screening

87
1
8

n
High
Low

85
0
8

98

High
Low

1
10

(1%)
(9%)

84
0
8

(9%)

85
0
11

(10%)

84
0
7

(8%)

81
0
12

(13%)

86
1
9

(1%)
(10%)

84
0
10

98
(1%)
(10%)

1
18

99
(1%)
(18%)

1
13

(15%)

90
0
8

(12%)

90
0
10

97
(1%)
(13%)

(1%)
(18%)

(11%)

95
0
17

(18%)

99
(13%)

0
12

100
(12%)

1
24

(1%)
(24%)

YM2008/00019/00
B2C109575

Note: Any visit post screening may also contain unscheduled visits

0
13

(9%)

89
1
16

CONFIDENTIAL

Day 28

n
High
Low

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 13
Table 8.15
Summary of Haematology Data Outside the Normal Range

Lab Test: Hemoglobin (G/L)


Normal Range Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Screening
n
99
93
91
93
98
96
High
2
(2%)
1
(1%)
0
1
(1%)
0
0
Low
7
(7%)
8
(9%)
9 (10%)
7
(8%)
5
(5%)
16 (17%)
Day 14

566

Any Visit Post


Screening

87
0
11

n
High
Low

85
0
13

98

High
Low

0
17

(13%)

84
0
20

(15%)

85
0
18

(24%)

84
0
15

(21%)

86
0
20

98
(17%)

0
28

(18%)

81
0
18

(23%)

84
0
19

99
(29%)

0
23

(22%)

90
0
19

(23%)

90
0
18

97
(23%)

(25%)

(20%)

95
0
23

(24%)

99
(25%)

0
27

100
(27%)

0
31

(31%)

YM2008/00019/00
B2C109575

Note: Any visit post screening may also contain unscheduled visits

0
24

(21%)

89
0
22

CONFIDENTIAL

Day 28

n
High
Low

Protocol: B2C109575
Population: Intent-to-Treat

Page 5 of 13
Table 8.15
Summary of Haematology Data Outside the Normal Range

Lab Test: Lymphocytes (GI/L)


Normal Range Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Screening
n
99
93
91
93
98
96
High
5
(5%)
6
(6%)
1
(1%)
2
(2%)
5
(5%)
4
(4%)
Low
1
(1%)
0
0
0
0
0
n
High
Low

87
3
0

(3%)

84
0
0

Day 28

n
High
Low

84
3
0

(4%)

85
1
0

Any Visit Post


Screening

98

High
Low

4
0

83
0
0
(1%)

98
(4%)

1
0

86
1
0

(1%)

99
(1%)

2
0

81
3
0

(4%)

90
1
0

(1%)

88
3
0

(3%)

83
3
0

(4%)

90
3
0

(3%)

95
1
0

(1%)

97
(2%)

(5%)

3
0

100
(3%)

5
1

(5%)
(1%)

YM2008/00019/00
B2C109575

Note: Any visit post screening may also contain unscheduled visits

5
0

99

CONFIDENTIAL

567

Day 14

Protocol: B2C109575
Population: Intent-to-Treat

Page 6 of 13
Table 8.15
Summary of Haematology Data Outside the Normal Range

Lab Test: Mean Corpuscle Hemoglobin (PG)


Normal Range Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Screening
n
99
93
91
93
98
96
High
2
(2%)
2
(2%)
4
(4%)
2
(2%)
2
(2%)
4
(4%)
Low
3
(3%)
3
(3%)
5
(5%)
8
(9%)
5
(5%)
10 (10%)
n
High
Low

87
2
3

(2%)
(3%)

84
1
2

(1%)
(2%)

84
3
6

(4%)
(7%)

81
1
8

(1%)
(10%)

90
1
6

(1%)
(7%)

89
1
6

(1%)
(7%)

Day 28

n
High
Low

85
2
4

(2%)
(5%)

85
1
1

(1%)
(1%)

86
6
5

(7%)
(6%)

84
3
9

(4%)
(11%)

90
1
6

(1%)
(7%)

95
3
8

(3%)
(8%)

Any Visit Post


Screening

98

High
Low

3
5

98
(3%)
(5%)

2
2

99
(2%)
(2%)

6
8

97
(6%)
(8%)

(5%)
(9%)

1
6

100
(1%)
(6%)

3
9

(3%)
(9%)

YM2008/00019/00
B2C109575

Note: Any visit post screening may also contain unscheduled visits

5
9

99

CONFIDENTIAL

568

Day 14

Protocol: B2C109575
Population: Intent-to-Treat

Page 7 of 13
Table 8.15
Summary of Haematology Data Outside the Normal Range

Lab Test: Mean Corpuscle Hemoglobin concentration (G/L)


Normal Range Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Screening
n
99
93
91
93
98
96
High
0
0
0
0
0
0
Low
10 (10%)
11 (12%)
15 (16%)
9 (10%)
11 (11%)
12 (13%)
Day 14

569

Any Visit Post


Screening

87
0
15

n
High
Low

85
0
12

98

High
Low

0
20

(17%)

84
0
13

(14%)

85
0
12

(15%)

84
0
10

(14%)

86
0
15

98
(20%)

0
19

(12%)

81
0
18

(17%)

84
0
16

99
(19%)

0
19

(22%)

90
0
15

(19%)

90
0
12

97
(19%)

(24%)

(13%)

95
0
13

(14%)

99
(27%)

0
20

100
(20%)

0
26

(26%)

YM2008/00019/00
B2C109575

Note: Any visit post screening may also contain unscheduled visits

0
26

(17%)

89
0
21

CONFIDENTIAL

Day 28

n
High
Low

Protocol: B2C109575
Population: Intent-to-Treat

Page 8 of 13
Table 8.15
Summary of Haematology Data Outside the Normal Range

Lab Test: Mean Corpuscle Volume (FL)


Normal Range Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Screening
n
99
93
91
93
98
96
High
1
(1%)
2
(2%)
3
(3%)
3
(3%)
1
(1%)
3
(3%)
Low
2
(2%)
1
(1%)
3
(3%)
2
(2%)
2
(2%)
7
(7%)
n
High
Low

87
3
1

(3%)
(1%)

84
4
0

(5%)

84
3
4

(4%)
(5%)

81
3
3

(4%)
(4%)

90
4
3

(4%)
(3%)

89
5
3

(6%)
(3%)

Day 28

n
High
Low

85
2
2

(2%)
(2%)

85
5
0

(6%)

85
4
3

(5%)
(4%)

84
2
3

(2%)
(4%)

90
3
3

(3%)
(3%)

95
4
5

(4%)
(5%)

Any Visit Post


Screening

98

High
Low

3
2

98
(3%)
(2%)

8
0

99
(8%)

5
4

97
(5%)
(4%)

(4%)
(3%)

4
3

100
(4%)
(3%)

5
6

(5%)
(6%)

YM2008/00019/00
B2C109575

Note: Any visit post screening may also contain unscheduled visits

4
3

99

CONFIDENTIAL

570

Day 14

Protocol: B2C109575
Population: Intent-to-Treat

Page 9 of 13
Table 8.15
Summary of Haematology Data Outside the Normal Range

Lab Test: Monocytes (GI/L)


Normal Range Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Screening
n
99
93
91
93
98
96
High
0
0
0
1
(1%)
0
0
Low
11 (11%)
9 (10%)
9 (10%)
12 (13%)
11 (11%)
10 (10%)
Day 14

571

Any Visit Post


Screening

87
0
13

n
High
Low

84
1
12

98

High
Low

1
20

(15%)

84
0
9

(11%)

83
0
15

(1%)
(14%)

85
1
16

(1%)
(19%)

86
0
17

98
(1%)
(20%)

1
20

(18%)

81
0
13

(20%)

83
0
14

99
(1%)
(20%)

0
28

(16%)

90
1
12

(17%)

90
0
10

97
(28%)

88
2
14

(2%)
(16%)

(11%)

95
0
15

(16%)

99
(24%)

1
21

100
(1%)
(21%)

3
24

(3%)
(24%)

YM2008/00019/00
B2C109575

Note: Any visit post screening may also contain unscheduled visits

0
23

(1%)
(13%)

CONFIDENTIAL

Day 28

n
High
Low

Protocol: B2C109575
Population: Intent-to-Treat

Page 10 of 13
Table 8.15
Summary of Haematology Data Outside the Normal Range

Lab Test: Platelet count (GI/L)


Normal Range Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Screening
n
98
93
89
93
98
93
High
4
(4%)
4
(4%)
1
(1%)
0
5
(5%)
7
(8%)
Low
0
1
(1%)
0
0
1
(1%)
1
(1%)
Day 14

87
3
0

Day 28

n
High
Low

82
5
1

Any Visit Post


Screening

98

High
Low

5
1

(3%)

(6%)
(1%)

82
2
0

(2%)

83
1
0

84
2
0

(2%)

84
1
1

98
(5%)
(1%)

3
1

(1%)

(1%)
(1%)

99
(3%)
(1%)

1
1

79
0
1
83
2
0

(1%)
(2%)

96
(1%)
(1%)

(3%)

87
4
0

(5%)

87
5
0

(6%)

93
3
0

(3%)

98
(2%)
(1%)

6
0

99
(6%)

5
0

(5%)

YM2008/00019/00
B2C109575

Note: Any visit post screening may also contain unscheduled visits

2
1

89
3
0

CONFIDENTIAL

572

n
High
Low

Protocol: B2C109575
Population: Intent-to-Treat

Page 11 of 13
Table 8.15
Summary of Haematology Data Outside the Normal Range

Lab Test: Red Blood Cell count (TI/L)


Normal Range Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Screening
n
99
93
91
93
98
96
High
2
(2%)
1
(1%)
2
(2%)
0
1
(1%)
2
(2%)
Low
3
(3%)
5
(5%)
2
(2%)
5
(5%)
3
(3%)
6
(6%)
Day 14

573

Any Visit Post


Screening

87
1
8

(1%)
(9%)

84
0
8

n
High
Low

85
2
10

(2%)
(12%)

85
0
9

98

High
Low

2
13

(10%)

84
0
10

(11%)

86
0
14

98
(2%)
(13%)

0
15

(12%)

81
0
6

(16%)

84
0
10

99
(15%)

0
15

(7%)

90
2
8

(2%)
(9%)

89
1
11

(1%)
(12%)

(12%)

90
2
10

(2%)
(11%)

95
1
7

(1%)
(7%)

97
(15%)

(11%)

3
13

100
(3%)
(13%)

1
16

(1%)
(16%)

YM2008/00019/00
B2C109575

Note: Any visit post screening may also contain unscheduled visits

0
11

99

CONFIDENTIAL

Day 28

n
High
Low

Protocol: B2C109575
Population: Intent-to-Treat

Page 12 of 13
Table 8.15
Summary of Haematology Data Outside the Normal Range

Lab Test: Total Neutrophils (GI/L)


Normal Range Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Screening
n
99
93
91
93
98
96
High
5
(5%)
3
(3%)
2
(2%)
3
(3%)
2
(2%)
3
(3%)
Low
0
2
(2%)
0
0
2
(2%)
2
(2%)
n
High
Low

87
9
1

(10%)
(1%)

84
3
2

(4%)
(2%)

83
1
0

(1%)

81
0
0

Day 28

n
High
Low

84
6
1

(7%)
(1%)

85
3
1

(4%)
(1%)

86
1
0

(1%)

83
1
0

Any Visit Post


Screening

98

High
Low

14
2

98
(14%)
(2%)

7
3

99
(7%)
(3%)

1
1

(1%)

97
(1%)
(1%)

(3%)
(1%)

88
4
0

90
3
1

(3%)
(1%)

95
3
1

99
(2%)

6
1

(5%)

(3%)
(1%)

100
(6%)
(1%)

7
1

(7%)
(1%)

YM2008/00019/00
B2C109575

Note: Any visit post screening may also contain unscheduled visits

2
0

90
3
1

CONFIDENTIAL

574

Day 14

Protocol: B2C109575
Population: Intent-to-Treat

Page 13 of 13
Table 8.15
Summary of Haematology Data Outside the Normal Range

Lab Test: White Blood Cell count (GI/L)


Normal Range Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Screening
n
99
93
91
93
98
96
High
10 (10%)
8
(9%)
5
(5%)
7
(8%)
7
(7%)
12 (13%)
Low
1
(1%)
0
0
0
0
2
(2%)
n
High
Low

87
8
1

(9%)
(1%)

84
4
1

Day 28

n
High
Low

84
8
1

(10%)
(1%)

85
7
0

Any Visit Post


Screening

98

High
Low

13
2

(5%)
(1%)
(8%)

98
(13%)
(2%)

11
1

83
1
0

(1%)

81
5
0

(6%)

90
6
0

(7%)

88
8
0

86
2
0

(2%)

83
3
0

(4%)

90
7
0

(8%)

95
5
2

99
(11%)
(1%)

3
0

97
(3%)

(7%)

11
0

(5%)
(2%)

100
(11%)

12
2

(12%)
(2%)

YM2008/00019/00
B2C109575

Note: Any visit post screening may also contain unscheduled visits

7
0

99

(9%)

CONFIDENTIAL

575

Day 14

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 8

Table 8.16
Summary of Haematology Changes from Baseline Relative to the Normal Range

Visit: Day 14
Parameter/
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Basophils (GI/L)
n
78
79
76
73
78
74
To Normal or No Change
75 (96%)
72 (91%)
69 (91%)
69 (95%)
76 (97%)
69 (93%)
To High
0
0
0
0
0
0
Missing
3
(4%)
7
(9%)
7
(9%)
4
(5%)
2
(3%)
5
(7%)

(1%)
(91%)
(5%)
(3%)

84
2
72
3
7

Hematocrit (1)
n
To Low
To Normal or No Change
To High
Missing

87
7
76
1
3

(8%)
(87%)
(1%)
(3%)

84
4
73
0
7

Hemoglobin (G/L)
n
To Low
To Normal or No Change
To High
Missing

87
6
78
0
3

(7%)
(90%)
(3%)

84
10
67
0
7

(2%)
(86%)
(4%)
(8%)

(5%)
(87%)
(8%)

(12%)
(80%)
(8%)

83
1
67
6
9
84
1
74
0
9
84
4
71
0
9

(1%)
(81%)
(7%)
(11%)

(1%)
(88%)
(11%)

(5%)
(85%)
(11%)

81
4
69
4
4
81
6
71
0
4
81
10
67
0
4

(5%)
(85%)
(5%)
(5%)

(7%)
(88%)
(5%)

(12%)
(83%)
(5%)

90
1
81
6
2
90
6
82
0
2
90
15
73
0
2

(1%)
(90%)
(7%)
(2%)

(7%)
(91%)
(2%)

(17%)
(81%)
(2%)

88
4
73
6
5
89
10
74
0
5
89
11
73
0
5

(5%)
(83%)
(7%)
(6%)

(11%)
(83%)
(6%)

(12%)
(82%)
(6%)

Note: Subjects are counted in the category that their value changes to (low, normal or high), unless there
is no change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
whose value became normal, are recorded in the "To Normal or No Change" category.

YM2008/00019/00
B2C109575

87
1
79
4
3

CONFIDENTIAL

576

Eosinophils (GI/L)
n
To Low
To Normal or No Change
To High
Missing

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 8

Table 8.16
Summary of Haematology Changes from Baseline Relative to the Normal Range

Visit: Day 14
Parameter/
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Lymphocytes (GI/L)
n
87
84
83
81
90
88
To Low
0
0
0
0
0
0
To Normal or No Change
83 (95%)
77 (92%)
74 (89%)
76 (94%)
88 (98%)
81 (92%)
To High
1
(1%)
0
0
1
(1%)
0
2
(2%)
Missing
3
(3%)
7
(8%)
9 (11%)
4
(5%)
2
(2%)
5
(6%)

Mean Corpuscle Hemoglobin


concentration (G/L)
n
To Low
To Normal or No Change
To High
Missing

87
11
73
0
3

Mean Corpuscle Volume (FL)


n
To Low
To Normal or No Change
To High
Missing

87
0
82
2
3

(2%)
(92%)
(2%)
(3%)

84
0
77
0
7

(3%)

84
6
71
0
7

(94%)
(2%)
(3%)

84
0
76
1
7

(13%)
(84%)

(92%)
(8%)

84
1
74
0
9

(8%)

84
2
73
0
9

(90%)
(1%)
(8%)

84
0
75
0
9

(7%)
(85%)

(1%)
(88%)
(11%)

(2%)
(87%)
(11%)

(89%)
(11%)

81
0
77
0
4

81
11
66
0
4
81
1
75
1
4

(95%)
(5%)

90
0
88
0
2

(5%)

90
8
80
0
2

(1%)
(93%)
(1%)
(5%)

90
0
85
3
2

(14%)
(81%)

(98%)
(2%)

89
0
84
0
5

(2%)

89
12
72
0
5

(94%)
(3%)
(2%)

89
0
81
3
5

(9%)
(89%)

(94%)
(6%)

(13%)
(81%)
(6%)

(91%)
(3%)
(6%)

Note: Subjects are counted in the category that their value changes to (low, normal or high), unless there
is no change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
whose value became normal, are recorded in the "To Normal or No Change" category.

YM2008/00019/00
B2C109575

87
2
80
2
3

CONFIDENTIAL

577

Mean Corpuscle Hemoglobin (PG)


n
To Low
To Normal or No Change
To High
Missing

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 8

Table 8.16
Summary of Haematology Changes from Baseline Relative to the Normal Range

Visit: Day 14
Parameter/
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Monocytes (GI/L)
n
87
84
83
81
90
88
To Low
10 (11%)
7
(8%)
9 (11%)
10 (12%)
10 (11%)
11 (13%)
To Normal or No Change
74 (85%)
70 (83%)
65 (78%)
67 (83%)
77 (86%)
70 (80%)
To High
0
0
0
0
1
(1%)
2
(2%)
Missing
3
(3%)
7
(8%)
9 (11%)
4
(5%)
2
(2%)
5
(6%)

Red Blood Cell count (TI/L)


n
To Low
To Normal or No Change
To High
Missing

87
5
79
0
3

Total Neutrophils (GI/L)


n
To Low
To Normal or No Change
To High
Missing

87
1
77
6
3

(95%)
(5%)

82
0
75
0
7

(3%)

84
5
72
0
7

(1%)
(89%)
(7%)
(3%)

84
1
75
1
7

(6%)
(91%)

(91%)
(9%)

83
0
73
0
10

(8%)

84
7
68
0
9

(1%)
(89%)
(1%)
(8%)

83
0
74
0
9

(6%)
(86%)

(88%)
(12%)

(8%)
(81%)
(11%)

(89%)
(11%)

79
1
74
0
4
81
1
76
0
4
81
0
77
0
4

(1%)
(94%)
(5%)

(1%)
(94%)
(5%)

(95%)
(5%)

89
0
87
0
2
90
6
82
0
2
90
0
85
3
2

(98%)
(2%)

88
0
79
1
8

(2%)

89
8
76
0
5

(94%)
(3%)
(2%)

88
0
80
3
5

(7%)
(91%)

(90%)
(1%)
(9%)

(9%)
(85%)
(6%)

(91%)
(3%)
(6%)

Note: Subjects are counted in the category that their value changes to (low, normal or high), unless there
is no change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
whose value became normal, are recorded in the "To Normal or No Change" category.

YM2008/00019/00
B2C109575

87
0
83
0
4

CONFIDENTIAL

578

Platelet count (GI/L)


n
To Low
To Normal or No Change
To High
Missing

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 8

Table 8.16
Summary of Haematology Changes from Baseline Relative to the Normal Range

Visit: Day 14
Parameter/
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------White Blood Cell count (GI/L)
n
87
84
83
81
90
88
To Low
1
(1%)
1
(1%)
0
0
0
0
To Normal or No Change
80 (92%)
76 (90%)
74 (89%)
76 (94%)
84 (93%)
78 (89%)
To High
3
(3%)
0
0
1
(1%)
4
(4%)
5
(6%)
Missing
3
(3%)
7
(8%)
9 (11%)
4
(5%)
2
(2%)
5
(6%)

CONFIDENTIAL

579

YM2008/00019/00
B2C109575

Note: Subjects are counted in the category that their value changes to (low, normal or high), unless there
is no change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
whose value became normal, are recorded in the "To Normal or No Change" category.

Protocol: B2C109575
Population: Intent-to-Treat

Page 5 of 8

Table 8.16
Summary of Haematology Changes from Baseline Relative to the Normal Range

Visit: Day 28
Parameter/
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Basophils (GI/L)
n
76
80
80
76
78
81
To Normal or No Change
73 (96%)
72 (90%)
73 (91%)
70 (92%)
77 (99%)
77 (95%)
To High
0
0
0
0
0
0
Missing
3
(4%)
8 (10%)
7
(9%)
6
(8%)
1
(1%)
4
(5%)

Hematocrit (1)
n
To Low
To Normal or No Change
To High
Missing

85
7
75
0
3

Hemoglobin (G/L)
n
To Low
To Normal or No Change
To High
Missing

85
9
73
0
3

(1%)
(90%)
(5%)
(4%)

(8%)
(88%)
(4%)

(11%)
(86%)
(4%)

85
3
70
4
8
85
8
69
0
8
85
12
65
0
8

(4%)
(82%)
(5%)
(9%)

(9%)
(81%)
(9%)

(14%)
(76%)
(9%)

86
1
68
8
9
86
7
70
0
9
86
9
68
0
9

(1%)
(79%)
(9%)
(10%)

(8%)
(81%)
(10%)

(10%)
(79%)
(10%)

83
3
71
3
6
84
5
73
0
6
84
12
66
0
6

(4%)
(86%)
(4%)
(7%)

(6%)
(87%)
(7%)

(14%)
(79%)
(7%)

90
2
80
7
1
90
8
81
0
1
90
16
73
0
1

(2%)
(89%)
(8%)
(1%)

(9%)
(90%)
(1%)

(18%)
(81%)
(1%)

95
4
80
7
4
95
8
83
0
4
95
9
82
0
4

(4%)
(84%)
(7%)
(4%)

(8%)
(87%)
(4%)

(9%)
(86%)
(4%)

Note: Subjects are counted in the category that their value changes to (low, normal or high), unless there
is no change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
whose value became normal, are recorded in the "To Normal or No Change" category.

YM2008/00019/00
B2C109575

84
1
76
4
3

CONFIDENTIAL

580

Eosinophils (GI/L)
n
To Low
To Normal or No Change
To High
Missing

Protocol: B2C109575
Population: Intent-to-Treat

Page 6 of 8

Table 8.16
Summary of Haematology Changes from Baseline Relative to the Normal Range

Visit: Day 28
Parameter/
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Lymphocytes (GI/L)
n
84
85
86
83
90
95
To Low
0
0
0
0
0
0
To Normal or No Change
81 (96%)
76 (89%)
76 (88%)
76 (92%)
88 (98%)
90 (95%)
To High
0
1
(1%)
1
(1%)
1
(1%)
1
(1%)
1
(1%)
Missing
3
(4%)
8
(9%)
9 (10%)
6
(7%)
1
(1%)
4
(4%)

Mean Corpuscle Hemoglobin


concentration (G/L)
n
To Low
To Normal or No Change
To High
Missing

85
7
75
0
3

Mean Corpuscle Volume (FL)


n
To Low
To Normal or No Change
To High
Missing

85
0
81
1
3

(1%)
(93%)
(2%)
(4%)

85
0
76
1
8

(4%)

85
7
70
0
8

(95%)
(1%)
(4%)

85
0
74
3
8

(8%)
(88%)

(89%)
(1%)
(9%)

86
0
75
2
9

(9%)

86
5
72
0
9

(87%)
(4%)
(9%)

85
0
75
1
9

(8%)
(82%)

(87%)
(2%)
(10%)

84
1
75
2
6

(10%)

84
8
70
0
6

(88%)
(1%)
(11%)

84
1
76
1
6

(6%)
(84%)

(1%)
(89%)
(2%)
(7%)

90
0
89
0
1

(7%)

90
5
84
0
1

(1%)
(90%)
(1%)
(7%)

90
0
87
2
1

(10%)
(83%)

(99%)
(1%)

95
0
91
0
4

(1%)

95
4
87
0
4

(97%)
(2%)
(1%)

95
0
89
2
4

(6%)
(93%)

(96%)
(4%)

(4%)
(92%)
(4%)

(94%)
(2%)
(4%)

Note: Subjects are counted in the category that their value changes to (low, normal or high), unless there
is no change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
whose value became normal, are recorded in the "To Normal or No Change" category.

YM2008/00019/00
B2C109575

85
1
79
2
3

CONFIDENTIAL

581

Mean Corpuscle Hemoglobin (PG)


n
To Low
To Normal or No Change
To High
Missing

Protocol: B2C109575
Population: Intent-to-Treat

Page 7 of 8

Table 8.16
Summary of Haematology Changes from Baseline Relative to the Normal Range

Visit: Day 28
Parameter/
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Monocytes (GI/L)
n
84
85
86
83
90
95
To Low
9 (11%)
10 (12%)
11 (13%)
12 (14%)
9 (10%)
13 (14%)
To Normal or No Change
72 (86%)
66 (78%)
66 (77%)
65 (78%)
80 (89%)
78 (82%)
To High
0
1
(1%)
0
0
0
0
Missing
3
(4%)
8
(9%)
9 (10%)
6
(7%)
1
(1%)
4
(4%)

Red Blood Cell count (TI/L)


n
To Low
To Normal or No Change
To High
Missing

85
7
75
0
3

Total Neutrophils (GI/L)


n
To Low
To Normal or No Change
To High
Missing

84
1
74
6
3

(93%)
(2%)
(5%)

84
0
75
1
8

(4%)

85
7
70
0
8

(1%)
(88%)
(7%)
(4%)

85
1
74
2
8

(8%)
(88%)

(89%)
(1%)
(10%)

84
0
74
0
10

(9%)

86
10
67
0
9

(1%)
(87%)
(2%)
(9%)

86
0
77
0
9

(8%)
(82%)

(88%)
(12%)

(12%)
(78%)
(10%)

(90%)
(10%)

83
0
75
2
6
84
4
74
0
6
83
0
76
1
6

87
0
85
1
1

(98%)
(1%)
(1%)

93
0
87
0
6

(7%)

90
7
81
1
1

(8%)
(90%)
(1%)
(1%)

95
3
88
0
4

(92%)
(1%)
(7%)

90
0
86
3
1

(96%)
(3%)
(1%)

95
1
88
2
4

(90%)
(2%)
(7%)

(5%)
(88%)

(94%)
(6%)

(3%)
(93%)
(4%)

(1%)
(93%)
(2%)
(4%)

Note: Subjects are counted in the category that their value changes to (low, normal or high), unless there
is no change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
whose value became normal, are recorded in the "To Normal or No Change" category.

YM2008/00019/00
B2C109575

82
0
76
2
4

CONFIDENTIAL

582

Platelet count (GI/L)


n
To Low
To Normal or No Change
To High
Missing

Protocol: B2C109575
Population: Intent-to-Treat

Page 8 of 8

Table 8.16
Summary of Haematology Changes from Baseline Relative to the Normal Range

Visit: Day 28
Parameter/
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------White Blood Cell count (GI/L)
n
84
85
86
83
90
95
To Low
0
0
0
0
0
1
(1%)
To Normal or No Change
77 (92%)
74 (87%)
76 (88%)
76 (92%)
84 (93%)
88 (93%)
To High
4
(5%)
3
(4%)
1
(1%)
1
(1%)
5
(6%)
2
(2%)
Missing
3
(4%)
8
(9%)
9 (10%)
6
(7%)
1
(1%)
4
(4%)

CONFIDENTIAL

583

YM2008/00019/00
B2C109575

Note: Subjects are counted in the category that their value changes to (low, normal or high), unless there
is no change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
whose value became normal, are recorded in the "To Normal or No Change" category.

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 4
Table 8.17
Summary of Urine Dipstick Results

Visit: Screening

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Lab Test
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Urine Glucose
n
101
96
97
95
95
99
(dipstick)
TRACE
1 (<1%)
1
(1%)
0
1
(1%)
0
0
2+
0
0
0
0
1
(1%)
0
3+
1 (<1%)
1
(1%)
0
1
(1%)
0
2
(2%)
NEGATIVE
99 (98%)
94 (98%)
97 (100%)
93 (98%)
94 (99%)
97 (98%)

584
Urine Protein
(dipstick)

n
TRACE
1+
2+
NEGATIVE
n
TRACE
1+
2+
3+
NEGATIVE

101
4
2
1
94

96
(4%)
(2%)
(<1%)
(93%)

101
9
10
2
0
80

5
1
0
90

97
(5%)
(1%)
(94%)

96
(9%)
(10%)
(2%)
(79%)

8
5
0
1
82

3
0
1
93

95
(3%)
(1%)
(96%)

97
(8%)
(5%)
(1%)
(85%)

6
1
0
0
90

3
1
0
91

95
(3%)
(1%)
(96%)

95
(6%)
(1%)
(93%)

7
3
1
0
84

1
0
0
94

99
(1%)
(99%)

95
(7%)
(3%)
(1%)
(88%)

5
5
1
0
84

3
0
0
96

(3%)
(97%)

99
(5%)
(5%)
(1%)
(88%)

8
7
0
0
84

(8%)
(7%)

CONFIDENTIAL

Urine Ketones
(dipstick)

(85%)

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 4
Table 8.17
Summary of Urine Dipstick Results

Visit: Screening

585

Urine pH

n
Mean
SD
Median
Min.
Max.

101
5.94
0.392
6.00
5.5
7.5

96
6.04
0.392
6.00
5.0
7.5

97
6.02
0.448
6.00
5.5
7.0

95
6.04
0.474
6.00
5.5
7.5

95
5.92
0.429
6.00
5.5
7.5

99
6.03
0.459
6.00
5.5
7.5

Urine Specific
Gravity

101

96

97

95

95

99

1.0219
0.00806
1.0230
1.006
1.039

1.0225
0.00716
1.0230
1.007
1.043

1.0215
0.00758
1.0220
1.005
1.038

1.0226
0.00744
1.0230
1.007
1.039

1.0245
0.02942
1.0220
1.006
1.300

1.0512
0.30049
1.0220
1.006
4.010

YM2008/00019/00
B2C109575

Mean
SD
Median
Min.
Max.

CONFIDENTIAL

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Lab Test
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Urine Leukocyte
n
101
96
97
95
95
99
Esterase test for
detecting WBC
(dipstick)
MODERATE
1 (<1%)
0
0
0
0
1
(1%)
TRACE
4
(4%)
5
(5%)
3
(3%)
1
(1%)
6
(6%)
6
(6%)
1+
6
(6%)
3
(3%)
2
(2%)
4
(4%)
5
(5%)
7
(7%)
2+
3
(3%)
1
(1%)
1
(1%)
3
(3%)
4
(4%)
0
3+
1 (<1%)
1
(1%)
1
(1%)
0
0
0
NEGATIVE
86 (85%)
86 (90%)
90 (93%)
87 (92%)
80 (84%)
85 (86%)

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 4
Table 8.17
Summary of Urine Dipstick Results

Visit: Day 28

Urine Ketones
(dipstick)

586
Urine Protein
(dipstick)

85

TRACE
1+
NEGATIVE

4
2
79

85

TRACE
1+
2+
3+
NEGATIVE

10
7
1
0
67

85
(5%)
(2%)
(93%)

2
1
82

86
(2%)
(1%)
(96%)

85
(12%)
(8%)
(1%)
(79%)

7
3
0
1
74

1
0
85

85
(1%)
(99%)

86
(8%)
(4%)
(1%)
(87%)

6
3
0
1
76

4
0
81

90
(5%)
(95%)

85
(7%)
(3%)
(1%)
(88%)

5
5
1
0
74

2
0
88

95
(2%)
(98%)

90
(6%)
(6%)
(1%)
(87%)

9
2
1
0
78

0
0
95 (100%)
95

(10%)
(2%)
(1%)
(87%)

11
4
0
1
79

CONFIDENTIAL

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Lab Test
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Urine Glucose
n
85
85
86
85
90
95
(dipstick)
TRACE
1
(1%)
0
1
(1%)
0
1
(1%)
0
1+
0
0
0
0
0
1
(1%)
2+
0
0
1
(1%)
2
(2%)
0
0
3+
0
1
(1%)
0
0
1
(1%)
1
(1%)
4+
0
0
0
0
0
1
(1%)
NEGATIVE
84 (99%)
84 (99%)
84 (98%)
83 (98%)
88 (98%)
92 (97%)

(12%)
(4%)
(1%)
(83%)

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 4
Table 8.17
Summary of Urine Dipstick Results

Visit: Day 28

587

Urine pH

n
Mean
SD
Median
Min.
Max.

85
6.00
0.415
6.00
5.5
7.0

85
6.05
0.408
6.00
5.0
8.0

86
6.08
0.534
6.00
5.5
8.5

85
6.00
0.408
6.00
5.0
7.0

90
5.86
0.361
6.00
5.0
7.0

95
6.08
0.544
6.00
5.0
8.5

Urine Specific
Gravity

85

85

86

85

90

95

1.0213
0.00821
1.0210
1.005
1.042

1.0227
0.00714
1.0220
1.008
1.048

1.0211
0.00762
1.0230
1.001
1.038

1.0223
0.00753
1.0230
1.006
1.042

1.0224
0.00767
1.0230
1.006
1.040

1.0221
0.00681
1.0240
1.005
1.035

YM2008/00019/00
B2C109575

Mean
SD
Median
Min.
Max.

CONFIDENTIAL

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Lab Test
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Urine Leukocyte
n
85
85
86
85
90
95
Esterase test for
detecting WBC
(dipstick)
SMALL
0
0
1
(1%)
0
0
2
(2%)
MODERATE
0
0
0
0
1
(1%)
0
TRACE
2
(2%)
3
(4%)
2
(2%)
4
(5%)
5
(6%)
6
(6%)
1+
1
(1%)
2
(2%)
1
(1%)
3
(4%)
9 (10%)
4
(4%)
2+
3
(4%)
3
(4%)
2
(2%)
1
(1%)
4
(4%)
0
3+
0
2
(2%)
1
(1%)
2
(2%)
2
(2%)
0
NEGATIVE
79 (93%)
75 (88%)
79 (92%)
75 (88%)
69 (77%)
83 (87%)

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 18
Table 8.18
Summary of Vital Signs

Planned relative
Treatment
N Visit
time
n
Mean
SD
Median Min. Max.
-----------------------------------------------------------------------------------------------------------Systolic BP (mmHg)
Placebo
102 Screening
102 124.1 13.26 124.0
90
150
102
102
102
102
102

123.3
123.6
124.2
124.4
124.4

15.42
14.65
15.20
15.01
15.46

121.0
122.0
124.0
122.0
125.5

90
92
85
92
90

159
158
158
159
160

Day 7

Pre-dose
10 mins
1 hour
2 hours
4 hours

95
93
93
93
93

122.6
122.3
123.1
123.4
123.1

14.70
14.30
15.58
15.59
14.68

122.0
122.0
122.0
123.0
121.0

90
92
88
88
88

152
163
159
163
160

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

93
90
90
90
89

123.2
122.3
123.3
123.5
123.8

15.03
14.67
14.50
16.00
14.34

121.0
121.5
121.0
120.5
122.0

90
90
96
88
96

155
161
153
156
165

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

88
87
87
87
87

122.6
123.0
122.9
123.0
125.1

14.66
15.37
14.17
15.15
15.34

122.5
122.0
122.0
123.0
126.0

88
86
92
90
92

155
166
164
161
174

YM2008/00019/00
B2C109575

Pre-dose
10 mins
1 hour
2 hours
4 hours

CONFIDENTIAL

588

Day 1

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 18
Table 8.18
Summary of Vital Signs

Planned relative
Treatment
N Visit
time
n
Mean
SD
Median Min. Max.
-----------------------------------------------------------------------------------------------------------Systolic BP (mmHg)
3mcg
101 Screening
101 122.5 14.84 123.0
87
154
101
101
101
101
101

123.2
123.8
125.0
125.1
124.2

14.38
15.63
16.20
16.05
15.87

123.0
122.0
127.0
124.0
124.0

90
90
88
90
90

160
165
172
165
159

Day 7

Pre-dose
10 mins
1 hour
2 hours
4 hours

95
93
93
93
93

122.7
122.6
123.1
124.0
124.4

14.38
15.03
15.50
15.43
13.80

121.0
122.0
123.0
126.0
124.0

92
84
86
87
90

160
167
180
172
150

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

91
86
86
86
86

122.1
121.9
121.3
121.5
122.7

13.98
13.31
14.13
14.46
14.15

124.0
122.0
120.0
122.5
123.5

90
95
83
85
90

155
162
159
155
158

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

86
85
85
84
84

121.5
121.2
122.4
122.9
122.8

14.73
14.36
13.41
15.30
13.89

122.0
120.0
122.0
121.0
120.0

88
90
92
90
89

157
166
158
168
164

YM2008/00019/00
B2C109575

Pre-dose
10 mins
1 hour
2 hours
4 hours

CONFIDENTIAL

589

Day 1

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 18
Table 8.18
Summary of Vital Signs

Planned relative
Treatment
N Visit
time
n
Mean
SD
Median Min. Max.
-----------------------------------------------------------------------------------------------------------Systolic BP (mmHg)
6.25mcg
101 Screening
101 124.7 13.83 123.0
90
159
101
101
101
101
101

123.9
123.6
124.0
125.3
124.9

13.95
13.57
14.41
14.09
13.83

123.0
124.0
122.0
124.0
125.0

98
92
98
98
99

175
171
167
162
170

Day 7

Pre-dose
10 mins
1 hour
2 hours
4 hours

99
97
97
97
97

121.3
120.8
121.9
122.2
122.4

11.88
13.19
13.58
12.85
13.85

120.0
120.0
120.0
120.0
120.0

91
91
96
93
91

148
151
155
150
163

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

95
93
93
93
93

121.1
121.2
122.1
122.5
122.8

12.30
12.72
13.41
14.10
14.58

122.0
120.0
120.0
120.0
122.0

94
97
94
85
91

149
149
152
160
170

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

91
91
91
91
91

122.3
120.4
121.3
122.0
123.2

13.05
12.40
12.72
11.82
13.92

122.0
120.0
120.0
122.0
125.0

94
96
97
100
98

155
150
161
145
163

YM2008/00019/00
B2C109575

Pre-dose
10 mins
1 hour
2 hours
4 hours

CONFIDENTIAL

590

Day 1

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 18
Table 8.18
Summary of Vital Signs

Planned relative
Treatment
N Visit
time
n
Mean
SD
Median Min. Max.
-----------------------------------------------------------------------------------------------------------Systolic BP (mmHg)
12.5mcg
100 Screening
100 125.1 14.80 125.5
92
159
100
100
99
99
99

125.6
125.0
124.8
124.8
125.9

13.60
13.69
13.77
13.63
14.49

126.0
124.5
122.0
126.0
124.0

96
96
98
90
94

160
158
159
160
164

Day 7

Pre-dose
10 mins
1 hour
2 hours
4 hours

97
96
95
95
93

123.1
123.8
125.4
125.6
126.7

13.54
14.16
13.60
14.72
14.31

120.0
122.0
124.0
127.0
127.0

90
98
98
95
92

153
156
158
161
164

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

91
91
91
91
91

123.7
122.6
125.4
125.1
125.4

14.83
16.41
15.50
14.45
15.07

122.0
122.0
126.0
125.0
125.0

88
86
90
80
80

155
161
161
158
166

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

89
88
88
88
88

125.1
124.9
124.2
124.9
124.7

13.13
12.82
13.06
14.54
13.54

126.0
124.5
124.0
122.0
124.0

90
95
90
90
90

156
155
159
165
157

YM2008/00019/00
B2C109575

Pre-dose
10 mins
1 hour
2 hours
4 hours

CONFIDENTIAL

591

Day 1

Protocol: B2C109575
Population: Intent-to-Treat

Page 5 of 18
Table 8.18
Summary of Vital Signs

Planned relative
Treatment
N Visit
time
n
Mean
SD
Median Min. Max.
-----------------------------------------------------------------------------------------------------------Systolic BP (mmHg)
25mcg
101 Screening
101 121.9 13.42 122.0
90
153
101
101
101
101
101

123.6
123.8
124.1
123.6
123.8

12.62
14.07
14.21
13.57
14.44

125.0
122.0
122.0
122.0
122.0

98
90
94
95
95

153
160
160
156
170

Day 7

Pre-dose
10 mins
1 hour
2 hours
4 hours

97
95
96
96
96

122.9
121.8
122.1
123.6
123.7

14.16
14.31
15.00
14.46
13.63

122.0
120.0
120.0
120.0
122.5

86
100
94
98
90

155
150
151
158
153

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

95
94
94
94
94

120.8
121.7
123.1
122.1
122.6

15.02
14.89
14.94
14.44
13.51

122.0
121.0
120.5
124.0
124.0

86
88
96
88
96

146
150
152
150
150

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

94
93
93
93
93

122.8
121.8
121.6
122.8
122.7

13.15
14.15
14.04
14.36
13.48

121.5
120.0
120.0
122.0
120.0

90
97
88
95
95

165
153
149
152
152

YM2008/00019/00
B2C109575

Pre-dose
10 mins
1 hour
2 hours
4 hours

CONFIDENTIAL

592

Day 1

Protocol: B2C109575
Population: Intent-to-Treat

Page 6 of 18
Table 8.18
Summary of Vital Signs

Planned relative
Treatment
N Visit
time
n
Mean
SD
Median Min. Max.
-----------------------------------------------------------------------------------------------------------Systolic BP (mmHg)
50mcg
102 Screening
102 122.9 12.28 120.5
96
152
102
102
102
102
102

122.3
123.0
123.0
122.8
123.2

12.97
14.02
14.50
13.37
12.83

120.0
121.0
122.0
122.0
120.0

96
95
84
95
95

158
179
173
170
159

Day 7

Pre-dose
10 mins
1 hour
2 hours
4 hours

100
100
100
100
99

120.4
120.0
122.6
123.4
122.8

13.25
13.51
13.31
12.77
12.80

120.0
120.0
121.0
120.5
120.0

93
90
98
100
93

165
162
173
163
160

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

98
97
97
97
97

121.8
122.8
122.9
123.1
123.1

13.48
13.69
13.00
13.67
13.19

120.0
120.0
120.0
120.0
121.0

90
94
96
96
87

170
161
169
163
162

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

98
98
98
98
98

122.5
120.8
122.2
121.8
122.8

15.51
14.22
13.62
13.52
13.17

120.0
120.0
121.5
120.0
120.0

90
92
92
99
100

174
164
169
162
163

YM2008/00019/00
B2C109575

Pre-dose
10 mins
1 hour
2 hours
4 hours

CONFIDENTIAL

593

Day 1

Protocol: B2C109575
Population: Intent-to-Treat

Page 7 of 18
Table 8.18
Summary of Vital Signs

Planned relative
Treatment
N Visit
time
n
Mean
SD
Median Min. Max.
-----------------------------------------------------------------------------------------------------------Diastolic BP (mmHg)
Placebo
102 Screening
102
77.9
9.37
78.0
56
99
102
102
102
102
102

77.3
78.4
77.9
79.2
79.2

9.59
10.13
10.55
10.03
10.55

78.0
78.5
78.0
80.0
80.0

52
54
50
54
56

96
97
102
100
100

Day 7

Pre-dose
10 mins
1 hour
2 hours
4 hours

95
93
93
93
93

76.9
76.3
76.2
76.7
76.5

10.57
9.58
9.77
9.49
9.91

76.0
76.0
75.0
77.0
77.0

52
57
58
54
50

98
96
97
94
100

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

93
90
90
90
89

77.2
77.2
77.4
76.5
76.7

10.17
10.29
9.94
10.28
10.12

77.0
78.0
80.0
78.0
78.0

51
52
58
50
40

98
98
98
97
98

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

88
87
87
87
87

77.3
76.8
77.7
77.4
77.5

10.23
9.48
9.78
10.35
11.13

76.0
78.0
77.0
78.0
78.0

57
54
54
52
46

100
96
100
100
101

YM2008/00019/00
B2C109575

Pre-dose
10 mins
1 hour
2 hours
4 hours

CONFIDENTIAL

594

Day 1

Protocol: B2C109575
Population: Intent-to-Treat

Page 8 of 18
Table 8.18
Summary of Vital Signs

Planned relative
Treatment
N Visit
time
n
Mean
SD
Median Min. Max.
-----------------------------------------------------------------------------------------------------------Diastolic BP (mmHg)
3mcg
101 Screening
101
77.7
9.44
78.0
60
101
101
101
101
101
101

76.2
76.9
77.5
77.6
77.9

9.83
9.95
9.97
10.42
10.47

78.0
76.0
78.0
76.0
76.0

57
56
58
58
56

98
100
101
100
109

Day 7

Pre-dose
10 mins
1 hour
2 hours
4 hours

95
93
93
93
93

77.3
76.8
76.2
77.1
77.5

9.57
9.70
10.35
9.10
9.77

76.0
76.0
75.0
76.0
76.0

56
58
49
60
52

100
98
100
100
100

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

91
86
86
86
86

76.7
77.1
75.8
75.3
75.2

9.21
8.81
9.84
9.34
9.17

77.0
77.5
76.0
75.0
75.0

52
56
51
56
57

100
100
100
104
96

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

86
85
85
84
84

76.0
75.9
77.2
77.2
76.5

9.45
9.30
8.65
9.94
9.41

74.5
75.0
77.0
76.0
76.0

58
52
58
54
53

100
98
100
100
100

YM2008/00019/00
B2C109575

Pre-dose
10 mins
1 hour
2 hours
4 hours

CONFIDENTIAL

595

Day 1

Protocol: B2C109575
Population: Intent-to-Treat

Page 9 of 18
Table 8.18
Summary of Vital Signs

Planned relative
Treatment
N Visit
time
n
Mean
SD
Median Min. Max.
-----------------------------------------------------------------------------------------------------------Diastolic BP (mmHg)
6.25mcg
101 Screening
101
78.1
8.05
80.0
60
96
101
101
101
101
101

77.2
78.0
76.8
78.1
77.5

8.55
8.79
8.66
7.89
8.92

78.0
79.0
76.0
80.0
78.0

60
54
58
60
58

99
100
95
96
100

Day 7

Pre-dose
10 mins
1 hour
2 hours
4 hours

99
97
97
97
97

75.9
76.1
77.0
76.0
76.4

8.93
8.70
9.29
9.60
9.19

76.0
78.0
78.0
76.0
78.0

56
55
53
52
51

95
98
107
105
109

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

95
93
93
93
93

75.2
75.8
76.4
76.0
76.8

8.38
8.54
9.32
9.63
9.33

74.0
76.0
77.0
75.0
76.0

55
53
59
54
52

96
97
105
103
104

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

91
91
91
91
91

77.6
75.7
76.3
77.2
78.5

8.51
9.24
8.51
8.60
7.58

78.0
75.0
76.0
78.0
79.0

58
53
57
45
60

94
98
96
97
96

YM2008/00019/00
B2C109575

Pre-dose
10 mins
1 hour
2 hours
4 hours

CONFIDENTIAL

596

Day 1

Protocol: B2C109575
Population: Intent-to-Treat

Page 10 of 18
Table 8.18
Summary of Vital Signs

Planned relative
Treatment
N Visit
time
n
Mean
SD
Median Min. Max.
-----------------------------------------------------------------------------------------------------------Diastolic BP (mmHg)
12.5mcg
100 Screening
100
77.9
8.81
79.5
52
100
100
100
99
99
99

77.7
77.3
78.3
77.5
78.5

10.04
9.26
9.39
9.68
9.81

77.0
77.5
79.0
78.0
80.0

60
58
58
50
58

100
100
103
103
102

Day 7

Pre-dose
10 mins
1 hour
2 hours
4 hours

97
96
95
95
93

76.8
76.1
77.5
76.7
78.0

9.50
9.22
9.14
8.95
9.48

78.0
77.0
79.0
78.0
79.0

51
52
54
54
51

95
96
98
96
98

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

91
91
91
91
91

76.0
75.6
77.2
76.3
77.5

9.24
9.56
9.73
8.68
10.00

78.0
75.0
78.0
77.0
78.0

52
51
58
59
56

99
99
110
94
99

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

89
88
88
88
88

76.8
76.4
76.7
77.4
76.6

8.30
9.71
9.18
9.41
9.40

78.0
75.0
77.0
76.5
76.0

60
54
60
60
55

96
98
100
100
102

YM2008/00019/00
B2C109575

Pre-dose
10 mins
1 hour
2 hours
4 hours

CONFIDENTIAL

597

Day 1

Protocol: B2C109575
Population: Intent-to-Treat

Page 11 of 18
Table 8.18
Summary of Vital Signs

Planned relative
Treatment
N Visit
time
n
Mean
SD
Median Min. Max.
-----------------------------------------------------------------------------------------------------------Diastolic BP (mmHg)
25mcg
101 Screening
101
76.2
9.85
78.0
58
100
101
101
101
101
101

76.6
77.8
77.3
78.0
78.4

9.20
9.26
9.15
9.19
9.14

77.0
78.0
77.0
78.0
78.0

50
59
60
60
60

96
98
98
100
99

Day 7

Pre-dose
10 mins
1 hour
2 hours
4 hours

97
95
96
96
96

75.8
75.8
76.4
75.8
76.6

9.08
9.67
10.24
9.30
9.59

76.0
76.0
76.0
76.0
77.0

54
57
54
55
53

96
96
97
98
95

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

95
94
94
94
94

76.0
75.1
76.2
75.8
75.4

9.85
10.18
10.13
10.73
10.10

76.0
74.5
76.5
75.0
76.0

47
55
49
43
58

95
100
98
100
99

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

94
93
93
93
93

76.4
75.1
76.1
76.8
76.2

10.00
9.68
10.20
10.60
9.85

77.0
75.0
75.0
77.0
74.0

58
52
54
56
48

98
99
100
107
99

YM2008/00019/00
B2C109575

Pre-dose
10 mins
1 hour
2 hours
4 hours

CONFIDENTIAL

598

Day 1

Protocol: B2C109575
Population: Intent-to-Treat

Page 12 of 18
Table 8.18
Summary of Vital Signs

Planned relative
Treatment
N Visit
time
n
Mean
SD
Median Min. Max.
-----------------------------------------------------------------------------------------------------------Diastolic BP (mmHg)
50mcg
102 Screening
102
76.5
8.77
78.0
50
95
102
102
102
102
102

75.6
75.7
75.9
76.4
76.9

8.94
10.03
9.59
8.84
8.62

76.0
75.0
74.5
76.0
77.0

58
53
53
56
58

100
100
97
98
94

Day 7

Pre-dose
10 mins
1 hour
2 hours
4 hours

100
100
100
100
99

75.3
75.6
75.2
77.1
76.1

9.46
10.42
9.01
9.27
9.25

75.0
76.0
76.0
80.0
77.0

52
45
55
52
55

98
100
95
100
100

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

98
97
97
97
97

75.6
75.1
75.1
75.8
75.6

9.24
10.69
8.01
9.19
8.51

75.0
75.0
76.0
76.0
76.0

52
45
58
50
57

98
100
96
99
94

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

98
98
98
98
98

76.4
74.9
76.0
76.6
77.1

9.35
9.21
8.62
9.08
8.98

76.0
75.0
76.0
76.0
77.0

57
51
55
58
47

100
96
98
98
96

YM2008/00019/00
B2C109575

Pre-dose
10 mins
1 hour
2 hours
4 hours

CONFIDENTIAL

599

Day 1

Protocol: B2C109575
Population: Intent-to-Treat

Page 13 of 18
Table 8.18
Summary of Vital Signs

Planned relative
Treatment
N Visit
time
n
Mean
SD
Median Min. Max.
-----------------------------------------------------------------------------------------------------------Heart rate (beats/min) Placebo
102 Screening
102
75.6 10.64
76.0
50
107
102
102
102
102
102

72.8
71.6
69.6
70.6
70.7

9.74
10.44
11.18
10.89
10.21

73.0
72.0
71.0
71.0
72.0

47
51
40
38
40

94
96
99
99
99

Day 7

Pre-dose
10 mins
1 hour
2 hours
4 hours

95
93
93
93
93

74.0
72.6
71.8
72.3
72.9

9.90
9.52
9.88
10.17
8.98

72.0
72.0
72.0
72.0
72.0

54
54
51
51
57

104
100
96
96
97

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

93
90
90
90
89

74.5
72.6
72.0
72.7
73.9

10.96
8.65
9.01
9.83
9.43

73.0
72.0
71.0
72.0
74.0

53
56
53
48
55

102
100
94
100
98

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

88
87
87
87
87

73.7
71.4
71.1
69.8
70.8

10.18
9.40
9.38
9.31
9.03

72.0
70.0
70.0
70.0
72.0

54
54
52
49
52

115
96
92
95
91

YM2008/00019/00
B2C109575

Pre-dose
10 mins
1 hour
2 hours
4 hours

CONFIDENTIAL

600

Day 1

Protocol: B2C109575
Population: Intent-to-Treat

Page 14 of 18
Table 8.18
Summary of Vital Signs

Planned relative
Treatment
N Visit
time
n
Mean
SD
Median Min. Max.
-----------------------------------------------------------------------------------------------------------Heart rate (beats/min) 3mcg
101 Screening
101
72.0
9.00
72.0
50
100
101
101
101
101
101

71.2
69.6
69.3
67.6
68.9

9.60
9.41
10.93
10.52
10.34

70.0
70.0
68.0
67.0
68.0

50
50
47
45
44

100
90
98
98
100

Day 7

Pre-dose
10 mins
1 hour
2 hours
4 hours

95
93
93
93
93

71.3
70.6
69.7
70.2
71.2

9.25
9.83
10.08
10.45
9.34

72.0
70.0
69.0
69.0
72.0

46
49
45
45
48

101
99
102
100
103

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

91
86
86
86
86

72.4
70.3
69.5
70.2
70.3

10.28
8.64
8.76
10.13
9.41

73.0
71.5
70.5
70.5
70.0

49
48
42
43
47

116
88
87
97
90

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

86
85
85
84
84

71.6
70.1
69.8
68.5
69.3

10.54
10.01
10.00
9.89
11.13

71.0
70.0
70.0
68.0
68.0

43
46
46
42
41

96
93
98
92
100

YM2008/00019/00
B2C109575

Pre-dose
10 mins
1 hour
2 hours
4 hours

CONFIDENTIAL

601

Day 1

Protocol: B2C109575
Population: Intent-to-Treat

Page 15 of 18
Table 8.18
Summary of Vital Signs

Planned relative
Treatment
N Visit
time
n
Mean
SD
Median Min. Max.
-----------------------------------------------------------------------------------------------------------Heart rate (beats/min) 6.25mcg
101 Screening
101
72.3
9.03
71.0
55
110
101
101
101
101
101

70.7
70.1
68.4
67.7
68.3

9.12
8.47
9.05
9.01
9.33

70.0
70.0
69.0
67.0
68.0

54
52
48
48
47

89
88
87
88
89

Day 7

Pre-dose
10 mins
1 hour
2 hours
4 hours

99
97
97
97
97

72.3
72.4
70.0
69.9
69.9

10.38
9.77
9.80
9.22
8.41

72.0
72.0
71.0
70.0
70.0

51
53
46
51
50

97
94
97
95
92

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

95
93
93
93
93

72.7
72.2
70.0
69.9
70.3

11.91
8.75
8.56
8.52
9.31

72.0
72.0
70.0
70.0
71.0

52
51
51
50
54

112
90
89
89
94

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

91
91
91
91
91

72.4
70.8
69.2
68.6
67.8

10.19
9.93
9.79
9.95
9.92

72.0
70.0
69.0
68.0
68.0

52
53
50
51
42

99
94
92
93
94

YM2008/00019/00
B2C109575

Pre-dose
10 mins
1 hour
2 hours
4 hours

CONFIDENTIAL

602

Day 1

Protocol: B2C109575
Population: Intent-to-Treat

Page 16 of 18
Table 8.18
Summary of Vital Signs

Planned relative
Treatment
N Visit
time
n
Mean
SD
Median Min. Max.
-----------------------------------------------------------------------------------------------------------Heart rate (beats/min) 12.5mcg
100 Screening
99
71.9
8.25
72.0
49
89
100
100
99
99
99

72.8
70.6
69.0
68.5
69.3

9.00
9.48
9.44
8.54
8.59

72.0
70.0
68.0
68.0
68.0

54
51
44
52
47

98
95
92
93
88

Day 7

Pre-dose
10 mins
1 hour
2 hours
4 hours

97
96
95
95
93

72.6
71.9
70.3
70.5
71.6

8.63
9.04
9.81
9.41
9.38

72.0
72.0
70.0
71.0
72.0

53
53
50
51
51

90
100
93
95
95

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

91
91
91
91
91

73.7
73.3
72.3
72.7
71.3

10.71
10.20
10.05
10.06
9.01

72.0
72.0
70.0
70.0
70.0

58
52
52
51
46

106
97
99
100
102

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

89
88
88
88
88

72.2
71.2
69.9
68.9
68.3

9.10
9.76
9.56
8.55
8.31

72.0
71.0
70.0
68.0
69.5

55
44
53
53
48

94
94
102
88
90

YM2008/00019/00
B2C109575

Pre-dose
10 mins
1 hour
2 hours
4 hours

CONFIDENTIAL

603

Day 1

Protocol: B2C109575
Population: Intent-to-Treat

Page 17 of 18
Table 8.18
Summary of Vital Signs

Planned relative
Treatment
N Visit
time
n
Mean
SD
Median Min. Max.
-----------------------------------------------------------------------------------------------------------Heart rate (beats/min) 25mcg
101 Screening
101
71.9
9.53
72.0
50
90
101
101
101
101
101

72.6
72.6
70.7
69.2
70.1

9.76
10.21
10.22
9.12
9.68

72.0
74.0
72.0
69.0
72.0

47
47
48
45
48

102
98
94
91
89

Day 7

Pre-dose
10 mins
1 hour
2 hours
4 hours

97
95
96
96
96

74.2
73.5
71.9
71.1
71.9

10.34
9.81
9.37
9.08
9.76

74.0
74.0
71.5
71.0
72.0

50
49
50
50
47

100
92
90
92
90

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

95
94
94
94
94

74.3
74.2
72.2
72.9
72.5

10.66
10.32
10.63
10.44
10.01

74.0
72.0
71.5
72.5
72.0

47
52
54
50
50

100
101
103
101
98

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

94
93
93
93
93

73.6
73.1
71.6
70.3
69.6

10.17
9.43
10.72
10.32
9.95

73.0
73.0
72.0
69.0
69.0

46
50
48
48
46

95
102
104
99
90

YM2008/00019/00
B2C109575

Pre-dose
10 mins
1 hour
2 hours
4 hours

CONFIDENTIAL

604

Day 1

Protocol: B2C109575
Population: Intent-to-Treat

Page 18 of 18
Table 8.18
Summary of Vital Signs

Planned relative
Treatment
N Visit
time
n
Mean
SD
Median Min. Max.
-----------------------------------------------------------------------------------------------------------Heart rate (beats/min) 50mcg
102 Screening
102
70.9
9.17
70.0
52
99
102
102
102
102
102

71.5
71.0
69.9
69.6
69.6

10.26
10.33
10.85
10.40
10.66

70.0
70.0
68.0
68.5
69.0

50
47
48
50
48

105
100
110
100
102

Day 7

Pre-dose
10 mins
1 hour
2 hours
4 hours

100
100
100
100
99

72.0
73.3
72.2
72.1
72.2

9.95
10.56
9.52
9.74
10.68

70.5
74.0
72.0
72.0
71.0

49
42
50
52
51

110
110
109
104
105

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

98
97
97
97
97

73.1
74.9
74.1
73.2
72.0

8.66
9.49
9.71
10.21
8.98

72.5
76.0
74.0
73.0
72.0

54
50
54
50
50

105
101
110
112
112

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

98
98
98
98
98

72.8
74.6
72.8
70.9
71.1

10.15
9.52
9.98
9.76
10.74

72.0
74.0
72.0
70.0
70.0

53
54
54
49
49

100
99
99
102
102

YM2008/00019/00
B2C109575

Pre-dose
10 mins
1 hour
2 hours
4 hours

CONFIDENTIAL

605

Day 1

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 18
Table 8.19
Summary of Change from Baseline in Vital Signs

Planned relative
Treatment
N Visit
time
n
Mean SD
Median Min. Max.
----------------------------------------------------------------------------------------------------------Systolic BP (mmHg)
Placebo
102 Day 1
10 mins
102
0.4
9.56
0.0
-38
40
1 hour
102
0.9 10.70
2.0
-32
32
2 hours
102
1.2 12.02
1.0
-31
35
4 hours
102
1.1 12.13
0.0
-34
37
95
93
93
93
93

-1.1
-1.5
-0.8
-0.5
-0.8

12.25
12.28
13.52
12.95
10.73

0.0
0.0
0.0
0.0
0.0

-54
-30
-40
-40
-26

26
38
34
38
25

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

93
90
90
90
89

-0.7
-1.6
-0.7
-0.5
-0.1

12.49
12.20
12.61
12.76
12.92

-1.0
-0.5
0.0
0.0
0.0

-39
-44
-44
-46
-44

28
24
24
36
28

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

88
87
87
87
87

-1.3
-0.9
-1.0
-0.9
1.2

12.92
13.02
13.09
13.86
15.01

-0.5
-2.0
0.0
0.0
2.0

-33
-35
-28
-31
-31

32
41
39
36
49

YM2008/00019/00
B2C109575

Note: Baseline is pre-dose at Day 1

CONFIDENTIAL

Pre-dose
10 mins
1 hour
2 hours
4 hours

606

Day 7

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 18
Table 8.19
Summary of Change from Baseline in Vital Signs

Planned relative
Treatment
N Visit
time
n
Mean SD
Median Min. Max.
----------------------------------------------------------------------------------------------------------Systolic BP (mmHg)
3mcg
101 Day 1
10 mins
101
0.6
7.06
0.0
-16
19
1 hour
101
1.8
9.81
0.0
-21
37
2 hours
101
1.9 11.01
0.0
-24
32
4 hours
101
1.0 10.34
0.0
-20
35
95
93
93
93
93

-0.2
-0.8
-0.3
0.6
1.0

12.07
12.68
12.26
11.04
11.11

0.0
0.0
0.0
0.0
0.0

-26
-34
-28
-23
-23

26
35
32
33
35

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

91
86
86
86
86

-1.2
-1.1
-1.7
-1.5
-0.3

10.18
10.06
10.22
10.14
10.91

0.0
-1.5
-1.0
-2.0
0.0

-24
-20
-28
-33
-26

30
25
30
24
30

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

86
85
85
84
84

-1.5
-1.8
-0.5
-0.3
-0.3

11.71
11.26
11.43
11.70
10.88

0.0
-1.0
0.0
0.0
1.5

-24
-22
-20
-30
-23

25
31
35
33
27

YM2008/00019/00
B2C109575

Note: Baseline is pre-dose at Day 1

CONFIDENTIAL

Pre-dose
10 mins
1 hour
2 hours
4 hours

607

Day 7

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 18
Table 8.19
Summary of Change from Baseline in Vital Signs

Planned relative
Treatment
N Visit
time
n
Mean SD
Median Min. Max.
----------------------------------------------------------------------------------------------------------Systolic BP (mmHg)
6.25mcg
101 Day 1
10 mins
101 -0.3
8.86
0.0
-22
26
1 hour
101
0.0
8.74
0.0
-21
20
2 hours
101
1.4
9.70
0.0
-22
22
4 hours
101
1.0
8.61
0.0
-20
28
99
97
97
97
97

-2.4
-3.1
-2.0
-1.8
-1.5

11.01
11.63
12.69
11.47
11.90

0.0
-3.0
-1.0
-2.0
-2.0

-39
-39
-41
-36
-37

23
25
35
23
33

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

95
93
93
93
93

-3.0
-3.3
-2.4
-1.9
-1.7

10.63
10.92
10.66
11.49
12.14

-3.0
-4.0
-1.0
-3.0
-4.0

-28
-34
-29
-38
-30

21
25
24
32
45

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

91
91
91
91
91

-2.2
-4.1
-3.3
-2.5
-1.3

11.45
11.17
12.98
11.62
12.82

-2.0
-5.0
-5.0
-2.0
-3.0

-35
-45
-60
-44
-27

34
28
26
22
31

YM2008/00019/00
B2C109575

Note: Baseline is pre-dose at Day 1

CONFIDENTIAL

Pre-dose
10 mins
1 hour
2 hours
4 hours

608

Day 7

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 18
Table 8.19
Summary of Change from Baseline in Vital Signs

Planned relative
Treatment
N Visit
time
n
Mean SD
Median Min. Max.
----------------------------------------------------------------------------------------------------------Systolic BP (mmHg)
12.5mcg
100 Day 1
10 mins
100 -0.6
7.94
0.0
-30
18
1 hour
99 -0.7
9.63
0.0
-25
19
2 hours
99 -0.6
9.34
0.0
-24
25
4 hours
99
0.4
8.79
0.0
-22
34
97
96
95
95
93

-2.4
-1.8
-0.4
-0.1
1.2

8.87
9.78
11.24
10.31
10.68

0.0
0.0
0.0
0.0
0.0

-29
-27
-28
-26
-20

20
22
27
24
42

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

91
91
91
91
91

-1.6
-2.8
0.0
-0.3
0.0

11.17
12.58
12.25
11.91
11.16

0.0
-2.0
0.0
0.0
1.0

-35
-35
-45
-41
-35

21
22
27
31
26

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

89
88
88
88
88

-0.3
-0.5
-1.2
-0.5
-0.7

10.81
11.02
11.03
11.35
10.73

0.0
0.0
-1.0
0.0
-2.0

-24
-33
-31
-32
-28

35
30
32
35
40

YM2008/00019/00
B2C109575

Note: Baseline is pre-dose at Day 1

CONFIDENTIAL

Pre-dose
10 mins
1 hour
2 hours
4 hours

609

Day 7

Protocol: B2C109575
Population: Intent-to-Treat

Page 5 of 18
Table 8.19
Summary of Change from Baseline in Vital Signs

Planned relative
Treatment
N Visit
time
n
Mean SD
Median Min. Max.
----------------------------------------------------------------------------------------------------------Systolic BP (mmHg)
25mcg
101 Day 1
10 mins
101
0.2
8.70
0.0
-35
23
1 hour
101
0.5
9.70
0.0
-25
36
2 hours
101
0.0
8.63
0.0
-34
26
4 hours
101
0.2
9.74
0.0
-33
46
97
95
96
96
96

-1.2
-2.2
-2.0
-0.5
-0.4

9.06
9.89
9.91
9.85
8.91

0.0
-2.0
0.0
0.0
0.0

-26
-32
-38
-30
-30

24
22
20
30
20

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

95
94
94
94
94

-3.1
-2.3
-0.9
-1.9
-1.4

10.64
10.47
11.34
10.73
10.36

-3.0
-3.0
0.0
-2.0
-2.0

-37
-26
-38
-33
-30

22
27
24
26
29

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

94
93
93
93
93

-1.2
-2.5
-2.6
-1.5
-1.6

10.68
11.05
10.91
10.87
10.80

0.0
0.0
-2.0
0.0
0.0

-30
-28
-25
-30
-35

29
26
28
22
22

YM2008/00019/00
B2C109575

Note: Baseline is pre-dose at Day 1

CONFIDENTIAL

Pre-dose
10 mins
1 hour
2 hours
4 hours

610

Day 7

Protocol: B2C109575
Population: Intent-to-Treat

Page 6 of 18
Table 8.19
Summary of Change from Baseline in Vital Signs

Planned relative
Treatment
N Visit
time
n
Mean SD
Median Min. Max.
----------------------------------------------------------------------------------------------------------Systolic BP (mmHg)
50mcg
102 Day 1
10 mins
102
0.7
9.03
0.0
-34
39
1 hour
102
0.7
9.67
0.0
-36
33
2 hours
102
0.5
9.76
0.0
-26
31
4 hours
102
0.9
9.89
0.0
-27
23
100
100
100
100
99

-2.1
-2.4
0.2
0.9
0.3

11.04
10.63
10.99
10.69
10.44

-2.0
-2.0
0.0
0.0
0.0

-27
-25
-21
-36
-28

25
22
33
23
28

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

98
97
97
97
97

-0.6
0.3
0.6
0.7
0.8

9.79
11.19
10.68
12.27
10.84

0.0
0.0
0.0
0.0
0.0

-30
-32
-30
-29
-33

30
26
29
41
26

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

98
98
98
98
98

0.1
-1.6
-0.2
-0.6
0.4

11.11
12.09
11.54
11.89
10.73

0.0
0.0
0.0
0.0
0.0

-28
-41
-28
-32
-26

30
24
29
32
33

YM2008/00019/00
B2C109575

Note: Baseline is pre-dose at Day 1

CONFIDENTIAL

Pre-dose
10 mins
1 hour
2 hours
4 hours

611

Day 7

Protocol: B2C109575
Population: Intent-to-Treat

Page 7 of 18
Table 8.19
Summary of Change from Baseline in Vital Signs

Planned relative
Treatment
N Visit
time
n
Mean SD
Median Min. Max.
----------------------------------------------------------------------------------------------------------Diastolic BP (mmHg)
Placebo
102 Day 1
10 mins
102
1.2
6.07
1.0
-18
20
1 hour
102
0.6
7.67
0.0
-20
32
2 hours
102
1.9
7.25
1.0
-24
20
4 hours
102
1.9
8.55
0.5
-28
30
95
93
93
93
93

-0.3
-0.9
-1.0
-0.5
-0.7

8.46
8.41
8.69
8.39
7.75

-1.0
-1.0
-1.0
0.0
0.0

-24
-26
-28
-26
-28

22
23
24
21
20

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

93
90
90
90
89

0.0
0.2
0.5
-0.5
-0.2

10.13
9.69
9.46
9.50
9.71

0.0
0.0
0.5
-1.0
0.0

-25
-32
-24
-24
-24

42
24
30
24
23

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

88
87
87
87
87

0.5
0.0
0.9
0.6
0.7

8.46
8.24
9.35
8.96
9.47

0.0
0.0
1.0
0.0
0.0

-24
-20
-18
-19
-20

25
24
26
30
31

YM2008/00019/00
B2C109575

Note: Baseline is pre-dose at Day 1

CONFIDENTIAL

Pre-dose
10 mins
1 hour
2 hours
4 hours

612

Day 7

Protocol: B2C109575
Population: Intent-to-Treat

Page 8 of 18
Table 8.19
Summary of Change from Baseline in Vital Signs

Planned relative
Treatment
N Visit
time
n
Mean SD
Median Min. Max.
----------------------------------------------------------------------------------------------------------Diastolic BP (mmHg)
3mcg
101 Day 1
10 mins
101
0.7
6.23
0.0
-20
24
1 hour
101
1.3
7.30
0.0
-22
20
2 hours
101
1.4
7.58
1.0
-15
26
4 hours
101
1.7
8.85
2.0
-21
24
95
93
93
93
93

1.0
0.4
-0.2
0.7
1.1

8.17
8.05
8.24
7.56
7.66

0.0
0.0
0.0
0.0
0.0

-18
-17
-20
-21
-20

25
20
20
18
16

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

91
86
86
86
86

0.4
0.9
-0.4
-0.9
-0.9

8.07
7.55
7.99
8.55
8.38

0.0
0.0
0.0
-0.5
0.0

-23
-19
-17
-27
-23

16
19
18
16
20

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

86
85
85
84
84

-0.1
-0.1
1.2
1.3
0.6

7.44
8.09
8.33
9.57
8.27

0.0
0.0
2.0
0.5
0.0

-18
-20
-27
-28
-25

18
20
23
24
19

YM2008/00019/00
B2C109575

Note: Baseline is pre-dose at Day 1

CONFIDENTIAL

Pre-dose
10 mins
1 hour
2 hours
4 hours

613

Day 7

Protocol: B2C109575
Population: Intent-to-Treat

Page 9 of 18
Table 8.19
Summary of Change from Baseline in Vital Signs

Planned relative
Treatment
N Visit
time
n
Mean SD
Median Min. Max.
----------------------------------------------------------------------------------------------------------Diastolic BP (mmHg)
6.25mcg
101 Day 1
10 mins
101
0.9
7.09
0.0
-24
25
1 hour
101 -0.3
7.40
0.0
-24
22
2 hours
101
1.0
7.23
0.0
-15
20
4 hours
101
0.3
8.52
0.0
-25
20
99
97
97
97
97

-1.3
-1.2
-0.3
-1.3
-0.9

8.60
8.20
9.39
9.05
8.20

0.0
0.0
0.0
0.0
0.0

-28
-28
-25
-23
-22

22
17
22
20
20

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

95
93
93
93
93

-2.3
-2.0
-1.3
-1.8
-0.9

9.13
8.43
9.61
9.78
9.55

-2.0
-2.0
0.0
-1.0
-2.0

-26
-27
-25
-28
-21

31
17
20
24
21

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

91
91
91
91
91

-0.2
-2.2
-1.6
-0.7
0.6

8.01
8.67
8.57
8.64
8.49

0.0
-2.0
-2.0
0.0
0.0

-18
-25
-19
-23
-18

19
25
25
19
28

YM2008/00019/00
B2C109575

Note: Baseline is pre-dose at Day 1

CONFIDENTIAL

Pre-dose
10 mins
1 hour
2 hours
4 hours

614

Day 7

Protocol: B2C109575
Population: Intent-to-Treat

Page 10 of 18
Table 8.19
Summary of Change from Baseline in Vital Signs

Planned relative
Treatment
N Visit
time
n
Mean SD
Median Min. Max.
----------------------------------------------------------------------------------------------------------Diastolic BP (mmHg)
12.5mcg
100 Day 1
10 mins
100 -0.4
5.23
0.0
-20
14
1 hour
99
0.5
6.87
0.0
-19
16
2 hours
99 -0.3
7.59
0.0
-27
22
4 hours
99
0.7
7.15
0.0
-22
26
97
96
95
95
93

-1.2
-1.9
-0.7
-1.4
0.1

8.07
7.90
8.17
7.44
7.71

-1.0
-2.0
0.0
0.0
0.0

-25
-24
-24
-20
-16

20
24
18
20
27

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

91
91
91
91
91

-1.7
-2.1
-0.5
-1.5
-0.2

9.44
9.64
9.46
8.78
9.29

-1.0
0.0
0.0
0.0
0.0

-30
-33
-30
-30
-25

20
15
25
15
22

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

89
88
88
88
88

-1.0
-1.3
-1.0
-0.3
-1.0

7.66
8.49
8.33
9.13
8.78

0.0
-1.5
-1.0
0.0
0.0

-21
-21
-16
-22
-26

22
20
18
32
20

YM2008/00019/00
B2C109575

Note: Baseline is pre-dose at Day 1

CONFIDENTIAL

Pre-dose
10 mins
1 hour
2 hours
4 hours

615

Day 7

Protocol: B2C109575
Population: Intent-to-Treat

Page 11 of 18
Table 8.19
Summary of Change from Baseline in Vital Signs

Planned relative
Treatment
N Visit
time
n
Mean SD
Median Min. Max.
----------------------------------------------------------------------------------------------------------Diastolic BP (mmHg)
25mcg
101 Day 1
10 mins
101
1.2
6.49
1.0
-18
28
1 hour
101
0.7
7.05
0.0
-21
26
2 hours
101
1.4
7.61
1.0
-26
30
4 hours
101
1.8
7.62
1.0
-30
28
97
95
96
96
96

-1.1
-1.1
-0.5
-1.0
-0.3

8.15
8.90
8.80
7.84
8.17

-2.0
0.0
0.0
0.0
0.0

-20
-30
-26
-30
-32

20
30
22
14
20

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

95
94
94
94
94

-0.8
-1.7
-0.6
-1.0
-1.3

9.19
9.30
9.43
9.69
9.62

-1.0
0.0
0.0
0.0
0.0

-29
-26
-30
-26
-26

22
22
22
27
21

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

94
93
93
93
93

-0.4
-1.8
-0.8
-0.0
-0.7

9.57
8.90
8.54
9.99
9.52

0.0
-1.0
0.0
0.0
0.0

-28
-25
-20
-30
-30

29
22
20
29
22

YM2008/00019/00
B2C109575

Note: Baseline is pre-dose at Day 1

CONFIDENTIAL

Pre-dose
10 mins
1 hour
2 hours
4 hours

616

Day 7

Protocol: B2C109575
Population: Intent-to-Treat

Page 12 of 18
Table 8.19
Summary of Change from Baseline in Vital Signs

Planned relative
Treatment
N Visit
time
n
Mean SD
Median Min. Max.
----------------------------------------------------------------------------------------------------------Diastolic BP (mmHg)
50mcg
102 Day 1
10 mins
102
0.1
7.00
0.0
-21
20
1 hour
102
0.3
7.43
0.0
-23
26
2 hours
102
0.8
7.99
0.0
-20
21
4 hours
102
1.3
7.53
1.0
-16
17
100
100
100
100
99

-0.3
-0.1
-0.5
1.5
0.4

8.04
8.21
8.40
8.59
8.18

0.0
0.0
0.0
1.0
0.0

-20
-24
-20
-20
-21

25
20
20
32
18

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

98
97
97
97
97

-0.1
-0.7
-0.5
0.1
-0.0

8.21
8.37
8.10
8.08
8.53

0.0
0.0
0.0
0.0
0.0

-18
-31
-20
-20
-22

25
21
17
22
20

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

98
98
98
98
98

0.7
-0.8
0.3
0.9
1.4

8.58
8.82
8.78
8.76
8.72

0.0
0.0
0.0
0.0
2.0

-30
-30
-26
-30
-29

23
19
23
19
20

YM2008/00019/00
B2C109575

Note: Baseline is pre-dose at Day 1

CONFIDENTIAL

Pre-dose
10 mins
1 hour
2 hours
4 hours

617

Day 7

Protocol: B2C109575
Population: Intent-to-Treat

Page 13 of 18
Table 8.19
Summary of Change from Baseline in Vital Signs

Planned relative
Treatment
N Visit
time
n
Mean SD
Median Min. Max.
----------------------------------------------------------------------------------------------------------Heart rate (beats/min) Placebo
102 Day 1
10 mins
102 -1.2
7.53
0.0
-25
29
1 hour
102 -3.2
7.91
-2.0
-25
13
2 hours
102 -2.2
9.03
-0.5
-27
21
4 hours
102 -2.0
8.99
-2.0
-27
28
95
93
93
93
93

1.3
0.2
-0.5
-0.0
0.6

9.01
10.52
9.78
10.68
9.76

0.0
1.0
0.0
0.0
0.0

-22
-28
-24
-21
-34

24
39
40
34
29

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

93
90
90
90
89

2.1
0.1
-0.5
0.2
1.4

11.84
9.97
10.13
10.14
11.14

2.0
0.0
0.0
0.0
2.0

-26
-23
-26
-22
-24

39
44
38
30
30

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

88
87
87
87
87

1.2
-1.1
-1.4
-2.7
-1.8

10.91
10.40
10.32
9.61
9.64

1.0
-1.0
-2.0
-2.0
-1.0

-30
-31
-29
-30
-24

36
22
30
25
29

YM2008/00019/00
B2C109575

Note: Baseline is pre-dose at Day 1

CONFIDENTIAL

Pre-dose
10 mins
1 hour
2 hours
4 hours

618

Day 7

Protocol: B2C109575
Population: Intent-to-Treat

Page 14 of 18
Table 8.19
Summary of Change from Baseline in Vital Signs

Planned relative
Treatment
N Visit
time
n
Mean SD
Median Min. Max.
----------------------------------------------------------------------------------------------------------Heart rate (beats/min) 3mcg
101 Day 1
10 mins
101 -1.7
5.76
-2.0
-19
12
1 hour
101 -2.0
7.44
-2.0
-27
16
2 hours
101 -3.6
6.86
-4.0
-24
13
4 hours
101 -2.4
8.43
-2.0
-26
22
95
93
93
93
93

0.3
-0.6
-1.5
-1.0
0.0

9.00
7.87
8.19
8.94
8.65

0.0
-1.0
-2.0
0.0
0.0

-23
-19
-26
-30
-28

24
26
22
17
20

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

91
86
86
86
86

1.3
-0.5
-1.3
-0.6
-0.5

10.65
8.68
8.36
9.26
8.57

0.0
-1.0
-1.0
-1.5
-1.0

-29
-29
-24
-26
-21

43
22
16
22
19

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

86
85
85
84
84

0.8
-0.5
-0.9
-2.0
-1.2

9.37
9.09
8.75
9.50
10.29

0.0
0.0
-1.0
-2.5
-1.0

-24
-28
-30
-28
-24

24
26
28
26
36

YM2008/00019/00
B2C109575

Note: Baseline is pre-dose at Day 1

CONFIDENTIAL

Pre-dose
10 mins
1 hour
2 hours
4 hours

619

Day 7

Protocol: B2C109575
Population: Intent-to-Treat

Page 15 of 18
Table 8.19
Summary of Change from Baseline in Vital Signs

Planned relative
Treatment
N Visit
time
n
Mean SD
Median Min. Max.
----------------------------------------------------------------------------------------------------------Heart rate (beats/min) 6.25mcg
101 Day 1
10 mins
101 -0.6
6.40
-1.0
-16
26
1 hour
101 -2.3
6.28
-2.0
-18
14
2 hours
101 -3.0
8.07
-2.0
-22
34
4 hours
101 -2.4
8.23
-2.0
-23
30
99
97
97
97
97

1.6
1.6
-0.8
-0.8
-0.9

9.90
9.58
9.97
9.40
9.40

2.0
1.0
-2.0
-2.0
-1.0

-25
-20
-20
-21
-20

29
34
35
22
30

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

95
93
93
93
93

2.1
1.4
-0.8
-0.8
-0.4

12.32
9.35
8.98
9.40
10.03

0.0
0.0
-2.0
-2.0
0.0

-20
-18
-20
-23
-23

45
27
21
23
32

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

91
91
91
91
91

1.5
-0.1
-1.6
-2.3
-3.0

11.25
10.29
10.90
10.65
9.95

0.0
0.0
-2.0
-3.0
-2.0

-26
-20
-27
-28
-31

29
31
29
34
26

YM2008/00019/00
B2C109575

Note: Baseline is pre-dose at Day 1

CONFIDENTIAL

Pre-dose
10 mins
1 hour
2 hours
4 hours

620

Day 7

Protocol: B2C109575
Population: Intent-to-Treat

Page 16 of 18
Table 8.19
Summary of Change from Baseline in Vital Signs

Planned relative
Treatment
N Visit
time
n
Mean SD
Median Min. Max.
----------------------------------------------------------------------------------------------------------Heart rate (beats/min) 12.5mcg
100 Day 1
10 mins
100 -2.1
7.02
-2.0
-28
16
1 hour
99 -3.8
7.39
-4.0
-34
14
2 hours
99 -4.4
7.95
-4.0
-38
12
4 hours
99 -3.6
8.26
-3.0
-26
12
97
96
95
95
93

-0.4
-1.0
-2.7
-2.5
-1.3

9.27
9.89
10.59
9.90
8.34

0.0
-2.0
-4.0
-3.0
-2.0

-24
-22
-25
-24
-22

26
31
36
25
23

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

91
91
91
91
91

1.2
0.8
-0.2
0.2
-1.1

9.80
9.99
11.46
9.55
8.12

0.0
0.0
0.0
0.0
-1.0

-23
-30
-31
-25
-22

24
25
45
27
17

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

89
88
88
88
88

-0.2
-1.3
-2.7
-3.6
-4.3

10.34
9.92
10.57
10.12
9.62

-1.0
-1.0
-4.0
-3.5
-3.5

-32
-30
-33
-34
-33

31
27
38
20
16

YM2008/00019/00
B2C109575

Note: Baseline is pre-dose at Day 1

CONFIDENTIAL

Pre-dose
10 mins
1 hour
2 hours
4 hours

621

Day 7

Protocol: B2C109575
Population: Intent-to-Treat

Page 17 of 18
Table 8.19
Summary of Change from Baseline in Vital Signs

Planned relative
Treatment
N Visit
time
n
Mean SD
Median Min. Max.
----------------------------------------------------------------------------------------------------------Heart rate (beats/min) 25mcg
101 Day 1
10 mins
101 -0.1
7.03
0.0
-20
20
1 hour
101 -1.9
6.84
-1.0
-20
15
2 hours
101 -3.5
7.18
-4.0
-26
15
4 hours
101 -2.5
7.88
-2.0
-26
31
97
95
96
96
96

1.8
1.0
-0.6
-1.4
-0.6

7.77
7.74
7.31
8.25
8.27

1.0
1.0
-0.5
-2.0
-2.0

-15
-17
-20
-31
-20

23
20
18
18
23

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

95
94
94
94
94

2.0
1.9
-0.0
0.6
0.3

8.98
8.54
8.59
8.59
9.42

2.0
1.0
0.0
0.0
1.0

-22
-21
-27
-18
-21

30
27
22
21
20

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

94
93
93
93
93

1.4
0.7
-0.8
-2.1
-2.8

8.36
8.97
9.27
9.21
8.96

2.0
1.0
-1.0
-2.0
-3.0

-20
-21
-22
-25
-25

26
28
25
25
19

YM2008/00019/00
B2C109575

Note: Baseline is pre-dose at Day 1

CONFIDENTIAL

Pre-dose
10 mins
1 hour
2 hours
4 hours

622

Day 7

Protocol: B2C109575
Population: Intent-to-Treat

Page 18 of 18
Table 8.19
Summary of Change from Baseline in Vital Signs

Planned relative
Treatment
N Visit
time
n
Mean SD
Median Min. Max.
----------------------------------------------------------------------------------------------------------Heart rate (beats/min) 50mcg
102 Day 1
10 mins
102 -0.5
6.10
0.0
-20
22
1 hour
102 -1.7
6.73
-1.0
-24
12
2 hours
102 -1.9
6.70
-2.0
-20
24
4 hours
102 -1.9
8.14
-0.5
-25
20
100
100
100
100
99

0.8
2.2
1.0
0.9
0.9

9.00
10.04
8.67
8.69
9.05

0.0
1.5
2.0
1.5
0.0

-22
-32
-19
-24
-23

26
32
23
24
25

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

98
97
97
97
97

2.0
3.6
3.1
2.2
1.0

10.12
10.44
10.14
10.06
9.62

2.0
2.0
3.0
2.0
3.0

-21
-21
-25
-23
-25

34
44
46
32
31

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

98
98
98
98
98

1.6
3.5
1.7
-0.2
-0.1

10.18
9.80
8.97
9.02
9.51

2.0
3.0
2.0
0.0
0.5

-20
-19
-20
-21
-20

38
37
31
26
20

YM2008/00019/00
B2C109575

Note: Baseline is pre-dose at Day 1

CONFIDENTIAL

Pre-dose
10 mins
1 hour
2 hours
4 hours

623

Day 7

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 8.20
Summary of Maximum Increase from Baseline in Systolic Blood Pressure (mmHg) (0-4hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 1
n
102
101
101
100
101
102
Mean
6.6
7.0
6.4
5.1
5.3
6.2
SD
10.76
10.08
8.61
8.56
9.08
8.97
Median
6.0
4.0
6.0
4.0
4.0
5.0
Min.
-31
-14
-13
-21
-25
-14
Max.
40
37
28
34
46
39
93
4.1
11.43
3.0
-26
38

93
6.0
10.48
5.0
-20
35

97
3.9
11.60
4.0
-35
35

96
5.3
10.34
4.0
-18
42

96
3.5
9.13
4.0
-30
30

100
5.9
10.26
5.0
-13
33

Day 14

n
Mean
SD
Median
Min.
Max.

90
5.2
12.21
6.0
-44
36

86
3.9
9.11
2.5
-16
30

93
3.8
11.75
1.0
-29
45

91
4.4
11.14
3.0
-35
31

94
3.9
10.97
3.0
-26
29

98
6.4
11.19
5.0
-24
41

Day 28

n
Mean
SD
Median
Min.
Max.

87
4.8
13.60
5.0
-27
49

85
5.4
10.58
6.0
-15
35

91
3.1
11.16
0.0
-27
31

88
4.4
11.10
4.0
-28
40

93
2.9
10.74
5.0
-25
28

98
5.1
10.65
5.5
-22
33

YM2008/00019/00
B2C109575

n
Mean
SD
Median
Min.
Max.

CONFIDENTIAL

624

Day 7

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 8.21
Summary of Maximum Increase from Pre-Dose in Systolic Blood Pressure (mmHg) (0-4hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 7
n
93
93
97
96
96
100
Mean
5.4
6.5
6.5
7.8
4.6
7.9
SD
7.70
9.75
9.08
8.69
7.41
8.44
Median
5.0
7.0
5.0
7.0
4.0
8.0
Min.
-26
-22
-12
-12
-19
-6
Max.
28
36
44
33
20
41
n
Mean
SD
Median
Min.
Max.

90
6.6
9.08
6.0
-20
26

86
5.4
7.65
4.5
-10
28

93
7.0
10.12
6.0
-22
42

91
6.0
6.98
6.0
-8
32

94
7.1
8.64
5.5
-9
36

98
7.0
8.60
5.0
-10
48

Day 28

n
Mean
SD
Median
Min.
Max.

87
6.1
7.42
6.0
-16
27

85
7.0
8.56
5.0
-14
30

91
5.3
9.52
6.0
-12
43

88
4.7
8.93
4.0
-20
45

93
4.2
7.71
2.0
-14
28

98
4.9
9.00
4.0
-17
26

CONFIDENTIAL

625

Day 14

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 4

Table 8.22
Statistical Analysis of Maximum Increase from Baseline in Systolic Blood Pressure (mmHg) (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
LS Mean Change (SE)
6.5 (0.86)
6.5 (0.87)
6.0 (0.86)
6.2 (0.87)
5.5 (0.86)
6.0 (0.86)
Column vs Placebo
Difference
95% C.I.
p-value

0.0
(-2.4, 2.4)
0.981

-0.5
(-2.9, 1.9)
0.667

-0.3
(-2.7, 2.1)
0.823

-1.0
(-3.4, 1.4)
0.430

-0.5
(-2.9, 1.9)
0.665

CONFIDENTIAL

626

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 4

Table 8.22
Statistical Analysis of Maximum Increase from Baseline in Systolic Blood Pressure (mmHg) (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
93
93
97
96
96
100
LS Mean Change (SE) 3.9 (0.97)
5.2 (0.97)
3.4 (0.95)
6.5 (0.95)
4.0 (0.95)
5.8 (0.94)
Column vs Placebo
Difference
95% C.I.
p-value

1.3
(-1.4, 4.0)
0.346

-0.5
(-3.1, 2.2)
0.720

2.7
(0.0, 5.3)
0.052

0.1
(-2.5, 2.8)
0.930

1.9
(-0.8, 4.6)
0.162

CONFIDENTIAL

627

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 4

Table 8.22
Statistical Analysis of Maximum Increase from Baseline in Systolic Blood Pressure (mmHg) (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
90
86
93
91
94
98
LS Mean Change (SE) 4.7 (1.03)
3.2 (1.06)
3.3 (1.01)
5.6 (1.02)
4.5 (1.01)
6.2 (0.99)
Column vs Placebo
Difference
95% C.I.
p-value

-1.5
(-4.4, 1.5)
0.328

-1.3
(-4.2, 1.5)
0.353

0.9
(-1.9, 3.8)
0.521

-0.2
(-3.1, 2.6)
0.879

1.5
(-1.4, 4.3)
0.305

CONFIDENTIAL

628

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 4

Table 8.22
Statistical Analysis of Maximum Increase from Baseline in Systolic Blood Pressure (mmHg) (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
87
85
91
88
93
98
LS Mean Change (SE) 4.5 (1.02)
4.3 (1.03)
2.9 (0.99)
5.6 (1.01)
3.6 (0.98)
4.8 (0.96)
Column vs Placebo
Difference
95% C.I.
p-value

-0.2
(-3.0, 2.7)
0.897

-1.5
(-4.3, 1.3)
0.285

1.1
(-1.7, 3.9)
0.433

-0.9
(-3.7, 1.9)
0.528

0.3
(-2.5, 3.1)
0.833

CONFIDENTIAL

629

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 8.23
Summary of Maximum Decrease from Baseline in Diastolic Blood Pressure (mmHg) (0-4hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 1
n
102
101
101
100
101
102
Mean
-3.0
-3.5
-4.0
-4.2
-2.5
-4.5
SD
6.88
6.60
7.23
6.22
7.01
6.88
Median
-3.0
-2.0
-4.0
-4.0
-2.0
-4.0
Min.
-28
-22
-25
-27
-30
-23
Max.
20
12
18
10
26
10
93
-5.0
7.87
-4.0
-28
13

93
-4.1
7.42
-4.0
-21
14

97
-5.5
8.21
-4.0
-28
16

96
-5.1
7.78
-5.5
-24
24

96
-5.1
7.35
-4.0
-32
14

100
-4.7
7.92
-4.0
-24
12

Day 14

n
Mean
SD
Median
Min.
Max.

90
-4.7
9.00
-4.5
-32
20

86
-4.3
7.78
-4.0
-27
14

93
-6.6
8.55
-6.0
-28
11

91
-5.6
8.95
-4.0
-33
15

94
-5.2
9.13
-4.0
-30
21

98
-4.8
7.56
-4.5
-31
11

Day 28

n
Mean
SD
Median
Min.
Max.

87
-3.3
7.99
-3.0
-20
24

85
-3.6
8.22
-3.0
-28
14

91
-5.6
8.09
-5.0
-25
16

88
-5.3
8.04
-5.0
-26
16

93
-5.3
8.77
-6.0
-30
16

98
-4.3
8.57
-3.5
-30
11

YM2008/00019/00
B2C109575

n
Mean
SD
Median
Min.
Max.

CONFIDENTIAL

630

Day 7

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 8.24
Summary of Maximum Decrease from Pre-Dose in Diastolic Blood Pressure (mmHg) (0-4hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 7
n
93
93
97
96
96
100
Mean
-4.5
-5.0
-4.2
-3.9
-4.0
-4.5
SD
6.71
6.32
6.00
5.79
6.04
7.41
Median
-4.0
-4.0
-4.0
-3.0
-3.0
-3.5
Min.
-26
-21
-22
-27
-20
-25
Max.
12
20
8
16
10
12
n
Mean
SD
Median
Min.
Max.

90
-4.5
7.30
-4.0
-37
26

86
-4.5
5.78
-4.0
-19
9

93
-4.1
6.75
-3.0
-34
12

91
-4.0
5.75
-3.0
-17
10

94
-4.5
6.74
-4.0
-22
18

98
-4.7
6.72
-4.0
-29
10

Day 28

n
Mean
SD
Median
Min.
Max.

87
-3.7
6.00
-4.0
-22
26

85
-3.5
5.56
-4.0
-20
10

91
-5.4
5.54
-5.0
-24
6

88
-4.4
5.30
-4.0
-20
7

93
-4.8
6.09
-4.0
-26
8

98
-5.0
7.11
-4.0
-28
6

CONFIDENTIAL

631

Day 14

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 4

Table 8.25
Statistical Analysis of Maximum Decrease from Baseline in Diastolic Blood Pressure (mmHg) (0-4hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
LS Mean Change (SE) -2.5 (0.61) -4.0 (0.61)
-4.1 (0.61)
-3.6 (0.61)
-2.3 (0.61)
-5.1 (0.61)
Column vs Placebo
Difference
95% C.I.
p-value

-1.5
(-3.2, 0.2)
0.088

-1.5
(-3.2, 0.2)
0.078

-1.1
(-2.8, 0.6)
0.211

0.2
(-1.5, 1.9)
0.827

-2.5
(-4.2, -0.8)
0.004

CONFIDENTIAL

632

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 4

Table 8.25
Statistical Analysis of Maximum Decrease from Baseline in Diastolic Blood Pressure (mmHg) (0-4hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
93
93
97
96
96
100
LS Mean Change (SE) -4.6 (0.69)
-4.6 (0.69)
-5.5 (0.67)
-4.4 (0.67)
-4.8 (0.67)
-5.6 (0.66)
Column vs Placebo
Difference
95% C.I.
p-value

0.0
(-1.9, 1.9)
0.986

-0.9
(-2.8, 0.9)
0.329

0.2
(-1.7, 2.1)
0.835

-0.2
(-2.1, 1.6)
0.807

-1.0
(-2.9, 0.9)
0.300

CONFIDENTIAL

633

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 4

Table 8.25
Statistical Analysis of Maximum Decrease from Baseline in Diastolic Blood Pressure (mmHg) (0-4hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
90
86
93
91
94
98
LS Mean Change (SE) -4.3 (0.75)
-5.0 (0.77)
-6.4 (0.73)
-5.0 (0.74)
-4.9 (0.73)
-5.7 (0.72)
Column vs Placebo
Difference
95% C.I.
p-value

-0.7
(-2.8, 1.5)
0.540

-2.1
(-4.1, 0.0)
0.049

-0.7
(-2.8, 1.4)
0.516

-0.5
(-2.6, 1.5)
0.600

-1.4
(-3.4, 0.7)
0.187

CONFIDENTIAL

634

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 4

Table 8.25
Statistical Analysis of Maximum Decrease from Baseline in Diastolic Blood Pressure (mmHg) (0-4hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
87
85
91
88
93
98
LS Mean Change (SE) -3.1 (0.77)
-4.2 (0.78)
-5.2 (0.75)
-4.8 (0.77)
-5.2 (0.74)
-4.9 (0.73)
Column vs Placebo
Difference
95% C.I.
p-value

-1.1
(-3.2, 1.1)
0.338

-2.0
(-4.2, 0.1)
0.058

-1.7
(-3.8, 0.4)
0.120

-2.0
(-4.2, 0.1)
0.057

-1.8
(-3.9, 0.3)
0.095

CONFIDENTIAL

635

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 8.26
Summary of Maximum Increase from Baseline in Pulse Rate (beats/min) (0-4hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 1
n
102
101
101
100
101
102
Mean
3.2
2.0
2.0
1.1
2.9
3.0
SD
7.45
7.01
6.81
7.11
6.98
6.38
Median
4.0
2.0
1.0
2.0
2.0
2.5
Min.
-15
-19
-12
-26
-16
-15
Max.
29
22
34
16
31
24
93
4.7
10.02
4.0
-20
40

93
4.4
8.34
4.0
-19
26

97
4.7
9.58
4.0
-18
35

96
3.4
9.59
2.0
-20
36

96
3.8
7.60
4.0
-15
23

100
6.4
9.05
6.0
-13
32

Day 14

n
Mean
SD
Median
Min.
Max.

90
5.1
10.74
4.0
-20
44

86
4.0
9.01
4.0
-18
22

93
4.4
9.56
4.0
-18
32

91
5.5
10.09
4.0
-22
45

94
5.3
8.32
5.5
-18
27

98
7.1
10.40
6.0
-21
46

Day 28

n
Mean
SD
Median
Min.
Max.

87
2.8
10.09
3.0
-21
30

85
3.4
9.14
4.0
-20
36

91
3.4
10.74
3.0
-19
34

88
2.3
9.85
1.5
-22
38

93
3.7
9.07
4.0
-20
28

98
5.9
9.30
4.5
-13
37

YM2008/00019/00
B2C109575

n
Mean
SD
Median
Min.
Max.

CONFIDENTIAL

636

Day 7

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 8.27
Summary of Maximum Increase from Pre-Dose in Pulse Rate (beats/min) (0-4hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 7
n
93
93
97
96
96
100
Mean
3.3
4.3
3.2
3.8
1.9
5.7
SD
7.48
6.54
6.46
7.23
6.05
7.28
Median
2.0
4.0
2.0
2.5
2.0
4.0
Min.
-12
-12
-12
-15
-14
-12
Max.
30
33
24
24
16
30
n
Mean
SD
Median
Min.
Max.

90
3.0
8.92
2.0
-33
40

86
3.0
6.80
2.0
-11
23

93
2.3
8.65
2.0
-23
31

91
4.2
6.15
4.0
-8
33

94
3.4
6.23
3.5
-12
19

98
5.1
6.37
4.5
-8
20

Day 28

n
Mean
SD
Median
Min.
Max.

87
1.6
6.54
1.0
-20
20

85
2.6
5.45
2.0
-15
16

91
1.9
6.68
2.0
-15
18

88
2.6
5.21
2.0
-11
18

93
2.5
6.40
2.0
-14
27

98
4.2
6.24
4.0
-14
30

CONFIDENTIAL

637

Day 14

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 4

Table 8.28
Statistical Analysis of Maximum Increase from Baseline in Pulse Rate (beats/min) (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
LS Mean Change (SE)
3.2 (0.64)
1.9 (0.64)
1.6 (0.64)
1.3 (0.64)
3.1 (0.64)
3.1 (0.64)
Column vs Placebo
Difference
95% C.I.
p-value

-1.4
(-3.1, 0.4)
0.134

-1.7
(-3.4, 0.1)
0.068

-1.9
(-3.7, -0.1)
0.035

-0.2
(-1.9, 1.6)
0.858

-0.1
(-1.9, 1.6)
0.871

CONFIDENTIAL

638

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 4

Table 8.28
Statistical Analysis of Maximum Increase from Baseline in Pulse Rate (beats/min) (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
93
93
97
96
96
100
LS Mean Change (SE) 4.7 (0.80)
4.1 (0.80)
4.1 (0.78)
4.0 (0.78)
4.1 (0.78)
6.3 (0.77)
Column vs Placebo
Difference
95% C.I.
p-value

-0.6
(-2.8, 1.6)
0.590

-0.6
(-2.8, 1.5)
0.561

-0.7
(-2.9, 1.5)
0.533

-0.6
(-2.8, 1.6)
0.592

1.6
(-0.6, 3.8)
0.157

CONFIDENTIAL

639

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 4

Table 8.28
Statistical Analysis of Maximum Increase from Baseline in Pulse Rate (beats/min) (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
90
86
93
91
94
98
LS Mean Change (SE) 5.2 (0.87)
3.4 (0.89)
3.7 (0.85)
6.1 (0.86)
5.8 (0.85)
7.2 (0.83)
Column vs Placebo
Difference
95% C.I.
p-value

-1.8
(-4.2, 0.7)
0.156

-1.5
(-3.9, 0.9)
0.212

0.9
(-1.5, 3.3)
0.479

0.6
(-1.8, 2.9)
0.642

2.0
(-0.4, 4.3)
0.103

CONFIDENTIAL

640

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 4

Table 8.28
Statistical Analysis of Maximum Increase from Baseline in Pulse Rate (beats/min) (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
87
85
91
88
93
98
LS Mean Change (SE) 3.0 (0.88)
3.1 (0.89)
2.7 (0.86)
2.8 (0.88)
4.0 (0.85)
5.7 (0.83)
Column vs Placebo
Difference
95% C.I.
p-value

0.1
(-2.3, 2.6)
0.910

-0.3
(-2.7, 2.1)
0.801

-0.2
(-2.6, 2.3)
0.904

1.0
(-1.4, 3.4)
0.406

2.7
(0.3, 5.1)
0.026

CONFIDENTIAL

641

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 8.29
Summary of Weighted Mean Change from Baseline in Systolic Blood Pressure (mmHg) (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 1
n
102
99
101
99
99
102
Mean
0.99
1.49
0.75
-0.35
0.16
0.69
SD
10.132
8.686
7.493
7.646
7.752
7.794
Median
1.79
0.46
0.41
0.00
0.34
0.00
Min.
-32.5
-17.3
-16.5
-23.8
-31.3
-19.2
Max.
29.2
24.8
19.0
21.7
27.0
23.8
92
-0.76
11.526
-0.32
-31.1
31.5

92
0.23
10.267
-0.39
-20.1
30.4

97
-1.92
10.634
-1.92
-37.4
26.5

93
-0.06
9.288
0.00
-22.1
24.9

96
-1.04
8.680
-0.44
-29.8
22.2

99
0.16
9.329
-0.37
-23.7
22.9

Day 14

n
Mean
SD
Median
Min.
Max.

89
-0.65
11.574
0.00
-44.6
26.8

86
-1.20
9.271
-2.64
-25.4
25.4

93
-2.16
10.118
-3.02
-33.0
21.4

91
-0.49
11.019
-0.15
-39.7
23.7

94
-1.62
9.515
-0.40
-31.9
17.8

96
0.62
10.157
1.42
-26.8
27.7

Day 28

n
Mean
SD
Median
Min.
Max.

87
-0.42
13.123
0.50
-30.1
40.4

84
-0.66
9.794
0.00
-22.6
25.4

91
-2.53
10.985
-3.26
-43.5
23.1

88
-0.70
10.034
-0.78
-30.7
32.1

93
-1.90
9.908
-0.08
-27.5
20.1

97
-0.27
10.499
0.63
-28.9
24.7

YM2008/00019/00
B2C109575

n
Mean
SD
Median
Min.
Max.

CONFIDENTIAL

642

Day 7

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 8.30
Summary of Weighted Mean Change from Pre-Dose in Systolic Blood Pressure (mmHg) (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 7
n
92
92
97
93
96
99
Mean
0.45
0.77
0.65
2.32
0.14
2.16
SD
7.995
9.094
7.441
7.254
6.761
7.009
Median
1.09
1.18
-0.30
1.30
0.00
2.09
Min.
-28.8
-27.3
-15.1
-13.8
-21.4
-15.0
Max.
22.9
28.3
21.7
26.3
14.6
27.7
n
Mean
SD
Median
Min.
Max.

89
0.81
8.207
1.68
-23.9
17.1

86
0.29
7.062
0.35
-14.4
19.6

93
1.06
8.968
1.13
-28.9
27.8

91
1.15
6.304
1.29
-13.5
17.8

94
1.57
7.708
1.11
-15.0
28.1

96
1.39
7.557
0.00
-12.2
33.3

Day 28

n
Mean
SD
Median
Min.
Max.

87
0.90
7.139
0.95
-21.5
23.5

84
1.11
8.229
0.12
-21.9
22.6

91
-0.30
8.223
0.26
-22.3
17.6

88
-0.35
7.723
-0.06
-23.5
25.8

93
-0.61
7.789
-1.08
-25.6
23.9

97
-0.62
8.707
-0.72
-23.9
18.7

CONFIDENTIAL

643

Day 14

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 4

Table 8.31
Statistical Analysis of Weighted Mean Change from Baseline in Systolic Blood Pressure
(mmHg) (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
102
99
101
99
99
102
LS Mean Change (SE)
1.0 (0.74)
1.0 (0.75)
0.4 (0.74)
0.7 (0.75)
0.4 (0.75)
0.3 (0.74)
Column vs Placebo
Difference
95% C.I.
p-value

0.0
(-2.1, 2.1)
0.997

-0.6
(-2.6, 1.5)
0.582

-0.3
(-2.4, 1.8)
0.785

-0.6
(-2.7, 1.5)
0.573

-0.7
(-2.7, 1.4)
0.526

CONFIDENTIAL

644

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 4

Table 8.31
Statistical Analysis of Weighted Mean Change from Baseline in Systolic Blood Pressure
(mmHg) (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
92
92
97
93
96
99
LS Mean Change (SE) -0.8 (0.92)
-0.5 (0.92)
-2.4 (0.89)
1.0 (0.91)
-0.6 (0.89)
-0.1 (0.88)
Column vs Placebo
Difference
95% C.I.
p-value

0.4
(-2.2, 2.9)
0.788

-1.6
(-4.1, 0.9)
0.218

1.9
(-0.7, 4.4)
0.148

0.3
(-2.2, 2.8)
0.837

0.7
(-1.8, 3.2)
0.577

CONFIDENTIAL

645

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 4

Table 8.31
Statistical Analysis of Weighted Mean Change from Baseline in Systolic Blood Pressure
(mmHg) (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
89
86
93
91
94
96
LS Mean Change (SE) -1.1 (0.95)
-1.8 (0.97)
-2.5 (0.93)
0.7 (0.94)
-1.1 (0.92)
0.3 (0.91)
Column vs Placebo
Difference
95% C.I.
p-value

-0.7
(-3.4, 2.0)
0.601

-1.5
(-4.1, 1.1)
0.269

1.7
(-0.9, 4.3)
0.200

-0.1
(-2.7, 2.5)
0.947

1.3
(-1.3, 3.9)
0.319

CONFIDENTIAL

646

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 4

Table 8.31
Statistical Analysis of Weighted Mean Change from Baseline in Systolic Blood Pressure
(mmHg) (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
87
84
91
88
93
97
LS Mean Change (SE) -0.6 (0.97)
-1.5 (0.99)
-2.6 (0.95)
0.4 (0.96)
-1.5 (0.94)
-0.7 (0.92)
Column vs Placebo
Difference
95% C.I.
p-value

-0.9
(-3.6, 1.8)
0.524

-2.0
(-4.7, 0.6)
0.134

0.9
(-1.8, 3.6)
0.491

-0.9
(-3.6, 1.7)
0.502

-0.1
(-2.8, 2.5)
0.913

CONFIDENTIAL

647

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 8.32
Summary of Weighted Mean Change from Baseline in Diastolic Blood Pressure (mmHg) (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 1
n
102
99
101
99
99
102
Mean
1.49
1.37
0.49
0.13
1.39
0.74
SD
6.324
6.480
6.476
5.742
6.444
6.017
Median
1.40
1.79
0.85
0.29
0.81
0.92
Min.
-23.2
-13.0
-17.4
-17.3
-23.2
-13.0
Max.
22.0
19.7
19.9
16.4
27.9
14.4
92
-0.67
7.464
-0.66
-26.5
18.4

92
0.46
6.722
-0.07
-14.2
15.3

97
-0.98
7.885
-0.39
-21.8
18.7

93
-0.87
6.468
-1.13
-15.5
16.5

96
-0.72
7.325
-0.04
-29.3
18.0

99
0.51
7.249
0.50
-19.1
18.1

Day 14

n
Mean
SD
Median
Min.
Max.

89
-0.09
8.692
-0.08
-24.0
23.4

86
-0.56
7.530
-0.19
-21.8
15.5

93
-1.50
8.662
-1.49
-22.8
18.3

91
-1.01
8.247
0.00
-27.4
17.5

94
-1.03
8.864
-0.18
-27.0
23.6

96
-0.22
7.107
-1.09
-15.8
17.8

Day 28

n
Mean
SD
Median
Min.
Max.

87
0.61
8.411
0.01
-18.3
27.0

84
0.87
7.861
0.78
-18.0
17.6

91
-0.73
7.453
-0.65
-16.2
19.6

88
-0.74
7.866
-0.04
-21.3
22.5

93
-0.59
8.529
-0.70
-26.0
21.2

97
0.66
7.675
0.43
-25.8
15.2

YM2008/00019/00
B2C109575

n
Mean
SD
Median
Min.
Max.

CONFIDENTIAL

648

Day 7

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 8.33
Summary of Weighted Mean Change from Pre-Dose in Diastolic Blood Pressure (mmHg) (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 7
n
92
92
97
93
96
99
Mean
-0.28
-0.25
0.32
0.54
0.41
0.77
SD
5.652
5.663
5.665
5.076
5.598
5.954
Median
0.07
-0.17
0.00
0.14
0.00
0.53
Min.
-18.5
-17.1
-14.2
-11.8
-13.8
-14.9
Max.
15.4
19.7
13.9
20.5
17.5
18.3
n
Mean
SD
Median
Min.
Max.

89
0.18
7.001
0.64
-35.3
27.9

86
-0.77
5.709
-0.58
-12.6
15.4

93
0.98
6.463
1.17
-23.3
17.6

91
0.66
5.382
0.66
-11.8
19.4

94
-0.29
6.384
0.10
-21.5
22.5

96
-0.14
5.523
-0.01
-25.6
16.4

Day 28

n
Mean
SD
Median
Min.
Max.

87
0.19
5.552
0.16
-11.1
28.1

84
1.02
5.089
1.13
-11.1
17.3

91
-0.50
4.900
0.00
-13.2
9.8

88
0.16
4.900
0.00
-14.8
12.4

93
-0.08
5.097
0.00
-12.1
13.6

97
-0.17
6.602
0.00
-17.2
22.8

CONFIDENTIAL

649

Day 14

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 4

Table 8.34
Statistical Analysis of Weighted Mean Change from Baseline in Diastolic Blood Pressure
(mmHg) (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
102
99
101
99
99
102
LS Mean Change (SE)
1.9 (0.54)
0.8 (0.55)
0.4 (0.54)
0.7 (0.55)
1.5 (0.55)
0.2 (0.54)
Column vs Placebo
Difference
95% C.I.
p-value

-1.1
(-2.7, 0.4)
0.148

-1.5
(-3.0, 0.0)
0.052

-1.2
(-2.7, 0.3)
0.111

-0.4
(-1.9, 1.1)
0.629

-1.7
(-3.2, -0.2)
0.030

CONFIDENTIAL

650

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 4

Table 8.34
Statistical Analysis of Weighted Mean Change from Baseline in Diastolic Blood Pressure
(mmHg) (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
92
92
97
93
96
99
LS Mean Change (SE) -0.3 (0.64)
0.0 (0.64)
-1.0 (0.62)
-0.2 (0.63)
-0.5 (0.62)
-0.1 (0.61)
Column vs Placebo
Difference
95% C.I.
p-value

0.3
(-1.4, 2.1)
0.710

-0.7
(-2.4, 1.0)
0.437

0.1
(-1.6, 1.9)
0.894

-0.1
(-1.9, 1.6)
0.879

0.2
(-1.5, 1.9)
0.819

CONFIDENTIAL

651

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 4

Table 8.34
Statistical Analysis of Weighted Mean Change from Baseline in Diastolic Blood Pressure
(mmHg) (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
89
86
93
91
94
96
LS Mean Change (SE) 0.1 (0.73)
-1.1 (0.74)
-1.3 (0.71)
-0.4 (0.72)
-0.7 (0.71)
-1.0 (0.70)
Column vs Placebo
Difference
95% C.I.
p-value

-1.3
(-3.3, 0.8)
0.230

-1.4
(-3.4, 0.6)
0.177

-0.5
(-2.5, 1.5)
0.632

-0.8
(-2.8, 1.2)
0.406

-1.1
(-3.1, 0.9)
0.277

CONFIDENTIAL

652

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 4

Table 8.34
Statistical Analysis of Weighted Mean Change from Baseline in Diastolic Blood Pressure
(mmHg) (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
87
84
91
88
93
97
LS Mean Change (SE) 0.7 (0.73)
0.2 (0.74)
-0.3 (0.71)
-0.3 (0.72)
-0.4 (0.70)
0.1 (0.69)
Column vs Placebo
Difference
95% C.I.
p-value

-0.5
(-2.6, 1.5)
0.613

-1.0
(-3.0, 1.0)
0.312

-1.0
(-3.0, 1.0)
0.332

-1.1
(-3.1, 0.9)
0.280

-0.6
(-2.6, 1.4)
0.550

CONFIDENTIAL

653

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 8.35
Summary of Weighted Mean Change from Baseline in Pulse Rate (beats/min) (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 1
n
102
99
101
99
99
102
Mean
-2.20
-2.59
-2.36
-3.74
-2.37
-1.64
SD
7.064
6.355
6.517
6.699
6.051
5.850
Median
-1.38
-2.12
-1.71
-4.00
-2.01
-1.02
Min.
-21.9
-24.1
-16.8
-32.0
-23.2
-18.5
Max.
16.3
12.2
24.9
10.5
16.7
15.2
92
-0.03
9.330
-0.10
-24.8
34.5

92
-0.89
7.372
-0.13
-24.8
14.1

97
-0.52
8.686
-1.30
-19.1
26.3

93
-2.01
8.670
-2.34
-21.3
25.5

96
-0.67
7.098
-0.52
-23.3
17.3

99
1.12
7.797
1.26
-16.4
19.0

Day 14

n
Mean
SD
Median
Min.
Max.

89
0.32
9.615
-0.14
-22.5
33.7

86
-0.68
7.929
-1.10
-21.8
14.2

93
-0.37
8.659
-0.66
-20.3
19.0

91
-0.14
8.493
-0.31
-25.7
26.9

94
0.57
7.863
0.51
-21.2
17.4

96
2.34
9.247
2.52
-22.4
32.0

Day 28

n
Mean
SD
Median
Min.
Max.

87
-1.93
9.028
-1.01
-27.6
25.0

84
-1.32
8.678
-1.00
-23.3
26.3

91
-1.98
9.643
-1.82
-27.2
29.6

88
-3.22
9.066
-3.51
-30.2
18.7

93
-1.56
8.070
-1.16
-20.6
14.3

97
0.76
8.557
1.04
-17.8
25.8

YM2008/00019/00
B2C109575

n
Mean
SD
Median
Min.
Max.

CONFIDENTIAL

654

Day 7

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 8.36
Summary of Weighted Mean Change from Pre-Dose in Pulse Rate (beats/min) (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 7
n
92
92
97
93
96
99
Mean
-1.32
-0.77
-2.05
-1.43
-2.54
0.34
SD
6.813
6.571
6.234
6.141
5.809
6.436
Median
-1.02
-0.48
-1.19
-2.78
-1.08
0.75
Min.
-16.8
-22.4
-21.2
-13.9
-19.0
-17.8
Max.
21.5
30.3
11.9
13.1
10.3
17.5
n
Mean
SD
Median
Min.
Max.

89
-1.65
8.133
-0.73
-35.1
29.8

86
-1.67
6.656
-1.71
-17.5
16.0

93
-2.51
8.524
-1.38
-35.5
18.0

91
-1.38
5.963
-1.04
-17.4
14.9

94
-1.41
5.708
-1.76
-17.3
9.5

96
0.29
5.850
0.63
-13.5
16.1

Day 28

n
Mean
SD
Median
Min.
Max.

87
-3.12
6.373
-2.62
-31.2
11.1

84
-2.18
5.152
-1.49
-21.1
12.5

91
-3.51
6.674
-3.07
-24.7
10.4

88
-2.90
5.372
-2.41
-19.8
9.0

93
-2.78
6.104
-2.55
-22.9
14.5

97
-0.86
6.683
-0.17
-20.4
24.3

CONFIDENTIAL

655

Day 14

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 4

Table 8.37
Statistical Analysis of Weighted Mean Change from Baseline in Pulse Rate (beats/min) (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
102
99
101
99
99
102
LS Mean Change (SE) -2.0 (0.57) -2.8 (0.58)
-2.8 (0.57)
-3.4 (0.58)
-2.3 (0.58)
-1.6 (0.57)
Column vs Placebo
Difference
95% C.I.
p-value

-0.8
(-2.4, 0.8)
0.315

-0.8
(-2.4, 0.8)
0.343

-1.4
(-3.0, 0.2)
0.093

-0.3
(-1.9, 1.3)
0.731

0.4
(-1.2, 2.0)
0.615

CONFIDENTIAL

656

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 4

Table 8.37
Statistical Analysis of Weighted Mean Change from Baseline in Pulse Rate (beats/min) (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
92
92
97
93
96
99
LS Mean Change (SE) 0.1 (0.71)
-1.1 (0.71)
-1.0 (0.69)
-1.5 (0.71)
-0.4 (0.70)
1.0 (0.69)
Column vs Placebo
Difference
95% C.I.
p-value

-1.2
(-3.2, 0.8)
0.234

-1.1
(-3.1, 0.8)
0.261

-1.6
(-3.6, 0.4)
0.120

-0.5
(-2.5, 1.4)
0.600

0.9
(-1.1, 2.8)
0.380

CONFIDENTIAL

657

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 4

Table 8.37
Statistical Analysis of Weighted Mean Change from Baseline in Pulse Rate (beats/min) (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
89
86
93
91
94
96
LS Mean Change (SE) 0.6 (0.76)
-1.2 (0.78)
-1.0 (0.74)
0.4 (0.75)
0.9 (0.74)
2.4 (0.73)
Column vs Placebo
Difference
95% C.I.
p-value

-1.8
(-3.9, 0.4)
0.104

-1.5
(-3.6, 0.5)
0.147

-0.1
(-2.2, 2.0)
0.897

0.4
(-1.7, 2.5)
0.717

1.8
(-0.3, 3.9)
0.090

CONFIDENTIAL

658

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 4

Table 8.37
Statistical Analysis of Weighted Mean Change from Baseline in Pulse Rate (beats/min) (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
87
84
91
88
93
97
LS Mean Change (SE) -1.7 (0.79)
-1.6 (0.80)
-2.6 (0.77)
-2.6 (0.78)
-1.2 (0.76)
0.5 (0.74)
Column vs Placebo
Difference
95% C.I.
p-value

0.1
(-2.1, 2.3)
0.929

-0.9
(-3.1, 1.2)
0.404

-1.0
(-3.1, 1.2)
0.389

0.4
(-1.7, 2.6)
0.696

2.2
(0.0, 4.3)
0.047

CONFIDENTIAL

659

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 36
Table 8.38
Summary of ECG Values

Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------Heart Rate (bpm)
Placebo
102 Day 1
Pre-dose
102
69.8 10.87
70.0
42
105
10 mins
102
65.6 10.84
64.0
30
92
1 hour
101
64.7 10.75
65.0
32
94
2 hours
101
65.0 11.45
63.0
34
108
4 hours
101
67.0 10.95
69.0
35
98
Pre-dose
10 mins
1 hour
2 hours
4 hours

95
92
93
93
93

70.3
68.0
67.4
68.5
69.5

10.32
10.50
10.04
10.40
9.71

70.0
67.0
67.0
68.0
68.0

49
47
47
48
50

93
93
91
92
101

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

92
91
90
90
88

69.7
68.1
65.7
68.7
69.9

11.13
10.26
10.53
11.14
10.17

68.0
67.0
65.0
69.0
69.5

48
48
46
47
48

94
90
96
92
94

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

89
85
87
87
86

70.2
69.3
66.8
64.7
66.8

10.95
10.46
10.23
9.54
10.29

68.0
68.0
65.0
63.0
67.5

52
51
48
45
48

100
97
95
95
93

CONFIDENTIAL

660

Day 7

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 36
Table 8.38
Summary of ECG Values

Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------Heart Rate (bpm)
3mcg
101 Day 1
Pre-dose
101
70.4 11.62
69.0
43
101
10 mins
97
67.1 11.05
66.0
43
98
1 hour
101
66.4 11.33
65.0
40
92
2 hours
101
64.3 10.15
63.0
40
90
4 hours
101
65.3 11.07
64.0
41
101
Pre-dose
10 mins
1 hour
2 hours
4 hours

98
91
93
93
93

69.9
68.5
67.4
67.3
68.5

10.41
10.21
10.69
9.89
9.04

70.0
68.0
67.0
67.0
67.0

46
48
45
44
46

96
101
94
94
96

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

92
85
86
86
86

71.6
69.4
66.9
68.3
68.2

12.04
10.13
9.96
9.43
9.42

72.0
70.0
67.0
68.0
67.0

43
46
44
42
49

112
90
92
91
91

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

87
83
84
84
84

68.8
68.0
65.8
64.2
65.4

10.25
10.17
9.65
9.01
10.13

69.0
68.0
66.0
65.5
65.0

44
45
44
41
44

89
91
88
85
93

CONFIDENTIAL

661

Day 7

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 36
Table 8.38
Summary of ECG Values

Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------Heart Rate (bpm)
6.25mcg
101 Day 1
Pre-dose
101
68.8
9.91
68.0
47
94
10 mins
100
66.0
9.17
66.0
46
92
1 hour
100
65.1 10.03
65.5
47
90
2 hours
101
63.0
9.66
62.0
46
91
4 hours
101
64.7 10.79
63.0
44
92
Pre-dose
10 mins
1 hour
2 hours
4 hours

99
95
96
97
97

70.3
70.1
66.9
68.1
67.5

10.87
10.53
10.50
10.14
9.58

69.0
69.0
67.0
68.0
67.0

46
50
44
48
44

95
92
91
96
93

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

95
93
93
93
92

70.6
70.7
67.5
67.8
68.5

10.68
10.61
9.87
10.50
10.82

70.0
70.0
66.0
67.0
67.0

47
49
49
48
48

99
94
91
94
98

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

91
90
91
91
90

68.7
68.1
65.6
64.2
63.9

11.55
10.29
9.83
10.14
10.69

67.0
67.0
64.0
63.0
63.0

51
47
50
46
41

100
110
94
95
94

CONFIDENTIAL

662

Day 7

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 36
Table 8.38
Summary of ECG Values

Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------Heart Rate (bpm)
12.5mcg
100 Day 1
Pre-dose
100
70.0
9.68
70.0
44
95
10 mins
99
67.2
9.65
66.0
48
90
1 hour
98
65.1
8.38
65.5
44
82
2 hours
98
64.2
8.59
64.5
44
87
4 hours
99
66.6
9.57
66.0
44
94
Pre-dose
10 mins
1 hour
2 hours
4 hours

97
96
95
95
94

69.8
70.4
67.4
67.7
68.1

9.05
9.33
9.43
9.73
9.41

68.0
70.0
67.0
67.0
68.0

49
50
48
46
47

95
96
90
93
103

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

92
91
91
91
91

70.0
70.9
68.5
69.4
68.0

10.72
10.73
10.15
9.79
9.03

68.0
71.0
67.0
67.0
67.0

49
45
46
48
44

100
102
94
99
87

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

89
88
88
88
88

69.2
69.6
65.7
64.6
65.3

10.03
9.24
8.31
9.37
8.08

68.0
69.0
66.0
64.0
65.0

51
51
49
44
48

102
94
84
93
88

CONFIDENTIAL

663

Day 7

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 5 of 36
Table 8.38
Summary of ECG Values

Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------Heart Rate (bpm)
25mcg
101 Day 1
Pre-dose
101
68.9 10.71
68.0
40
96
10 mins
98
68.8 11.13
68.5
42
93
1 hour
100
66.1 11.01
67.0
40
91
2 hours
100
64.5 10.15
63.5
41
89
4 hours
101
65.3 10.76
63.0
43
100
Pre-dose
10 mins
1 hour
2 hours
4 hours

99
95
96
96
95

70.2
71.7
67.7
68.1
69.7

11.08
10.21
9.18
10.57
10.12

69.0
72.0
68.0
69.0
70.0

44
48
49
47
48

102
104
85
89
94

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

95
92
93
93
93

71.8
73.0
70.2
70.8
69.8

11.19
10.52
10.34
10.14
11.19

72.0
72.0
68.0
70.0
69.0

43
50
52
47
44

103
102
102
103
94

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

94
93
93
93
93

69.8
71.5
67.3
65.9
66.1

11.42
11.27
10.68
11.18
11.12

68.0
72.0
66.0
64.0
66.0

47
46
43
42
42

98
105
94
93
94

CONFIDENTIAL

664

Day 7

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 6 of 36
Table 8.38
Summary of ECG Values

Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------Heart Rate (bpm)
50mcg
102 Day 1
Pre-dose
102
68.8 10.49
68.0
50
108
10 mins
102
70.0 10.95
68.5
48
101
1 hour
100
67.8 11.09
67.0
47
112
2 hours
101
67.0 11.19
65.0
47
101
4 hours
99
66.2 11.78
66.0
44
102
Pre-dose
10 mins
1 hour
2 hours
4 hours

100
100
99
99
98

69.7
74.9
70.1
68.7
69.8

9.81
10.73
10.17
9.49
10.24

69.0
73.5
70.0
69.0
70.0

46
53
50
48
47

99
104
95
93
96

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

97
96
97
97
97

70.5
75.8
71.4
71.0
69.3

8.98
10.21
11.08
10.77
9.90

70.0
75.0
70.0
71.0
69.0

48
53
49
47
47

94
103
108
95
91

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

98
95
98
97
97

70.2
74.8
68.9
67.2
67.3

10.89
10.89
10.30
10.21
10.49

68.0
74.0
68.0
67.0
66.0

49
54
52
49
45

99
102
97
98
98

CONFIDENTIAL

665

Day 7

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 7 of 36
Table 8.38
Summary of ECG Values

Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------Uncorrected QT
Placebo
102 Day 1
Pre-dose
102 376.7 26.48 377.5
304
470
Interval (msec)
10 mins
102 383.8 28.77 387.5
314
466
1 hour
101 384.7 28.76 388.0
314
477
2 hours
101 387.5 27.35 389.0
305
459
4 hours
101 385.3 30.18 391.0
290
477
Pre-dose
10 mins
1 hour
2 hours
4 hours

95
92
93
93
93

376.4
379.6
382.0
383.0
379.3

24.72
25.49
26.60
25.04
25.02

380.0
380.0
380.0
384.0
378.0

320
315
322
326
324

449
442
469
463
446

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

92
91
90
90
88

376.5
379.8
382.5
379.1
379.1

25.35
25.65
25.99
26.08
25.46

378.0
379.0
383.0
381.0
375.5

320
330
315
309
319

442
434
443
438
435

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

89
85
87
87
86

377.2
377.8
382.7
388.3
387.1

25.94
26.24
26.35
23.94
25.18

376.0
379.0
383.0
388.0
388.0

321
313
330
339
321

457
446
462
435
437

CONFIDENTIAL

666

Day 7

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 8 of 36
Table 8.38
Summary of ECG Values

Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------Uncorrected QT
3mcg
101 Day 1
Pre-dose
101 374.3 27.78 373.0
302
439
Interval (msec)
10 mins
97 379.9 27.08 381.0
316
462
1 hour
101 381.1 29.19 378.0
313
468
2 hours
101 386.5 27.77 386.0
317
466
4 hours
101 385.6 29.20 383.0
313
475
Pre-dose
10 mins
1 hour
2 hours
4 hours

98
91
93
93
93

377.1
379.3
382.2
384.2
379.3

29.18
27.64
28.60
27.87
27.90

375.5
377.0
380.0
383.0
377.0

310
314
305
322
304

467
469
469
472
447

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

92
85
86
86
86

374.2
376.1
382.5
379.0
379.3

30.39
28.96
27.73
29.24
25.91

372.5
372.0
378.5
374.0
374.5

307
303
322
293
321

460
456
474
469
449

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

87
83
84
84
84

378.5
377.7
379.8
386.3
384.9

29.55
29.73
26.93
26.92
27.41

376.0
374.0
377.0
383.0
385.0

319
317
328
330
322

492
488
460
469
465

CONFIDENTIAL

667

Day 7

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 9 of 36
Table 8.38
Summary of ECG Values

Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------Uncorrected QT
6.25mcg
101 Day 1
Pre-dose
101 379.8 26.10 376.0
329
448
Interval (msec)
10 mins
100 387.0 26.28 385.0
322
449
1 hour
100 387.4 26.14 384.0
321
452
2 hours
101 391.0 27.44 386.0
330
475
4 hours
101 391.1 27.26 392.0
329
457
Pre-dose
10 mins
1 hour
2 hours
4 hours

99
95
96
97
97

374.6
373.3
379.6
379.4
379.8

25.77
25.09
24.66
26.47
25.83

375.0
372.0
380.5
379.0
378.0

319
321
327
316
326

441
451
436
442
448

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

95
93
93
93
92

373.6
374.4
378.5
377.9
375.5

27.18
27.39
25.82
28.07
29.90

372.0
372.0
377.0
372.0
371.5

320
314
323
315
317

442
441
459
458
444

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

91
90
91
91
90

377.5
378.4
383.2
385.4
389.3

27.32
26.51
27.39
26.47
29.03

376.0
376.0
379.0
384.0
389.0

302
306
315
324
333

442
446
449
447
451

CONFIDENTIAL

668

Day 7

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 10 of 36
Table 8.38
Summary of ECG Values

Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------Uncorrected QT
12.5mcg
100 Day 1
Pre-dose
100 375.0 29.91 370.0
308
469
Interval (msec)
10 mins
99 381.7 28.59 377.0
329
460
1 hour
98 383.5 27.90 376.5
332
475
2 hours
98 387.8 27.12 384.0
343
464
4 hours
99 385.6 28.88 384.0
326
471
Pre-dose
10 mins
1 hour
2 hours
4 hours

97
96
95
95
94

376.2
375.9
382.2
383.0
381.0

26.41
27.49
27.10
28.52
28.77

378.0
375.5
385.0
389.0
382.0

325
324
309
319
313

440
442
441
464
461

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

92
91
91
91
91

375.6
375.4
378.1
378.4
380.6

26.76
28.25
27.95
29.60
28.75

373.5
374.0
376.0
376.0
379.0

312
316
317
310
317

459
455
470
476
498

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

89
88
88
88
88

378.3
376.6
384.6
388.0
387.1

24.76
25.27
26.22
27.74
28.03

374.0
374.0
380.5
385.5
389.5

322
322
329
325
308

444
445
467
485
455

CONFIDENTIAL

669

Day 7

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 11 of 36
Table 8.38
Summary of ECG Values

Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------Uncorrected QT
25mcg
101 Day 1
Pre-dose
101 378.3 26.05 378.0
321
458
Interval (msec)
10 mins
98 379.3 27.13 379.0
311
441
1 hour
100 382.1 30.37 377.0
329
479
2 hours
100 386.8 27.57 385.0
328
451
4 hours
101 385.7 29.49 386.0
321
452
Pre-dose
10 mins
1 hour
2 hours
4 hours

99
95
96
96
95

374.7
373.4
380.4
380.2
377.4

25.40
25.53
25.71
26.92
27.02

377.0
373.0
379.0
377.5
380.0

327
318
332
322
319

454
440
458
439
440

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

95
92
93
93
93

373.5
371.4
377.3
375.7
376.7

24.63
25.41
24.90
24.01
26.03

376.0
372.5
379.0
376.0
374.0

310
305
314
317
317

442
432
426
432
443

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

94
93
93
93
93

376.7
375.7
380.9
384.7
386.9

28.31
29.53
29.78
30.36
27.94

375.5
376.0
381.0
382.0
389.0

297
292
292
303
320

483
472
469
468
462

CONFIDENTIAL

670

Day 7

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 12 of 36
Table 8.38
Summary of ECG Values

Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------Uncorrected QT
50mcg
102 Day 1
Pre-dose
102 380.2 26.49 377.0
321
450
Interval (msec)
10 mins
102 380.7 27.60 378.0
319
449
1 hour
100 383.1 28.94 382.5
323
461
2 hours
101 387.1 30.53 388.0
299
456
4 hours
99 387.7 30.42 385.0
308
459
Pre-dose
10 mins
1 hour
2 hours
4 hours

100
100
99
99
98

378.1
372.5
379.3
379.7
380.6

24.81
25.63
25.74
26.19
27.74

376.0
370.5
378.0
379.0
376.0

322
311
314
282
322

445
440
446
460
469

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

97
96
97
97
97

372.0
369.6
373.8
374.3
379.8

25.21
25.34
25.66
26.10
25.70

370.0
369.5
372.0
372.0
377.0

309
321
317
322
321

449
450
450
450
455

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

98
95
98
97
97

377.8
372.3
382.0
384.6
384.8

27.07
28.62
26.25
29.03
27.98

377.0
374.0
382.0
383.0
386.0

324
304
329
303
321

459
445
460
466
459

CONFIDENTIAL

671

Day 7

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 13 of 36
Table 8.38
Summary of ECG Values

Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------QTc Interval
Placebo
102 Day 1
Pre-dose
102 395.9 19.00 398.5
336
439
(Fridericia) (msec)
10 mins
102 395.0 22.36 396.0
330
445
1 hour
101 394.0 22.08 395.0
338
448
2 hours
101 397.3 21.54 398.0
340
450
4 hours
101 399.1 22.42 400.0
335
437
Pre-dose
10 mins
1 hour
2 hours
4 hours

95
92
93
93
93

396.7
395.8
397.0
400.5
398.8

19.45
19.37
18.83
19.67
19.32

397.0
398.5
396.0
400.0
396.0

342
345
346
352
360

441
443
447
442
442

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

92
91
90
90
88

395.6
396.3
394.3
396.3
399.0

18.83
19.10
20.98
20.53
20.00

397.0
400.0
396.5
397.5
399.0

332
327
318
333
341

433
438
446
445
443

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

89
85
87
87
86

397.4
396.2
396.6
398.4
401.3

19.31
18.83
20.62
19.49
19.72

397.0
396.0
397.0
399.0
402.5

351
356
352
342
351

457
446
461
459
468

CONFIDENTIAL

672

Day 7

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 14 of 36
Table 8.38
Summary of ECG Values

Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------QTc Interval
3mcg
101 Day 1
Pre-dose
101 394.2 22.53 393.0
351
456
(Fridericia) (msec)
10 mins
97 394.1 21.43 392.0
347
455
1 hour
101 393.8 22.30 394.0
346
454
2 hours
101 395.2 19.02 394.0
361
454
4 hours
101 396.2 22.01 396.0
344
461
Pre-dose
10 mins
1 hour
2 hours
4 hours

98
91
93
93
93

396.6
396.3
396.9
399.2
396.7

21.33
20.46
20.13
20.46
21.76

397.0
395.0
400.0
399.0
399.0

341
331
350
356
327

454
452
450
451
459

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

92
85
86
86
86

396.3
394.6
396.6
396.0
396.0

23.08
21.90
21.88
25.17
20.08

395.5
394.0
395.5
398.5
395.0

342
336
352
325
340

470
454
450
470
446

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

87
83
84
84
84

396.0
393.7
391.6
395.3
396.0

22.44
22.50
20.85
22.61
21.36

396.0
395.0
393.5
397.5
399.0

333
347
344
337
347

481
470
451
471
455

CONFIDENTIAL

673

Day 7

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 15 of 36
Table 8.38
Summary of ECG Values

Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------QTc Interval
6.25mcg
101 Day 1
Pre-dose
101 397.8 23.02 397.0
342
459
(Fridericia) (msec)
10 mins
100 399.7 21.65 400.5
348
453
1 hour
100 398.1 21.07 396.0
346
451
2 hours
101 397.5 19.86 398.0
357
460
4 hours
101 400.6 20.31 400.0
358
455
Pre-dose
10 mins
1 hour
2 hours
4 hours

99
95
96
97
97

394.6
393.2
393.7
396.0
395.1

20.18
20.36
19.96
21.20
19.52

394.0
393.0
393.5
397.0
396.0

357
356
350
340
346

445
458
455
454
447

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

95
93
93
93
92

394.3
395.4
393.7
393.3
392.3

21.03
22.41
20.51
21.20
23.84

395.0
396.0
394.0
394.0
394.0

320
343
353
339
327

445
446
442
443
454

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

91
90
91
91
90

394.7
395.0
395.0
394.2
397.2

21.31
21.29
21.37
21.32
21.80

394.0
395.0
399.0
397.0
401.0

344
331
347
343
338

449
441
445
443
437

CONFIDENTIAL

674

Day 7

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 16 of 36
Table 8.38
Summary of ECG Values

Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------QTc Interval
12.5mcg
100 Day 1
Pre-dose
100 394.7 23.92 396.0
343
454
(Fridericia) (msec)
10 mins
99 396.6 24.72 397.0
327
457
1 hour
98 394.5 22.95 395.5
337
453
2 hours
98 396.9 23.44 395.0
339
454
4 hours
99 399.5 23.19 397.0
343
468
Pre-dose
10 mins
1 hour
2 hours
4 hours

97
96
95
95
94

396.1
396.8
397.5
398.8
397.5

23.86
24.18
22.83
22.30
22.31

391.0
393.0
396.0
396.0
396.5

346
348
352
355
343

469
470
461
461
464

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

92
91
91
91
91

395.3
396.9
395.3
397.3
397.1

20.40
22.36
22.65
23.45
21.63

392.0
397.0
396.0
393.0
396.0

351
347
344
336
356

470
471
467
455
456

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

89
88
88
88
88

396.9
396.1
396.9
398.0
398.7

20.12
21.00
22.28
22.68
24.05

397.0
396.0
391.0
394.0
399.5

354
342
355
347
320

440
444
455
455
458

CONFIDENTIAL

675

Day 7

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 17 of 36
Table 8.38
Summary of ECG Values

Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------QTc Interval
25mcg
101 Day 1
Pre-dose
101 396.0 19.80 393.0
350
444
(Fridericia) (msec)
10 mins
98 396.7 23.15 397.5
341
447
1 hour
100 394.2 22.33 394.0
330
448
2 hours
100 396.2 20.25 396.0
352
442
4 hours
101 396.4 19.49 397.0
346
445
Pre-dose
10 mins
1 hour
2 hours
4 hours

99
95
96
96
95

394.8
396.3
396.3
396.6
396.8

22.15
22.34
20.52
21.91
22.70

396.0
399.0
394.0
397.0
399.0

338
338
358
349
334

453
458
453
458
455

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

95
92
93
93
93

396.4
396.5
397.6
397.1
395.9

20.57
20.96
20.10
19.12
19.26

397.0
398.5
397.0
397.0
395.0

340
342
344
363
349

447
447
444
466
452

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

94
93
93
93
93

395.7
398.1
395.5
396.4
399.4

21.36
22.82
21.98
22.01
23.05

397.0
398.0
399.0
399.0
401.0

332
334
337
336
337

452
461
457
451
454

CONFIDENTIAL

676

Day 7

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 18 of 36
Table 8.38
Summary of ECG Values

Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------QTc Interval
50mcg
102 Day 1
Pre-dose
102 398.0 20.04 396.5
352
452
(Fridericia) (msec)
10 mins
102 400.7 22.36 398.0
346
468
1 hour
100 398.7 22.22 399.0
350
479
2 hours
101 400.9 20.89 402.0
339
472
4 hours
99 400.0 21.62 399.0
346
483
Pre-dose
10 mins
1 hour
2 hours
4 hours

100
100
99
99
98

397.6
401.0
399.4
397.5
400.4

19.33
18.10
21.22
21.59
20.81

398.0
402.5
401.0
398.0
399.0

347
366
340
318
351

462
458
462
469
481

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

97
96
97
97
97

392.9
399.7
395.8
395.7
398.5

18.92
19.22
18.42
19.40
19.29

395.0
399.0
396.0
392.0
398.0

313
363
338
332
352

455
456
450
463
449

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

98
95
98
97
97

397.8
400.5
400.0
399.2
399.5

19.84
21.17
19.06
21.89
20.30

398.0
401.0
398.5
399.0
398.0

347
331
354
341
354

451
450
461
461
451

CONFIDENTIAL

677

Day 7

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 19 of 36
Table 8.38
Summary of ECG Values

Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------QTc Interval
Placebo
102 Day 1
Pre-dose
102 405.9 22.51 403.5
323
457
(Bazetts) (msec)
10 mins
102 400.9 26.58 402.5
312
453
1 hour
101 398.9 26.08 399.0
322
458
2 hours
101 402.4 26.77 401.0
321
467
4 hours
101 406.4 25.50 406.0
326
450
Pre-dose
10 mins
1 hour
2 hours
4 hours

95
92
93
93
93

407.3
404.1
404.6
409.5
408.7

23.01
22.98
21.17
23.82
21.89

408.0
405.5
407.0
408.0
409.0

338
332
333
343
359

455
454
447
456
459

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

92
91
90
90
88

405.4
404.6
400.2
405.2
409.2

22.92
22.14
25.29
25.10
23.13

408.0
407.0
400.0
405.5
408.5

324
324
319
324
330

448
453
461
467
454

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

89
85
87
87
86

407.8
405.6
403.9
403.5
408.5

22.64
21.28
23.88
23.52
23.56

407.0
406.0
401.0
403.0
410.5

354
360
353
338
341

468
466
461
478
483

CONFIDENTIAL

678

Day 7

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 20 of 36
Table 8.38
Summary of ECG Values

Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------QTc Interval
3mcg
101 Day 1
Pre-dose
101 404.6 26.64 404.0
341
474
(Bazetts) (msec)
10 mins
97 401.4 25.31 401.0
334
471
1 hour
101 400.3 25.89 403.0
331
459
2 hours
101 399.6 21.42 399.0
357
451
4 hours
101 401.6 25.40 399.0
330
497
Pre-dose
10 mins
1 hour
2 hours
4 hours

98
91
93
93
93

406.6
405.1
404.4
406.9
405.6

23.06
22.64
22.63
22.67
23.22

407.0
404.0
405.0
408.0
408.0

334
326
355
355
339

465
459
448
461
466

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

92
85
86
86
86

407.9
404.2
403.8
404.8
404.5

25.98
24.12
24.88
27.93
22.32

407.0
406.0
404.5
408.0
405.0

337
352
342
337
331

474
453
469
469
454

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

87
83
84
84
84

404.9
401.8
397.7
399.8
401.5

24.84
24.78
24.14
25.99
24.95

408.0
402.0
398.5
400.5
403.0

316
340
336
330
330

475
460
455
475
460

CONFIDENTIAL

679

Day 7

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 21 of 36
Table 8.38
Summary of ECG Values

Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------QTc Interval
6.25mcg
101 Day 1
Pre-dose
101 407.0 26.90 407.0
348
473
(Bazetts) (msec)
10 mins
100 406.1 24.64 407.0
342
463
1 hour
100 403.5 25.02 403.0
351
459
2 hours
101 400.8 22.63 400.0
353
466
4 hours
101 405.5 24.50 404.0
353
463
Pre-dose
10 mins
1 hour
2 hours
4 hours

99
95
96
97
97

405.1
403.5
400.9
404.3
403.1

24.21
24.39
24.82
24.49
22.28

404.0
404.0
399.5
407.0
403.0

351
356
347
339
347

462
470
471
464
452

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

95
93
93
93
92

405.1
406.3
401.4
401.2
400.9

24.11
25.96
23.86
23.97
26.49

405.0
409.0
402.0
401.0
399.0

315
342
348
331
329

458
468
461
451
462

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

91
90
91
91
90

403.7
403.4
400.8
398.7
401.3

24.91
24.06
24.06
24.96
25.16

402.0
407.5
403.0
399.0
406.5

347
329
347
340
331

454
454
453
448
448

CONFIDENTIAL

680

Day 7

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 22 of 36
Table 8.38
Summary of ECG Values

Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------QTc Interval
12.5mcg
100 Day 1
Pre-dose
100 404.9 25.63 407.0
343
475
(Bazetts) (msec)
10 mins
99 404.2 27.76 405.0
326
470
1 hour
98 400.1 25.01 403.0
335
469
2 hours
98 401.6 26.53 401.0
336
463
4 hours
99 406.5 25.66 406.0
335
475
Pre-dose
10 mins
1 hour
2 hours
4 hours

97
96
95
95
94

406.3
407.6
405.2
406.7
405.8

26.61
26.55
25.54
24.33
23.60

405.0
405.0
403.0
405.0
403.0

352
346
347
352
344

484
484
474
473
468

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

92
91
91
91
91

405.4
407.8
404.1
406.9
405.5

23.09
24.89
25.16
24.84
22.53

400.5
408.0
406.0
408.0
406.0

350
360
344
339
361

483
484
476
462
465

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

89
88
88
88
88

406.5
406.1
402.9
402.9
404.5

23.58
23.82
24.89
25.66
25.90

408.0
407.5
401.0
402.5
405.0

351
346
355
335
327

467
467
477
467
464

CONFIDENTIAL

681

Day 7

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 23 of 36
Table 8.38
Summary of ECG Values

Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------QTc Interval
25mcg
101 Day 1
Pre-dose
101 405.0 23.55 408.0
330
471
(Bazetts) (msec)
10 mins
98 405.6 27.83 405.5
322
469
1 hour
100 400.4 25.68 401.5
326
472
2 hours
100 401.0 23.32 402.0
349
457
4 hours
101 401.9 21.30 403.0
344
465
Pre-dose
10 mins
1 hour
2 hours
4 hours

99
95
96
96
95

405.2
408.2
404.5
405.0
406.7

27.09
26.30
23.31
25.99
25.88

407.0
409.0
404.0
404.0
406.0

337
348
349
352
333

469
482
464
480
470

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

95
92
93
93
93

408.3
409.6
408.1
408.2
405.9

25.30
24.38
23.64
22.91
23.47

409.0
411.0
403.0
406.0
409.0

323
346
352
360
357

475
485
471
510
481

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

94
93
93
93
93

405.5
409.6
403.0
402.5
405.9

24.97
25.54
24.11
25.06
28.04

403.5
408.0
405.0
404.0
405.0

350
347
344
326
327

479
476
452
464
466

CONFIDENTIAL

682

Day 7

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 24 of 36
Table 8.38
Summary of ECG Values

Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------QTc Interval
50mcg
102 Day 1
Pre-dose
102 407.2 22.96 404.0
361
468
(Bazetts) (msec)
10 mins
102 411.0 26.19 412.0
351
487
1 hour
100 406.6 25.30 405.5
361
494
2 hours
101 407.9 22.94 409.0
361
482
4 hours
99 406.3 25.16 405.0
356
507
Pre-dose
10 mins
1 hour
2 hours
4 hours

100
100
99
99
98

407.7
415.9
409.7
406.5
410.6

22.23
20.32
25.19
24.47
23.41

408.5
417.0
408.0
409.0
408.0

352
378
353
338
358

469
470
470
473
486

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

97
96
97
97
97

403.6
415.4
407.2
406.8
408.1

20.26
21.37
21.55
22.65
22.10

405.0
416.0
408.0
406.0
408.0

314
362
345
336
361

457
461
457
468
463

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

98
95
98
97
97

408.2
415.4
409.2
406.7
407.0

22.72
22.31
21.28
23.75
22.81

409.0
418.0
410.5
410.0
408.0

351
335
351
344
350

477
455
466
476
460

CONFIDENTIAL

683

Day 7

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 25 of 36
Table 8.38
Summary of ECG Values

Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------PR Interval (msec)
Placebo
102 Day 1
Pre-dose
102 154.7 20.17 153.5
105
209
10 mins
102 157.1 21.31 154.0
111
211
1 hour
101 157.0 21.05 155.0
104
207
2 hours
101 156.8 21.25 156.0
110
229
4 hours
101 159.3 21.95 157.0
109
230
Pre-dose
10 mins
1 hour
2 hours
4 hours

95
92
93
93
93

157.6
158.0
158.1
161.2
158.8

21.71
20.31
22.89
22.71
23.30

154.0
156.0
155.0
158.0
157.0

111
121
109
119
109

209
215
224
229
229

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

92
91
90
90
88

158.9
158.1
160.5
158.5
160.5

19.94
20.30
19.90
20.22
22.61

156.0
156.0
158.0
157.0
157.0

120
122
125
116
121

202
213
212
214
226

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

89
85
87
87
86

157.4
158.2
158.7
158.8
160.2

21.11
19.68
20.69
22.86
21.73

158.0
157.0
155.0
157.0
159.0

105
124
127
114
121

236
205
202
240
232

CONFIDENTIAL

684

Day 7

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 26 of 36
Table 8.38
Summary of ECG Values

Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------PR Interval (msec)
3mcg
101 Day 1
Pre-dose
101 159.5 23.05 159.0
102
231
10 mins
97 161.7 25.49 159.0
111
246
1 hour
101 162.6 24.25 159.0
108
230
2 hours
101 162.7 23.98 165.0
88
229
4 hours
101 163.9 24.46 164.0
113
250
Pre-dose
10 mins
1 hour
2 hours
4 hours

98
91
93
93
93

160.8
161.4
163.3
164.8
164.3

22.43
22.78
24.29
23.48
23.11

159.5
161.0
166.0
165.0
165.0

105
105
105
105
107

226
230
236
230
225

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

92
85
86
86
86

161.6
162.5
163.7
163.7
163.2

21.05
22.36
23.81
23.47
23.31

157.0
161.0
161.5
165.0
161.0

108
102
99
102
117

220
213
221
215
224

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

87
83
84
84
84

161.3
162.4
160.2
162.7
164.5

23.41
23.15
24.41
24.18
25.02

160.0
162.0
160.0
163.5
165.0

107
109
96
110
107

218
217
205
215
215

CONFIDENTIAL

685

Day 7

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 27 of 36
Table 8.38
Summary of ECG Values

Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------PR Interval (msec)
6.25mcg
101 Day 1
Pre-dose
101 163.6 22.40 161.0
101
216
10 mins
100 165.0 24.33 163.5
103
225
1 hour
100 165.2 24.26 165.0
101
226
2 hours
101 166.3 26.22 167.0
97
235
4 hours
101 167.3 27.24 167.0
103
237
Pre-dose
10 mins
1 hour
2 hours
4 hours

99
95
96
97
97

163.5
166.1
165.9
165.5
166.6

23.87
23.43
25.28
26.18
25.21

161.0
164.0
164.5
166.0
165.0

109
112
115
104
114

224
223
236
245
236

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

95
93
93
93
92

162.4
162.9
163.4
165.6
167.4

22.56
22.91
24.42
24.29
23.47

161.0
160.0
163.0
163.0
163.5

111
98
107
120
111

218
216
225
239
233

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

91
90
91
91
90

162.8
163.6
164.6
164.1
165.2

21.27
23.11
20.59
22.51
23.38

160.0
164.0
163.0
165.0
163.5

112
112
114
104
108

219
228
218
230
230

CONFIDENTIAL

686

Day 7

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 28 of 36
Table 8.38
Summary of ECG Values

Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------PR Interval (msec)
12.5mcg
100 Day 1
Pre-dose
100 159.3 21.67 157.0
109
225
10 mins
99 161.0 21.63 159.0
104
229
1 hour
98 159.8 22.53 158.0
111
226
2 hours
98 162.9 23.63 160.0
105
238
4 hours
99 163.6 23.10 161.0
105
244
Pre-dose
10 mins
1 hour
2 hours
4 hours

97
96
95
95
94

159.7
160.8
162.0
163.2
163.5

23.04
21.23
20.53
23.78
22.49

159.0
157.0
162.0
160.0
161.0

110
111
109
115
112

229
234
221
259
234

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

92
91
91
91
91

158.6
159.5
161.7
162.7
162.9

22.82
21.79
21.38
20.82
21.76

154.5
157.0
158.0
161.0
162.0

108
105
110
110
110

250
234
231
224
226

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

89
88
88
88
88

161.0
161.0
160.5
163.4
162.4

23.23
23.23
24.14
25.08
25.37

156.0
157.0
157.5
159.0
161.5

112
118
114
105
97

238
238
233
249
238

CONFIDENTIAL

687

Day 7

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 29 of 36
Table 8.38
Summary of ECG Values

Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------PR Interval (msec)
25mcg
101 Day 1
Pre-dose
101 159.8 23.01 158.0
108
228
10 mins
98 159.8 23.31 158.5
104
238
1 hour
100 160.4 23.79 159.5
106
250
2 hours
100 161.8 24.22 161.0
102
244
4 hours
101 162.6 24.07 164.0
103
251
Pre-dose
10 mins
1 hour
2 hours
4 hours

99
95
96
96
95

159.4
159.2
161.6
162.7
163.4

20.86
23.57
23.15
22.95
23.95

159.0
162.0
161.5
164.0
163.0

111
106
107
106
115

210
214
224
221
219

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

95
92
93
93
93

157.2
158.0
159.7
160.8
160.9

22.05
21.05
21.96
22.66
22.49

154.0
157.0
159.0
161.0
161.0

101
112
95
97
90

225
237
209
215
230

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

94
93
93
93
93

158.0
156.8
158.4
159.4
162.2

22.26
21.92
23.33
22.72
24.97

157.0
155.0
155.0
157.0
159.0

112
111
107
108
107

213
208
235
228
237

CONFIDENTIAL

688

Day 7

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 30 of 36
Table 8.38
Summary of ECG Values

Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------PR Interval (msec)
50mcg
102 Day 1
Pre-dose
102 158.5 20.29 156.0
110
214
10 mins
102 158.9 18.91 158.5
114
227
1 hour
100 160.2 20.11 160.0
122
233
2 hours
101 161.3 20.34 162.0
121
239
4 hours
99 163.1 21.19 164.0
118
239
Pre-dose
10 mins
1 hour
2 hours
4 hours

100
100
99
99
98

158.5
156.9
160.1
162.6
161.9

19.81
21.11
21.03
20.43
21.75

156.5
156.0
159.0
163.0
163.0

120
116
120
131
121

220
219
235
236
225

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

97
96
97
97
97

158.1
156.8
160.6
160.6
161.5

19.30
19.45
18.95
19.41
18.58

156.0
154.0
160.0
158.0
160.0

119
121
124
121
122

204
215
214
223
229

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

98
95
98
97
97

159.3
158.4
158.1
159.7
161.8

21.39
20.45
21.65
20.79
22.09

158.5
159.0
157.5
160.0
159.0

122
121
121
121
121

214
212
226
216
234

CONFIDENTIAL

689

Day 7

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 31 of 36
Table 8.38
Summary of ECG Values

Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------QRS Duration (msec) Placebo
102 Day 1
Pre-dose
102
83.4
9.87
84.0
63
112
10 mins
102
83.5
9.79
83.5
64
108
1 hour
101
83.7
9.60
85.0
63
105
2 hours
101
83.5
9.77
82.0
63
112
4 hours
101
83.5 10.01
83.0
57
107
Pre-dose
10 mins
1 hour
2 hours
4 hours

95
92
93
93
93

83.0
81.7
83.1
83.0
82.3

10.60
11.36
10.87
10.80
11.84

82.0
82.0
83.0
82.0
83.0

51
53
54
52
51

118
116
118
124
117

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

92
91
90
90
88

82.4
83.9
83.6
83.5
83.0

9.69
10.31
10.47
10.69
10.47

82.5
85.0
84.0
83.0
83.5

59
54
53
60
56

110
115
112
117
108

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

89
85
87
87
86

81.5
82.8
82.7
82.7
83.9

10.85
9.82
10.91
11.25
10.74

81.0
83.0
84.0
84.0
84.0

58
62
60
55
60

115
111
108
113
116

CONFIDENTIAL

690

Day 7

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 32 of 36
Table 8.38
Summary of ECG Values

Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------QRS Duration (msec) 3mcg
101 Day 1
Pre-dose
101
84.3
9.55
86.0
56
106
10 mins
97
84.6
9.75
85.0
51
102
1 hour
101
84.5 10.27
85.0
55
109
2 hours
101
86.0
9.85
85.0
64
124
4 hours
101
86.8 10.30
86.0
57
132
Pre-dose
10 mins
1 hour
2 hours
4 hours

98
91
93
93
93

84.3
85.3
85.8
85.5
85.9

11.48
12.25
11.47
11.11
11.49

84.0
86.0
86.0
85.0
86.0

56
57
55
62
56

129
136
133
136
135

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

92
85
86
86
86

84.8
84.0
85.1
85.8
85.3

11.83
11.43
11.24
12.04
11.89

85.5
84.0
86.0
87.0
85.0

57
57
56
50
50

137
138
134
141
137

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

87
83
84
84
84

83.7
82.6
83.6
83.7
84.0

11.47
11.58
11.35
11.54
10.70

83.0
83.0
83.0
84.0
82.5

58
59
62
56
60

144
140
130
131
130

CONFIDENTIAL

691

Day 7

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 33 of 36
Table 8.38
Summary of ECG Values

Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------QRS Duration (msec) 6.25mcg
101 Day 1
Pre-dose
101
85.7 12.59
85.0
58
141
10 mins
100
86.0 11.48
86.0
61
136
1 hour
100
85.8 12.26
83.0
61
139
2 hours
101
86.6 11.49
85.0
62
138
4 hours
101
86.3 12.35
85.0
63
136
Pre-dose
10 mins
1 hour
2 hours
4 hours

99
95
96
97
97

84.2
84.3
84.4
85.1
85.2

10.48
10.47
10.40
10.18
10.37

85.0
86.0
84.0
85.0
86.0

56
54
53
56
59

100
103
100
100
101

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

95
93
93
93
92

83.9
83.8
84.7
84.6
85.3

9.16
9.35
9.80
9.83
8.84

84.0
84.0
86.0
86.0
86.5

62
63
61
65
64

100
100
100
100
100

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

91
90
91
91
90

84.3
84.7
83.9
84.2
84.8

9.69
9.78
10.86
10.13
9.89

84.0
85.0
84.0
84.0
84.5

60
55
46
61
61

100
100
102
101
101

CONFIDENTIAL

692

Day 7

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 34 of 36
Table 8.38
Summary of ECG Values

Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------QRS Duration (msec) 12.5mcg
100 Day 1
Pre-dose
100
84.2
9.52
83.0
62
112
10 mins
99
84.1 10.10
83.0
63
114
1 hour
98
83.6 11.24
83.0
61
127
2 hours
98
84.5 10.51
83.5
65
125
4 hours
99
85.4 10.84
85.0
63
132
Pre-dose
10 mins
1 hour
2 hours
4 hours

97
96
95
95
94

83.5
84.2
85.2
85.6
85.0

10.87
10.08
9.05
10.91
10.47

84.0
85.0
85.0
85.0
85.0

60
61
66
60
62

124
120
109
126
117

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

92
91
91
91
91

83.9
83.8
83.8
85.0
84.9

10.95
11.01
10.83
10.53
10.96

84.0
84.0
83.0
85.0
84.0

59
58
61
60
59

120
118
118
121
133

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

89
88
88
88
88

83.5
83.5
83.8
83.9
84.8

8.82
9.13
9.72
9.45
8.83

83.0
83.5
84.0
85.0
85.0

60
59
59
59
61

100
101
103
100
100

CONFIDENTIAL

693

Day 7

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 35 of 36
Table 8.38
Summary of ECG Values

Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------QRS Duration (msec) 25mcg
101 Day 1
Pre-dose
101
82.6 11.00
83.0
56
111
10 mins
98
83.3 11.32
84.0
52
115
1 hour
100
82.5 11.14
83.0
55
117
2 hours
100
82.4 11.28
82.0
51
105
4 hours
101
83.1 10.88
82.0
58
111
Pre-dose
10 mins
1 hour
2 hours
4 hours

99
95
96
96
95

82.4
82.2
82.4
83.3
83.4

11.09
11.16
11.43
11.65
11.31

82.0
82.0
81.5
82.0
82.0

58
55
51
55
55

108
107
106
112
116

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

95
92
93
93
93

82.9
82.5
83.8
83.5
84.1

10.26
10.97
10.81
10.13
11.30

82.0
82.0
84.0
84.0
84.0

56
49
59
59
48

104
109
111
105
113

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

94
93
93
93
93

82.1
83.5
82.6
83.4
83.7

11.13
11.45
11.05
11.02
12.03

83.0
84.0
83.0
84.0
85.0

58
56
51
58
51

111
114
107
115
115

CONFIDENTIAL

694

Day 7

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 36 of 36
Table 8.38
Summary of ECG Values

Treatment
Planned Relative
Group
N
Visit
Time
n
Mean
SD
Median Min. Max.
--------------------------------------------------------------------------------------------------------QRS Duration (msec) 50mcg
102 Day 1
Pre-dose
102
83.4
8.96
84.0
55
106
10 mins
102
84.0 10.01
85.0
50
106
1 hour
100
83.7 10.36
85.0
53
106
2 hours
101
84.2
9.22
85.0
54
107
4 hours
99
83.6
9.38
84.0
51
107
Pre-dose
10 mins
1 hour
2 hours
4 hours

100
100
99
99
98

84.1
84.2
84.7
85.6
85.4

9.03
9.03
9.61
8.43
8.91

86.0
85.0
85.0
87.0
87.0

59
59
56
55
60

101
101
100
101
101

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

97
96
97
97
97

84.2
84.6
84.3
84.8
85.0

8.62
9.03
9.07
9.33
10.19

85.0
85.0
86.0
86.0
87.0

59
59
55
59
59

100
100
99
100
109

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

98
95
98
97
97

82.5
82.7
83.5
83.6
84.1

10.22
10.72
11.03
9.98
9.51

84.0
84.0
85.0
85.0
85.0

59
57
56
56
56

108
108
106
102
103

CONFIDENTIAL

695

Day 7

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 21
Table 8.39
Summary of ECG Findings

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Any time post-baseline
n
102
101
101
100
101
102
Normal
49 (48%)
38 (38%)
41 (41%)
50 (50%)
42 (42%)
50 (49%)
Abnormal - not clinically
45 (44%)
51 (50%)
54 (53%)
40 (40%)
47 (47%)
45 (44%)
significant
Abnormal - clinically significant
8
(8%)
12 (12%)
6
(6%)
10 (10%)
12 (12%)
7
(7%)
Not available
0
0
0
0
0
0
102
1

(<1%)

101
0

101
0

100
0

101
0

102
0

18

(18%)

19

(19%)

17

(17%)

17

(17%)

18

(18%)

17

(17%)

77
6
0

(75%)
(6%)

79
3
0

(78%)
(3%)

80
4
0

(79%)
(4%)

81
2
0

(81%)
(2%)

76
7
0

(75%)
(7%)

82
3
0

(80%)
(3%)

YM2008/00019/00
B2C109575

Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.

CONFIDENTIAL

696

n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 21
Table 8.39
Summary of ECG Findings

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 1
Pre-dose
n
102
101
101
100
101
102
Normal
82 (80%)
78 (77%)
78 (77%)
81 (81%)
83 (82%)
87 (85%)
Abnormal - not clinically
16 (16%)
18 (18%)
17 (17%)
16 (16%)
14 (14%)
12 (12%)
significant
Abnormal - clinically significant
3
(3%)
2
(2%)
5
(5%)
2
(2%)
2
(2%)
1 (<1%)
Not available
1 (<1%)
3
(3%)
1 (<1%)
1
(1%)
2
(2%)
2
(2%)
102
0

101
0

101
0

100
0

101
0

102
0

0
102 (100%)
0

0
101 (100%)
0

0
101 (100%)
0

0
100 (100%)
0

0
101 (100%)
0

0
102 (100%)
0

YM2008/00019/00
B2C109575

Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.

CONFIDENTIAL

697

n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 21
Table 8.39
Summary of ECG Findings

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 1
10 mins
n
102
97
100
99
98
102
Normal
80 (78%)
73 (75%)
80 (80%)
79 (80%)
78 (80%)
88 (86%)
Abnormal - not clinically
13 (13%)
19 (20%)
16 (16%)
17 (17%)
17 (17%)
13 (13%)
significant
Abnormal - clinically significant
5
(5%)
4
(4%)
4
(4%)
1
(1%)
2
(2%)
1 (<1%)
Not available
4
(4%)
1
(1%)
0
2
(2%)
1
(1%)
0
102
3

(3%)

97
2

(2%)

100
1

(1%)

99
0

(2%)

(3%)

(3%)

74
23
0

(73%)
(23%)

70
22
0

(72%)
(23%)

73
23
0

(73%)
(23%)

80
18
0

98
0

102
3

(3%)

(1%)

(2%)

(81%)
(18%)

81
17
0

80
17
0

(78%)
(17%)

(83%)
(17%)

YM2008/00019/00
B2C109575

Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.

CONFIDENTIAL

698

n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 21
Table 8.39
Summary of ECG Findings

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 1
1 hour
n
101
101
100
98
100
100
Normal
77 (76%)
71 (70%)
76 (76%)
76 (78%)
79 (79%)
86 (86%)
Abnormal - not clinically
18 (18%)
25 (25%)
18 (18%)
18 (18%)
15 (15%)
12 (12%)
significant
Abnormal - clinically significant
4
(4%)
4
(4%)
4
(4%)
2
(2%)
5
(5%)
2
(2%)
Not available
2
(2%)
1 (<1%)
2
(2%)
2
(2%)
1
(1%)
0
101
2

(2%)

101
4

(4%)

100
0

98
0

(3%)

(6%)

(6%)

76
20
0

(75%)
(20%)

72
19
0

(71%)
(19%)

74
20
0

(74%)
(20%)

82
14
0

100
1

(1%)

100
1

(2%)

(3%)

(84%)
(14%)

78
18
0

(78%)
(18%)

82
17
0

(1%)

(82%)
(17%)

YM2008/00019/00
B2C109575

Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.

CONFIDENTIAL

699

n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change

Protocol: B2C109575
Population: Intent-to-Treat

Page 5 of 21
Table 8.39
Summary of ECG Findings

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 1
2 hours
n
101
101
101
98
100
101
Normal
78 (77%)
74 (73%)
72 (71%)
78 (80%)
79 (79%)
86 (85%)
Abnormal - not clinically
16 (16%)
23 (23%)
23 (23%)
17 (17%)
19 (19%)
14 (14%)
significant
Abnormal - clinically significant
5
(5%)
3
(3%)
4
(4%)
1
(1%)
2
(2%)
1 (<1%)
Not available
2
(2%)
1 (<1%)
2
(2%)
2
(2%)
0
0
101
1

(<1%)

101
3

(3%)

101
3

(3%)

98
0

(<1%)

(8%)

(4%)

81
18
0

(80%)
(18%)

71
19
0

(70%)
(19%)

71
23
0

(70%)
(23%)

84
12
0

100
1

(1%)

101
1

(<1%)

(2%)

(3%)

(<1%)

(86%)
(12%)

76
20
0

(76%)
(20%)

84
15
0

(83%)
(15%)

YM2008/00019/00
B2C109575

Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.

CONFIDENTIAL

700

n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change

Protocol: B2C109575
Population: Intent-to-Treat

Page 6 of 21
Table 8.39
Summary of ECG Findings

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 1
4 hours
n
101
101
101
99
101
99
Normal
79 (78%)
78 (77%)
72 (71%)
70 (71%)
77 (76%)
76 (77%)
Abnormal - not clinically
16 (16%)
16 (16%)
25 (25%)
26 (26%)
19 (19%)
20 (20%)
significant
Abnormal - clinically significant
4
(4%)
6
(6%)
3
(3%)
2
(2%)
2
(2%)
1
(1%)
Not available
2
(2%)
1 (<1%)
1 (<1%)
1
(1%)
3
(3%)
2
(2%)
101
2

(2%)

101
4

(4%)

101
4

(4%)

99
0

(3%)

(6%)

(5%)

77
19
0

(76%)
(19%)

71
20
0

(70%)
(20%)

70
22
0

(69%)
(22%)

81
14
0

101
2

(2%)

99
1

(1%)

(4%)

(2%)

(4%)

(82%)
(14%)

75
22
0

(74%)
(22%)

79
15
0

(80%)
(15%)

YM2008/00019/00
B2C109575

Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.

CONFIDENTIAL

701

n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change

Protocol: B2C109575
Population: Intent-to-Treat

Page 7 of 21
Table 8.39
Summary of ECG Findings

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 7
Pre-dose
n
95
98
99
97
99
100
Normal
81 (85%)
77 (79%)
77 (78%)
75 (77%)
84 (85%)
88 (88%)
Abnormal - not clinically
10 (11%)
16 (16%)
18 (18%)
19 (20%)
13 (13%)
10 (10%)
significant
Abnormal - clinically significant
2
(2%)
4
(4%)
2
(2%)
2
(2%)
2
(2%)
1
(1%)
Not available
2
(2%)
1
(1%)
2
(2%)
1
(1%)
0
1
(1%)
95
2

(2%)

98
0

99
0

(1%)

(2%)

64
28
0

(67%)
(29%)

70
26
0

(71%)
(27%)

68
29
0

97
2

(2%)

99
2

(2%)

100
3

(3%)

(2%)

(3%)

(2%)

(2%)

(69%)
(29%)

67
25
0

(69%)
(26%)

63
32
0

(64%)
(32%)

60
35
0

(60%)
(35%)

YM2008/00019/00
B2C109575

Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.

CONFIDENTIAL

702

n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change

Protocol: B2C109575
Population: Intent-to-Treat

Page 8 of 21
Table 8.39
Summary of ECG Findings

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 7
10 mins
n
92
91
95
96
95
100
Normal
75 (82%)
71 (78%)
73 (77%)
78 (81%)
83 (87%)
86 (86%)
Abnormal - not clinically
14 (15%)
16 (18%)
18 (19%)
16 (17%)
8
(8%)
12 (12%)
significant
Abnormal - clinically significant
0
2
(2%)
1
(1%)
2
(2%)
3
(3%)
2
(2%)
Not available
3
(3%)
2
(2%)
3
(3%)
0
1
(1%)
0
92
1

(1%)

91
2

(2%)

95
0

(2%)

(2%)

81
8
0

(88%)
(9%)

77
10
0

(85%)
(11%)

80
14
0

96
1

(1%)

95
3

(3%)

100
0

(1%)

(2%)

(2%)

(2%)

(84%)
(15%)

84
9
0

(88%)
(9%)

79
11
0

(83%)
(12%)

86
12
0

(86%)
(12%)

YM2008/00019/00
B2C109575

Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.

CONFIDENTIAL

703

n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change

Protocol: B2C109575
Population: Intent-to-Treat

Page 9 of 21
Table 8.39
Summary of ECG Findings

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 7
1 hour
n
93
93
96
95
96
99
Normal
77 (83%)
73 (78%)
69 (72%)
78 (82%)
83 (86%)
87 (88%)
Abnormal - not clinically
10 (11%)
16 (17%)
23 (24%)
14 (15%)
10 (10%)
12 (12%)
significant
Abnormal - clinically significant
3
(3%)
3
(3%)
2
(2%)
2
(2%)
3
(3%)
0
Not available
3
(3%)
1
(1%)
2
(2%)
1
(1%)
0
0
93
2

(2%)

93
3

(3%)

96
2

(2%)

95
4

(4%)

96
3

(3%)

99
1

(1%)

(3%)

(2%)

(4%)

(1%)

(3%)

(2%)

77
11
0

(83%)
(12%)

77
11
0

(83%)
(12%)

74
16
0

(77%)
(17%)

81
9
0

(85%)
(9%)

81
9
0

(84%)
(9%)

85
11
0

(86%)
(11%)

YM2008/00019/00
B2C109575

Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.

CONFIDENTIAL

704

n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change

Protocol: B2C109575
Population: Intent-to-Treat

Page 10 of 21
Table 8.39
Summary of ECG Findings

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 7
2 hours
n
93
93
97
95
96
99
Normal
78 (84%)
75 (81%)
73 (75%)
75 (79%)
79 (82%)
81 (82%)
Abnormal - not clinically
12 (13%)
15 (16%)
21 (22%)
14 (15%)
12 (13%)
16 (16%)
significant
Abnormal - clinically significant
2
(2%)
2
(2%)
2
(2%)
4
(4%)
4
(4%)
1
(1%)
Not available
1
(1%)
1
(1%)
1
(1%)
2
(2%)
1
(1%)
1
(1%)
93
3

(3%)

93
2

(3%)

76
11
0

(82%)
(12%)

83
8
0

(2%)

(89%)
(9%)

97
1

(1%)

95
2

(2%)

96
3

(3%)

99
1

(1%)

(5%)

(1%)

(2%)

(4%)

76
15
0

(78%)
(15%)

82
10
0

(86%)
(11%)

80
11
0

(83%)
(11%)

82
12
0

(83%)
(12%)

YM2008/00019/00
B2C109575

Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.

CONFIDENTIAL

705

n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change

Protocol: B2C109575
Population: Intent-to-Treat

Page 11 of 21
Table 8.39
Summary of ECG Findings

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 7
4 hours
n
93
93
97
94
95
98
Normal
77 (83%)
74 (80%)
75 (77%)
75 (80%)
76 (80%)
84 (86%)
Abnormal - not clinically
13 (14%)
15 (16%)
22 (23%)
14 (15%)
11 (12%)
13 (13%)
significant
Abnormal - clinically significant
3
(3%)
3
(3%)
0
3
(3%)
5
(5%)
0
Not available
0
1
(1%)
0
2
(2%)
3
(3%)
1
(1%)
93
2

(2%)

93
1

(1%)

97
2

(2%)

94
2

(2%)

95
3

(3%)

98
1

(1%)

(3%)

(2%)

(1%)

(1%)

(6%)

(3%)

80
8
0

(86%)
(9%)

78
12
0

(84%)
(13%)

81
13
0

(84%)
(13%)

81
10
0

(86%)
(11%)

72
14
0

(76%)
(15%)

81
13
0

(83%)
(13%)

YM2008/00019/00
B2C109575

Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.

CONFIDENTIAL

706

n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change

Protocol: B2C109575
Population: Intent-to-Treat

Page 12 of 21
Table 8.39
Summary of ECG Findings

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 14
Pre-dose
n
92
92
95
92
95
97
Normal
81 (88%)
71 (77%)
78 (82%)
78 (85%)
79 (83%)
86 (89%)
Abnormal - not clinically
10 (11%)
19 (21%)
16 (17%)
12 (13%)
13 (14%)
7
(7%)
significant
Abnormal - clinically significant
1
(1%)
2
(2%)
0
1
(1%)
1
(1%)
0
Not available
0
0
1
(1%)
1
(1%)
2
(2%)
4
(4%)
92
3

(3%)

0
69
20
0

(75%)
(22%)

92
0

95
2

(1%)

69
22
0

(75%)
(24%)

67
26
0

(2%)

92
1

(1%)

0
(71%)
(27%)

71
20
0

95
1

(1%)

0
(77%)
(22%)

70
24
0

97
3

(3%)

0
(74%)
(25%)

72
22
0

(74%)
(23%)

YM2008/00019/00
B2C109575

Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.

CONFIDENTIAL

707

n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change

Protocol: B2C109575
Population: Intent-to-Treat

Page 13 of 21
Table 8.39
Summary of ECG Findings

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 14
10 mins
n
91
85
93
91
92
96
Normal
78 (86%)
66 (78%)
74 (80%)
78 (86%)
78 (85%)
83 (86%)
Abnormal - not clinically
11 (12%)
17 (20%)
18 (19%)
11 (12%)
12 (13%)
11 (11%)
significant
Abnormal - clinically significant
1
(1%)
1
(1%)
0
2
(2%)
0
1
(1%)
Not available
1
(1%)
1
(1%)
1
(1%)
0
2
(2%)
1
(1%)
91
0

85
0

93
1

(1%)

91
0

92
2

(2%)

(1%)

(2%)

(1%)

81
8
0

(89%)
(9%)

80
4
0

(94%)
(5%)

76
14
0

(82%)
(15%)

86
4
0

(95%)
(4%)

74
16
0

(2%)

(80%)
(17%)

96
0
2

(2%)

80
14
0

(83%)
(15%)

YM2008/00019/00
B2C109575

Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.

CONFIDENTIAL

708

n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change

Protocol: B2C109575
Population: Intent-to-Treat

Page 14 of 21
Table 8.39
Summary of ECG Findings

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 14
1 hour
n
90
86
93
91
93
97
Normal
74 (82%)
66 (77%)
76 (82%)
75 (82%)
82 (88%)
83 (86%)
Abnormal - not clinically
13 (14%)
17 (20%)
17 (18%)
13 (14%)
9 (10%)
12 (12%)
significant
Abnormal - clinically significant
2
(2%)
1
(1%)
0
2
(2%)
1
(1%)
0
Not available
1
(1%)
2
(2%)
0
1
(1%)
1
(1%)
2
(2%)
90
0

86
0

93
2

(2%)

91
0

93
2

(2%)

(1%)

(1%)

(2%)

79
9
0

(88%)
(10%)

80
5
0

(93%)
(6%)

80
10
0

(86%)
(11%)

85
4
0

(93%)
(4%)

72
19
0

(2%)

97
1

(1%)

0
(77%)
(20%)

82
14
0

(85%)
(14%)

YM2008/00019/00
B2C109575

Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.

CONFIDENTIAL

709

n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change

Protocol: B2C109575
Population: Intent-to-Treat

Page 15 of 21
Table 8.39
Summary of ECG Findings

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 14
2 hours
n
90
86
93
91
93
97
Normal
73 (81%)
67 (78%)
73 (78%)
76 (84%)
79 (85%)
78 (80%)
Abnormal - not clinically
15 (17%)
18 (21%)
20 (22%)
13 (14%)
9 (10%)
17 (18%)
significant
Abnormal - clinically significant
2
(2%)
1
(1%)
0
1
(1%)
2
(2%)
0
Not available
0
0
0
1
(1%)
3
(3%)
2
(2%)
90
0

86
0

93
3

(3%)

91
1

(1%)

93
1

(1%)

97
0

(1%)

(1%)

(1%)

(1%)

(1%)

(1%)

83
6
0

(92%)
(7%)

78
7
0

(91%)
(8%)

77
12
0

(83%)
(13%)

84
5
0

(92%)
(5%)

73
18
0

(78%)
(19%)

83
13
0

(86%)
(13%)

YM2008/00019/00
B2C109575

Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.

CONFIDENTIAL

710

n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change

Protocol: B2C109575
Population: Intent-to-Treat

Page 16 of 21
Table 8.39
Summary of ECG Findings

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 14
4 hours
n
88
86
92
91
93
97
Normal
74 (84%)
67 (78%)
73 (79%)
78 (86%)
77 (83%)
86 (89%)
Abnormal - not clinically
13 (15%)
18 (21%)
19 (21%)
12 (13%)
15 (16%)
10 (10%)
significant
Abnormal - clinically significant
1
(1%)
1
(1%)
0
1
(1%)
1
(1%)
0
Not available
0
0
0
0
0
1
(1%)
88
0

86
1

(1%)

79
8
0

(90%)
(9%)

80
5
0

(1%)

(93%)
(6%)

92
1

(1%)

91
1

(1%)

93
1

(2%)

(1%)

79
10
0

(86%)
(11%)

86
3
0

(95%)
(3%)

74
18
0

(1%)

(80%)
(19%)

97
1

(1%)

(2%)

81
13
0

(84%)
(13%)

YM2008/00019/00
B2C109575

Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.

CONFIDENTIAL

711

n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change

Protocol: B2C109575
Population: Intent-to-Treat

Page 17 of 21
Table 8.39
Summary of ECG Findings

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 28
Pre-dose
n
89
87
91
89
94
98
Normal
76 (85%)
68 (78%)
74 (81%)
76 (85%)
77 (82%)
85 (87%)
Abnormal - not clinically
10 (11%)
18 (21%)
17 (19%)
12 (13%)
13 (14%)
10 (10%)
significant
Abnormal - clinically significant
2
(2%)
1
(1%)
0
1
(1%)
4
(4%)
1
(1%)
Not available
1
(1%)
0
0
0
0
2
(2%)
89
1

(1%)

87
1

(1%)

91
1

(1%)

(2%)

69
18
0

(78%)
(20%)

68
16
0

(78%)
(18%)

68
22
0

(1%)

89
1

(1%)

0
(75%)
(24%)

75
13
0

(84%)
(15%)

94
0

98
2

(2%)

(3%)

(1%)

75
16
0

(80%)
(17%)

77
18
0

(79%)
(18%)

YM2008/00019/00
B2C109575

Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.

CONFIDENTIAL

712

n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change

Protocol: B2C109575
Population: Intent-to-Treat

Page 18 of 21
Table 8.39
Summary of ECG Findings

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 28
10 mins
n
85
83
90
88
93
95
Normal
76 (89%)
67 (81%)
72 (80%)
76 (86%)
70 (75%)
79 (83%)
Abnormal - not clinically
7
(8%)
13 (16%)
17 (19%)
10 (11%)
17 (18%)
12 (13%)
significant
Abnormal - clinically significant
1
(1%)
3
(4%)
0
1
(1%)
5
(5%)
2
(2%)
Not available
1
(1%)
0
1
(1%)
1
(1%)
1
(1%)
2
(2%)
85
2

(2%)

0
72
11
0

(85%)
(13%)

83
1

(1%)

90
0

88
0

93
0

95
0

(2%)

(2%)

74
6
0

(89%)
(7%)

79
11
0

84
9
0

(88%)
(9%)

(88%)
(12%)

81
7
0

(92%)
(8%)

80
13
0

(86%)
(14%)

YM2008/00019/00
B2C109575

Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.

CONFIDENTIAL

713

n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change

Protocol: B2C109575
Population: Intent-to-Treat

Page 19 of 21
Table 8.39
Summary of ECG Findings

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 28
1 hour
n
87
84
91
88
93
98
Normal
75 (86%)
63 (75%)
76 (84%)
71 (81%)
77 (83%)
83 (85%)
Abnormal - not clinically
10 (11%)
18 (21%)
14 (15%)
13 (15%)
13 (14%)
12 (12%)
significant
Abnormal - clinically significant
1
(1%)
2
(2%)
0
1
(1%)
2
(2%)
1
(1%)
Not available
1
(1%)
1
(1%)
1
(1%)
3
(3%)
1
(1%)
2
(2%)
87
2

(2%)

0
74
11
0

(85%)
(13%)

84
0

91
0

88
0

93
1

(2%)

73
9
0

(87%)
(11%)

81
10
0

(89%)
(11%)

80
8
0

(91%)
(9%)

83
9
0

(1%)

(89%)
(10%)

98
0
1

(1%)

88
9
0

(90%)
(9%)

YM2008/00019/00
B2C109575

Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.

CONFIDENTIAL

714

n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change

Protocol: B2C109575
Population: Intent-to-Treat

Page 20 of 21
Table 8.39
Summary of ECG Findings

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 28
2 hours
n
87
84
91
88
93
97
Normal
70 (80%)
66 (79%)
75 (82%)
71 (81%)
75 (81%)
82 (85%)
Abnormal - not clinically
15 (17%)
15 (18%)
15 (16%)
13 (15%)
15 (16%)
13 (13%)
significant
Abnormal - clinically significant
1
(1%)
3
(4%)
0
1
(1%)
3
(3%)
1
(1%)
Not available
1
(1%)
0
1
(1%)
3
(3%)
0
1
(1%)
87
0

84
1

(1%)

91
0

88
0

93
2

(2%)

97
1

(1%)

(3%)

(4%)

(1%)

(2%)

(3%)

(2%)

74
10
0

(85%)
(11%)

73
7
0

(87%)
(8%)

76
14
0

(84%)
(15%)

77
9
0

(88%)
(10%)

80
8
0

(86%)
(9%)

83
11
0

(86%)
(11%)

YM2008/00019/00
B2C109575

Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.

CONFIDENTIAL

715

n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change

Protocol: B2C109575
Population: Intent-to-Treat

Page 21 of 21
Table 8.39
Summary of ECG Findings

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 28
4 hours
n
86
84
90
88
93
97
Normal
72 (84%)
61 (73%)
68 (76%)
73 (83%)
75 (81%)
83 (86%)
Abnormal - not clinically
12 (14%)
17 (20%)
20 (22%)
13 (15%)
16 (17%)
12 (12%)
significant
Abnormal - clinically significant
2
(2%)
4
(5%)
0
1
(1%)
2
(2%)
0
Not available
0
2
(2%)
2
(2%)
1
(1%)
0
2
(2%)
86
1

(1%)

84
1

(1%)

90
1

(1%)

88
0

93
1

(1%)

(2%)

(2%)

(2%)

76
8
0

(88%)
(9%)

70
11
0

(83%)
(13%)

75
12
0

(83%)
(13%)

79
7
0

(90%)
(8%)

85
7
0

(1%)

(91%)
(8%)

97
1

(1%)

(2%)

82
12
0

(85%)
(12%)

YM2008/00019/00
B2C109575

Note: Baseline for pre-dose assessments is defined as the pre-dose value on Day 1. Baseline for post-dose
assessments is defined as the pre-dose value for the corresponding visit.
Note: Abnormality and clinical significance determined by the central cardiologist. Findings may include
conditions not listed in the protocol.

CONFIDENTIAL

716

n
Clinically significant change:
favorable
Clinically significant change:
unfavorable
No change or insignificant change
No result
Clinically significant change

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Table 8.40
Summary of Maximum Post-Dose QTc(F) Interval (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------------Day 1
n
102
101
101
100
101
102
<= 450 102 (100%)
98 (97%)
100 (>99%)
96 (96%)
101 (100%)
100 (98%)
450 < - <= 480
0
3
(3%)
1 (<1%)
4
(4%)
0
1 (<1%)
480 < - <= 500
0
0
0
0
0
1 (<1%)
> 500
0
0
0
0
0
0

717

<=
450 < - <=
480 < - <=
>

Day 14
n

<=
450 < - <=
480 < - <=
>

Day 28
n

93
93 (100%)
0
0
0

93
92
1
0
0

450
480
500
500

91
91 (100%)
0
0
0

86
85
1
0
0

450
480
500
500

87
85
2
0
0

85
84
1
0
0

(98%)
(2%)

(99%)
(1%)

(99%)
(1%)

(99%)
(1%)

97
95
2
0
0
93
92
1
0
0

(98%)
(2%)

(99%)
(1%)

91
91 (100%)
0
0
0

96
92
4
0
0
91
88
3
0
0
88
85
3
0
0

(96%)
(4%)

(97%)
(3%)

(97%)
(3%)

96
91
5
0
0
94
93
1
0
0
93
90
3
0
0

(95%)
(5%)

(99%)
(1%)

(97%)
(3%)

100
99
0
1
0
97
96
1
0
0
98
94
4
0
0

(99%)
(1%)

(99%)
(1%)

(96%)
(4%)

YM2008/00019/00
B2C109575

<=
450 < - <=
480 < - <=
>

450
480
500
500

CONFIDENTIAL

Day 7
n

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Table 8.41
Summary of Maximum Post-Dose QTc(B) Interval (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------------Day 1
n
102
101
101
100
101
102
<= 450
95 (93%)
94 (93%)
96 (95%)
95 (95%)
94 (93%)
92 (90%)
450 < - <= 480
7 (7%)
6 (6%)
5 (5%)
5 (5%)
7 (7%)
7 (7%)
480 < - <= 500
0
1 (<1%)
0
0
0
2 (2%)
> 500
0
0
0
0
0
1 (<1%)

718

<=
450 < - <=
480 < - <=
>

Day 14
n

<=
450 < - <=
480 < - <=
>

Day 28
n

93
86 (92%)
7 (8%)
0
0

93
87 (94%)
6 (6%)
0
0

97
92 (95%)
5 (5%)
0
0

96
88 (92%)
7 (7%)
1 (1%)
0

96
88 (92%)
6 (6%)
2 (2%)
0

100
90 (90%)
9 (9%)
1 (1%)
0

450
480
500
500

91
86 (95%)
5 (5%)
0
0

86
78 (91%)
8 (9%)
0
0

93
85 (91%)
8 (9%)
0
0

91
84 (92%)
6 (7%)
1 (1%)
0

94
83 (88%)
9 (10%)
1 (1%)
1 (1%)

97
87 (90%)
10 (10%)
0
0

450
480
500
500

87
80 (92%)
6 (7%)
1 (1%)
0

85
81 (95%)
4 (5%)
0
0

91
89 (98%)
2 (2%)
0
0

88
81 (92%)
7 (8%)
0
0

93
84 (90%)
9 (10%)
0
0

98
90 (92%)
8 (8%)
0
0

YM2008/00019/00
B2C109575

<=
450 < - <=
480 < - <=
>

450
480
500
500

CONFIDENTIAL

Day 7
n

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 2

Table 8.42
Summary of Maximum Change From Baseline (0-4 hours) in QTc(F) Interval (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------------Day 1
n
102
101
101
100
101
102
< -60
0
0
0
0
0
0
-60 <= - < -30
0
0
0
1 (1%)
0
0
-30 <= - <
0
20 (20%)
23 (23%)
20 (20%)
18 (18%)
18 (18%)
14 (14%)
0 <= - < 30
72 (71%)
66 (65%)
73 (72%)
74 (74%)
75 (74%)
81 (79%)
30 <= - < 60
10 (10%)
10 (10%)
7 (7%)
5 (5%)
8 (8%)
7 (7%)
>= 60
0
2 (2%)
1 (<1%)
2 (2%)
0
0

719

-60
-30
0
30

<=
<=
<=
<=

93
0
1 (1%)
23 (25%)
56 (60%)
13 (14%)
0

93
0
1 (1%)
13 (14%)
65 (70%)
13 (14%)
1 (1%)

97
0
2 (2%)
31 (32%)
55 (57%)
9 (9%)
0

96
0
1 (1%)
21 (22%)
62 (65%)
10 (10%)
2 (2%)

96
0
0
28 (29%)
58 (60%)
9 (9%)
1 (1%)

100
0
0
20 (20%)
63 (63%)
17 (17%)
0

< -60
< -30
<
0
< 30
< 60
>= 60

91
0
1 (1%)
14 (15%)
66 (73%)
10 (11%)
0

86
0
2 (2%)
15 (17%)
59 (69%)
9 (10%)
1 (1%)

93
0
1 (1%)
28 (30%)
56 (60%)
8 (9%)
0

91
0
1 (1%)
21 (23%)
62 (68%)
7 (8%)
0

94
0
0
20 (21%)
64 (68%)
10 (11%)
0

97
0
0
16 (16%)
73 (75%)
8 (8%)
0

Day 14
n
-60
-30
0
30

<=
<=
<=
<=

YM2008/00019/00
B2C109575

< -60
< -30
<
0
< 30
< 60
>= 60

CONFIDENTIAL

Day 7
n

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 2

Table 8.42
Summary of Maximum Change From Baseline (0-4 hours) in QTc(F) Interval (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------------Day 28
n
87
85
91
88
93
98
< -60
0
0
0
0
0
0
-60 <= - < -30
0
1 (1%)
1 (1%)
1 (1%)
1 (1%)
0
-30 <= - <
0
19 (22%)
23 (27%)
23 (25%)
15 (17%)
23 (25%)
18 (18%)
0 <= - < 30
53 (61%)
50 (59%)
55 (60%)
64 (73%)
54 (58%)
65 (66%)
30 <= - < 60
15 (17%)
10 (12%)
12 (13%)
7 (8%)
15 (16%)
15 (15%)
>= 60
0
1 (1%)
0
1 (1%)
0
0

CONFIDENTIAL

720

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 2

Table 8.43
Summary of Maximum Change From Baseline (0-4 hours) in QTc(B) Interval (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------------Day 1
n
102
101
101
100
101
102
< -60
0
0
0
0
0
0
-60 <= - < -30
3 (3%)
0
0
1 (1%)
1 (<1%)
0
-30 <= - <
0
23 (23%)
30 (30%)
30 (30%)
27 (27%)
26 (26%)
19 (19%)
0 <= - < 30
66 (65%)
55 (54%)
59 (58%)
56 (56%)
61 (60%)
69 (68%)
30 <= - < 60
10 (10%)
14 (14%)
11 (11%)
15 (15%)
13 (13%)
14 (14%)
>= 60
0
2 (2%)
1 (<1%)
1 (1%)
0
0

721

-60
-30
0
30

<=
<=
<=
<=

93
0
2 (2%)
26 (28%)
46 (49%)
19 (20%)
0

93
0
1 (1%)
16 (17%)
60 (65%)
14 (15%)
2 (2%)

97
0
4 (4%)
25 (26%)
55 (57%)
13 (13%)
0

96
0
1 (1%)
23 (24%)
55 (57%)
14 (15%)
3 (3%)

96
0
0
25 (26%)
53 (55%)
15 (16%)
3 (3%)

100
0
1 (1%)
15 (15%)
56 (56%)
27 (27%)
1 (1%)

< -60
< -30
<
0
< 30
< 60
>= 60

91
0
2 (2%)
22 (24%)
53 (58%)
13 (14%)
1 (1%)

86
0
2 (2%)
19 (22%)
47 (55%)
17 (20%)
1 (1%)

93
1 (1%)
2 (2%)
28 (30%)
40 (43%)
22 (24%)
0

91
0
2 (2%)
19 (21%)
52 (57%)
18 (20%)
0

94
0
0
22 (23%)
52 (55%)
20 (21%)
0

97
0
0
12 (12%)
61 (63%)
23 (24%)
1 (1%)

Day 14
n
-60
-30
0
30

<=
<=
<=
<=

YM2008/00019/00
B2C109575

< -60
< -30
<
0
< 30
< 60
>= 60

CONFIDENTIAL

Day 7
n

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 2

Table 8.43
Summary of Maximum Change From Baseline (0-4 hours) in QTc(B) Interval (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------------Day 28
n
87
85
91
88
93
98
< -60
0
0
1 (1%)
0
0
0
-60 <= - < -30
2 (2%)
4 (5%)
1 (1%)
3 (3%)
1 (1%)
0
-30 <= - <
0
17 (20%)
27 (32%)
27 (30%)
18 (20%)
22 (24%)
17 (17%)
0 <= - < 30
49 (56%)
39 (46%)
52 (57%)
54 (61%)
49 (53%)
55 (56%)
30 <= - < 60
18 (21%)
13 (15%)
9 (10%)
12 (14%)
20 (22%)
23 (23%)
>= 60
1 (1%)
2 (2%)
1 (1%)
1 (1%)
1 (1%)
3 (3%)

CONFIDENTIAL

722

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 8.44
Summary of Weighted Mean Change From Baseline (0-4 hours) in QTc(F) Interval (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------------Day 1
n
101
101
101
99
101
99
Mean
0.8
0.8
0.9
2.0
0.0
1.9
SD
12.89
12.27
12.71
13.93
11.39
10.91
Median
1.3
-0.1
0.1
2.4
0.3
1.1
Min.
-41
-34
-42
-53
-31
-28
Max.
35
53
37
62
28
38
93
3.9
16.41
3.7
-46
72

97
-2.1
15.94
-0.7
-50
45

94
2.5
20.28
1.2
-68
103

95
-0.4
15.78
-0.4
-33
46

98
1.9
15.85
0.4
-59
38

Day 14

n
Mean
SD
Median
Min.
Max.

87
-0.3
15.58
-3.1
-38
42

86
1.8
18.28
0.4
-69
76

92
-3.0
17.22
-1.4
-71
39

91
0.4
16.87
2.3
-45
39

93
0.7
15.36
1.5
-38
49

96
-0.5
13.59
-1.2
-40
30

Day 28

n
Mean
SD
Median
Min.
Max.

86
1.8
15.50
1.4
-29
36

84
0.6
17.64
-2.3
-40
82

90
-0.9
16.99
1.1
-63
36

88
1.6
15.93
2.1
-39
57

93
1.6
18.06
-0.5
-60
46

97
2.2
15.62
1.0
-35
42

CONFIDENTIAL

93
1.8
16.37
0.9
-40
41

YM2008/00019/00
B2C109575

n
Mean
SD
Median
Min.
Max.

723

Day 7

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 8.45
Summary of Weighted Mean Change From Pre-Dose (0-4 hours) in QTc(F) Interval (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------------Day 7
n
93
93
97
94
95
98
Mean
1.6
1.4
0.1
1.3
1.2
1.4
SD
10.92
11.57
11.29
10.84
12.52
11.52
Median
0.5
2.3
0.4
2.1
1.1
2.1
Min.
-29
-34
-31
-27
-32
-47
Max.
27
33
26
28
30
28
87
1.6
9.96
1.8
-31
25

86
-0.3
9.20
1.0
-26
19

92
-1.0
11.46
-0.9
-32
34

91
1.2
11.86
1.4
-40
32

93
0.5
11.00
0.2
-32
26

96
3.7
12.19
2.8
-21
76

Day 28

n
Mean
SD
Median
Min.
Max.

86
1.2
10.35
1.0
-25
26

84
-1.4
10.42
-0.8
-26
21

90
0.3
13.79
-0.5
-57
57

88
0.8
11.82
1.4
-26
40

93
1.9
11.13
3.1
-34
27

97
1.9
11.51
2.0
-28
31

CONFIDENTIAL

n
Mean
SD
Median
Min.
Max.

724

Day 14

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 8.46
Summary of Weighted Mean Change From Baseline (0-4 hours) in QTc(B) Interval (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------------Day 1
n
101
101
101
99
101
99
Mean
-3.3
-3.9
-3.6
-2.1
-3.1
0.3
SD
15.63
15.68
15.41
17.31
13.44
14.00
Median
-2.8
-4.4
-2.9
-1.5
-2.0
-0.3
Min.
-45
-39
-50
-87
-41
-33
Max.
38
56
32
61
28
46
93
1.9
18.96
1.3
-58
81

97
-2.9
19.11
-0.3
-64
44

94
0.8
23.04
-1.1
-85
92

95
-0.6
19.44
-3.7
-39
64

98
3.8
19.64
4.4
-61
43

Day 14

n
Mean
SD
Median
Min.
Max.

87
-1.7
18.57
-1.4
-46
38

86
0.4
21.02
-0.5
-86
90

92
-3.5
20.76
-1.6
-81
33

91
-0.5
19.96
0.3
-72
38

93
2.1
16.81
3.2
-34
44

96
2.3
17.64
1.7
-46
38

Day 28

n
Mean
SD
Median
Min.
Max.

86
-1.2
18.82
-1.9
-44
38

84
-3.4
21.47
-5.1
-46
94

90
-4.5
19.28
-3.1
-77
28

88
-2.3
18.19
-2.3
-53
58

93
-0.6
20.18
-1.7
-58
45

97
2.4
17.92
1.9
-36
52

CONFIDENTIAL

93
0.8
20.46
-0.4
-52
38

YM2008/00019/00
B2C109575

n
Mean
SD
Median
Min.
Max.

725

Day 7

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 8.47
Summary of Weighted Mean Change From Pre-Dose (0-4 hours) in QTc(B) Interval (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------------Day 7
n
93
93
97
94
95
98
Mean
0.2
-0.1
-2.0
-0.5
-0.4
1.6
SD
13.70
14.01
13.36
13.26
16.44
14.83
Median
-0.5
0.8
-1.8
0.8
0.1
3.0
Min.
-36
-46
-36
-36
-50
-50
Max.
34
33
38
27
40
37
87
0.3
13.56
1.5
-32
31

86
-2.6
13.07
-2.2
-36
28

92
-3.5
13.83
-4.3
-46
35

91
0.2
15.42
1.3
-48
39

93
-0.6
14.30
-1.4
-36
38

96
4.4
14.51
3.4
-28
81

Day 28

n
Mean
SD
Median
Min.
Max.

86
-2.4
13.42
-3.1
-44
36

84
-4.5
13.21
-4.6
-37
25

90
-3.5
16.68
-2.9
-64
54

88
-2.5
14.67
-2.6
-38
49

93
-0.8
14.88
0.2
-48
45

97
0.3
13.76
0.3
-39
31

CONFIDENTIAL

n
Mean
SD
Median
Min.
Max.

726

Day 14

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 16

Table 8.48
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(F) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1, 10 mins
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
102
97
100
99
98
102
LS Mean Change (SE) -1.0 (1.34)
0.2 (1.37)
2.7 (1.34)
1.7 (1.35)
1.4 (1.36)
3.1 (1.34)
Column vs Placebo
Difference
95% C.I.
p-value

1.3
(-2.5, 5.0)
0.516

3.7
(0.0, 7.4)
0.051

2.7
(-1.0, 6.5)
0.152

2.4
(-1.3, 6.2)
0.200

4.1
(0.4, 7.9)
0.030

CONFIDENTIAL

727

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 16

Table 8.48
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(F) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1, 1 hour
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
101
101
100
98
100
100
LS Mean Change (SE) -2.2 (1.43) -0.6 (1.43)
0.6 (1.44)
-0.4 (1.45)
-2.1 (1.43)
0.9 (1.44)
Column vs Placebo
Difference
95% C.I.
p-value

1.6
(-2.4, 5.6)
0.443

2.8
(-1.2, 6.7)
0.174

1.7
(-2.3, 5.7)
0.396

0.1
(-3.9, 4.0)
0.973

3.0
(-1.0, 7.1)
0.136

CONFIDENTIAL

728

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 16

Table 8.48
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(F) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1, 2 hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
101
101
101
98
100
101
LS Mean Change (SE)
1.1 (1.36)
0.9 (1.36)
0.5 (1.36)
1.5 (1.37)
-0.2 (1.36)
3.2 (1.36)
Column vs Placebo
Difference
95% C.I.
p-value

-0.2
(-4.0, 3.6)
0.910

-0.6
(-4.4, 3.2)
0.761

0.4
(-3.4, 4.2)
0.833

-1.3
(-5.0, 2.5)
0.509

2.2
(-1.6, 5.9)
0.266

CONFIDENTIAL

729

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 16

Table 8.48
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(F) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1, 4 hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
101
101
101
99
101
99
LS Mean Change (SE)
3.3 (1.48)
1.5 (1.48)
3.7 (1.48)
4.3 (1.49)
0.0 (1.47)
2.5 (1.49)
Column vs Placebo
Difference
95% C.I.
p-value

-1.8
(-6.0, 2.3)
0.384

0.4
(-3.7, 4.5)
0.854

1.0
(-3.1, 5.1)
0.630

-3.3
(-7.4, 0.8)
0.114

-0.8
(-5.0, 3.4)
0.704

CONFIDENTIAL

730

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 5 of 16

Table 8.48
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(F) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7, 10 mins
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
92
91
95
96
95
100
LS Mean Change (SE) -0.9 (1.70)
2.0 (1.71)
-2.9 (1.67)
1.3 (1.66)
-0.6 (1.67)
4.1 (1.63)
Column vs Placebo
Difference
95% C.I.
p-value

2.9
(-1.9, 7.6)
0.239

-2.0
(-6.7, 2.6)
0.394

2.2
(-2.5, 6.9)
0.356

0.3
(-4.4, 5.0)
0.904

5.0
(0.4, 9.7)
0.035

CONFIDENTIAL

731

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 6 of 16

Table 8.48
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(F) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7, 1 hour
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
93
93
96
95
96
99
LS Mean Change (SE) 0.3 (1.68)
2.7 (1.69)
-2.4 (1.65)
1.5 (1.66)
-0.6 (1.65)
2.3 (1.63)
Column vs Placebo
Difference
95% C.I.
p-value

2.3
(-2.4, 7.0)
0.329

-2.7
(-7.3, 1.9)
0.250

1.2
(-3.4, 5.9)
0.604

-0.9
(-5.6, 3.7)
0.687

2.0
(-2.7, 6.6)
0.403

CONFIDENTIAL

732

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 7 of 16

Table 8.48
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(F) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7, 2 hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
93
93
97
95
96
99
LS Mean Change (SE) 3.7 (1.77)
5.0 (1.77)
0.1 (1.73)
2.8 (1.74)
-0.3 (1.74)
0.6 (1.71)
Column vs Placebo
Difference
95% C.I.
p-value

1.2
(-3.7, 6.2)
0.620

-3.6
(-8.4, 1.3)
0.147

-0.9
(-5.8, 4.0)
0.720

-4.0
(-8.9, 0.8)
0.103

-3.1
(-8.0, 1.7)
0.205

CONFIDENTIAL

733

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 8 of 16

Table 8.48
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(F) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7, 4 hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
93
93
97
94
95
98
LS Mean Change (SE) 2.1 (1.73)
2.7 (1.73)
-0.6 (1.69)
1.3 (1.72)
-0.5 (1.71)
3.5 (1.68)
Column vs Placebo
Difference
95% C.I.
p-value

0.7
(-4.2, 5.5)
0.790

-2.7
(-7.4, 2.1)
0.270

-0.7
(-5.5, 4.1)
0.767

-2.5
(-7.3, 2.2)
0.300

1.4
(-3.4, 6.2)
0.565

CONFIDENTIAL

734

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 9 of 16

Table 8.48
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(F) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14, 10 mins
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
91
85
93
91
92
96
LS Mean Change (SE) 0.1 (1.70)
-0.3 (1.75)
-0.3 (1.67)
0.5 (1.69)
-0.2 (1.68)
2.4 (1.65)
Column vs Placebo
Difference
95% C.I.
p-value

-0.4
(-5.2, 4.4)
0.877

-0.3
(-5.0, 4.3)
0.885

0.4
(-4.3, 5.1)
0.870

-0.3
(-5.0, 4.4)
0.907

2.3
(-2.4, 7.0)
0.338

CONFIDENTIAL

735

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 10 of 16

Table 8.48
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(F) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14, 1 hour
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
90
86
93
91
93
97
LS Mean Change (SE) -1.9 (1.67)
1.6 (1.71)
-2.0 (1.63)
-1.1 (1.65)
1.2 (1.63)
-1.2 (1.60)
Column vs Placebo
Difference
95% C.I.
p-value

3.5
(-1.2, 8.2)
0.149

-0.2
(-4.8, 4.4)
0.944

0.8
(-3.8, 5.4)
0.737

3.0
(-1.5, 7.6)
0.192

0.7
(-3.9, 5.2)
0.777

CONFIDENTIAL

736

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 11 of 16

Table 8.48
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(F) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14, 2 hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
90
86
93
91
93
97
LS Mean Change (SE) 0.2 (1.80)
1.0 (1.84)
-2.4 (1.76)
1.1 (1.77)
0.7 (1.76)
-1.5 (1.72)
Column vs Placebo
Difference
95% C.I.
p-value

0.9
(-4.2, 6.0)
0.731

-2.6
(-7.5, 2.4)
0.307

1.0
(-4.0, 5.9)
0.707

0.5
(-4.4, 5.5)
0.828

-1.6
(-6.5, 3.3)
0.520

CONFIDENTIAL

737

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 12 of 16

Table 8.48
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(F) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14, 4 hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
88
86
92
91
93
97
LS Mean Change (SE) 2.5 (1.73)
1.0 (1.75)
-3.4 (1.68)
0.6 (1.69)
-0.7 (1.67)
1.5 (1.64)
Column vs Placebo
Difference
95% C.I.
p-value

-1.5
(-6.4, 3.4)
0.544

-5.9
(-10.7, -1.2)
0.014

-1.9
(-6.7, 2.9)
0.431

-3.2
(-7.9, 1.5)
0.185

-1.0
(-5.7, 3.7)
0.677

CONFIDENTIAL

738

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 13 of 16

Table 8.48
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(F) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28, 10 mins
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
85
83
90
88
93
95
LS Mean Change (SE) -0.4 (1.81)
-0.6 (1.83)
-0.6 (1.75)
-0.1 (1.77)
2.1 (1.73)
4.1 (1.71)
Column vs Placebo
Difference
95% C.I.
p-value

-0.3
(-5.3, 4.8)
0.922

-0.2
(-5.1, 4.8)
0.943

0.2
(-4.8, 5.2)
0.925

2.5
(-2.4, 7.4)
0.320

4.5
(-0.4, 9.4)
0.072

CONFIDENTIAL

739

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 14 of 16

Table 8.48
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(F) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28, 1 hour
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
87
84
91
88
93
98
LS Mean Change (SE) 0.1 (1.69)
-2.3 (1.72)
-0.2 (1.65)
0.5 (1.67)
-0.7 (1.63)
3.2 (1.59)
Column vs Placebo
Difference
95% C.I.
p-value

-2.4
(-7.1, 2.4)
0.331

-0.3
(-5.0, 4.3)
0.889

0.4
(-4.3, 5.0)
0.881

-0.8
(-5.4, 3.8)
0.742

3.1
(-1.5, 7.7)
0.186

CONFIDENTIAL

740

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 15 of 16

Table 8.48
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(F) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28, 2 hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
87
84
91
88
93
97
LS Mean Change (SE) 1.9 (1.83)
0.9 (1.86)
-1.0 (1.79)
1.7 (1.81)
0.2 (1.77)
2.6 (1.73)
Column vs Placebo
Difference
95% C.I.
p-value

-0.9
(-6.1, 4.2)
0.720

-2.9
(-7.9, 2.1)
0.259

-0.2
(-5.3, 4.9)
0.935

-1.6
(-6.6, 3.4)
0.522

0.7
(-4.2, 5.7)
0.768

CONFIDENTIAL

741

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 16 of 16

Table 8.48
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(F) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28, 4 hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
86
84
90
88
93
97
LS Mean Change (SE) 4.5 (1.88)
1.6 (1.90)
1.8 (1.83)
2.5 (1.85)
3.3 (1.80)
2.6 (1.76)
Column vs Placebo
Difference
95% C.I.
p-value

-3.0
(-8.2, 2.3)
0.268

-2.7
(-7.9, 2.4)
0.295

-2.1
(-7.2, 3.1)
0.438

-1.3
(-6.4, 3.9)
0.630

-1.9
(-7.0, 3.2)
0.455

CONFIDENTIAL

742

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 16

Table 8.49
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(B) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1, 10 mins
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
102
97
100
99
98
102
LS Mean Change (SE) -5.1 (1.69) -2.8 (1.74)
-0.3 (1.70)
-0.8 (1.71)
1.0 (1.72)
4.2 (1.69)
Column vs Placebo
Difference
95% C.I.
p-value

2.3
(-2.5, 7.1)
0.350

4.9
(0.1, 9.6)
0.043

4.3
(-0.4, 9.0)
0.075

6.1
(1.3, 10.8)
0.012

9.3
(4.6, 14.1)
<0.001

CONFIDENTIAL

743

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 16

Table 8.49
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(B) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1, 1 hour
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
101
101
100
98
100
100
LS Mean Change (SE) -7.2 (1.73) -4.3 (1.73)
-3.1 (1.73)
-4.8 (1.75)
-5.2 (1.73)
-0.5 (1.74)
Column vs Placebo
Difference
95% C.I.
p-value

2.8
(-2.0, 7.7)
0.250

4.1
(-0.8, 8.9)
0.099

2.4
(-2.5, 7.2)
0.337

2.0
(-2.8, 6.8)
0.411

6.6
(1.8, 11.5)
0.007

CONFIDENTIAL

744

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 16

Table 8.49
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(B) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1, 2 hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
101
101
101
98
100
101
LS Mean Change (SE) -3.7 (1.66) -4.8 (1.66)
-5.3 (1.65)
-4.0 (1.68)
-4.8 (1.66)
0.9 (1.66)
Column vs Placebo
Difference
95% C.I.
p-value

-1.1
(-5.7, 3.6)
0.646

-1.6
(-6.2, 3.0)
0.494

-0.3
(-4.9, 4.4)
0.908

-1.1
(-5.7, 3.5)
0.643

4.6
(0.0, 9.3)
0.050

CONFIDENTIAL

745

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 16

Table 8.49
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(B) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1, 4 hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
101
101
101
99
101
99
LS Mean Change (SE)
0.8 (1.79) -3.5 (1.79)
-0.7 (1.78)
1.2 (1.80)
-3.8 (1.78)
-0.4 (1.80)
Column vs Placebo
Difference
95% C.I.
p-value

-4.3
(-9.3, 0.7)
0.091

-1.6
(-6.5, 3.4)
0.536

0.4
(-4.6, 5.4)
0.880

-4.7
(-9.6, 0.3)
0.065

-1.2
(-6.2, 3.8)
0.632

CONFIDENTIAL

746

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 5 of 16

Table 8.49
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(B) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7, 10 mins
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
92
91
95
96
95
100
LS Mean Change (SE) -2.4 (1.97)
1.0 (1.98)
-2.0 (1.93)
2.1 (1.92)
1.8 (1.93)
10.1 (1.88)
Column vs Placebo
Difference
95% C.I.
p-value

3.5
(-2.0, 9.0)
0.215

0.5
(-4.9, 5.9)
0.860

4.6
(-0.8, 10.0)
0.096

4.2
(-1.2, 9.6)
0.125

12.5
(7.1, 17.9)
<0.001

CONFIDENTIAL

747

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 6 of 16

Table 8.49
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(B) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7, 1 hour
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
93
93
96
95
96
99
LS Mean Change (SE) -1.9 (2.03)
0.4 (2.03)
-4.3 (1.99)
-0.7 (2.00)
-2.0 (1.99)
3.6 (1.96)
Column vs Placebo
Difference
95% C.I.
p-value

2.3
(-3.3, 8.0)
0.418

-2.4
(-8.0, 3.2)
0.395

1.2
(-4.4, 6.8)
0.664

-0.1
(-5.7, 5.4)
0.965

5.5
(0.0, 11.1)
0.051

CONFIDENTIAL

748

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 7 of 16

Table 8.49
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(B) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7, 2 hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
93
93
97
95
96
99
LS Mean Change (SE) 3.0 (2.09)
2.7 (2.09)
-0.8 (2.04)
1.0 (2.06)
-1.5 (2.05)
0.7 (2.02)
Column vs Placebo
Difference
95% C.I.
p-value

-0.3
(-6.1, 5.5)
0.918

-3.8
(-9.5, 2.0)
0.196

-2.0
(-7.8, 3.8)
0.500

-4.4
(-10.2, 1.3)
0.128

-2.2
(-8.0, 3.5)
0.443

CONFIDENTIAL

749

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 8 of 16

Table 8.49
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(B) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7, 4 hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
93
93
97
94
95
98
LS Mean Change (SE) 2.3 (2.01)
1.6 (2.01)
-2.1 (1.96)
-0.2 (1.99)
0.0 (1.98)
4.8 (1.95)
Column vs Placebo
Difference
95% C.I.
p-value

-0.7
(-6.3, 4.9)
0.804

-4.4
(-9.9, 1.1)
0.120

-2.5
(-8.0, 3.1)
0.385

-2.3
(-7.8, 3.2)
0.416

2.5
(-3.0, 8.0)
0.379

CONFIDENTIAL

750

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 9 of 16

Table 8.49
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(B) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14, 10 mins
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
91
85
93
91
92
96
LS Mean Change (SE) -1.4 (1.98)
-0.4 (2.04)
1.3 (1.95)
1.6 (1.96)
3.7 (1.96)
9.3 (1.92)
Column vs Placebo
Difference
95% C.I.
p-value

1.0
(-4.6, 6.6)
0.724

2.7
(-2.8, 8.2)
0.331

3.1
(-2.4, 8.6)
0.270

5.1
(-0.4, 10.6)
0.067

10.8
(5.3, 16.2)
<0.001

CONFIDENTIAL

751

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 10 of 16

Table 8.49
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(B) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14, 1 hour
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
90
86
93
91
93
97
LS Mean Change (SE) -5.8 (1.98)
-1.0 (2.02)
-3.6 (1.94)
-2.2 (1.96)
2.4 (1.94)
1.5 (1.90)
Column vs Placebo
Difference
95% C.I.
p-value

4.8
(-0.8, 10.4)
0.093

2.2
(-3.2, 7.7)
0.426

3.6
(-1.9, 9.1)
0.199

8.2
(2.7, 13.6)
0.003

7.3
(1.9, 12.8)
0.008

CONFIDENTIAL

752

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 11 of 16

Table 8.49
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(B) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14, 2 hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
90
86
93
91
93
97
LS Mean Change (SE) -0.6 (2.12)
-0.2 (2.17)
-4.0 (2.08)
0.9 (2.10)
2.6 (2.08)
0.9 (2.04)
Column vs Placebo
Difference
95% C.I.
p-value

0.4
(-5.6, 6.4)
0.903

-3.3
(-9.2, 2.5)
0.260

1.5
(-4.4, 7.4)
0.617

3.2
(-2.6, 9.0)
0.280

1.5
(-4.3, 7.4)
0.605

CONFIDENTIAL

753

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 12 of 16

Table 8.49
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(B) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14, 4 hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
88
86
92
91
93
97
LS Mean Change (SE) 2.9 (2.04)
-0.3 (2.06)
-4.2 (1.98)
-0.8 (1.99)
-0.2 (1.97)
2.4 (1.93)
Column vs Placebo
Difference
95% C.I.
p-value

-3.2
(-9.0, 2.5)
0.268

-7.1
(-12.7, -1.5)
0.013

-3.8
(-9.4, 1.9)
0.190

-3.1
(-8.7, 2.4)
0.272

-0.6
(-6.1, 5.0)
0.843

CONFIDENTIAL

754

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 13 of 16

Table 8.49
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(B) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28, 10 mins
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
85
83
90
88
93
95
LS Mean Change (SE) -0.6 (2.03)
-1.6 (2.05)
-1.3 (1.96)
0.2 (1.98)
4.3 (1.93)
10.2 (1.91)
Column vs Placebo
Difference
95% C.I.
p-value

-1.0
(-6.7, 4.7)
0.720

-0.7
(-6.2, 4.9)
0.809

0.8
(-4.7, 6.4)
0.768

4.9
(-0.6, 10.4)
0.081

10.8
(5.3, 16.3)
<0.001

CONFIDENTIAL

755

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 14 of 16

Table 8.49
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(B) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28, 1 hour
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
87
84
91
88
93
98
LS Mean Change (SE) -2.5 (1.90)
-5.5 (1.93)
-3.5 (1.85)
-3.2 (1.88)
-2.6 (1.83)
3.4 (1.79)
Column vs Placebo
Difference
95% C.I.
p-value

-3.0
(-8.3, 2.3)
0.270

-0.9
(-6.2, 4.3)
0.721

-0.7
(-6.0, 4.6)
0.799

0.0
(-5.2, 5.2)
0.991

6.0
(0.8, 11.1)
0.023

CONFIDENTIAL

756

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 15 of 16

Table 8.49
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(B) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28, 2 hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
87
84
91
88
93
97
LS Mean Change (SE) -2.7 (2.10)
-3.9 (2.14)
-5.5 (2.05)
-3.1 (2.08)
-3.1 (2.03)
1.2 (1.99)
Column vs Placebo
Difference
95% C.I.
p-value

-1.3
(-7.2, 4.7)
0.677

-2.8
(-8.6, 2.9)
0.335

-0.5
(-6.3, 5.4)
0.873

-0.4
(-6.2, 5.3)
0.886

3.9
(-1.9, 9.6)
0.186

CONFIDENTIAL

757

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 16 of 16

Table 8.49
Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(B) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28, 4 hours
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
86
84
90
88
93
97
LS Mean Change (SE) 2.1 (2.21)
-2.2 (2.23)
-3.3 (2.15)
-1.5 (2.17)
0.4 (2.12)
1.2 (2.07)
Column vs Placebo
Difference
95% C.I.
p-value

-4.3
(-10.5, 1.9)
0.172

-5.4
(-11.5, 0.6)
0.080

-3.7
(-9.8, 2.5)
0.241

-1.7
(-7.7, 4.3)
0.571

-0.9
(-6.9, 5.0)
0.757

CONFIDENTIAL

758

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 4

Table 8.50
Statistical Analysis of Change from Baseline in Maximum Value (0-4 hrs) QTc(F) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
LS Mean Change (SE)
9.8 (1.28) 11.0 (1.28)
11.8 (1.28)
11.3 (1.28)
9.9 (1.28)
12.1 (1.28)
Column vs Placebo
Difference
95% C.I.
p-value

1.2
(-2.4, 4.7)
0.520

2.0
(-1.6, 5.5)
0.275

1.5
(-2.1, 5.0)
0.416

0.0
(-3.5, 3.6)
0.987

2.2
(-1.3, 5.8)
0.219

CONFIDENTIAL

759

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 4

Table 8.50
Statistical Analysis of Change from Baseline in Maximum Value (0-4 hrs) QTc(F) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
93
93
97
96
96
100
LS Mean Change (SE) 11.0 (1.57)
13.3 (1.57)
7.5 (1.53)
11.6 (1.54)
9.2 (1.54)
12.3 (1.51)
Column vs Placebo
Difference
95% C.I.
p-value

2.3
(-2.1, 6.7)
0.299

-3.5
(-7.8, 0.8)
0.113

0.6
(-3.7, 5.0)
0.775

-1.7
(-6.0, 2.6)
0.432

1.3
(-3.0, 5.7)
0.538

CONFIDENTIAL

760

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 4

Table 8.50
Statistical Analysis of Change from Baseline in Maximum Value (0-4 hrs) QTc(F) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
91
86
93
91
94
97
LS Mean Change (SE) 10.3 (1.51)
10.6 (1.55)
7.7 (1.48)
10.1 (1.50)
10.5 (1.47)
10.5 (1.45)
Column vs Placebo
Difference
95% C.I.
p-value

0.2
(-4.0, 4.5)
0.909

-2.6
(-6.8, 1.5)
0.211

-0.3
(-4.4, 3.9)
0.904

0.1
(-4.0, 4.3)
0.952

0.2
(-3.9, 4.3)
0.926

CONFIDENTIAL

761

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 4

Table 8.50
Statistical Analysis of Change from Baseline in Maximum Value (0-4 hrs) QTc(F) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
87
85
91
88
93
98
LS Mean Change (SE) 11.7 (1.58)
8.9 (1.60)
10.2 (1.55)
10.6 (1.57)
11.7 (1.53)
14.1 (1.49)
Column vs Placebo
Difference
95% C.I.
p-value

-2.8
(-7.3, 1.6)
0.211

-1.5
(-5.9, 2.8)
0.493

-1.1
(-5.5, 3.3)
0.611

-0.1
(-4.4, 4.2)
0.969

2.4
(-1.9, 6.7)
0.278

CONFIDENTIAL

762

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 4

Table 8.51
Statistical Analysis of Change from Baseline in Maximum Value (0-4 hrs) QTc(B) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
102
101
101
100
101
102
LS Mean Change (SE)
9.1 (1.59) 10.3 (1.60)
10.5 (1.60)
10.1 (1.60)
10.0 (1.59)
13.5 (1.59)
Column vs Placebo
Difference
95% C.I.
p-value

1.2
(-3.3, 5.6)
0.608

1.4
(-3.1, 5.8)
0.541

1.0
(-3.5, 5.4)
0.664

0.9
(-3.5, 5.3)
0.693

4.4
(-0.1, 8.8)
0.055

CONFIDENTIAL

763

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 4

Table 8.51
Statistical Analysis of Change from Baseline in Maximum Value (0-4 hrs) QTc(B) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
93
93
97
96
96
100
LS Mean Change (SE) 12.8 (1.86)
15.0 (1.86)
8.8 (1.82)
12.8 (1.83)
13.0 (1.83)
18.0 (1.79)
Column vs Placebo
Difference
95% C.I.
p-value

2.2
(-3.0, 7.4)
0.417

-4.0
(-9.1, 1.1)
0.126

0.0
(-5.2, 5.1)
0.986

0.2
(-4.9, 5.3)
0.943

5.2
(0.1, 10.3)
0.047

CONFIDENTIAL

764

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 4

Table 8.51
Statistical Analysis of Change from Baseline in Maximum Value (0-4 hrs) QTc(B) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
91
86
93
91
94
97
LS Mean Change (SE) 12.3 (1.82)
11.5 (1.87)
10.4 (1.79)
13.6 (1.81)
15.7 (1.78)
17.7 (1.75)
Column vs Placebo
Difference
95% C.I.
p-value

-0.7
(-5.9, 4.4)
0.778

-1.8
(-6.8, 3.2)
0.475

1.3
(-3.7, 6.4)
0.601

3.4
(-1.6, 8.4)
0.177

5.4
(0.5, 10.4)
0.033

CONFIDENTIAL

765

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 4

Table 8.51
Statistical Analysis of Change from Baseline in Maximum Value (0-4 hrs) QTc(B) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
87
85
91
88
93
98
LS Mean Change (SE) 12.3 (1.86)
8.0 (1.88)
9.0 (1.81)
10.0 (1.84)
13.4 (1.79)
18.5 (1.75)
Column vs Placebo
Difference
95% C.I.
p-value

-4.2
(-9.5, 1.0)
0.111

-3.2
(-8.3, 1.9)
0.213

-2.3
(-7.5, 2.9)
0.381

1.1
(-3.9, 6.2)
0.659

6.3
(1.2, 11.3)
0.015

CONFIDENTIAL

766

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 4

Table 8.52
Statistical Analysis of Weighted Mean Change from Baseline (0-4 hrs) QTc(F) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
101
101
101
99
101
99
LS Mean Change (SE)
0.6 (1.12)
0.6 (1.12)
1.6 (1.12)
1.7 (1.13)
-0.4 (1.11)
2.4 (1.13)
Column vs Placebo
Difference
95% C.I.
p-value

0.0
(-3.1, 3.1)
0.996

1.0
(-2.1, 4.1)
0.542

1.1
(-2.0, 4.3)
0.477

-1.0
(-4.1, 2.1)
0.530

1.7
(-1.4, 4.9)
0.278

CONFIDENTIAL

767

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 4

Table 8.52
Statistical Analysis of Weighted Mean Change from Baseline (0-4 hrs) QTc(F) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
93
93
97
94
95
98
LS Mean Change (SE) 1.8 (1.47)
3.5 (1.47)
-1.0 (1.43)
1.9 (1.46)
-0.8 (1.45)
2.2 (1.43)
Column vs Placebo
Difference
95% C.I.
p-value

1.6
(-2.5, 5.7)
0.436

-2.9
(-6.9, 1.2)
0.165

0.0
(-4.1, 4.1)
0.994

-2.6
(-6.7, 1.4)
0.205

0.3
(-3.7, 4.4)
0.870

CONFIDENTIAL

768

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 4

Table 8.52
Statistical Analysis of Weighted Mean Change from Baseline (0-4 hrs) QTc(F) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
87
86
92
91
93
96
LS Mean Change (SE) 0.4 (1.47)
1.0 (1.48)
-2.4 (1.42)
0.3 (1.43)
0.3 (1.42)
-0.4 (1.40)
Column vs Placebo
Difference
95% C.I.
p-value

0.6
(-3.5, 4.7)
0.780

-2.8
(-6.8, 1.2)
0.174

0.0
(-4.1, 4.0)
0.988

0.0
(-4.1, 4.0)
0.981

-0.8
(-4.8, 3.2)
0.687

CONFIDENTIAL

769

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 4

Table 8.52
Statistical Analysis of Weighted Mean Change from Baseline (0-4 hrs) QTc(F) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
86
84
90
88
93
97
LS Mean Change (SE) 1.8 (1.55)
0.1 (1.56)
-0.1 (1.51)
1.3 (1.52)
1.0 (1.48)
2.7 (1.45)
Column vs Placebo
Difference
95% C.I.
p-value

-1.7
(-6.0, 2.7)
0.452

-1.9
(-6.2, 2.3)
0.371

-0.5
(-4.8, 3.8)
0.825

-0.8
(-5.0, 3.4)
0.702

0.9
(-3.3, 5.1)
0.660

CONFIDENTIAL

770

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 4

Table 8.53
Statistical Analysis of Weighted Mean Change from Baseline (0-4 hrs) QTc(B) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
101
101
101
99
101
99
LS Mean Change (SE) -3.4 (1.33) -4.0 (1.33)
-2.9 (1.33)
-2.3 (1.34)
-3.8 (1.32)
0.6 (1.34)
Column vs Placebo
Difference
95% C.I.
p-value

-0.5
(-4.3, 3.2)
0.776

0.5
(-3.1, 4.2)
0.770

1.1
(-2.6, 4.8)
0.561

-0.3
(-4.0, 3.3)
0.852

4.0
(0.3, 7.8)
0.034

CONFIDENTIAL

771

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 4

Table 8.53
Statistical Analysis of Weighted Mean Change from Baseline (0-4 hrs) QTc(B) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
93
93
97
94
95
98
LS Mean Change (SE) 0.9 (1.68)
1.7 (1.69)
-2.0 (1.64)
0.4 (1.67)
-1.0 (1.66)
3.8 (1.64)
Column vs Placebo
Difference
95% C.I.
p-value

0.8
(-3.9, 5.5)
0.731

-2.9
(-7.5, 1.7)
0.215

-0.5
(-5.2, 4.2)
0.831

-1.9
(-6.5, 2.8)
0.429

2.9
(-1.8, 7.5)
0.225

CONFIDENTIAL

772

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 4

Table 8.53
Statistical Analysis of Weighted Mean Change from Baseline (0-4 hrs) QTc(B) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
87
86
92
91
93
96
LS Mean Change (SE) -0.9 (1.67)
-0.5 (1.68)
-3.3 (1.62)
-0.2 (1.62)
1.9 (1.61)
2.0 (1.59)
Column vs Placebo
Difference
95% C.I.
p-value

0.4
(-4.3, 5.1)
0.860

-2.4
(-7.0, 2.2)
0.306

0.6
(-3.9, 5.2)
0.782

2.8
(-1.8, 7.3)
0.230

2.9
(-1.7, 7.4)
0.218

CONFIDENTIAL

773

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 4

Table 8.53
Statistical Analysis of Weighted Mean Change from Baseline (0-4 hrs) QTc(B) (msec)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------n
86
84
90
88
93
97
LS Mean Change (SE) -1.2 (1.71)
-3.5 (1.73)
-4.0 (1.67)
-2.3 (1.68)
-1.2 (1.64)
2.6 (1.61)
Column vs Placebo
Difference
95% C.I.
p-value

-2.3
(-7.1, 2.5)
0.343

-2.8
(-7.5, 1.8)
0.234

-1.2
(-5.9, 3.6)
0.632

0.0
(-4.7, 4.7)
>0.999

3.8
(-0.9, 8.4)
0.109

CONFIDENTIAL

774

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 6
Table 8.54
Summary of Fasting Potassium and Glucose

84
86
87
86
86

5.20
5.16
5.02
5.13
5.16

1.350
1.187
1.019
1.078
0.944

4.90
5.00
4.90
4.90
5.00

3.8
3.9
4.1
4.2
4.3

14.0
13.9
13.4
13.2
12.0

3mcg

101

Day 1

Pre-dose
10 mins
1 hour
2 hours
4 hours

100
98
101
101
99

5.23
5.21
5.19
5.19
5.25

1.462
1.384
1.359
1.280
1.049

5.00
5.00
5.00
5.00
5.00

3.7
4.0
4.0
3.8
3.8

17.2
17.0
17.0
16.2
12.7

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

84
82
84
81
83

5.21
5.13
5.08
5.20
5.17

1.474
1.100
0.824
0.963
0.873

4.90
4.90
4.90
5.00
5.00

3.9
3.9
2.5
4.0
3.7

15.1
12.0
9.4
9.1
9.2

Note: Includes fasting and non-fasting samples.


Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.
Note: Glucose values below 1.1 were set to 0.55.

YM2008/00019/00
B2C109575

Pre-dose
10 mins
1 hour
2 hours
4 hours

775

Day 28

CONFIDENTIAL

Planned
Relative
Lab Test
Treatment
N Visit
Time
n
Mean SD
Median Min. Max.
-------------------------------------------------------------------------------------------Glucose
Placebo
102 Day 1
Pre-dose
100 5.07 1.039 5.00
1.7
13.4
(plasma efficacy)
(MMOL/L)
10 mins
102 5.15 1.161 5.00
3.9
12.7
1 hour
101 5.13 1.135 4.90
4.1
12.8
2 hours
100 5.19 1.152 4.95
3.9
12.8
4 hours
100 5.24 1.092 4.90
4.0
12.7

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 6
Table 8.54
Summary of Fasting Potassium and Glucose

91
89
89
91
88

5.03
5.00
4.95
5.04
5.09

0.674
0.654
0.615
0.871
0.763

4.90
4.90
4.90
4.90
4.95

3.3
3.7
3.9
3.6
3.8

8.1
8.1
8.2
9.3
7.7

12.5mcg

100

Day 1

Pre-dose
10 mins
1 hour
2 hours
4 hours

99
98
98
98
97

5.19
5.16
5.18
5.20
5.25

1.399
1.380
1.225
1.240
1.344

5.00
4.95
5.00
4.90
5.10

3.8
3.8
2.8
3.8
1.8

14.8
14.4
14.0
13.8
14.4

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

89
87
86
88
87

5.20
5.07
5.32
5.33
5.35

0.975
0.974
1.341
1.321
1.329

5.00
4.90
5.00
5.05
5.00

3.5
0.6
1.7
2.3
3.9

11.5
10.4
13.8
13.3
13.9

Note: Includes fasting and non-fasting samples.


Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.
Note: Glucose values below 1.1 were set to 0.55.

YM2008/00019/00
B2C109575

Pre-dose
10 mins
1 hour
2 hours
4 hours

776

Day 28

CONFIDENTIAL

Planned
Relative
Lab Test
Treatment
N Visit
Time
n
Mean SD
Median Min. Max.
-------------------------------------------------------------------------------------------Glucose
6.25mcg
101 Day 1
Pre-dose
100 4.98 0.743 4.90
3.8
8.8
(plasma efficacy)
(MMOL/L)
10 mins
99 4.91 0.700 4.80
3.7
8.6
1 hour
101 4.93 0.763 4.80
3.6
9.5
2 hours
100 4.94 0.826 4.80
3.8
9.5
4 hours
101 5.02 0.731 4.90
3.8
9.5

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 6
Table 8.54
Summary of Fasting Potassium and Glucose

92
92
92
93
92

5.17
5.19
5.16
5.17
5.38

1.194
1.051
0.863
0.684
1.065

5.00
5.10
5.00
5.10
5.10

3.8
3.6
3.9
3.7
3.7

14.3
13.2
11.5
9.4
10.1

50mcg

102

Day 1

Pre-dose
10 mins
1 hour
2 hours
4 hours

99
99
98
97
98

5.24
5.31
5.41
5.43
5.46

1.835
1.710
1.860
1.725
1.528

5.00
5.10
5.10
5.10
5.15

0.6
3.9
4.1
4.0
3.8

20.1
20.2
20.6
18.5
16.5

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

95
94
96
95
94

5.28
5.35
5.41
5.33
5.27

1.770
1.774
1.667
1.575
1.333

4.90
4.95
5.10
5.00
4.95

3.3
3.5
3.5
3.5
2.5

17.4
17.7
17.0
15.3
14.9

Note: Includes fasting and non-fasting samples.


Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.
Note: Glucose values below 1.1 were set to 0.55.

YM2008/00019/00
B2C109575

Pre-dose
10 mins
1 hour
2 hours
4 hours

777

Day 28

CONFIDENTIAL

Planned
Relative
Lab Test
Treatment
N Visit
Time
n
Mean SD
Median Min. Max.
-------------------------------------------------------------------------------------------Glucose
25mcg
101 Day 1
Pre-dose
101 5.11 0.766 5.10
3.4
9.8
(plasma efficacy)
(MMOL/L)
10 mins
100 5.16 0.885 5.10
3.9
9.5
1 hour
99 5.15 0.910 5.00
3.4
10.4
2 hours
100 5.13 0.827 5.10
3.9
9.2
4 hours
100 5.32 0.865 5.20
3.9
8.6

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 6
Table 8.54
Summary of Fasting Potassium and Glucose

Planned
Relative
Lab Test
Treatment
N Visit
Time
n
Mean SD
Median Min. Max.
-------------------------------------------------------------------------------------------Potassium
Placebo
102 Day 1
Pre-dose
89 4.33 0.417 4.30
3.7
5.5
(MMOL/L)
10 mins
93 4.36 0.681 4.20
3.4
6.9
1 hour
97 4.35 0.782 4.20
2.9
8.4
2 hours
94 4.33 0.646 4.20
3.4
7.9
4 hours
91 4.24 0.757 4.10
3.4
8.6
4.36
4.31
4.39
4.41
4.35

0.499
0.496
0.507
0.723
0.647

4.20
4.20
4.30
4.20
4.25

3.7
3.5
3.6
3.5
3.3

6.4
6.6
6.2
7.8
7.8

3mcg

101

Day 1

Pre-dose
10 mins
1 hour
2 hours
4 hours

97
92
97
94
95

4.23
4.32
4.24
4.25
4.17

0.420
0.708
0.480
0.564
0.582

4.20
4.20
4.10
4.10
4.10

3.3
3.2
3.3
2.9
3.1

5.7
8.3
5.7
6.3
6.7

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

80
78
80
77
76

4.19
4.18
4.37
4.38
4.22

0.360
0.403
0.694
0.846
0.597

4.10
4.10
4.20
4.20
4.10

3.6
3.4
3.5
3.5
3.4

5.4
5.7
8.2
9.1
6.5

Note: Includes fasting and non-fasting samples.


Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.
Note: Glucose values below 1.1 were set to 0.55.

CONFIDENTIAL

86
83
84
83
80

YM2008/00019/00
B2C109575

Pre-dose
10 mins
1 hour
2 hours
4 hours

778

Day 28

Protocol: B2C109575
Population: Intent-to-Treat

Page 5 of 6
Table 8.54
Summary of Fasting Potassium and Glucose

Planned
Relative
Lab Test
Treatment
N Visit
Time
n
Mean SD
Median Min. Max.
-------------------------------------------------------------------------------------------Potassium
6.25mcg
101 Day 1
Pre-dose
94 4.21 0.501 4.10
3.2
7.0
(MMOL/L)
10 mins
94 4.24 0.526 4.10
3.5
6.8
1 hour
98 4.24 0.451 4.10
3.6
5.7
2 hours
95 4.26 0.560 4.10
3.1
6.6
4 hours
96 4.34 0.802 4.10
3.3
9.1
4.21
4.24
4.33
4.24
4.20

0.587
0.469
0.567
0.505
0.599

4.20
4.20
4.20
4.20
4.10

3.5
3.3
3.4
3.1
3.3

8.2
5.9
6.1
6.0
7.7

12.5mcg

100

Day 1

Pre-dose
10 mins
1 hour
2 hours
4 hours

95
91
95
93
88

4.27
4.24
4.34
4.28
4.31

0.568
0.578
0.712
0.613
0.884

4.20
4.10
4.20
4.20
4.15

3.4
3.1
3.1
3.5
1.0

6.8
6.6
7.7
6.5
8.3

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

87
85
86
86
83

4.16
4.28
4.28
4.24
4.16

0.389
0.639
0.651
0.551
0.557

4.10
4.20
4.20
4.15
4.00

3.5
3.3
3.4
3.4
3.3

5.7
7.9
8.5
6.7
6.4

Note: Includes fasting and non-fasting samples.


Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.
Note: Glucose values below 1.1 were set to 0.55.

CONFIDENTIAL

86
89
87
83
84

YM2008/00019/00
B2C109575

Pre-dose
10 mins
1 hour
2 hours
4 hours

779

Day 28

Protocol: B2C109575
Population: Intent-to-Treat

Page 6 of 6
Table 8.54
Summary of Fasting Potassium and Glucose

Planned
Relative
Lab Test
Treatment
N Visit
Time
n
Mean SD
Median Min. Max.
-------------------------------------------------------------------------------------------Potassium
25mcg
101 Day 1
Pre-dose
94 4.24 0.486 4.20
2.9
6.4
(MMOL/L)
10 mins
94 4.35 0.734 4.20
2.7
8.3
1 hour
88 4.35 0.755 4.20
2.6
7.3
2 hours
92 4.33 0.665 4.20
2.9
6.5
4 hours
93 4.32 0.721 4.20
3.0
6.8
4.33
4.29
4.42
4.36
4.37

0.466
0.653
0.734
0.610
0.739

4.20
4.10
4.20
4.20
4.10

3.4
2.9
3.4
3.3
3.0

6.1
8.2
7.3
6.7
7.4

50mcg

102

Day 1

Pre-dose
10 mins
1 hour
2 hours
4 hours

95
91
94
92
94

4.42
4.28
4.32
4.24
4.31

0.877
0.654
0.828
0.701
0.826

4.20
4.10
4.10
4.10
4.10

3.3
3.2
3.2
3.1
3.2

9.1
7.0
8.8
7.1
7.6

Day 28

Pre-dose
10 mins
1 hour
2 hours
4 hours

94
89
92
94
92

4.34
4.30
4.34
4.28
4.28

0.728
0.651
0.625
0.630
0.723

4.20
4.10
4.20
4.10
4.10

3.5
3.4
3.5
3.3
3.3

8.3
7.6
6.8
8.1
7.4

Note: Includes fasting and non-fasting samples.


Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.
Note: Glucose values below 1.1 were set to 0.55.

CONFIDENTIAL

89
89
89
92
87

YM2008/00019/00
B2C109575

Pre-dose
10 mins
1 hour
2 hours
4 hours

780

Day 28

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 3
Table 8.55
Summary of Non-Fasting Potassium

Planned
Relative
Lab Test
Treatment
N Visit
Time
n
Mean SD
Median Min. Max.
------------------------------------------------------------------------------------------Potassium
Placebo
102 Day 7
Pre-dose
90 4.24 0.358 4.20
3.5
5.4
(MMOL/L)
10 mins
90 4.18 0.401 4.10
3.5
5.4
1 hour
87 4.19 0.509 4.10
3.4
6.3
2 hours
90 4.10 0.463 4.00
3.1
5.7
4 hours
88 4.04 0.380 4.00
3.3
5.2
4.26
4.27
4.26
4.14
4.17

0.480
0.650
0.674
0.513
0.563

4.20
4.10
4.10
4.00
4.10

3.3
3.2
3.4
3.4
3.4

6.4
7.1
8.6
7.3
7.2

3mcg

101

Day 7

Pre-dose
10 mins
1 hour
2 hours
4 hours

92
91
92
92
93

4.22
4.11
4.13
4.11
4.03

0.404
0.330
0.323
0.421
0.384

4.20
4.10
4.10
4.10
4.00

3.5
3.4
3.5
3.3
3.1

5.7
4.9
5.0
5.7
5.0

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

84
83
85
84
81

4.15
4.07
4.13
4.10
4.02

0.322
0.304
0.427
0.361
0.358

4.10
4.00
4.00
4.00
4.00

3.5
3.5
3.3
3.4
3.4

5.0
4.9
5.8
5.7
5.1

Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.

CONFIDENTIAL

87
86
83
84
86

YM2008/00019/00
B2C109575

Pre-dose
10 mins
1 hour
2 hours
4 hours

781

Day 14

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 3
Table 8.55
Summary of Non-Fasting Potassium

Planned
Relative
Lab Test
Treatment
N Visit
Time
n
Mean SD
Median Min. Max.
------------------------------------------------------------------------------------------Potassium
6.25mcg
101 Day 7
Pre-dose
95 4.22 0.428 4.10
3.2
5.6
(MMOL/L)
10 mins
92 4.10 0.409 4.10
3.4
5.3
1 hour
91 4.11 0.449 4.10
3.2
5.7
2 hours
94 4.08 0.399 4.10
3.2
5.4
4 hours
94 4.04 0.394 4.00
3.2
5.5
4.13
4.11
4.11
4.09
4.01

0.332
0.385
0.382
0.432
0.369

4.10
4.10
4.10
4.00
4.00

3.2
3.1
3.3
3.2
3.2

5.3
5.3
5.4
5.7
5.3

12.5mcg

100

Day 7

Pre-dose
10 mins
1 hour
2 hours
4 hours

92
94
91
92
88

4.21
4.16
4.16
4.06
4.01

0.415
0.470
0.461
0.424
0.489

4.20
4.10
4.10
4.00
4.00

3.2
3.0
3.0
3.1
3.2

6.0
6.5
6.6
6.2
6.2

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

85
87
88
85
86

4.22
4.16
4.13
4.09
4.05

0.364
0.362
0.396
0.445
0.469

4.20
4.10
4.10
4.00
4.00

3.6
3.6
3.3
2.6
3.4

5.8
6.1
6.1
6.1
6.6

Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.

CONFIDENTIAL

92
90
89
91
93

YM2008/00019/00
B2C109575

Pre-dose
10 mins
1 hour
2 hours
4 hours

782

Day 14

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 3
Table 8.55
Summary of Non-Fasting Potassium

Planned
Relative
Lab Test
Treatment
N Visit
Time
n
Mean SD
Median Min. Max.
------------------------------------------------------------------------------------------Potassium
25mcg
101 Day 7
Pre-dose
90 4.27 0.448 4.20
3.3
5.5
(MMOL/L)
10 mins
91 4.20 0.451 4.10
3.3
5.7
1 hour
89 4.18 0.480 4.10
3.2
6.5
2 hours
91 4.11 0.491 4.00
3.1
6.2
4 hours
91 4.11 0.693 4.00
3.1
8.6
4.25
4.17
4.12
4.11
4.10

0.450
0.382
0.429
0.492
0.518

4.20
4.10
4.00
4.00
4.05

3.2
3.2
3.2
3.2
3.2

6.7
5.8
5.8
6.3
6.2

50mcg

102

Day 7

Pre-dose
10 mins
1 hour
2 hours
4 hours

92
94
94
91
93

4.31
4.18
4.16
4.13
4.09

0.567
0.681
0.701
0.753
0.753

4.20
4.10
4.10
4.00
3.90

2.9
3.1
2.2
2.7
2.9

7.2
9.1
9.1
9.1
9.1

Day 14

Pre-dose
10 mins
1 hour
2 hours
4 hours

93
94
94
93
92

4.18
4.18
4.10
4.10
4.02

0.459
0.557
0.442
0.531
0.508

4.10
4.10
4.00
4.10
4.00

3.1
2.9
3.3
3.3
3.0

6.7
7.3
5.9
7.2
6.8

Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.

CONFIDENTIAL

92
88
90
86
88

YM2008/00019/00
B2C109575

Pre-dose
10 mins
1 hour
2 hours
4 hours

783

Day 14

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 6

Table 8.56
Summary of Fasting Potassium and Glucose Changes from Baseline Relative to the Normal Range

Lab Test: Glucose (plasma - efficacy) (MMOL/L)


Planned
Relative
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit Time
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
------------------------------------------------------------------------------------------------------Day 1 10 mins n
102
98
99
98
100
99
To Low
0
0
1
(1%)
0
0
0
To Normal or No
97 (95%)
91 (93%)
95 (96%)
91 (93%)
97 (97%)
95 (96%)
Change
To High
3
(3%)
6
(6%)
2
(2%)
7
(7%)
3
(3%)
3
(3%)
Missing
2
(2%)
1
(1%)
1
(1%)
0
0
1
(1%)

784
2 hours

101
0
94

(93%)

101
0
90

5
2

n
To Low
To Normal or No
Change
To High
Missing

(89%)

101
1
95

(<1%)
(94%)

98
2
90

(5%)
(2%)

10
1

(10%)
(<1%)

4
1

(4%)
(<1%)

6
0

100
0
89

(89%)

101
1
90

(<1%)
(89%)

100
2
93

(2%)
(93%)

98
0
89

(91%)

100
0
88

9
2

(9%)
(2%)

9
1

(9%)
(<1%)

4
1

(4%)
(1%)

8
1

(8%)
(1%)

12
0

(2%)
(92%)
(6%)

99
1
90
8
0

(1%)
(91%)
(8%)

(88%)
(12%)

98
0
89

(91%)

8
1

(8%)
(1%)

97
0
86

(89%)

10
1

(10%)
(1%)

Subjects are counted in the category that their value changes to (low, normal or high), unless there
change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
value became normal, are recorded in the "To Normal or No Change" category.
Includes fasting and non-fasting samples.
Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.
Glucose values below 1.1 were set to 0.55.

YM2008/00019/00
B2C109575

Note:
is no
whose
Note:
Note:
Note:

n
To Low
To Normal or No
Change
To High
Missing

CONFIDENTIAL

1 hour

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 6

Table 8.56
Summary of Fasting Potassium and Glucose Changes from Baseline Relative to the Normal Range

Lab Test: Glucose (plasma - efficacy) (MMOL/L)


Planned
Relative
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit Time
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
------------------------------------------------------------------------------------------------------Day 1 4 hours n
100
99
101
97
100
98
To Low
0
1
(1%)
1 (<1%)
2
(2%)
0
1
(1%)
To Normal or No
86 (86%)
81 (82%)
91 (90%)
83 (86%)
81 (81%)
84 (86%)
Change
To High
12 (12%)
16 (16%)
8
(8%)
11 (11%)
19 (19%)
13 (13%)
Missing
2
(2%)
1
(1%)
1 (<1%)
1
(1%)
0
0

10 mins

(1%)
(85%)

84
0
75

(89%)

91
2
75

(2%)
(82%)

89
1
73

(1%)
(82%)

92
1
83

10
2

(12%)
(2%)

8
1

(10%)
(1%)

13
1

(14%)
(1%)

14
1

(16%)
(1%)

8
0

86
0
77

(90%)

82
0
73

(89%)

89
1
76

(1%)
(85%)

87
1
76

(1%)
(87%)

92
1
81

7
2

(8%)
(2%)

8
1

(10%)
(1%)

11
1

(12%)
(1%)

9
1

(10%)
(1%)

10
0

(1%)
(90%)
(9%)

(1%)
(88%)
(11%)

95
4
78

(4%)
(82%)

11
2

(12%)
(2%)

94
2
83

(2%)
(88%)

8
1

(9%)
(1%)

Subjects are counted in the category that their value changes to (low, normal or high), unless there
change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
value became normal, are recorded in the "To Normal or No Change" category.
Includes fasting and non-fasting samples.
Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.
Glucose values below 1.1 were set to 0.55.

YM2008/00019/00
B2C109575

Note:
is no
whose
Note:
Note:
Note:

n
To Low
To Normal or No
Change
To High
Missing

84
1
71

CONFIDENTIAL

785

Day 28 Pre-dose n
To Low
To Normal or No
Change
To High
Missing

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 6

Table 8.56
Summary of Fasting Potassium and Glucose Changes from Baseline Relative to the Normal Range

Lab Test: Glucose (plasma - efficacy) (MMOL/L)


Planned
Relative
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit Time
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
------------------------------------------------------------------------------------------------------Day 28 1 hour
n
87
84
89
86
92
96
To Low
0
0
0
1
(1%)
0
1
(1%)
To Normal or No
79 (91%)
77 (92%)
80 (90%)
71 (83%)
84 (91%)
80 (83%)
Change
To High
6
(7%)
6
(7%)
8
(9%)
13 (15%)
8
(9%)
13 (14%)
Missing
2
(2%)
1
(1%)
1
(1%)
1
(1%)
0
2
(2%)

786
4 hours

86
0
76

(88%)

81
0
71

8
2

n
To Low
To Normal or No
Change
To High
Missing

(88%)

91
1
81

(1%)
(89%)

88
1
69

(1%)
(78%)

93
1
78

(9%)
(2%)

9
1

(11%)
(1%)

8
1

(9%)
(1%)

17
1

(19%)
(1%)

14
0

86
0
78

(91%)

83
1
73

(1%)
(88%)

88
1
76

(1%)
(86%)

87
0
69

(79%)

92
1
75

6
2

(7%)
(2%)

8
1

(10%)
(1%)

10
1

(11%)
(1%)

17
1

(20%)
(1%)

16
0

(1%)
(84%)
(15%)

(1%)
(82%)
(17%)

95
1
80

(1%)
(84%)

12
2

(13%)
(2%)

94
1
80

(1%)
(85%)

12
1

(13%)
(1%)

Subjects are counted in the category that their value changes to (low, normal or high), unless there
change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
value became normal, are recorded in the "To Normal or No Change" category.
Includes fasting and non-fasting samples.
Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.
Glucose values below 1.1 were set to 0.55.

YM2008/00019/00
B2C109575

Note:
is no
whose
Note:
Note:
Note:

n
To Low
To Normal or No
Change
To High
Missing

CONFIDENTIAL

2 hours

Protocol: B2C109575
Population: Intent-to-Treat

Page 4 of 6

Table 8.56
Summary of Fasting Potassium and Glucose Changes from Baseline Relative to the Normal Range

Lab Test: Potassium (MMOL/L)


Planned
Relative
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit Time
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
------------------------------------------------------------------------------------------------------Day 1 10 mins n
93
92
94
91
94
91
To Low
0
1
(1%)
0
1
(1%)
1
(1%)
3
(3%)
To Normal or No
80 (86%)
86 (93%)
84 (89%)
86 (95%)
85 (90%)
80 (88%)
Change
To High
4
(4%)
2
(2%)
4
(4%)
0
5
(5%)
3
(3%)
Missing
9 (10%)
3
(3%)
6
(6%)
4
(4%)
3
(3%)
5
(5%)

787
2 hours

97
1
81

(1%)
(84%)

97
0
90

(93%)

98
0
89

5
10

(5%)
(10%)

3
4

n
To Low
To Normal or No
Change
To High
Missing

94
0
81
2
11

(91%)

95
0
88

(3%)
(4%)

(86%)

94
0
88

(2%)
(12%)

4
2

(93%)

88
0
77

3
6

(3%)
(6%)

4
3

(94%)

95
1
86

(1%)
(91%)

(4%)
(2%)

3
5

(3%)
(5%)

(88%)

94
2
84

(2%)
(89%)

(4%)
(3%)

6
5

(7%)
(6%)

3
5

(3%)
(5%)

93
0
86

(92%)

92
2
80

(2%)
(87%)

92
3
80

(3%)
(87%)

3
4

(3%)
(4%)

5
5

(5%)
(5%)

5
4

(5%)
(4%)

Subjects are counted in the category that their value changes to (low, normal or high), unless there
change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
value became normal, are recorded in the "To Normal or No Change" category.
Includes fasting and non-fasting samples.
Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.
Glucose values below 1.1 were set to 0.55.

YM2008/00019/00
B2C109575

Note:
is no
whose
Note:
Note:
Note:

n
To Low
To Normal or No
Change
To High
Missing

CONFIDENTIAL

1 hour

Protocol: B2C109575
Population: Intent-to-Treat

Page 5 of 6

Table 8.56
Summary of Fasting Potassium and Glucose Changes from Baseline Relative to the Normal Range

Lab Test: Potassium (MMOL/L)


Planned
Relative
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit Time
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
------------------------------------------------------------------------------------------------------Day 1 4 hours n
91
95
96
88
93
94
To Low
1
(1%)
2
(2%)
1
(1%)
2
(2%)
4
(4%)
1
(1%)
To Normal or No
76 (84%)
89 (94%)
83 (86%)
78 (89%)
79 (85%)
82 (87%)
Change
To High
3
(3%)
2
(2%)
7
(7%)
6
(7%)
5
(5%)
6
(6%)
Missing
11 (12%)
2
(2%)
5
(5%)
2
(2%)
5
(5%)
5
(5%)

10 mins

(84%)

80
0
75

3
11

(94%)

86
0
79

(3%)
(13%)

83
0
70
3
10

(92%)

87
0
81

1
4

(1%)
(5%)

(84%)

78
3
70

(4%)
(12%)

1
4

(93%)

89
0
80

1
6

(1%)
(7%)

(4%)
(90%)

89
1
80

(1%)
(5%)

2
6

(90%)

94
0
86

(91%)

1
5

(1%)
(6%)

2
7

(2%)
(8%)

2
6

(2%)
(6%)

(1%)
(90%)

85
1
76

(1%)
(89%)

89
0
79

(89%)

89
1
79

(1%)
(89%)

(2%)
(7%)

4
4

(5%)
(5%)

3
7

(3%)
(8%)

4
5

(4%)
(6%)

Subjects are counted in the category that their value changes to (low, normal or high), unless there
change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
value became normal, are recorded in the "To Normal or No Change" category.
Includes fasting and non-fasting samples.
Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.
Glucose values below 1.1 were set to 0.55.

YM2008/00019/00
B2C109575

Note:
is no
whose
Note:
Note:
Note:

n
To Low
To Normal or No
Change
To High
Missing

86
0
72

CONFIDENTIAL

788

Day 28 Pre-dose n
To Low
To Normal or No
Change
To High
Missing

Protocol: B2C109575
Population: Intent-to-Treat

Page 6 of 6

Table 8.56
Summary of Fasting Potassium and Glucose Changes from Baseline Relative to the Normal Range

Lab Test: Potassium (MMOL/L)


Planned
Relative
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit Time
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
------------------------------------------------------------------------------------------------------Day 28 1 hour
n
84
80
87
86
89
92
To Low
0
0
1
(1%)
0
0
0
To Normal or No
72 (86%)
73 (91%)
75 (86%)
79 (92%)
73 (82%)
84 (91%)
Change
To High
2
(2%)
4
(5%)
5
(6%)
3
(3%)
9 (10%)
3
(3%)
Missing
10 (12%)
3
(4%)
6
(7%)
4
(5%)
7
(8%)
5
(5%)

789
4 hours

83
0
67

(81%)

77
0
68

n
To Low
To Normal or No
Change
To High
Missing

(88%)

83
2
73

(2%)
(88%)

86
1
79

(1%)
(92%)

92
0
79

6
10

(7%)
(12%)

80
1
66
4
9

(86%)

94
3
84

(3%)
(89%)

5
4

(6%)
(5%)

3
5

(4%)
(6%)

2
4

(2%)
(5%)

6
7

(7%)
(8%)

2
5

(2%)
(5%)

(1%)
(83%)

76
1
68

(1%)
(89%)

84
3
73

(4%)
(87%)

83
1
76

(1%)
(92%)

87
0
76

(87%)

92
4
78

(4%)
(85%)

(5%)
(11%)

3
4

(4%)
(5%)

3
5

(4%)
(6%)

2
4

(2%)
(5%)

5
6

(6%)
(7%)

5
5

(5%)
(5%)

Subjects are counted in the category that their value changes to (low, normal or high), unless there
change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
value became normal, are recorded in the "To Normal or No Change" category.
Includes fasting and non-fasting samples.
Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.
Glucose values below 1.1 were set to 0.55.

YM2008/00019/00
B2C109575

Note:
is no
whose
Note:
Note:
Note:

n
To Low
To Normal or No
Change
To High
Missing

CONFIDENTIAL

2 hours

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 3

Table 8.57
Summary of Non-Fasting Potassium Changes from Baseline Relative to the Normal Range

Lab Test: Potassium (MMOL/L)


Planned
Relative
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit Time
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------------Day 7 Pre-dose
n
90
92
95
92
90
92
To Low
0
0
1
(1%)
1
(1%)
0
1
(1%)
To Normal or No Change 78 (87%) 88 (96%) 85 (89%) 86 (93%) 82 (91%) 84 (91%)
To High
1
(1%)
0
2
(2%)
1
(1%)
2
(2%)
1
(1%)
Missing
11 (12%)
4
(4%)
7
(7%)
4
(4%)
6
(7%)
6
(7%)

790

1 hour

2 hours

90
0
78
2
10

(87%)
(2%)
(11%)

91
1
86
0
4

n
To Low
To Normal or No Change
To High
Missing

87
1
75
1
10

(1%)
(86%)
(1%)
(11%)

92
0
88
0
4

n
To Low
To Normal or No Change
To High
Missing

90
3
77
0
10

(3%)
(86%)
(11%)

92
3
84
1
4

(8%)

94
1
88
0
5

(4%)

91
4
79
2
6

(4%)
(87%)
(2%)
(7%)

91
1
85
1
4

(3%)
(91%)
(1%)
(4%)

94
5
82
1
6

(5%)
(87%)
(1%)
(6%)

92
1
87
0
4

(1%)
(95%)
(4%)

(96%)

92
2
83
0
7

(2%)
(90%)

(5%)

91
0
82
3
6

(1%)
(93%)
(1%)
(4%)

89
0
81
2
6

(91%)
(2%)
(7%)

94
3
84
1
6

91
2
82
1
6

(2%)
(90%)
(1%)
(7%)

91
5
80
2
4

(1%)
(94%)

(1%)
(95%)
(4%)

(90%)
(3%)
(7%)

94
2
85
1
6

(2%)
(90%)
(1%)
(6%)
(3%)
(89%)
(1%)
(6%)
(5%)
(88%)
(2%)
(4%)

Subjects are counted in the category that their value changes to (low, normal or high), unless there
change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
value became normal, are recorded in the "To Normal or No Change" category.
Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.

YM2008/00019/00
B2C109575

Note:
is no
whose
Note:

n
To Low
To Normal or No Change
To High
Missing

CONFIDENTIAL

10 mins

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 3

Table 8.57
Summary of Non-Fasting Potassium Changes from Baseline Relative to the Normal Range

Lab Test: Potassium (MMOL/L)


Planned
Relative
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit Time
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------------Day 7 4 hours
n
88
93
94
88
91
93
To Low
3
(3%)
2
(2%)
5
(5%)
5
(6%)
3
(3%)
5
(5%)
To Normal or No Change 75 (85%) 87 (94%) 81 (86%) 80 (91%) 79 (87%) 80 (86%)
To High
0
0
1
(1%)
0
3
(3%)
2
(2%)
Missing
10 (11%)
4
(4%)
7
(7%)
3
(3%)
6
(7%)
6
(6%)

791

10 mins

1 hour

87
0
75
1
11

(86%)
(1%)
(13%)

84
0
80
0
4

n
To Low
To Normal or No Change
To High
Missing

86
1
72
2
11

(1%)
(84%)
(2%)
(13%)

83
0
79
0
4

n
To Low
To Normal or No Change
To High
Missing

83
1
70
2
10

(1%)
(84%)
(2%)
(12%)

85
1
79
1
4

(95%)
(5%)

92
2
84
0
6

(5%)

90
2
82
0
6

(1%)
(93%)
(1%)
(5%)

89
2
82
1
4

(95%)

(2%)
(91%)
(7%)

85
0
80
0
5

(7%)

87
0
83
0
4

(2%)
(92%)
(1%)
(4%)

88
2
81
0
5

(2%)
(91%)

(94%)
(6%)

(95%)
(5%)
(2%)
(92%)
(6%)

92
1
84
1
6
88
1
80
0
7
90
2
81
0
7

(1%)
(91%)
(1%)
(7%)
(1%)
(91%)
(8%)
(2%)
(90%)
(8%)

93
1
86
1
5

(1%)
(92%)
(1%)
(5%)

94
1
85
2
6

(1%)
(90%)
(2%)
(6%)

94
2
85
1
6

(2%)
(90%)
(1%)
(6%)

Subjects are counted in the category that their value changes to (low, normal or high), unless there
change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
value became normal, are recorded in the "To Normal or No Change" category.
Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.

YM2008/00019/00
B2C109575

Note:
is no
whose
Note:

n
To Low
To Normal or No Change
To High
Missing

CONFIDENTIAL

Day 14 Pre-dose

Protocol: B2C109575
Population: Intent-to-Treat

Page 3 of 3

Table 8.57
Summary of Non-Fasting Potassium Changes from Baseline Relative to the Normal Range

Lab Test: Potassium (MMOL/L)


Planned
Relative
Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Visit Time
Category
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------------Day 14 2 hours
n
84
84
91
85
86
93
To Low
2
(2%)
1
(1%)
3
(3%)
1
(1%)
2
(2%)
2
(2%)
To Normal or No Change 70 (83%) 78 (93%) 80 (88%) 80 (94%) 77 (90%) 84 (90%)
To High
2
(2%)
1
(1%)
2
(2%)
0
2
(2%)
1
(1%)
Missing
10 (12%)
4
(5%)
6
(7%)
4
(5%)
5
(6%)
6
(6%)

792

86
2
72
1
11

(2%)
(84%)
(1%)
(13%)

81
4
74
0
3

(5%)
(91%)
(4%)

93
3
84
0
6

(3%)
(90%)
(6%)

86
1
81
0
4

(1%)
(94%)
(5%)

88
3
78
1
6

(3%)
(89%)
(1%)
(7%)

92
5
80
1
6

(5%)
(87%)
(1%)
(7%)

Subjects are counted in the category that their value changes to (low, normal or high), unless there
change in their category. Subjects whose lab value category was unchanged (e.g., High to High), or
value became normal, are recorded in the "To Normal or No Change" category.
Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.

YM2008/00019/00
B2C109575

Note:
is no
whose
Note:

n
To Low
To Normal or No Change
To High
Missing

CONFIDENTIAL

4 hours

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 8.58
Summary of Maximum Decrease from Baseline in Fasting Potassium (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 1
n
89
97
94
95
94
94
Mean
-0.33
-0.26
-0.23
-0.30
-0.22
-0.35
SD
0.336
0.315
0.434
0.534
0.336
0.798
Median
-0.30
-0.20
-0.10
-0.20
-0.20
-0.25
Min.
-1.3
-1.0
-1.8
-2.6
-1.5
-5.4
Max.
0.5
0.7
0.4
1.4
0.7
4.1
Day 28

77
-0.21
0.379
-0.20
-1.4
1.1

78
-0.19
0.386
-0.10
-1.5
0.8

84
-0.27
0.517
-0.20
-2.7
0.7

84
-0.26
0.518
-0.15
-2.5
0.6

90
-0.43
0.817
-0.20
-5.3
1.0

YM2008/00019/00
B2C109575

Note: Includes fasting and non-fasting samples.


Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.

86
-0.21
0.425
-0.20
-1.5
0.7

CONFIDENTIAL

793

n
Mean
SD
Median
Min.
Max.

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 8.59
Summary of Maximum Decrease from Pre-Dose in Fasting Potassium (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 28
n
85
80
86
86
89
94
Mean
-0.29
-0.16
-0.24
-0.18
-0.32
-0.33
SD
0.454
0.315
0.563
0.288
0.413
0.652
Median
-0.20
-0.10
-0.20
-0.10
-0.20
-0.20
Min.
-1.6
-1.3
-3.9
-1.4
-1.9
-4.3
Max.
0.7
0.6
1.3
0.7
0.5
0.9

CONFIDENTIAL

794

YM2008/00019/00
B2C109575

Note: Includes fasting and non-fasting samples.


Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 8.60
Summary of Maximum Decrease from Baseline in Non-Fasting Potassium (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 7
n
81
89
89
89
88
91
Mean
-0.44
-0.33
-0.33
-0.39
-0.33
-0.50
SD
0.428
0.410
0.549
0.508
0.450
0.741
Median
-0.40
-0.30
-0.30
-0.30
-0.30
-0.40
Min.
-1.6
-1.9
-2.8
-2.7
-1.5
-5.4
Max.
0.4
0.5
0.8
0.8
0.8
1.4
Day 14

78
-0.31
0.487
-0.30
-1.2
1.8

82
-0.36
0.398
-0.35
-1.8
0.4

87
-0.33
0.519
-0.20
-2.9
0.5

84
-0.37
0.546
-0.30
-3.0
0.7

91
-0.56
0.851
-0.40
-5.3
1.2

YM2008/00019/00
B2C109575

Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.

86
-0.36
0.486
-0.30
-1.9
0.7

CONFIDENTIAL

795

n
Mean
SD
Median
Min.
Max.

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 8.61
Summary of Maximum Decrease from Pre-Dose in Non-Fasting Potassium (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 7
n
89
91
93
92
88
91
Mean
-0.33
-0.32
-0.34
-0.33
-0.31
-0.37
SD
0.361
0.307
0.301
0.311
0.302
0.422
Median
-0.30
-0.30
-0.30
-0.20
-0.30
-0.40
Min.
-1.9
-1.5
-1.1
-1.5
-1.0
-1.4
Max.
0.3
0.4
0.3
0.5
0.4
2.4
Day 14

86
-0.26
0.349
-0.25
-1.7
0.8

84
-0.27
0.259
-0.20
-1.0
0.2

92
-0.25
0.289
-0.20
-1.4
0.5

85
-0.33
0.350
-0.20
-1.8
0.3

93
-0.32
0.297
-0.30
-1.4
0.3

YM2008/00019/00
B2C109575

Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.

92
-0.33
0.315
-0.25
-1.1
0.5

CONFIDENTIAL

796

n
Mean
SD
Median
Min.
Max.

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 8.62
Summary of Maximum Increase from Baseline in Glucose (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 1
n
100
100
100
99
101
99
Mean
0.49
0.33
0.27
0.32
0.55
0.48
SD
1.092
0.679
0.686
0.738
1.036
1.117
Median
0.20
0.30
0.20
0.20
0.20
0.30
Min.
-0.9
-2.2
-0.9
-1.7
-1.5
-1.5
Max.
6.1
2.7
4.7
4.0
4.2
7.6
Day 28

85
0.38
0.908
0.30
-1.1
3.9

83
0.25
1.089
0.20
-5.2
4.0

87
0.43
1.066
0.30
-4.4
4.0

93
0.59
1.324
0.30
-4.1
5.9

94
0.55
1.562
0.40
-4.8
11.6

YM2008/00019/00
B2C109575

Note: Includes fasting and non-fasting samples.


Note: Glucose values below 1.1 were set to 0.55.

90
0.48
0.714
0.40
-1.0
2.9

CONFIDENTIAL

797

n
Mean
SD
Median
Min.
Max.

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 8.63
Summary of Maximum Increase from Pre-Dose in Glucose (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 28
n
83
84
91
88
92
94
Mean
0.29
0.27
0.38
0.45
0.55
0.47
SD
0.686
0.775
0.756
1.365
1.023
0.745
Median
0.20
0.25
0.20
0.20
0.30
0.30
Min.
-2.2
-3.1
-0.9
-1.1
-1.1
-1.0
Max.
4.1
2.8
3.6
10.0
4.9
3.5

CONFIDENTIAL

798

YM2008/00019/00
B2C109575

Note: Includes fasting and non-fasting samples.


Note: Glucose values below 1.1 were set to 0.55.

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 8.64
Summary of Weighted Mean Change from Baseline in Fasting Potassium (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 1
n
79
93
90
84
87
89
Mean
0.015
0.003
0.077
0.020
0.091
-0.140
SD
0.4182
0.3152
0.5099
0.4830
0.4102
0.6946
Median
-0.046
-0.054
0.092
-0.019
0.027
-0.075
Min.
-0.89
-0.68
-1.54
-1.46
-0.78
-5.17
Max.
2.25
1.28
1.74
1.48
1.79
1.64
Day 28

69
0.067
0.4668
0.046
-0.86
1.62

70
0.099
0.5072
0.041
-0.92
2.85

76
0.032
0.5935
0.106
-2.33
1.34

78
-0.047
0.5410
-0.020
-2.30
1.13

86
-0.050
0.6773
-0.021
-4.59
1.84

YM2008/00019/00
B2C109575

Note: Includes fasting and non-fasting samples.


Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.

77
0.138
0.4742
0.077
-0.78
1.64

CONFIDENTIAL

799

n
Mean
SD
Median
Min.
Max.

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 8.65
Summary of Weighted Mean Change from Pre-Dose in Fasting Potassium (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 28
n
78
74
81
82
83
91
Mean
-0.016
0.119
0.060
0.057
-0.001
-0.039
SD
0.5011
0.4849
0.5661
0.3556
0.4059
0.5720
Median
0.000
0.024
0.066
-0.012
-0.040
-0.037
Min.
-1.25
-0.87
-3.53
-0.62
-0.97
-3.86
Max.
1.68
2.35
1.65
1.23
1.34
1.12

CONFIDENTIAL

800

YM2008/00019/00
B2C109575

Note: Includes fasting and non-fasting samples.


Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 8.66
Summary of Weighted Mean Change from Baseline in Non-Fasting Potassium (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 7
n
75
87
85
84
81
82
Mean
-0.218
-0.140
-0.151
-0.186
-0.109
-0.302
SD
0.4083
0.4030
0.5569
0.5207
0.4803
0.7846
Median
-0.132
-0.140
-0.100
-0.083
-0.087
-0.143
Min.
-1.26
-1.41
-2.76
-2.48
-1.33
-5.33
Max.
0.78
0.77
0.85
1.15
1.24
1.58
Day 14

72
-0.095
0.5453
-0.121
-1.10
2.12

75
-0.159
0.4103
-0.142
-1.43
0.85

86
-0.135
0.5373
-0.082
-2.73
0.76

77
-0.118
0.4553
-0.085
-2.46
0.89

85
-0.359
0.8583
-0.225
-4.70
2.13

YM2008/00019/00
B2C109575

Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.

82
-0.167
0.4654
-0.113
-1.48
0.81

CONFIDENTIAL

801

n
Mean
SD
Median
Min.
Max.

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 8.67
Summary of Weighted Mean Change from Pre-Dose in Non-Fasting Potassium (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 7
n
85
91
92
87
86
88
Mean
-0.091
-0.117
-0.138
-0.124
-0.105
-0.172
SD
0.3460
0.2987
0.2797
0.2847
0.3097
0.4119
Median
-0.102
-0.095
-0.110
-0.075
-0.109
-0.161
Min.
-1.09
-1.32
-0.91
-0.98
-0.80
-1.01
Max.
0.94
0.78
0.55
0.78
1.04
2.35
Day 14

83
-0.064
0.3847
-0.085
-1.37
1.95

78
-0.056
0.2343
-0.051
-0.63
0.51

92
-0.049
0.2666
-0.040
-0.94
0.84

81
-0.128
0.2855
-0.084
-1.12
0.42

90
-0.084
0.2912
-0.065
-1.01
0.59

YM2008/00019/00
B2C109575

Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.

87
-0.140
0.2822
-0.111
-1.00
0.32

CONFIDENTIAL

802

n
Mean
SD
Median
Min.
Max.

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 8.68
Summary of Weighted Mean Change from Baseline in Glucose (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 1
n
97
98
99
94
99
98
Mean
0.118
-0.018
-0.023
-0.006
0.070
0.169
SD
0.7126
0.6182
0.5083
0.6195
0.5740
0.9904
Median
0.009
0.082
-0.023
0.021
0.001
0.121
Min.
-0.91
-2.34
-2.28
-2.31
-1.77
-2.25
Max.
4.49
1.61
2.02
2.51
1.88
6.45
Day 28

80
-0.057
0.5081
0.018
-1.35
1.26

82
-0.083
1.1318
0.005
-7.48
2.70

86
0.074
0.9454
0.084
-4.86
2.35

91
0.084
0.8351
0.062
-4.40
2.76

91
0.082
1.2058
0.169
-5.82
7.15

YM2008/00019/00
B2C109575

Note: Includes fasting and non-fasting samples.


Note: Glucose values below 1.1 were set to 0.55.

87
0.091
0.5082
0.063
-1.29
1.28

CONFIDENTIAL

803

n
Mean
SD
Median
Min.
Max.

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 8.69
Summary of Weighted Mean Change from Pre-Dose in Glucose (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------Day 28
n
82
83
88
87
91
92
Mean
-0.089
-0.064
-0.013
0.100
0.050
0.049
SD
0.6907
0.8699
0.7006
1.1355
0.7116
0.7074
Median
-0.011
0.004
-0.038
0.000
0.122
0.062
Min.
-4.03
-5.38
-2.44
-1.68
-4.24
-4.15
Max.
1.76
1.55
2.93
8.31
1.41
2.13

CONFIDENTIAL

804

YM2008/00019/00
B2C109575

Note: Includes fasting and non-fasting samples.


Note: Glucose values below 1.1 were set to 0.55.

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 2

Table 8.70
Statistical Analysis of Maximum Decrease from Baseline in Fasting Potassium (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
89
97
94
95
94
94
LS Mean Change (SE) -0.31 (0.041) -0.29 (0.039) -0.28 (0.040) -0.30 (0.040) -0.24 (0.040) -0.28 (0.040)
Column vs Placebo
Difference
95% C.I.
p-value

0.02
(-0.10, 0.13)
0.778

0.03
(-0.08, 0.14)
0.605

0.00
(-0.11, 0.11)
0.970

0.06
(-0.05, 0.18)
0.264

0.03
(-0.09, 0.14)
0.631

CONFIDENTIAL

805

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Note: Includes fasting and non-fasting samples.
Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 2

Table 8.70
Statistical Analysis of Maximum Decrease from Baseline in Fasting Potassium (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
77
78
84
84
86
90
LS Mean Change (SE) -0.18 (0.037) -0.23 (0.037) -0.32 (0.036) -0.27 (0.036) -0.25 (0.035) -0.32 (0.035)
Column vs Placebo
Difference
95% C.I.
p-value

-0.05
(-0.16, 0.05)
0.312

-0.14
-0.09
(-0.24, -0.04) (-0.19, 0.01)
0.006
0.080

-0.07
(-0.17, 0.03)
0.185

-0.14
(-0.25, -0.04)
0.005

CONFIDENTIAL

806

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Note: Includes fasting and non-fasting samples.
Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 2

Table 8.71
Statistical Analysis of Maximum Decrease from Baseline in Non-Fasting Potassium (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
81
89
89
89
88
91
LS Mean Change (SE) -0.41 (0.042) -0.37 (0.040) -0.39 (0.040) -0.39 (0.040) -0.35 (0.040) -0.40 (0.039)
Column vs Placebo
Difference
95% C.I.
p-value

0.04
(-0.08, 0.15)
0.520

0.02
(-0.09, 0.13)
0.717

0.03
(-0.09, 0.14)
0.649

0.06
(-0.05, 0.17)
0.296

0.01
(-0.10, 0.12)
0.837

CONFIDENTIAL

807

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 2

Table 8.71
Statistical Analysis of Maximum Decrease from Baseline in Non-Fasting Potassium (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
78
82
87
84
86
91
LS Mean Change (SE) -0.29 (0.040) -0.40 (0.039) -0.39 (0.038) -0.38 (0.039) -0.39 (0.038) -0.46 (0.037)
Column vs Placebo
Difference
95% C.I.
p-value

-0.11
(-0.22, 0.00)
0.052

-0.11
(-0.22, 0.00)
0.054

-0.09
(-0.20, 0.02)
0.099

-0.11
(-0.22, 0.00)
0.049

-0.17
(-0.28, -0.06)
0.002

CONFIDENTIAL

808

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 2

Table 8.72
Statistical Analysis of Maximum Increase from Baseline in Glucose (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
100
100
100
99
101
99
LS Mean Change (SE)
0.50
0.36 (0.087)
0.25 (0.087)
0.30 (0.088)
0.54 (0.087)
0.50 (0.088)
(0.087)
Column vs Placebo
Difference
95% C.I.
p-value

-0.14
(-0.38, 0.10)
0.259

-0.25
-0.19
(-0.49, -0.01) (-0.43, 0.05)
0.044
0.122

0.05
(-0.20, 0.29)
0.707

0.00
(-0.25, 0.24)
0.996

CONFIDENTIAL

809

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Note: Includes fasting and non-fasting samples.
Note: Glucose values below 1.1 were set to 0.55.

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 2

Table 8.72
Statistical Analysis of Maximum Increase from Baseline in Glucose (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
85
83
90
87
93
94
LS Mean Change (SE) 0.37 (0.114)
0.31 (0.115)
0.42 (0.110)
0.43 (0.112)
0.57 (0.108)
0.57 (0.108)
Column vs Placebo
Difference
95% C.I.
p-value

-0.06
(-0.38, 0.26)
0.716

0.05
(-0.27, 0.36)
0.776

0.06
(-0.26, 0.37)
0.723

0.20
(-0.11, 0.50)
0.213

0.20
(-0.11, 0.50)
0.214

CONFIDENTIAL

810

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Note: Includes fasting and non-fasting samples.
Note: Glucose values below 1.1 were set to 0.55.

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 2

Table 8.73
Statistical Analysis of Weighted Mean Change from Baseline in Fasting Potassium (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
79
93
90
84
87
89
LS Mean Change (SE) 0.036
-0.005
0.032
0.032
0.069
-0.095
(0.0469)
(0.0433)
(0.0439)
(0.0454)
(0.0445)
(0.0445)
Column vs Placebo
Difference
95% C.I.

-0.004
(-0.130,
0.122)
0.954

-0.003
(-0.132,
0.125)
0.959

0.033
(-0.093,
0.160)
0.607

-0.130
(-0.258,
-0.002)
0.046

811

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Note: Includes fasting and non-fasting samples.
Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.

CONFIDENTIAL

p-value

-0.041
(-0.166,
0.085)
0.528

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 2

Table 8.73
Statistical Analysis of Weighted Mean Change from Baseline in Fasting Potassium (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
69
70
76
78
77
86
LS Mean Change (SE) 0.094
0.084
-0.006
-0.034
0.084
0.010
(0.0525)
(0.0522)
(0.0500)
(0.0493)
(0.0497)
(0.0472)
Column vs Placebo
Difference
95% C.I.

-0.100
(-0.243,
0.042)
0.167

-0.128
(-0.270,
0.014)
0.077

-0.010
(-0.153,
0.132)
0.885

-0.084
(-0.224,
0.056)
0.237

812

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Note: Includes fasting and non-fasting samples.
Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.

CONFIDENTIAL

p-value

-0.011
(-0.156,
0.134)
0.883

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 2

Table 8.74
Statistical Analysis of Weighted Mean Change from Baseline in Non-Fasting Potassium (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 7
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
75
87
85
84
81
82
LS Mean Change (SE) -0.188
-0.176
-0.202
-0.184
-0.135
-0.214
(0.0465)
(0.0432)
(0.0435)
(0.0439)
(0.0447)
(0.0445)
Column vs Placebo
Difference
95% C.I.

-0.014
(-0.139,
0.111)
0.827

0.004
(-0.122,
0.131)
0.947

0.053
(-0.074,
0.180)
0.410

-0.025
(-0.152,
0.102)
0.699

813

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.

CONFIDENTIAL

p-value

0.012
(-0.113,
0.137)
0.849

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 2

Table 8.74
Statistical Analysis of Weighted Mean Change from Baseline in Non-Fasting Potassium (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 14
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
72
75
86
77
82
85
LS Mean Change (SE) -0.066
-0.192
-0.191
-0.158
-0.192
-0.236
(0.0469)
(0.0460)
(0.0428)
(0.0452)
(0.0437)
(0.0434)
Column vs Placebo
Difference
95% C.I.

-0.125
(-0.250,
0.000)
0.050

-0.092
(-0.221,
0.036)
0.159

-0.126
(-0.252,
0.000)
0.050

-0.170
(-0.297,
-0.044)
0.009

814

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Note: Potassium values above 9 were set to 9.1 and below 1.9 were set to 0.95.

CONFIDENTIAL

p-value

-0.126
(-0.256,
0.003)
0.056

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 2

Table 8.75
Statistical Analysis of Weighted Mean Change from Baseline in Glucose (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
97
98
99
94
99
98
LS Mean Change (SE) 0.117
0.010
-0.069
0.005
0.064
0.183
(0.0616)
(0.0614)
(0.0608)
(0.0623)
(0.0606)
(0.0613)
Column vs Placebo
Difference
95% C.I.

-0.185
(-0.355,
-0.015)
0.033

-0.111
(-0.283,
0.061)
0.204

-0.053
(-0.222,
0.117)
0.543

0.066
(-0.106,
0.238)
0.451

815

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Note: Includes fasting and non-fasting samples.
Note: Glucose values below 1.1 were set to 0.55.

CONFIDENTIAL

p-value

-0.107
(-0.278,
0.065)
0.222

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 2

Table 8.75
Statistical Analysis of Weighted Mean Change from Baseline in Glucose (0-4 hrs)

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
80
82
87
86
91
91
LS Mean Change (SE) -0.045
-0.041
-0.009
0.099
0.068
0.123
(0.0790)
(0.0777)
(0.0756)
(0.0758)
(0.0738)
(0.0737)
Column vs Placebo
Difference
95% C.I.

0.036
(-0.179,
0.251)
0.741

0.144
(-0.072,
0.359)
0.191

0.113
(-0.100,
0.325)
0.298

0.168
(-0.046,
0.381)
0.123

816

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose measurement on Day 1),
country, sex, age, stratum and treatment
Note: Includes fasting and non-fasting samples.
Note: Glucose values below 1.1 were set to 0.55.

CONFIDENTIAL

p-value

0.004
(-0.214,
0.223)
0.968

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Table 8.76
Summary of Subjects with Asthma Exacerbations

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
---------------------------------------------------------------------------------------------------------Any Asthma Exacerbations
4 (4%)
7 (7%)
2 (2%)
0
3 (3%)
1 (<1%)
1 (<1%)

Hospitalised due to an Exacerbation

ER Visit due to an Exacerbation

1 (<1%)

Corticosteroids or Hospitalised or ER

(2%)

None of the above

(2%)

817

0
0
0
0
1
0
1
0
0
0
1
0
1
0
0
0
0
0

(<1%)
(<1%)

(<1%)
(<1%)

(2%)

1 (<1%)

(2%)

1 (<1%)

(5%)

1 (<1%)

(2%)

(2%)

1 (<1%)

1 (<1%)
0
2 (2%)
0
3 (3%)
0
0
0
0
0
0
0
1 (<1%)
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0
1 (<1%)
1 (<1%)
1 (<1%)
0
0

0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0

0
0
0
1 (<1%)
1 (<1%)
0
0
0
0
0
0
0
0
1 (<1%)
0
0
0

0
0
0
0
0
1 (<1%)
0
0
0
0
0
0
0
0
0
0
0

(2%)

YM2008/00019/00
B2C109575

Primary Cause of Exacerbation


Cold air/Cold weather
Tobacco smoke
Upper respiratory infection
Air pollution
Allergy
Exercise
Stress/Emotions
Beta-blockers
Aspirin
Other NSAIDS
Withholding or reducing asthma meds
Withholding or reducing COPD meds
Unknown etiology
Lack of efficacy
Lower respiratory infection
Common cold
Upper respiratory infection other
than common cold
Other

(3%)

CONFIDENTIAL

Took Corticosteroids for an Exacerbation

CONFIDENTIAL

YM2008/00019/00
B2C109575

Pharmacokinetic Data Source Figures and Tables


Page

Figure 9.1 GW642444 Plasma Concentration-Time Profile Following 3-50 mcg


GW642444M by Study Visit : 3mcg GW642444 . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 9.2 Scatter Plot of Individual Observed GW642444 Cmax (2-30mins
post-dose) vs Patient Demographics : Age . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 9.1 Summary of % of NQ Values by Treatment, Day and Time for
GW642444, Triphenylacetate, GW630200 and GSK932009 (PK
Concentration Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 9.2 Summary (Median [range]) GW642444 Plasma Concentrations by Dose,
Visits and Sample Collection Window (PK Concentration Population) . . . . . . . .
Table 9.3 Summary GW642444 Cmax and tmax (estimated over period 2-10 mins
post-dose) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 9.4 Summary (Median [range]) for Covariate Analysis for Observed
GW642444 Cmax (pg/mL) (estimated over period 2-30 mins post-dose) . . . . . .

818

819
824

827
831
834
835

CONFIDENTIAL
CONFIDENTIAL

Figure 9.1

YM2008/00019/00
YM2008/00019/00
B2C109575
B2C109575

GW642444 Plasma Concentration-Time Profile Following 3-50 g


GW642444M by Study Visit : 3g GW642444M

---- : Lower Limit of quantification (30pg/mL)

819

CONFIDENTIAL
CONFIDENTIAL

Figure 9.1

YM2008/00019/00
YM2008/00019/00
B2C109575
B2C109575

GW642444 Plasma Concentration-Time Profile Following 3-50 g


GW642444M by Study Visit: 6.25 g GW642444M

---- : Lower Limit of quantification (30pg/mL)


820

CONFIDENTIAL
CONFIDENTIAL
Figure 9.1

YM2008/00019/00
YM2008/00019/00
B2C109575
B2C109575

GW642444 Plasma Concentration-Time Profile Following 3-50 g


GW642444M by Study Visit: 12.5 g GW642444M

---- : Lower Limit of quantification (30pg/mL)


821

CONFIDENTIAL
CONFIDENTIAL
Figure 9.1

YM2008/00019/00
YM2008/00019/00
B2C109575
B2C109575

GW642444 Plasma Concentration-Time Profile Following 3-50 g


GW642444M by Study Visit: 25 g GW642444M

---- : Lower Limit of quantification (30pg/mL)


822

CONFIDENTIAL
CONFIDENTIAL
Figure 9.1

YM2008/00019/00
YM2008/00019/00
B2C109575
B2C109575

GW642444 Plasma Concentration-Time Profile Following 3-50 g


GW642444M by Study Visit: 50 g GW642444M

---- : Lower Limit of quantification (30pg/mL)

823

CONFIDENTIAL

Figure 9.2

YM2008/00019/00
B2C109575

Scatter Plot of Individual Observed GW642444 Cmax (2-30mins post-dose) vs Patient Demographics : Age

CONFIDENTIAL

824

YM2008/00019/00
B2C109575

CONFIDENTIAL

Figure 9.2

YM2008/00019/00
B2C109575

Scatter Plot Of Individual GW642444 Observed Cmax (2-30mins post-dose) vs Patient Demographics: Weight

CONFIDENTIAL

825

YM2008/00019/00
B2C109575

CONFIDENTIAL

Figure 9.2

YM2008/00019/00
B2C109575

Scatter Plot of Individual Observed GW642444 Cmax (2-30mins post-dose) vs Patient Demographics : BMI

CONFIDENTIAL

826

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: PK Concentration

Page 1 of 4

Table 9.1
Summary of % of NQ Values by Treatment, Day and Time for
GW642444, Triphenylacetate, GW630200 and GSK932009

Analyte: GW642444
Planned
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
Day
Time
(N=100)
(N=101)
(N=100)
(N=101)
(N=102)
(N=505)
-----------------------------------------------------------------------------------------------------------DAY 1 PRE-DOSE 1 99/99 (100%)
98/99 (99%)
96/99 (97%)
98/100 (98%)
97/98 (99%)
488/495 (99%)
2 - 10 M
95/98 (97%)
82/98 (84%)
48/99 (48%)
21/99 (21%)
12/96 (13%)
258/490 (53%)
10 - 30 M
97/98 (99%)
92/99 (93%)
65/97 (67%)
40/98 (41%)
10/98 (10%)
304/490 (62%)
30 M - 2 H 100/100 (100%) 96/99 (97%)
89/97 (92%)
73/98 (74%)
19/96 (20%)
377/490 (77%)
2 H - 4 H
98/98 (100%)
98/100 (98%)
93/97 (96%)
92/98 (94%)
56/96 (58%)
437/489 (89%)
PRE-DOSE 1

827

93/93 (100%)

92/93 (99%)

93/95 (98%)

90/93 (97%)

83/93 (89%)

451/467 (97%)

DAY 14 2 M - 1 H

75/83 (90%)

57/90 (63%)

34/91 (37%)

24/91 (26%)

21/90 (23%)

211/445 (47%)

DAY 28 PRE-DOSE 1
2 - 10 M
10 - 30 M
30 M - 2 H
2 H - 4 H

80/81
71/81
77/82
81/82
80/80

88/89
51/89
77/88
89/89
87/87

85/89
18/88
37/85
77/86
83/87

83/89 (93%)
9/90 (10%)
18/91 (20%)
42/87 (48%)
72/92 (78%)

86/93 (92%)
9/94 (10%)
3/92 (3%)
3/95 (3%)
17/92 (18%)

422/441
158/442
212/438
292/439
339/438

(99%)
(88%)
(94%)
(99%)
(100%)

(99%)
(57%)
(88%)
(100%)
(100%)

(96%)
(20%)
(44%)
(90%)
(95%)

(96%)
(36%)
(48%)
(67%)
(77%)

CONFIDENTIAL

DAY 7

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: PK Concentration

Page 2 of 4

Table 9.1
Summary of % of NQ Values by Treatment, Day and Time for
GW642444, Triphenylacetate, GW630200 and GSK932009

Analyte: Triphenylacetate
Planned
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
Day
Time
(N=100)
(N=101)
(N=100)
(N=101)
(N=102)
(N=505)
-----------------------------------------------------------------------------------------------------------DAY 1 PRE-DOSE 1 98/98 (100%)
96/96 (100%)
99/99 (100%)
100/100 (100%) 100/100 (100%) 493/493 (100%)
2 - 10 M
97/97 (100%)
99/99 (100%)
99/99 (100%)
99/99 (100%)
96/98 (98%)
490/492 (>99%)
10 - 30 M
98/98 (100%)
99/100 (99%)
99/99 (100%)
98/98 (100%)
99/99 (100%)
493/494 (>99%)
30 M - 2 H 97/98 (99%)
100/100 (100%) 97/97 (100%)
100/100 (100%) 97/97 (100%)
491/492 (>99%)
2 H - 4 H
98/98 (100%)
98/98 (100%)
96/96 (100%)
99/99 (100%)
96/97 (99%)
487/488 (>99%)
PRE-DOSE 1

828

86/86 (100%)

88/88 (100%)

80/80 (100%)

86/86 (100%)

83/83 (100%)

423/423 (100%)

DAY 14 2 M - 1 H

82/83 (99%)

89/89 (100%)

91/91 (100%)

92/92 (100%)

90/91 (99%)

444/446 (>99%)

DAY 28 PRE-DOSE 1
2 - 10 M
10 - 30 M
30 M - 2 H
2 H - 4 H

81/81
81/81
81/82
81/81
81/81

90/90
89/90
90/91
90/90
88/89

89/89
85/86
88/88
86/87
87/87

92/92
90/90
91/91
92/92
91/91

97/97
90/95
95/95
96/97
92/94

449/449
435/442
445/447
445/447
439/442

(100%)
(100%)
(99%)
(100%)
(100%)

(100%)
(99%)
(99%)
(100%)
(99%)

(100%)
(99%)
(100%)
(99%)
(100%)

(100%)
(100%)
(100%)
(100%)
(100%)

(100%)
(95%)
(100%)
(99%)
(98%)

(100%)
(98%)
(>99%)
(>99%)
(>99%)

CONFIDENTIAL

DAY 7

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: PK Concentration

Page 3 of 4

Table 9.1
Summary of % of NQ Values by Treatment, Day and Time for
GW642444, Triphenylacetate, GW630200 and GSK932009

Analyte: GW630200
Planned
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
Day
Time
(N=100)
(N=101)
(N=100)
(N=101)
(N=102)
(N=505)
-----------------------------------------------------------------------------------------------------------DAY 1 PRE-DOSE 1 99/99 (100%)
99/99 (100%)
99/99 (100%)
101/101 (100%) 101/101 (100%) 499/499 (100%)
2 - 10 M
98/98 (100%)
99/99 (100%)
99/99 (100%)
99/99 (100%)
97/97 (100%)
492/492 (100%)
10 - 30 M
98/98 (100%)
99/99 (100%)
98/98 (100%)
98/98 (100%)
99/99 (100%)
492/492 (100%)
30 M - 2 H 100/100 (100%) 99/99 (100%)
97/97 (100%)
98/98 (100%)
96/96 (100%)
490/490 (100%)
2 H - 4 H
98/98 (100%)
100/100 (100%) 97/97 (100%)
98/98 (100%)
96/96 (100%)
489/489 (100%)
PRE-DOSE 1

829

93/93 (100%)

94/94 (100%)

95/95 (100%)

95/95 (100%)

95/95 (100%)

472/472 (100%)

DAY 14 2 M - 1 H

83/83 (100%)

90/90 (100%)

90/91 (99%)

91/91 (100%)

92/92 (100%)

446/447 (>99%)

DAY 28 PRE-DOSE 1
2 - 10 M
10 - 30 M
30 M - 2 H
2 H - 4 H

81/81
81/81
82/82
82/82
80/80

89/89
89/89
88/88
90/90
87/87

89/89
88/88
88/88
88/88
87/87

91/91
91/91
91/91
90/90
92/92

93/93
94/94
93/93
96/96
93/93

443/443
443/443
442/442
446/446
439/439

(100%)
(100%)
(100%)
(100%)
(100%)

(100%)
(100%)
(100%)
(100%)
(100%)

(100%)
(100%)
(100%)
(100%)
(100%)

(100%)
(100%)
(100%)
(100%)
(100%)

(100%)
(100%)
(100%)
(100%)
(100%)

(100%)
(100%)
(100%)
(100%)
(100%)

CONFIDENTIAL

DAY 7

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: PK Concentration

Page 4 of 4

Table 9.1
Summary of % of NQ Values by Treatment, Day and Time for
GW642444, Triphenylacetate, GW630200 and GSK932009

Analyte: GSK932009
Planned
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
Day
Time
(N=100)
(N=101)
(N=100)
(N=101)
(N=102)
(N=505)
-----------------------------------------------------------------------------------------------------------DAY 1 PRE-DOSE 1 99/99 (100%)
98/98 (100%)
99/99 (100%)
101/101 (100%) 101/101 (100%) 498/498 (100%)
2 - 10 M
98/98 (100%)
99/99 (100%)
99/99 (100%)
99/99 (100%)
96/96 (100%)
491/491 (100%)
10 - 30 M
97/97 (100%)
99/99 (100%)
98/98 (100%)
99/99 (100%)
99/99 (100%)
492/492 (100%)
30 M - 2 H 99/99 (100%)
99/99 (100%)
97/97 (100%)
98/98 (100%)
96/96 (100%)
489/489 (100%)
2 H - 4 H
98/98 (100%)
100/100 (100%) 96/96 (100%)
98/98 (100%)
96/96 (100%)
488/488 (100%)
PRE-DOSE 1

830

93/93 (100%)

94/94 (100%)

95/95 (100%)

96/96 (100%)

95/95 (100%)

473/473 (100%)

DAY 14 2 M - 1 H

83/83 (100%)

90/90 (100%)

91/91 (100%)

91/91 (100%)

92/92 (100%)

447/447 (100%)

DAY 28 PRE-DOSE 1
2 - 10 M
10 - 30 M
30 M - 2 H
2 H - 4 H

81/81
81/81
82/82
82/82
81/81

89/89
89/89
88/88
90/90
88/88

89/89
88/88
88/88
88/88
87/87

91/91
91/91
91/91
90/90
92/92

92/93
93/94
91/92
95/96
92/93

442/443
442/443
440/441
445/446
440/441

(100%)
(100%)
(100%)
(100%)
(100%)

(100%)
(100%)
(100%)
(100%)
(100%)

(100%)
(100%)
(100%)
(100%)
(100%)

(100%)
(100%)
(100%)
(100%)
(100%)

(99%)
(99%)
(99%)
(99%)
(99%)

(>99%)
(>99%)
(>99%)
(>99%)
(>99%)

CONFIDENTIAL

DAY 7

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: PK Concentration

Page 1 of 3

Table 9.2
Summary (Median [range]) GW642444 Plasma Concentrations by Dose, Visits and Sample Collection Window
Planned
Relative
No.
Treatment
N
Visit
Time
n
Imputed Median
Range
----------------------------------------------------------------------------------3mcg
100 DAY 1
PRE-DOSE 1
99
99
NQ
NQ - NQ
2 - 10 M
98
95
NQ
NQ - 36.70
10 - 30 M
98
97
NQ
NQ - 165.60
30 M - 2 H 100
100
NQ
NQ - NQ
2 H - 4 H
98
98
NQ
NQ - NQ
93

NQ

NQ - NQ

DAY 14

2 M - 1 H

83

75

NQ

NQ - 58.10

DAY 28

PRE-DOSE 1
2 - 10 M
10 - 30 M
30 M - 2 H
2 H - 4 H

81
81
82
82
80

80
71
77
81
80

NQ
NQ
NQ
NQ
NQ

NQ
NQ
NQ
NQ
NQ

54.70
90.80
201.60
31.00
NQ

6.25mcg

101

DAY 1

PRE-DOSE 1
2 - 10 M
10 - 30 M
30 M - 2 H
2 H - 4 H

99
98
99
99
100

98
82
92
96
98

NQ
NQ
NQ
NQ
NQ

NQ
NQ
NQ
NQ
NQ

173.30
121.70
108.60
81.70
109.10

DAY 7

PRE-DOSE 1

93

92

NQ

NQ - 196.40

DAY 14

2 M - 1 H

90

57

NQ

NQ - 166.30

DAY 28

PRE-DOSE 1
2 - 10 M
10 - 30 M
30 M - 2 H
2 H - 4 H

89
89
88
89
87

88
51
77
89
87

NQ
NQ
NQ
NQ
NQ

NQ
NQ
NQ
NQ
NQ

Lower Limit of Quantification (LLQ) = 30pg/mL, NQ = Non-Quantifiable

71.60
96.60
170.00
NQ
NQ

CONFIDENTIAL

93

YM2008/00019/00
B2C109575

PRE-DOSE 1

831

DAY 7

Protocol: B2C109575
Population: PK Concentration

Page 2 of 3

Table 9.2
Summary (Median [range]) GW642444 Plasma Concentrations by Dose, Visits and Sample Collection Window
Planned
Relative
No.
Treatment
N
Visit
Time
n
Imputed Median
Range
----------------------------------------------------------------------------------12.5mcg
100 DAY 1
PRE-DOSE 1
99
96
NQ
NQ - 144.20
2 - 10 M
99
48
31.500 NQ - 111.50
10 - 30 M
97
65
NQ
NQ - 215.10
30 M - 2 H
97
89
NQ
NQ - 65.70
2 H - 4 H
97
93
NQ
NQ - 126.30
93

NQ

NQ - 180.50

DAY 14

2 M - 1 H

91

34

43.600

NQ - 305.10

DAY 28

PRE-DOSE 1
2 - 10 M
10 - 30 M
30 M - 2 H
2 H - 4 H

89
88
85
86
87

85
18
37
77
83

NQ
55.450
35.400
NQ
NQ

NQ
NQ
NQ
NQ
NQ

172.40
169.10
200.30
79.30
98.30

25mcg

101

DAY 1

PRE-DOSE 1
2 - 10 M
10 - 30 M
30 M - 2 H
2 H - 4 H

100
99
98
98
98

98
21
40
73
92

NQ
60.200
36.500
NQ
NQ

NQ
NQ
NQ
NQ
NQ

60.20
260.70
188.40
106.50
76.70

DAY 7

PRE-DOSE 1

93

90

NQ

NQ - 132.30

DAY 14

2 M - 1 H

91

24

66.300

NQ - 324.90

DAY 28

PRE-DOSE 1
2 - 10 M
10 - 30 M
30 M - 2 H
2 H - 4 H

89
90
91
87
92

83
9
18
42
72

NQ
120.650
61.400
30.200
NQ

Lower Limit of Quantification (LLQ) = 30pg/mL, NQ = Non-Quantifiable

NQ
NQ
NQ
NQ
NQ

171.90
328.10
236.30
107.00
186.60

CONFIDENTIAL

95

YM2008/00019/00
B2C109575

PRE-DOSE 1

832

DAY 7

Protocol: B2C109575
Population: PK Concentration

Page 3 of 3

Table 9.2
Summary (Median [range]) GW642444 Plasma Concentrations by Dose, Visits and Sample Collection Window
Planned
Relative
No.
Treatment
N
Visit
Time
n
Imputed Median
Range
----------------------------------------------------------------------------------50mcg
102 DAY 1
PRE-DOSE 1
98
97
NQ
NQ - 104.40
2 - 10 M
96
12 127.400 NQ - 623.60
10 - 30 M
98
10 113.400 NQ - 587.70
30 M - 2 H
96
19
57.350 NQ - 177.80
2 H - 4 H
96
56
NQ
NQ - 92.90
PRE-DOSE 1

93

83

DAY 14

2 M - 1 H

90

21

166.050

NQ - 701.50

DAY 28

PRE-DOSE 1
2 - 10 M
10 - 30 M
30 M - 2 H
2 H - 4 H

93
94
92
95
92

86
9
3
3
17

NQ
249.800
140.600
71.800
42.450

NQ
NQ
NQ
NQ
NQ

NQ - 505.90

555.30
975.60
516.10
270.90
161.00

YM2008/00019/00
B2C109575

Lower Limit of Quantification (LLQ) = 30pg/mL, NQ = Non-Quantifiable

NQ

CONFIDENTIAL

833

DAY 7

YM2008/00019/00
YM2008/00019/00
B2C109575
B2C109575

CONFIDENTIAL
CONFIDENTIAL

Table 9.3
Summary GW642444 Cmax and tmax (estimated over period 2-10
mins post-dose)
Parameter
(units)
Cmax
(pg/mL)

tmax (h)

Dose
(g)
3

Visit

n*

2
5

100
82

100
82

96
69

Geometric
Mean
NA
NA

6.25

2
5

101
90

96
88

79
50

12.5

2
5

100
89

97
86

25

2
5

101
92

50

2
5
2
5

6.25

95% CI

Median

Range

NA
NA

NC
NC

NC - 165.6
NC - 201.6

NA
NA

NA
NA

NC
NC

NC 121.7
NC - 170.0

40
14

NA
NA

NA
NA

41.0
59.5

NC - 215.1
NC 200.3

98
91

17
9

59.3
95.4

50.5 - 69.7
81.1 112.2

64.8
119.6

NC - 260.7
NC - 328.1

102
97
100
82

93
89
4
13

6
3
96
69

139.1
223.0
ND
ND

117.8 164.1
189.6 262.4
ND
ND

142.1
267.4
0.15
0.15

NC - 623.6
NC - 975.6
0.05 - 0.48
0.05 - 0.50

2
5

101
90

17
38

79
50

ND
ND

ND
ND

0.20
0.17

0.05 - 0.42
0.05 - 0.37

12.5

2
5

100
89

57
72

40
14

ND
ND

ND
ND

0.17
0.17

0.03 - 0.45
0.03 - 0.45

25

2
5

101
92

81
82

17
9

ND
ND

ND
ND

0.17
0.17

0.03 - 0.53
0.05 - 0.47

0.17
ND
ND
6
87
102
2
0.05 0.52
0.17
ND
ND
3
86
97
5
0.05 - 0.48
NC =non calculable due to NQ concentrations
NA = not applicable due to insufficient data to derive summary measure
n = Number of subjects with non-missing values (including NC values)
n* = Number of subjects for whom parameter cannot be derived because of NQ concentrations, NCs were imputed
prior to derivation of summary statistics; No NC values were computed for tmax. Cmax imputed with LLQ (15
pg/mL).
50

834

YM2008/00019/00
YM2008/00019/00
B2C109575
B2C109575

CONFIDENTIAL
CONFIDENTIAL
Table 9.4

Summary (Median [range]) for Covariate Analysis for Observed


GW642444 Cmax (pg/mL) (estimated over period 2-30 mins postdose)
SEX

Visit 2 (Day1)

Males (M)
Females (F)

Visit 5 (Day28)

Males (M)
Females (F)

STRATA
Visit 2 (Day1)

Lower (L)
(65-90)
Upper (U)
(40-65)

Visit 5 (Day28)

Lower (L)
(65-90)
Upper (U)
(40-65)

12.5 g GW642444
(M44/F56)
42.6
[NC-98.8]
39.6
[NC-215.1]
12.5 g
(M37/F52)
62
[NC-200.3]
59.5
[NC-128.5]

25 g GW642444
(M40/F61)
47.5
[NC-133.3]
74.8
[NC-260.7]
25 g
(M36/F57)
98.4
[NC-325.9]
127
[NC-328.1]

50 g GW642444
(M45/F56)
133.6
[NC-412.4]
158.1
[NC-623.6]
50 g
(M44/F53)
215.1
[NC-647.4]
287.1
[NC-975.6]

12.5 g
(L58/U42)
47.8
[NC-215.1]
NC
[NC-98.8]
12.5 g
(L53/U36)
62.7
[NC-169.1]
49.5
[NC-200.3]

25 g
(L54/U47)
88.4
[NC-208.3]
44.2
[NC-260.7]
25 g
(L50/F43)
127.7
[NC-256.4]
92.3
[NC-328.1]

50 g
(L56/U45)
186.5
[NC-623.6]
131.0
[NC-423.4]
50 g
(U49/F40)
271.3
[NC-975.6]
266.9
[NC-471.9]

835

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Pharmacokinetic & Pharmacodynamic Data Source Figs and Tables


Page

Figure 9.3 Scatter Plots Of Systemic PD Endpoints versus GW642444 Cmax


(2-30mins post-dose): Pulse Rate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 9.4 Dose-Response for trough FEV1 (ITT population) at Day 28 ? OverlayObserved LSMean difference from placebo with Model simulated LSMean
profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 9.5 Distribution of Likely Response at Day 28 Trough (OD Dosing) ? diff
from placebo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 9.6 K-PD model based simulations versus observed time course of FEV1
for placebo and GW642444 25 mcg on day 28 . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 9.7 K-PD model based simulations of time course of FEV1 for placebo and
od versus bid GW642444 at steady state . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 9.8 Therapeutic Index mapping dose-response for efficacy and safety Day
28 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 9.9 Diagnostics-Goodness of fit for trough dose-response (Final) . . . . . . . . .
Figure 9.10 Visual Predictive Checks (Final) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 9.11 Observed Time course of LSMean FEV1 by dose (mcg) and day . . . . .
Figure 9.12 Observed Time course of LSMean FEV1 by dose (ug) and day . . . . . .
Figure 9.13 K-PD Model Diagnostics ? Residuals . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 9.14 K-PD Model Diagnostics ? Residuals . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 9.15 Distribution of standardised random effects by parameter . . . . . . . . . . .
Figure 9.16 Individual observed (symbol) and K-PD model predictions X-axis :
Time (h) on day 28 Y-axis : Fev1 (L) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 9.17 Individual observed (symbol) and K-PD model predictions X-axis :
Time (h) on day 28 Y-axis : Fev1 (L) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 9.18 Individual observed (symbol) and K-PD model predictions X-axis :
Time (h) on day 28 Y-axis : Fev1 (L) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 9.5 Dose-Response Model Parameters for trough FEV1 change from
Baseline on Day 28 (ITT Population Model) . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 9.6 Expected Response at a Certain Dose (OD Dosing) - adjusted for
placebo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 9.7 Probability (%) that a Certain Dose Will Exceed the Target Response
(OD Dosing) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 9.8 K-PD Model Characterising time course of FEV1 in asthmatic patients . .
Table 9.9 Output from Dose-Response Model Selection . . . . . . . . . . . . . . . . . . . . . .
Table 9.10 Covariate Selection for Dose Response Model . . . . . . . . . . . . . . . . . . . .
Table 9.11 Median [95%CI] DUR>=150mL parameter by dose. . . . . . . . . . . . . . . . .

836

837

842
843
844
845
846
847
848
849
850
851
852
853
854
855
856
857
858
859
860
861
862
863

CONFIDENTIAL

Figure 9.3

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Scatter Plots Of Systemic PD Endpoints versus GW642444 Cmax (2-30mins post-dose): Pulse Rate

CONFIDENTIAL

837

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CONFIDENTIAL

Figure 9.3

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Scatter Plots of Systemic PD Endpoints versus GW642444 Cmax (2-30mins post-dose): QTc(B)

CONFIDENTIAL

838

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Figure 9.3

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Scatter Plots of Systemic PD Endpoints and GW642444 Cmax (2-30mins post-dose): QTc(F)

CONFIDENTIAL

839

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CONFIDENTIAL

Figure 9.3

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Scatter Plot of Systemic PD Endpoints and GW642444 Cmax (2-30mins post-dose): Fasting Potassium

CONFIDENTIAL

840

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CONFIDENTIAL

Figure 9.3

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Scatter Plots of Systemic PD endpoints versus GW642444 Cmax (2-30mins post-dose): Glucose

CONFIDENTIAL

841

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Figure 9.4

Dose-Response for trough FEV1 (ITT population) at Day 28


Overlay- Observed LSMean difference from placebo with Model
simulated LSMean profile

LSMean difference from Placebo FEV1 (L)

0.30

LSMean [95 CIs]


Model fitted

0.25
0.20
0.15
0.10
0.05
0.00
-0.05
ED50: 16.1ug [95%CI: 12.5-19.7]

10

20

30

OD Dose (ug)
Source data: Figure 9.4

842

40

50

CONFIDENTIAL

Figure D.4

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Distribution of Likely Response at Day 28 Trough (OD Dosing)


diff from placebo

Source data: Figure 9.5

843

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Figure 9.6

0.40

K-PD model based simulations versus observed time course of FEV1


for placebo and GW642444 25 g on day 28
LSMean Obs
Mean model

Day 28 Placebo

Change from baseline FEV1 (L)

0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
-0.05
0

10

12

14

16

18

20

22

24

26

Time (h)

0.40

Day 28 25ug

Change from baseline FEV1 (L)

0.35
0.30
0.25

LSMean Obs
Mean model

0.20
0.15
0.10
0.05
0.00
-0.05
0

Source data: Figure 9.6

10

12

14

16

18

20

Time (h)

844

22

24

26

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CONFIDENTIAL

Figure 9.7

K-PD model based simulations of time course of FEV1 for placebo and
od versus bid GW642444 at steady state

0.50

'444 12.5ug bd
'444 25ug od
Obs Placebo '575
Modelled Placebo '575

Change from base FEV1 (L)

0.45
0.40
0.35
0.30
0.25
0.20
0.15

plac obs
plac simulate

0.10
0.05
0.00
0

10

12

14

16

Time (h) Steady state


Source data: Figure 9.7

845

18

20

22

24

26

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CONFIDENTIAL

Therapeutic Index mapping dose-response for efficacy and safety Day


28

15
14
13
12
11
10
9
8
7
6
5
4
3
2
1
0
-1
-2
-3

0.30

Trough LSMean FEV1 diff drom placebo (L)

FEV1 Obs LSMean [95CIs]


LSMean Model Fitted

0.25

Threshold Max HR

0.20
0.15
0.10
0.05

Max HR

0.00

-0.05
0

10

20

30

OD Dose (ug)
Source data: Figure 9.8

846

40

50

LSMean Max HR diff from placebo (bts/min)

Figure 9.8

CONFIDENTIAL

Figure 9.9

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Diagnostics-Goodness of fit for trough dose-response (Final)

This section contained data from each individual patient, rather than in aggregate. They have been
excluded to protect patient privacy. Anonymized data from each patient may be made available
subject to an approved research proposal. For further information please see the Patient Level Data
section of the GSK Clincal Study Register.

Source data: Figure 9.9

847

CONFIDENTIAL

Figure 9.10

Visual Predictive Checks (Final)

Source data: Figure 9.10

848

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CONFIDENTIAL

Figure 9.11

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Observed Time course of LSMean FEV1 by dose (ug) and day

Source data: Figure 9.11

849

CONFIDENTIAL

Figure 9.12

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Observed Time course of LSMean FEV1 by dose (ug) and day

Source data: Figure 9.12

850

CONFIDENTIAL

Figure 9.13

K-PD Model Diagnostics Residuals

Source data: Figure 9.13

851

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CONFIDENTIAL

Figure 9.14

K-PD Model Diagnostics Residuals

Source data: Figure 9.14

852

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CONFIDENTIAL

Figure 9.15

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Distribution of standardised random effects by parameter

Source data: Figure 9.15

853

CONFIDENTIAL

Figure 9.16

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Individual observed (symbol) and K-PD model predictions


X-axis : Time (h) on day 28
Y-axis : Fev1 (L)

This section contained data from each individual patient, rather than in aggregate. They have been
excluded to protect patient privacy. Anonymized data from each patient may be made available subject to
an approved research proposal. For further information please see the Patient Level Data section of the
GSK Clincal Study Register.

Source data: Figure 9.16

854

CONFIDENTIAL

Figure 9.17

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Individual observed (symbol) and K-PD model predictions


X-axis : Time (h) on day 28
Y-axis : Fev1 (L)

This section contained data from each individual patient, rather than in aggregate. They have been
excluded to protect patient privacy. Anonymized data from each patient may be made available
subject to an approved research proposal. For further information please see the Patient Level Data
section of the GSK Clincal Study Register.

Source data: Figure 9.17

855

CONFIDENTIAL

Figure 9.18

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Individual observed (symbol) and K-PD model predictions


X-axis : Time (h) on day 28
Y-axis : Fev1 (L)

This section contained data from each individual patient, rather than in aggregate. They
have been excluded to protect patient privacy. Anonymized data from each patient may be
made available subject to an approved research proposal. For further information please
see the Patient Level Data section of the GSK Clincal Study Register.

Source data: Figure 9.18

856

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Table 9.5
Dose Response Model Parameters for trough FEV1 change from
Baseline on Day 28 (ITT Population Model)

Parameters
Emax (L)
ED50 (g)
E0 (L) Placebo
Age on E0 (L/yr)
Baseline on E0
Gender on E0
Residual Error

Value
% RSE
0.243
20
16.1
11
0.733
18
-0.392
12
2.65
21
-0.166
24
Proportional: CV 12%
Additive: Standard Deviation 0.1

857

5th CI
0.149
12.5
0.480
-0.482
1.57
-0.245

95th CI
0.337
19.7
0.986
-0.302
3.73
-0.087

CONFIDENTIAL
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Table 9.6

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Expected Response at a Certain Dose (OD Dosing) adjusted for


placebo
Change from baseline FEV1 at trough (mL)
Dose (g)
3
6.25
12.5
25
50

Expected response
37
68
106
148
184

858

90% chance response is between


-24 - 99
5 - 130
45 - 167
85 - 210
122 - 246

CONFIDENTIAL
CONFIDENTIAL
Table 9.7

Dose (g)
3
6.25
12.5
25
50

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Probability (%) that a Certain Dose Will Exceed the Target Response
(OD Dosing)
100 mL
5
19
56
90
99

Change from baseline FEV1 at trough (Day 28)


150 mL
0.1
2
12
48
81

859

200 mL
0
0
0.7
9
33

CONFIDENTIAL
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Table 9.8

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K-PD Model Characterising time course of FEV1 in asthmatic


patients

Parameters
Value
Rm (L)
14.7
Baseline effect on Rm
0.414
Tz (h)
0.041
Tz1 (h)
2.41
Ramp
0.033
Ramp1
0.014
Kout (1/h)
16.1
EDK50 (ug)
15.9
Kde (1/h)
0.027
Emax (L)
0.275
Inter-patient variability
()
Value (CV%)
0.102 (32%)
Rm
8.99 (300%)
Tz
0.339 (58%)
Tz1
0.392 (63%)
Ramp
0.736 (86%)
Ramp1
0.149 (39%)
Kout
2.99 (173%)
EDK50
1.38 (117)
kde
0.358 (60%)
Ka
1.30 (114%)
Emax
Residual error (additive)
Value (SD)
0.131

SE : precision of parameter estimates. r.s.e : relative SE (%).

860

Standard Error (SE)


0.260
0.007
0.016
0.036
0.001
0.001
0.110
2.10
0.002
0.015

r.s.e. (%)
2
2
39
1
2
3
1
13
6
6

Standard Error (SE)


0.004
0.083
0.011
0.013
0.024
0.005
0.091
0.043
0.012
0.040
Std error (s.e.).
0.001

r.s.e.(%)
4
1
3
3
3
3
3
3
3
3
r.s.e.(%)
1

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Table 9.9

Output from Dose-Response Model Selection

Model
1

Description
Step

Step-Linear

Emax

Emax

Sigmoid Emax

Parameter
1 (L)
2
1
2
1
1
2
3
2
1
1
2
3
1
2
3
1
2
1
2
3
1
1
2
1
2
3
1
Gam
1
2

Definition
Intercept
Dose effect
Baseline variability
Drug eff. variab. shift
Additive error

Value
2.24
0.177
30%
105%
0.0527

Intercept
Dose effect
Slope D-R
Ind. Baseline shift
Additive error

OFV
245

Comments
FOCEI
Successful
Covariance

2.42
0.132
0.0022
31%
0.045

243

FOCEI
No
Covariance

Intercept
Emax
ED50
Indiv baseline shift
Indiv shift ED50
Indiv shift Emax
Additive Error
Exponential

2.22
0.236
2.95
29%
10%
0.10%
0.0705
0

240

FOCEI
No
Covariance
Overparameterise

Intercept
Emax
ED50
Indiv baseline shift
Additive Error
Exponential

2.22
0.236
0.295
29%
0.266
9%

240

FOCEI
Successful
Covariance
High Error on
ED50

Intercept
Emax
ED50
Indiv baseline shift
Slope of D-R
Additive Error
Exponential

0.343
0.15
3.96
89%
0.0128
0.01
26%

230

FOCEI
No
Covariance

861

SE(%)
3.4
46
10
50

3
46
147
14
39
42

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CONFIDENTIAL
CONFIDENTIAL
Table 9.10

Covariate Selection for Dose Response Model

Model

Description

Parameter

Definition

Value

SE
(%)

OFV

Comments

Model #4
Age on 1
Model #4
Base on 1
Model #4
Gender on 1
Model #4
Full Model

_age

Age on 1

-0.008

4.1

11.5

_base

Base on 1

5.18

-631

_gender

Gender on 1

-0.27

89

_age
_base
_gender
_gender
_base
_age
_gender
_age
_base
_age
_base
_gender

Age on 1
Base on 1
Gender on 1
Gender on 1
Base on 1
Age on 1
Gender on 1
Age on 1
Base on 1
Age on 1
Base on 1
Gender on 1

-0.39
2.65
-0.166

18
21
24
-

-688

FOCE1
Covariance OK
FOCE1
No Covariance
FOCE1
Covariance OK
FOCE1
Covariance OK

7
8
9

10
12
13
14

Model #4
Reduced Model
Model #4
Reduced Model
Model #4
Reduced Model
Model #9
Final Model
ED50=0

862

-0.32
-0.166
-0.488
4.26
-0.453
2.91
-0.188

-637

-674

14
24
26

-675

FOCE1
No Covariance
FOCE1
No Covariance
FOCE1
No Covariance
FOCE1
Covariance OK

CONFIDENTIAL
CONFIDENTIAL
Table 9.11

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Median [95%CI] DUR150mL parameter by dose

Dose (g)

DUR 150 mL Median


Time (h)

0
3
6.25
12.5
25
50

86
83
90
88
89
98

6.9
13.6
20.9
19.5
23
22.6

95th CI Median
5th
4.2
10.9
18.2
17.1
20.6
20.2

863

95th
9.6
16.3
23.6
22.0
25.4
25.0

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CONFIDENTIAL

ATTACHMENT 1: MEDICAL CONDITIONS AT SCREENING


Summary of Current Medical Conditions (ITT Population)
Number of
subjects, n (%)

Placebo

Total

n=102
84 (82)

3 g
GW642444M
n=101
79 (78)

6.25 g
GW642444M
n=101
76 (75)

12.5 g
GW642444M
n=100
86 (86)

25 g
GW642444M
n=101
78 (77)

50 g
GW642444
n=102
82 (80)

Respiratory,
thoracic and
mediastinal
disorders
Nervous system
disorders
Musculoskeletal
and connective
tissue disorders
Hypersensitivity /
anaphylaxis
related
Gastrointestinal
disorders
Immune system
disorders
Cardiac disorders

45 (44)

38 (38)

41 (41)

49 (49)

36 (36)

48 (47)

23 (23)

15 (15)

23 (23)

20 (20)

22 (22)

21 (21)

20 (20)

23 (23)

20 (20)

26 (26)

16 (16)

18 (18)

20 (20)

15 (15)

15 (15)

15 (15)

17 (17)

25 (25)

107
(18)

16 (16)

12 (12)

12 (12)

19 (19)

13 (13)

17 (17)

9 (9)

21 (21)

12 (12)

15 (15)

13 (13)

16 (16)

14 (14)

18 (18)

13 (13)

11 (11)

15 (15)

13 (13)

Skin and
subcutaneous
tissue disorders
Eye disorders
Vascular
disorders
Endocrine
disorders
Psychiatric
disorders
Metabolism and
nutrition disorders
Blood and
lymphatic system
disorders
Ear and labyrinth
disorders
Renal and urinary
disorders
Neoplasms
benign, malignant
and unspecified
(incl cysts and
polyps)
Infections and
infestations
Source Table 6.14.

13 (13)

16 (16)

7 (7)

12 (12)

9 (9)

16 (16)

89
(15)
86
(14)
84
(14)
73
(12)

10 (10)
13 (13)

5 (5)
5 (5)

11 (11)
8 (8)

11 (11)
11 (11)

8 (8)
10 (10)

12 (12)
9 (9)

57 (9)
56 (9)

10 (10)

8 (8)

10 (10)

5 (5)

4 (4)

12 (12)

49 (8)

8 (8)

6 (6)

5 (5)

8 (8)

4 (4)

6 (6)

37 (6)

7 (7)

5 (5)

5 (5)

6 (6)

9 (9)

5 (5)

37 (6)

4 (4)

3 (3)

3 (3)

5 (5)

6 (6)

21 (3)

5 (5)

1 (<1)

3 (3)

3 (3)

2 (2)

6 (6)

20 (3)

5 (5)

1 (<1)

3 (3)

6 (6)

2 (2)

1 (<1)

18 (3)

2 (2)

2 (2)

1 (<1)

2 (2)

1 (<1)

8 (1)

1 (<1)

2 (2)

3 (<1)

Any condition

-1864

n=607
485
(80)
257
(42)
124
(20)
123
(20)

CONFIDENTIAL
CONFIDENTIAL

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ATTACHMENT 2: INDIVIDUAL POTASSIUM PROFILES FOR


SUBJECTS WITH VALUES >7 MMOL/L
Elevated potassium levels of greater than 7 mmol/L were recorded for 34 subjects on at
least one of the 0-4 h time points on Days 1, 7, 14, 28, early withdrawal and unscheduled
Visits during the study (see Figure below). Of these, 6 were treated with placebo
(representing 6% of the placebo group in the ITT population), 5 (5%) were treated with 3
g GW642444M, 2 (2%) were treated with 6.25 g GW642444M, 4 (4%) were treated
with 12.5 g GW642444M, 7 (7%) were treated with 25 g GW642444M, and 10 (10%)
were treated with 50 g GW642444M, indicating that there was no dose response and
that the incidence of hyperkalemia was broadly similar across the treatment groups
including placebo.

For these subjects, single high potassium values were


recorded at some of the time points, and it is suspected by Quest Laboratories and GSK
that this was due to non-usable (e.g., haemolysed) samples.

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Potassium Profiles for Subjects with Values >7 (mmol/L)


This section contained data from each individual patient, rather than in aggregate. They have been excluded to
protect patient privacy. Anonymized data from each patient may be made available subject to an approved
research proposal. For further information please see the Patient Level Data section of the GSK Clincal Study
Register.

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ATTACHMENT 3: PHARMACOKINETIC ATTACHMENT


Summary of GW642444 Plasma Concentrations (pg/mL) by Treatment, Visit and
Sample Collection Window (PK Population)
Dose
(g)
3

N
100a

Visit
(Day +4/-2)
2 (Day 1)

3 (Day 7)
4 (Day 14)
5 (Day 28)

6.25

101

2 (Day 1)

3 (Day 7)
4 (Day 14)
5 (Day 28)

12.5

100

2 (Day 1)

3 (Day7)
4 (Day14)
5 (Day 28)

Time

n*

Median

Range

Pre-dose
2-10 min
10-30 min
30 min - 2h
2-4 h
Pre-dose
2 min -1 h
Pre-dose
2-10 min
10-30 min
30 min - 2h
2-4 h

99
98
98
100
98
93
83
81
81
82
82
80

99
95
97
100
98
93
75
80
71
77
81
80

NQ
NQ
NQ
NQ
NQ
NQ
NQ
NQ
NQ
NQ
NQ
NQ

NQ
NQ - 36.7
NQ - 165.6
NQ
NQ
NQ
NQ - 58.1
NQ - 54.7
NQ - 90.8
NQ - 201.6
NQ - 31
NQ

Pre-dose
2-10 min
10-30 min
30 min - 2h
2-4 h
Pre-dose
2 min -1 h
Pre-dose
2-10 min
10-30 min
30 min - 2h
2-4 h

99
98
99
99
100
93
90
89
89
88
89
87

98
82
92
96
98
92
57
88
51
77
89
87

NQ
NQ
NQ
NQ
NQ
NQ
NQ
NQ
NQ
NQ
NQ
NQ

NQ - 173.3
NQ - 121.7
NQ - 108.6
NQ - 81.7
NQ - 109.1
NQ - 196.4
NQ - 166.3
NQ - 71.6
NQ - 96.6
NQ - 170
NQ
NQ

Pre-dose
2-10 min
10-30 min
30 min - 2h
2-4 h
Pre-dose
2 min -1 h
Pre-dose
2-10 min
10-30 min
30 min - 2h
2-4 h

99
99
97
97
97
95
91
89
88
85
86
87

96
48
65
89
93
93
34
85
18
37
77
83

NQ
31.5
NQ
NQ
NQ
NQ
43.6
NQ
55.5
33.4
NQ
NQ

NQ-144.2
NQ - 111.5
NQ - 215.1
NQ - 65.7
NQ - 126.3
NQ-180.5
NQ - 305.1
NQ-172.4
NQ - 169.1
NQ - 200.3
NQ - 79.3
NQ - 98.3
Continued

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Summary of GW642444 Plasma Concentrations (pg/mL) by Treatment, Visit and


Sample Collection Window (PK Population) (continued)
25

101

2 (Day 1)

3 (Day7)
4 (Day14)
5 (Day 28)

50

102

2 (Day 1)

3 (Day7)
4 (Day14)
5 (Day 28)

Pre-dose
2-10 min
10-30 min
30 min - 2h
2-4 h
Pre-dose
2 min -1 h
Pre-dose
2-10 min
10-30 min
30 min - 2h
2-4 h

100
99
98
98
98
93
91
89
90
91
87
92

98
21
40
73
92
90
24
83
9
18
42
72

NQ
60.2
36.5
NQ
NQ
NQ
66.3
NQ
120.7
61.4
30.2
NQ

NQ - 60.2
NQ - 260.7
NQ - 188.4
NQ - 106.5
NQ 76.7
NQ - 132.3
NQ - 324.9
NQ - 171.9
NQ - 328.1
NQ - 236.3
NQ - 107
NQ - 186.6

Pre-dose
2-10 min
10-30 min
30 min - 2h
2-4 h
Pre-dose
2 min -1 h
Pre-dose
2-10 min
10-30 min
30 min - 2h
2-4 h

98
96
98
96
96
93
90
93
94
92
95
92

97
12
10
19
56
83
21
86
9
3
3
17

NQ
127.4
113.4
57.4
NQ
NQ
166.1
NQ
249.8
140.6
71.8
42.5

NQ - 104.4
NQ - 623.6
NQ - 587.7
NQ - 177.8
NQ - 92.9
NQ - 505.9
NQ -701.5
NQ - 555.3
NQ - 975.6
NQ - 516.1
NQ - 270.9
NQ-161.0

Source data: Table 9.2


a. Versus 101 in ITT population
n = Number of subjects with non-missing values (including NQ values).
n* = Number of subjects with NQ concentrations; NQ concentrations imputed with 0 pg/mL for estimation median
value.

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ATTACHMENT 4: PHARMACOKINETICS /PHARMACODYNAMICS


Population dose-response and Time Course of FEV1 Modelling (K-PD)
The attachment details the methods, analysis, results and applications of the doseresponse and dose-time-response analysis.
Method
Data set and Dose-Response Analysis
Primary endpoint (Trough data on day 28)
The intent-to-treat (ITT) population dataset was used for modelling the dose-response
relationship. The primary efficacy endpoint of mean change from baseline at Day 28 for
trough (evening pre-bronchodilator and pre-dose) FEV1 was derived from the mean of the
23 and 24 h post-dose assessments.
Thus the ITT dataset consisted of a total of 588 patients receiving a total of 6 treatments
including placebo.
Parametric Dose-Response Model
Non-linear mixed effects model with the program NONMEM V1 Level 2.0 as
implemented in PDxPop V3.10, ICON Dev. Solns (2008) was used.
To determine if a graded dose response relationship exists, a step model was compared to
a step-linear model. The step model states that as soon as the lowest treatment dose is
given, the maximum effect (increase in FEV1) due to drug (i.e an additional increase in
dose does not further increase FEV1 response).
Step model:
FEV1,ij = 1 (1 + 1 j ) Q1 j (1 + 2 j ) + ij

1 = placebo effect
Q1 j = 0 if dose =0

2 (change in FEV1 response due to drug regardless of dose, i.e , maximum effect,
Emax), otherwise

kj =kth element of j . 1 j is a proportional individual baseline (placebo) shift , whereas


2 j is a proportional population dose response shift
ij = residual error
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The step linear model states that a given response occurs with the lowest dose of drug and
there is a further additional response that increases linearly as dose increases.
Step-linear model:

FEV1,ij = 1 (1 + 1 j ) + Q1 j + (3 Doseij ) (1 + 2 j ) + ij
Q1 j = 0 if dose =0

2 (change in FEV1 response due to drug regardless of dose), otherwise


3 = slope of change in effect due to dose
If a graded response relationship is demonstrated (i.e the step-linear model was preferred
to step model), the data were fit to the more physiological Emax model below
The Emax model structure used to characterise the response (trough FEV1 day 28) over
the dose range 0-50ug is
Yij = E0i * exp(E0ij) + (Emax* exp(Emax, ij) * Doseij /(Doseij + ED50i *exp(ED50 ij)) + ij

Yij response (j) of individual i


E0 : baseline FEV1 (L) (placebo)
Emax : maximum FEV1 response (L) reflecting the maximum difference in response
between placebo and treatment
Dose : Dose of treatment (g)
ED50 : Potency dose (g) that produces 50% of Emax
A proportional or exponential model described the inter-subject variability in the model
parameters. For ik, the kth element of the ith individual parameter vector, the following
model was used

ik = pop ,k exp(ik )
where pop ,k is the mean population parameter of the kth element and ik represents the
shift in the parameter of the ith individual from the population mean. ik was further
assumed to be independent multivariate normally distributed, with mean 0 and variance
(2) to be estimated
For residual error in the population dose-response analysis, additive, proportional and
combined additive and exponential error models were tested. is random effect
representing the residual error, that is , the difference between observed and predicted
response for each individual using a combination of exponential and additive error. It is
assumed to be normally distributed with mean zero and a variance (2) to be estimated.
The fit to the different potential dose-response models were compared using the objective
function (OFV) calculated by NONMEM program. The OFV is proportional to the -

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2*log likelihood of the fits and can be used to compare the goodness of fit of the various
models in a sequential manner. A lower OFV value indicates a better fit. For example,
the OFV value obtained after the step-linear model was compared to the reference step
model with the difference between the 2 OFV being 2 distributed. Confidence intervals
on the parameter estimates were obtained from the usual approximate asymptotic
covariance matrix of the estimates.

Covariate models
To assess whether patient factors influenced the dose-response parameters of GW642444,
individual empirical Bayes estimates of the parameters were generated from the basic
model, and plots of the difference between these and the population estimates (the is vs
covariates were constructed to visualise potential relationships. The patient factors
(BASE, AGE, SEX) entered the model through the parameters (E0, Emax, ED50) of the
model using multiplicative equation

i1 = pop (1 + age Age / 45 + base / 2.2 baseline + gender Gender )


i1 individual parameter
pop population parameter
age , base , gender represents the fractional change in parameter value due to age, base and
gender. Median age was 45yrs and baseline FEV1 2.2 L
Using the exploratory graphics described above, the covariates age, gender and baseline
showed marked correlation with the intercept (placebo) parameter. Each covariate was
then tested on the intercept parameter using stepwise forward and backward procedure
for covariate model selection [EMEA, 2007; FDA, 1999].
Besides using the objective function (OFV) described above, other criteria for model
selection included: (i) improved fitting of the diagnostic scatter plots (observed versus
predicted concentration, weighted residual versus predicted concentration or time), (ii)
convergence of the minimisation, (iii) number of significant digits > 3, (iv) termination of
the covariance step without warning messages, (v) absolute value of correlation between
model parameters < 0.95, and (vi) significant decrease in the objective function.
Final model selection (structural, random and covariate) and internal model evaluation
(including visual predictive check) was performed using established regulatory guidelines
for population PK-PD modelling procedures [EMEA, 2007; FDA, 1999].

Test to detect a dose-response relationship for trough FEV1


To evaluate whether the final Emax model shows a true dose response, this final model
was re-run by fixing ED50 to 0 (i.e assumes all active doses of GW642444M have a
similar response). The difference in -2LL of the two models was evaluated using a 2 test
to calculate the p value of the preference of the Emax model versus the model assuming
all active doses to be similar. If the Emax model provides a significant improvement
(p<.05), it is concluded that the study shows a dose-response relationship.
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Application of dose-response model (Day 28 Trough FEV1)

The dose-response model was applied to simulate the dose-response relationship and its
associated uncertainty for the change in LSMean FEV1. The predictive distribution of the
dose-response relationships was derived by sampling 10000 sets of model parameters
from a multivariate normal distribution with mean and variance-covariance matrix
obtained from the above dose-response model. This set of model parameters reflects the
uncertainty in the dose-response model for the drug. The dose-response relationship is
calculated for each set of parameters, yielding a distribution, expressed in percentiles
(pctl), of the likely response as function of dose.

Estimation of duration of pharmacodynamic response (Observed FEV1 data


The duration of FEV1 response (change from baseline) was assessed using a clinically
relevant threshold parameter (total time above which FEV1 response of 150mL
(Dur150mL ) that is computed over the dose range 0-50ug at steady state (day 28). The
algorithm for estimating the Dur150mL parameter as implemented in WinNonlin Vers
5.2 was applied and this computes for each individual patient the total time associated
with a change in FEV1 from baseline of 150mL. The Dur150mL parameter by dose is
descriptively summarised. This procedure was performed for both the observed and
predicted individual time course of FEV1 change from baseline to confirm the predictive
nature of the K-PD model.

Results
The optimal structural model was the Emax model with inter-subject variance on the
intercept (placebo) parameter. Inclusion of inter-subject variability on the ED50 and
Emax showed over-parameterisation which is expected of parallel-type study design with
1 response per individual (i.e a population instead of individual dose-response can be
estimated). Table D1 summarises the various models and logical selection of the optimal
structural dose-response model.

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Table D1

Output of Model Selection for Dose-Response Model

Model
1

Description
Step

Step-Linear

Emax

Emax

Sigmoid Emax

Parameter
1 (L)
2
1
2
1
1
2
1
2
1
1
2
3
1
2
3
1
2
1
2
3
1
1
2
1
2
3
1
Gam
1
2

Definition
Intercept
Dose effect
Baseline variability
Drug eff. variab. Shift
Additive error

Value
2.24
0.177
30%
105%
0.0527

Intercept
Dose effect
Slope D-R
Ind. Baseline shift
Additive error

SE(%)
3.4
46
10
50

OFV
245

Comments
FOCEI
Succesful
Covariance

2.42
0.132
0.0022
31%
0.045

243

FOCEI
No Covariance

Intercept
Emax
ED50
Indiv baseline shift
Indiv shift ED50
Indiv shift Emax
Additive Error
Exponential

2.22
0.236
2.95
29%
10%
0.10%
0.0705
0

240

FOCEI
No Covariance
Overparameterise

Intercept
Emax
ED50
Indiv baseline shift
Additive Error
Exponential

2.22
0.236
0.295
29%
0.266
9%

240

FOCEI
Succesful
Covariance
High Error on
ED50

Intercept
Emax
ED50
Indiv baseline shift
Slope of D-R
Additive Error
Exponential

0.343
0.15
3.96
89%
0.0128
0.01
26%

3
46
147
14
39
42

FOCEI
No Covariance

Source data: Table 9.9

Model#4 was the optimal basic structural model and a stepwise forward and backward
selection was performed for each of the covariates on each of the parameter. Age, gender
and baseline appeared most influential in describing the intersubject variability in placebo
response (Model 9 in Table D2).

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Table D2

Covariate Section for Dose-Response Model

Model

Description

Parameter

Definition

Value

Model #4
Age on 1
Model #4
Base on 1
Model #4
Gender on 1
Model #4
Full Model

_age

Age on 1

_base

7
8
9

10

Model #4
Reduced Model
12
Model #4
Reduced Model
13
Model #4
Reduced Model
14
Model #9
Final Model
ED50=0
Source data: Table 9.10

OFV

Comments

-0.008

SE
(%)
4.1

11.5

Base on 1

5.18

-631

_gender

Gender on 1

-0.27

89

_age
_base
_gender
_gender
_base
_age
_gender
_age
_base
_age
_base
_gender

Age on 1
Base on 1
Gender on 1
Gender on 1
Base on 1
Age on 1
Gender on 1
Age on 1
Base on 1
Age on 1
Base on 1
Gender on 1

-0.39
2.65
-0.166

18
21
24
-

-688

FOCE1
Covariance OK
FOCE1
No Covariance
FOCE1
Covariance OK
FOCE1
Covariance OK

-0.32
-0.166
-0.488
4.26
-0.453
2.91
-0.188

-637

-674

14
24
26

-675

FOCE1
No Covariance
FOCE1
No Covariance
FOCE1
No Covariance
FOCE1
Covariance OK

Based on the parameters of the final model (#9), the coefficients for the covariate effects
suggest that there is a linear inverse relationship between age and placebo response- there
is on average a 0.9% /year decrease in baseline FEV1 values. Females tend to show on
average a 17% lower baseline values compared to males. Higher baseline FEV1 values
are associated with higher placebo response (20% higher placebo response).
When the final E-max model was rerun by fixing ED50 to 0 (model #14 assumes all
active doses are equal), the final Emax model #9 was superior to model #14 as the
loglikelihood ratio (OBJ) increased from -688 (model#9) to -675 (model#14) for
negative LLR, model is better the further it is from 0. The difference of 13 between the
models show significance at p<0.05 implying final Emax model#9 shows a true doseresponse relationship.
Model Diagnostics

Based on the graphical diagnostics (Figure D.1), the Emax model adequately describes
the dose-response relationship. Thus the population and individual predictions track the
observed trough FEV1 data (DV). The individual weighted residuals (IWRES) versus
individual predictions and weighted residuals (WRES) versus dose do not show any
obvious bias (note: Time refers to dose (g) in graph).
More commonly, simulation-based diagnostics known as predictive checks are applied
to illustrate model properties. The visual predictive check (VPC) is a model diagnostic
that can be used to: (i) allow comparison between alternative models, (ii) suggest model
improvements, and (iii) support appropriateness of a model. The VPC is constructed from
stochastic simulations from the model therefore all model components contribute and it

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can help in diagnosing both structural and stochastic contributions. Summary measures of
the distribution of predictions and observations are compared visually. Typical summary
measures are the median and an interval defined by the lower 5% and upper 5% of the
values.

Interpretation of visual predictive check (VPC) as diagnostic


If approximately 10% or less of the observed data fall outside the 90% confidence
interval for the simulated data, the model and parameter estimates adequately describe
the observed data. The plot of observed data versus quantile bands of the predicted data
also serve as model diagnostic. If a particular region of the plot shows preponderance of
points outside the quantile bands, it may indicate a component of the model that needs
refinement.
As shown in Figure D.2, about 11% of the data lie outside the 5th-95th CI range with an
equal distribution of these outliers across the dose range. This suggests the dose-response
model adequately describes the original data.
Figure D.1

Diagnostics-Goodness of fit for trough dose-response (Final)

This section contained data from each individual patient, rather than in aggregate. They have
been excluded to protect patient privacy. Anonymized data from each patient may be made
available subject to an approved research proposal. For further information please see the
Patient Level Data section of the GSK Clincal Study Register.

Source data: Figure 9.11


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Figure D.2

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Visual Predictive Checks (Final)

Source data: Figure 9.12

Distribution of likely dose-response relationship

A useful application of the population dose-response model is to simulate the expected


dose-response relationship and its associated uncertainty for the FEV1 response. The
predictive distribution of the dose-response relationships was derived by sampling 10,000
sets of individual model parameters from the covariance matrix of parameter estimates
yielding a distribution of likely response rates as function of dose. The monolix Version
2.4 was used to simulate the dose-response model and associated multivariate parameter
uncertainty. LSMean estimates of FEV1 (adjusted for baseline and placebo) from the
simulation were computed using ANCOVA. The simulated LSMean estimate of FEV1 is
plotted over the curve for the observed LSMean FEV1 (95%CI) response based on the
primary analysis (Figure D.3).
In addition, the 90% uncertainty interval is taken between the 5th and 95th percentile of
the predictive distribution. This is depicted in Figure D.4, where the distribution of the
individual dose responses is expressed in percentiles. Figure D.4 expresses the
uncertainty in the dose-response relationship for the drug and not between-subject
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variability. This figure can therefore be used to evaluate the probability (chance) of
achieving a certain response at a selected dose or to evaluate the probability of a certain
dose to achieve a selected response. For example, from Figure D.4 at 12.5 g dose, the
average response (50th pctl) is estimated at >100mL with 90% chance of the response
being between 45 mL to 167 mL. Table D4 provides the expected responses at the other
doses.
Figure D.3

Dose-Response for Trough FEV1 (ITT population) at Day 28


Overlay- Observed LSMean difference from Placebo with Model
Simulated LSMean Profile

LSMean difference from Placebo FEV1 (L)

0.30

LSMean [95 CIs]


Model fitted

0.25
0.20
0.15
0.10
0.05
0.00
-0.05
ED50: 16.1ug [95%CI: 12.5-19.7]

10

20

30

40

50

OD Dose (ug)

Source data: Figure 9.6

Table D3

DoseResponse Model Parameters for trough FEV1 change from


baseline on day 28 (ITT Population)

Parameters
Emax (L)
ED50 (g)
E0 (L) Placebo
Age on E0 (L/yr)
Baseline on E0
Gender on E0
Residual Error

Value
0.243
16.1
0.733
-0.392
2.65
-0.166
Proportional
Additive

% RSE
20
11
18
12
21
24
CV 12%
St Dev 0.16

Source data: Table 9.5

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5th CL
0.149
12.5
0.48
-0.482
1.57
-0.245

95th CI
0.337
19.7
0.986
-0.302
3.73
-0.087

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Figure D.4

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Distribution of Likely Response at Day 28 Trough (OD Dosing)


difference from placebo

Source data: Figure 9.7

Table D4

Expected Response at a Certain Dose (OD Dosing) - adjusted for


placebo
Dose (g)

3
6.25
12.5
25
50
Source data : Table 9.6

Change form baseline FEV1 at trough (mL)


Expected Response
90% Chance is Between
37
-24 - 99
68
5 - 130
106
45 - 167
148
85 - 210
184
122 - 246

A different view of the likely dose to achieve a certain response can also be estimated
from the above dose-response model simulations. The probability of a certain dose to
exceed an FEV1 response target can be estimated (Figure D.4 and Table D5). Thus, if the
target response of >100 mL FEV1 at trough is required, there is a 56% chance of
achieving this target response (Table D5).

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Table D5
Dose
(g)
3
6.25
12.5
25
50
Source Table 9.7

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Probability (%) That a Certain Dose Will Exceed the Target Response
(OD Dosing)
100 mL
5
19
56
90
99

Change from baseline FEV1 at Trough (Day 28)


150 mL
200 mL
0.1
0
2
0
12
0.7
48
9
81
33

Modelling of Time Course of 24-hours FEV1


The strategy for modelling the 24h time course of FEV1 in this study was as follows:

Exploratory graphical examination of individual and median time course of


observed FEV1 as function of dose on day 1 and day 28

Characterise the baseline (placebo) time course of FEV1 that best described the
observed data

Apply population K-PD model to simultaneously model the time course of FEV1 in
the placebo and GW642444M treatment groups.

Evaluate the influence of any patient covariates on the parameters of the K-PD
model

Evaluate predictability of the K-PD model for the 28 day trough FEV1 response and
compare with actual data

Application of population K-PD model to evaluate the impact of OD versus BD


dosing regimens on 24 hour time course of FEV1

Step 1: Model to describe the 24-hour FEV1 profile in placebo (without drug)

Graphical visualisation of time course of LSMean FEV1 (change from baseline and
difference from placebo) by dose show diurnal variations over 24h (Figure D.5) and is
consistent with the well recognised circadian variation in pulmonary function in
asthmatics [Medarov, 2008; Calverley, 2003]. It is therefore important that this diurnal
variation in baseline time course of pulmonary function be adequately characterised to
reliably model and predict the time course of FEV1 after drug treatment only.
Examination of the observed LSMean profile of FEV1 over 24h on day 1 and after
repeated once daily dosing on day 28 in placebo and treatment groups suggests no
marked difference in the diurnal FEV1 profile (Figure D.5).

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Figure D.5

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Observed Time course of LSMean FEV1 by dose (g) and day

Source data: Figure 9.13

Given the exploratory graphical analysis, cosine functions were evaluated on the placebo
profiles initially in a subset of 30 patients using day 1 data mainly due to computational
time to enable evaluation a a range of structural models including basic turnover (no
circadian), circadian using single and dual cosine functions as represented below:
n

2 (T 2i +1 exp( 2 i +1 )
Base(t ) = 1 exp(1 ) 1 + 2i exp(2i ) cos
exp( i ) .
24

i =1

Where n refers to number of cosine functions


Base(t) : Baseline FEV1 as function of time t.

1 : rhythm-adjusted 24-hour mean FEV1 (L)


2 i : amplitudes of cosine terms
2i +1 : parameter for phase shifts of cosine terms (i.e time to maximum FEV1)
T : Actual time
1 : interindividual variability on rhythm-adjusted 24-hour mean FEV1

2i : interindividual variability in amplitudes


i : Residual variability modelled as exponential distribution
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The time course of baseline FEV1 (Base(t)) was used as the circadian input for the
turnover rate model with Kout as the turnover rate constant of FEV1 response according
to

dR
= Base Kout R
dt
Step 2: Model to describe the 24-hour FEV1 profile for whole population ( placebo
and drug treatments).
Background on K-PD modelling approach

In the absence of PK information linking with PD effect in target tissue (e.g lung), an
alternative approach can be applied to characterise the time profile of PD marker (e.g
FEV1) as function of dose. Pharmacodynamic response versus time data , even in absence
of drug levels, inherently contain useful information about the turnover characteristics of
response (turnover rate, half-life of response), the drug biophase kinetics (relative
bioavailability, half life) as well as the pharmacodynamic characteristics (potency,
intrinsic activity).
Some of the underlying principles for modelling dose-response-time data and duration of
response have been extensively documented [Gabrielsson, 2000]. The general
applicability of the K-PD model when compared to corresponding PK-PD model (where
plasma kinetics are available) has been extensively studied. Some general requirements
for undertaking this K-PD model include availability of data such as different doses,
different dose regimens (e.g. single dose and repeat dose) and adequate response
measurements over the dosing interval.
It is assumed that the availability of an inhaled dose of GW642444M in the lung (virtual
compartment) will drive the pharmacology, and the duration of effect is driven by the
residency of the drug in equilibrium with the response at the target site receptors. The
product of the amount of drug at a certain time in the lung and its equilibrium rate
constant (KDE) will reflect the dose rate driving the pharmacodynamic effect over time.
The time course of pharmacodynamic response (FEV1) as function of dose, dose regimen
and time provide inherent information about the kinetics of drug action which can be
captured as a physiological E-max type model. Based on the prolonged duration of effect
of the drug, it is assumed an indirect response (turnover) mechanism is driving the
pharmacodynamics through stimulation of production of FEV1 and an offset rate which
are captured by the respective parameter rate constants (KS and KD).

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Schematic of K-PD model

KDE:
DDR:
EDK50:
:
Emax
A:
Biomarker:
Ks or Kin
Kd or Kout

Elimination rate constant from virtual compartment (Time-1)


Dose Driving Rate (AmountTime-1)
DDR that leads to 50% FEV1 response (DoseTime-1)
Sigmoidicity parameter
Maximum response from placebo
Amount of drug in virtual compartment (g)
FEV1
Baseline circadian input rate
Fractional turnover rate constant for FEV1 (Time-1)

The corresponding set of differential equations for the structural model are shown below:

dA
= KDE
dt
DDR = A * KDE
dR
= K in K o u t R
dt
K in
R (0 ) =
K out
where R=FEV1 , R(0) = Base

E max DDR
Kin = Base 1 +


EDK 50 + DDR
Base = circadian baseline FEV1 response as described in step1 above

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Statistical Model

Denoting f to be a function characterising the K-PD model described earlier, the


statistical model for response (FEV1) in individual i at time tij is:

yij = f ( i , tij ) + ij
where i denotes the vector of parameter value for individual i , and its components are
assumed to follow a log-normal distribution:

i = *ei
where i ~ N(0,) is the vector of individual random effects where the variance to be
estimated. is the population mean parameter value.

The residual errors ij are assumed to be independent, with distribution 0, ij 2 , where


the variance of the error is modelled using an exponential error model:

ij 2 = 2 e f

Model selection was based on both the Wald test and likelihood ratio test for nested
models; the final model selected should be the model which gives the smallest objective
function.

Model diagnostics & Evaluation


Model diagnostics and evaluation were based established regulatory guidelines
[EMEA, 2007; FDA, 1999]. The criteria for model selection included: (i) improved
fitting of the diagnostic scatter plots (observed versus predicted concentration, weighted
residual versus predicted concentration or time), (ii) convergence of the minimisation,
(iii) number of significant digits > 3, (iv) termination of the covariance step without
warning messages, (v) absolute value of correlation between model parameters < 0.95,
and (vi) significant decrease in the objective function. Various statistical criteria used
include Information criteria (AIC,BIC), Statistical tests (Likelihood ratio test (LRT),
Wald test), Goodness of fit plots include (individual fits, Weighted residuals, NPDE,
VPC).
Simulation-based diagnostics were also performed using the Normalised Prediction
Distribution Error (NPDE) and Visual Predictive Checks (VPC). With the NPDE
[Mentre, 2005], a reference distribution is created for each observation and correlations in
residuals within subject are taken into account. Standard Gaussian probability distribution
function and qqplots are displayed to check if the residuals are Gaussian.

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Softwares
Two softwares utilising different maximum likelihood estimation methods for non linear
mixed effects analysis were applied for modelling the time course of FEV1

The First Order Conditional Estimation method with Interaction (FOCEI) as


implemented in NONMEM VI Level 2.0 [Beal, 1994] was initially used. Although
the estimation method (maximum likelihood based on linearization of random
effects) did show convergence with all parameters estimated, the convergence time
was too long and the variance-covariance matrix could not be computed.

The second method is based on the stochastic approximation of the expectation


maximisation method (SAEM) as implemented in MONOLIX V2.4 [Lavieille, 2000]
that iteratively computes the maximum likelihood using simulation of one realisation
of the data at each iteration in combination Markov-Chain Monte-Carlo (MCMC)
procedure. The combination of SAEM-MCMC and simulated annealing ensures
convergence to a local maximum likelihood which has been proven under general
conditions [Delyon, 1999]. Hence the following procedures are performed by
MONOLIX:

Estimation of population parameters (including random effects) based on


maximum likelihood using SAEM algorithm combined with MCMC and
simulated annealing.

Estimation of individual parameters based on estimation/maximisation of


conditional distribution with MCMC

Estimation of objective (likelihood) function using Monte Carlo and minimum


variance importance sampling

Model selection and assessment as described above in Model diagnostics.

Other softwares used for data exploration and statistics, analysis-ready datasets,
model diagnostics and clinical trial simulation include R 2.7.0, SAS Version 9,
Xpose V4, Perl-Speaks-Nonmem (PsN) and Pharsight Trial simulator (V 2.2).

Estimation of duration of pharmacodynamic response (Observed FEV1


data)
The duration of FEV1 response (change from baseline) was assessed using a clinically
relevant threshold parameter (total time above which FEV1 response of 150mL
(Dur150mL ) that is computed over the dose range 0-50ug at steady state (day 28). The
algorithm for estimating the Dur150mL parameter as implemented in WinNonlin
Vers5.2 was applied and this computes for each individual patient the total time
associated with a change in FEV1 from baseline of 150mL. The Dur150mL parameter
by dose is descriptively summarised. This procedure was performed for both the
observed and predicted individual time course of FEV1 change from baseline to confirm
the predictive nature of the K-PD model.

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Results

The estimated parameters for the K-PD model showed good precision (Table D6) and
adequately described the FEV1 response data with time based on the model population
and individual predictions which are very close to the line of unity (Figure D.5). During
model development, baseline FEV1 showed highest correlation with the Rm parameter
(rhythm-adjusted mean FEV1) and was used in the basic model structure. Separate
analyses were performed on the time course of FEV1 for day 1 and repeat dose datasets.
As there was no marked deviation in the estimates of these parameters on the separate
data sets (data on file), the combined day 1 and repeat dose data were used in subsequent
analyses.
Model diagnostics based on the distribution of various types of residuals (Figure D.6) and
QQplots (Figure D.7) suggest no systematic deviations (i.e residuals evenly scattered ).
The residuals are PWRES (population weight residuals), IWRES (Individual weighted
residuals) and NPDE (normalised prediction distribution error) and corresponding
probability distribution function and QQplots. No marked bias in the distribution of the
structural parameters when plotted versus their respective random effects (Figure D.11).
Table D6

K-PD Model characterising time course of FEV1 in asthmatic patients

Parameters
Values
Rm (L)
14.7
Baseline effect on Rm
0.414
Tz (h)
0.0407
Tzl (h)
2.41
Ramp
0.0326
Ramp1
0.0139
Kout (l/h)
16.1
15.9
EDK50 (g)
Kde (l/h)
0.0269
Emax (L)
0.275
Value (CV%)
Inter-patient variability ()
0.102 (32%)
Rm
8.99 (300%)
Tz
0.339 (58%)
Tzl
0.392 (63%)
Ramp
0.736 (86%)
Ramp1
0.149
(39%)
Kout
2.99 (173%)
EDK50
1.38 (117)
kde
Residual Error (additive)
Value (CV%)
0.131

SE : precision of parameter estimates. r.s.e : relative SE (%).


Source data: Table 9.8

Std. error (SE)


0.26
0.0074
0.016
0.036
0.00056
0.0046
0.11
2.1
0.0016
0.015
Std. error (SE)
0.0038
0.083
0.011
0.013
0.024
0.005
0.091
0.043
Std. error (SE)
0.001

R.S.E (%)
2
2
39
1
2
3
1
13
6
6
R.S.E (%)
4
1
3
3
3
3
3
3
r.s.e (%)
1

Visual examination of the post-hoc parameter estimates of each of the model parameters
against the covariates showed correlation of age, gender and baseline with the Rm
parameter. However, after inclusion of the baseline covariate on Rm, the correlation of
age and gender on Rm was redundant. There was no obvious trend in the random
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residuals (etas) with the remaining covariates including weight, height, body mass index,
center and race. The K-PD model adequacy to predict the individual time course of
FEV1was also demonstrated for all the individual patients after single or repeat dose.
Some examples of the individual versus observed time course of FEV1 are depicted in
Figure D.8, Figure D.9 and Figure D.10.
The predicted population Emax of 0.275L (95%CI: 0.245-0.305L) is consistent with the
statistical output for repeated measures mixed effects analysis of serial FEV1. The
maximum LSMean FEV1 difference from placebo was 0.278L (95%CI: 0.192-0.365L) on
day 1 and 0.240L (95%CI: 0.146-0.333L) at the top dose of 50 g od.
Besides the estimation of diurnal baseline parameters for characterising the placebo time
course of FEV1, some key drug-related parameter estimates need to be put into context.
The EDK50 of 15 g/h is an apparent potency as it relates to the dose rate that achieves
50% of predicted maximum FEV1 response. This dose rate is the product of the
estimated amount of drug in the lung biophase at any time post dose and the estimated
geometric mean elimination half life of the drug (KDE: 26h (95%CI: 23-29h)) from the
lung. The KDE parameter estimated is a rate constant that expresses the equilibrium
between the amount of GW642444 in the lung biophase with time and its product with
dose (KDE * A(t)) drives the pharmacodynamic response in the lung biophase. It is
therefore expected that the duration of FEV1 response be dose-dependent.
Estimation of duration of effect parameter (Dur 150mL) using the observed time course
of FEV1(change from baseline) confirms the dose-dependent duration of FEV1 response
(Table D7). At the threshold clinical response of 150mL, there is a dose-dependent
increasing trend in the duration of FEV1 response (Dur 150mL) with increase in dose.
The 6.25, 12.5, 25 g and 50 g dose schedule provides a median Dur 150mL of 20h
compared to the lowest dose of 3 g that provides a Dur 150mL of about 14h. These
data also confirm the intrinsic long duration of activity of GW642444.
Table D7
Dose (g)

Median [95%CI] DUR150mL parameter by dose.


N

0
86
3
83
6.25
90
12.5
88
25
89
50
98
Source data : Table 9.9

95th CI Median

DUR 150 mL Median


Time (h)

5th
4.2
10.9
18.2
17.1
20.6
20.2

6.9
13.6
20.9
19.5
23
22.6

95th
9.6
16.3
23.6
22.0
25.4
25.0

Discussion
The K-PD approach allows the analysis of the kinetic of drug action in the absence of
pharmacokinetic data. This method can be applied optimally provided certain design
aspects are taken into account. These include adequate number of patients, a wide range
of doses, different dose regimens (e.g. single and repeat dose) and adequate
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pharmacodynamic measurements covering the dosing time interval. The present study
provides the necessary data to adequately apply the K-PD methodology. This is evident
from the reasonable precision (mostly below 30%) of the parameter estimates obtained
from the K-PD analysis.
A key aspect of this analysis was to adequately describe the diurnal variation of the
baseline (placebo) FEV1 response in the present study to be able to reliably predict the
time course of FEV1 due to GW642444 alone. The dual cosine function was optimal in
describing the pulmonary circadian profile in asthmatics. Further confirmation of this
model for placebo profile in studies where GW642444M is given in the morning or
evening is required. Examination of individual as well as LSMean time course of FEV1
(absolute and change from baseline) by dose and regimen suggests good concordance
with the observed and model fitted time course of FEV1 over the dose range of 0-50ug
after single and repeat od dosing at steady state.
The model-based analysis of the FEV1 response data in the present study has provided
additional insight on the trough dose response of GW642444M in terms of characterising
the potency and maximum predicted FEV1 effect. A key advantage of using all
individual response data for dose-response modelling ensures robust estimation of the
dose-response model parameters as well as the associated uncertainty distribution of
these parameters. Simulation of the likely dose-response distributions using the model
parameters and associated uncertainty showed that 12.5 g GW642444 and above can
achieve a target FEV1 response (change from baseline) of 100mL in at least half the
number of patients at trough. This is also reflected in the estimation of duration of
response (DUR150mL) parameter from the observed time course of FEV1 data. As
expected, there was an incremental increase in the DUR150mL parameter with dose,
with the 6.25 g to 50 g OD showing a sustained duration of effect of 20 h at steady
state and is consistent with the estimated long elimination half life of the drug in the lung
biophase.

Conclusions

Based on a population Emax model of trough FEV1 data, GW642444 is a potent


bronchodilator with geometric mean potency (16.1 g: 95%CI 12.5-19.7] and a
predicted maximum intrinsic efficacy at trough of 243 mL [95% CI: 149-337 mL).

Age, baseline FEV1 and gender were significant covariates accounting for variability
in the placebo response.

Simulation of the Emax dose-response model at trough and associated uncertainty in


model parameters provided insight into the potential for optimal clinical dose. The
25 g OD GW642444M has a 48% chance of delivering an adjusted mean change
from baseline in trough FEV1 of 150mL.

A population dose-time-response model (K-PD) was characterised that adequately


described the time course of FEV1 over dose range 0-50 g after single and at steady
state (Day 28) after taking into account the marked baseline diurnal variation in the
FEV1. Model parameters with inter-patient and residual variability were estimated
with good precision
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From the K-PD model, an elimination half life of 26 h (95%CI: 23-30h) of the drug
in the lung biophase in equilibrium with lung FEV1 response would be consistent
with the sustained duration of FEV1 response over 24 h dosing interval at all doses.

Using a clinical threshold of 100 mL FEV1 over the entire time course of FEV1
profile confirms the dose-dependent duration of FEV1 response. The 6.25 to 50 g
dose schedule provides a median duration 100 mL of 20 h compared to the 3 g
dose that provides a duration 100mL of about 14 h. This is consistent with the peak
to trough ratio of unity across all doses.

Overall, combination of high pulmonary potency of GW642444M, sustained


residency of the drug and peak to trough ratio close to unity would support the
rationale for once daily potential dosing regimen in asthmatics.

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Figure D.6

Model Diagnostics for K-PD model

Source data: Figure 9.14

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Figure D.7

K-PD Model Diagnostics Residuals

Source data: Figure 9.15

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Figure D.8

K-PD Model Diagnostics Residual Distributions

Source data: Figure 9.16

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Figure D.9

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Individual observed (symbol) and K-PD model predictions

This section contained data from each individual patient, rather than in aggregate. They have been
excluded to protect patient privacy. Anonymized data from each patient may be made available
subject to an approved research proposal. For further information please see the Patient Level Data
section of the GSK Clincal Study Register.

Source data: Figure 9.18

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Figure D.10

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Individual observed (symbol) and K-PD model predictions

This section contained data from each individual patient, rather than in aggregate. They have been
excluded to protect patient privacy. Anonymized data from each patient may be made available
subject to an approved research proposal. For further information please see the Patient Level Data
section of the GSK Clincal Study Register.

Source data: Figure 9.19

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Figure D.11

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Individual observed (symbol) and K-PD model predictions

This section contained data from each individual patient, rather than in aggregate. They have been
excluded to protect patient privacy. Anonymized data from each patient may be made available subject
to an approved research proposal. For further information please see the Patient Level Data section of
the GSK Clincal Study Register.

Source data: Figure 9.20

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Figure D.12

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Distribution of standardised random effects by parameters

Source data: Figure 9.17

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References
1.

Beal SL and Sheiner LS (1994) NONMEM manuals

2.

Calverley PM et al (2003): Effect of tiotropium bromide on circadian variation in


airflow limitation in COPD; Thorax, 58(10):855-6

3.

Delyon B & Lavielle M (1999) Computational Statistics and Data Analysis, 27:94128

4.

EMEA guidelines (2007) Guideline on reporting the results of population


pharmacokinetic analyses , CHMP/EWP/185990/06

5.

FDA (1999) Guidance for industry : Population pharmacokinetics, CP 1

6.

Gabrielsson J et al (2000): Modelling of dose-response-time data: Four examples of


estimating the turnover parameters and generating kinetic functions from response
profiles; Biopharm & Drug Dispos, 21:41-52

7.

Lavieille M (2000): Convergence of a stochastic approximation version of the EM


algorithm; The annals of statistics, 2(1): 94-128

8.

Medarov et al (2008), Diurnal variations in human pulmonary function, Int J Clin


Exp Med, 1, 267-273

9.

Mentre F & Escolano S (2005): Prediction of discrepancies for the evaluation of non
linear mixed effects models, J Pharmacokinetics & Pharmacodynamics , 33, 3, 345367

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Attachment 5. DATA LISTINGS

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This section contained data from each individual patient, rather than in aggregate. They have
been excluded to protect patient privacy. Anonymized data from each patient may be made
available subject to an approved research proposal. For further information please see the
Patient Level Data section of the GSK Clinical Study Register.

This section contained data from each individual patient, rather than in aggregate. They have
been excluded to protect patient privacy. Anonymized data from each patient may be made
available subject to an approved research proposal. For further information please see the
Patient Level Data section of the GSK Clinical Study Register.

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Synopsis
Identifier: YM2008/00019/00 Study Number: B2C109575
Title: A randomised, double-blind, placebo-controlled, parallel group, dose ranging
study evaluating the efficacy and safety of GW642444M administered once daily
compared with placebo for 28 days in adolescent and adult subjects with persistent
asthma.
Investigator(s): 88 Investigators screened subjects (84 Investigators with ITT subjects).
Study centre(s): Multi-centre study
Publication(s): None at the time of this report
Study Period: 29 Dec 2007 (FSFV) 10 Sept 2008 (LSLV)
Phase of Development: IIb
Objectives: The primary objective of this study was to evaluate the dose response,
efficacy and safety of five doses of GW642444M (3 g, 6.25 g, 12.5 g, 25 g and 50
g) over a 28-day treatment period in adolescent and adult subjects with persistent
asthma. The secondary objective was to characterise the population pharmacokinetics
(PK) of GW642444M in these subjects.
Methodology: This was a multi-centre, randomised, placebo-controlled, double-blind,
parallel group study. Subjects were screened at Visit 1, and those who met eligibility
criteria completed a 14-day pre-treatment Run-in period. At Visit 2, subjects were
stratified in an approximately 1:1 ratio according to their baseline forced expiratory
volume in one second (FEV1) as a percentage of predicted normal, with one stratum for
those with FEV1 percent predicted 40% - 65% and one for those with FEV1 percent
predicted > 65% - 90%. Subjects were then randomised to one of six treatments for 28
days: GW642444M 3 g, 6.25 g, 12.5 g, 25 g, 50 g, or placebo, administered via
the Novel Dry Powder Inhaler once-daily in the evening. At the end of the treatment
period, subjects entered a seven-day Follow-up period. Throughout the study (from
Screening to Follow-up), subjects remained on their current inhaled corticosteroid
therapy (ICS) at fixed doses. The overall study duration (Screening to Follow-up) for
each subject was 7 weeks.

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Number of subjects:
GW642444M
placebo
Total
3 g
6.25 g 12.5 g 25 g
50 g
Number of subjects planneda, N
99
99
99
99
99
99
594
Randomised, N
103
102
102
102
103
102
614
Completed, n (%)
86 (84)
84 (83) 91 (90)
88 (88) 93 (92) 97 (95) 539 (89)
Total nr subjects withdrawn, n (%)
16 (16)
17 (17) 10 (10)
12 (12)
8 (8)
5 (5)
68 (11)
Withdrawn due to AEs, n (%)
0
1 (<1)
0
0
1 (<1)
0
2 (<1)
Withdrawn due to lack of efficacy, n (%)
9 (9)
12 (12)
3 (3)
5 (5)
4 (4)
0
33 (5)
Withdrawn for other reasons, n (%)
7 (7)
4 (4)
7 (7)
7 (7)
3 (3)
5 (5)
33 (5)
a. 1140 subjects were screened with the aim of achieving 594 evaluable subjects (99 subjects per group).
Seven subjects were randomised in error but did not receive study drug. One subject was not randomised but took the
study drug in error. AE: Adverse event.

Diagnosis and main criteria for inclusion: Male and female subjects of 12 years of
age with persistent asthma. In Germany, the Russian Federation and South Africa, which
permitted enrolment of adults only, subjects were 18 years of age. In Chile one centre
was allowed to only recruit subjects >15 years of age and the other centre >18 years of
age.
Treatment administration: Subjects who at Visit 2 were randomised to one of the
double-blind 28-day treatments were instructed to administer one inhalation of study
medication using the Novel Dry Powder Inhaler once-daily in the evening following predose symptom assessment. The first dose of study medication was given on treatment
Day 1 during clinic Visit 2. On days 7, 14 and 28 (Visits 3, 4 and 5, respectively),
subjects were required to take their dose of study medication at the clinic. On other
treatment days, subjects administered their study medication at home.
Criteria for evaluation: The primary efficacy endpoint was the mean change from
baseline in clinic visit trough (pre-bronchodilator and pre-dose) FEV1 at the end of the
28-day treatment period. The trough FEV1 was defined as the mean of the FEV1 values
obtained 23 and 24 hours (h) after dosing on Day 28.
Secondary efficacy endpoints:

Change from baseline in weighted mean 24 h serial FEV1 on Days 1 and 28 (mean
post-dose FEV1 after 15, 30 and 60 minutes and 2, 3, 4, 6, 12, 16, 20, 22, 23 and 24
h). This endpoint was derived for all subjects but the 6 and 12 h time points were
only measured in a sub-group of subjects (66% of subjects).

Mean change from baseline in trough (pre-dose and pre-bronchodilator) daily


evening peak expiratory flow (PEF) averaged over the 28-day treatment period.

Mean change from baseline in daily morning PEF averaged over the 28-day
treatment period.

Mean change from baseline in the percentage of symptom-free 24-h periods during
the 28-day treatment period.

Mean change from baseline in the percentage of rescue-free 24-h periods during the
28-day treatment period.
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Difference in post salbutamol/albuterol FEV1 (FEV1 30 minutes after a single dose


of 400 g salbutamol/albuterol) between 24 h after dosing on Day 1 (Visit 2) and on
Day 28 (Visit 5); between screening (Visit 1) and 24 h after dosing on Day 1 (Visit
2); and between screening (Visit 1) and 24 h after dosing on Day 28 (Visit 5).

Other efficacy endpoints:

Maximum increase in FEV1 (0-4 h) on Days 1 and 28 compared with baseline.

Proportion of subjects obtaining 200 mL and 12% increase from baseline in FEV1
(0-4 h) on Days 1 and 28. An additional post-hoc analysis of Proportion of subjects
obtaining 200 mL and 12% increase from baseline in FEV1 (0-24 h) on Days 1
and 28 was performed.

Mean change from baseline in trough FEV1 at Visits 2/2A, 3 and 4 (i.e. after 23-24 h,
7 and 14 days of treatment).

Mean change from baseline in the percentage of symptom-free days during the 28day treatment period.

Mean change from baseline in the percentage of symptom-free nights during the 28day treatment period.

Mean change from baseline in the percentage of rescue-free days during the 28-day
treatment period.

Mean change from baseline in the percentage of rescue-free nights during the 28-day
treatment period.

Mean change from baseline in daily morning PEF during the first 14 days on study
treatment and over weeks 1, 2, 3, 4 and endpoint of the study.

Mean change from baseline in daily evening PEF during the first 14 days on study
treatment and over weeks 1, 2, 3, 4 and endpoint of the study.

Withdrawals due to lack of efficacy.

Exploratory efficacy endpoints:

Weighted mean change from baseline (0-4 h) for FEV1 on Days 1 and 28.

Proportion of subjects obtaining a greater or equal than 15% increase from baseline
in FEV1 (0-4 h) on Days 1 and 28.

Mean peak FEV1 (0-4 h) on Day 28.

Ratio of peak to trough in FEV1 on Day 28. The trough FEV1 was defined as the
mean of the FEV1 values obtained 23 and 24 hours (h) after dosing on Day 28, with
no imputation.

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Safety endpoints:
Safety endpoints included adverse event (AE) reporting throughout the 28-day treatment
period; haematological and clinical chemistry parameters after 14 days and 28 days of
treatment and dipstick urinalysis parameters after 28 days of treatment; vital signs (pulse
rate and systolic and diastolic blood pressure) on Days 1, 7, 14 and 28; 12-lead
electrocardiogram (ECG) on Days 1, 7, 14 and 28; and fasting potassium and glucose on
Days 1 and 28 and non-fasting potassium only on Days 7 and 14.
Pharmacokinetic endpoints:
Plasma concentrations of GW642444, the triphenylacetate counterion and the GW642444
metabolites GW630200 and GSK932009, and derived PK parameters for GW642444 in
subjects with persistent asthma following once-daily treatment for 28 days. Relationship
between systemic exposure to GW642444 (Cmax) and systemic pharmacodynamic
endpoints.
Statistical methods:
In total, 1140 subjects were screened with the aim of achieving 594 evaluable subjects
(with at least one pre-dose or 23-24 h post-dose FEV1 assessment on or after nominal
Day 7) or 99 subjects per group. This sample size was based on the primary endpoint of
change from baseline in trough FEV1 and was powered at 97% to detect a dose response
effect of 200 mL improvement per 50g of GW642444M. This assumed a standard
deviation of 430mL and significance declared at the two-sided 5% level. The primary
treatment comparison was a test of linear trend in dose response in trough (prebronchodilator and pre-dose) evening FEV1 derived from the mean of the 23 and 24 h
post-dose assessments at Day 28 across the five doses of GW642444M relative to
placebo to demonstrate overall efficacy of GW642444M. If this test was statistically
significant, two-sided pair-wise tests of each dose versus placebo were performed to
demonstrate superiority of individual doses over placebo. Pair-wise comparisons of each
dose versus placebo were also performed for the other key efficacy endpoints. The
primary analysis was performed using Analysis of Covariance (ANCOVA) with effects
due to baseline FEV1, centre grouping (country), age, sex, baseline percent predicted
FEV1 stratum and dose/treatment group, imputing missing data using last observation
carried forward (LOCF). For this analysis the Intent-To-Treat (ITT) Population was
used, which was the primary population for all analyses of efficacy and safety measures
comprising all subjects randomised to treatment and who received at least one dose of
trial medication. The primary comparisons were supported by the same tests performed
using the Per Protocol (PP) Population, which consisted of all subjects in the ITT
Population who did not have any full protocol deviations which were related to the
efficacy endpoints. They were also supported by the same tests performed using a
repeated measures mixed model on the ITT Population. The dose response across the
five doses of GW642444M was explored using the ITT Population excluding placebo
from the analysis. Plasma concentrations of GW642444, the triphenylacetate counterion
and the GW642444 metabolites GW630200 and GSK932009 from the PK concentration
population (ITT population for whom a PK sample was obtained and analysed) were

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summarised descriptively. Supporting analyses were performed to characterise the doseresponse parameters and a model framework for the time course of FEV1.
Summary:
Efficacy: The primary analysis, the test of linear trend in dose response in trough
evening FEV1 at Day 28 versus placebo, showed a statistically significant result, thus
allowing further pair-wise comparisons across the treatment groups. Statistically
significant dose-dependent improvements in trough FEV1 compared with placebo were
found for the 12.5 g, 25 g and 50 g GW642444M doses, with mean treatment
differences compared with placebo of 130 mL, 121 mL and 162 mL, respectively, despite
a placebo effect of 147 mL versus baseline. The superiority of these three highest
GW642444M doses relative to placebo was confirmed by Per Protocol analysis and
repeated measures analysis of the primary endpoint. A similar dose-response was found
for both FEV1 percent predicted strata, indicating that the dose-response relationship was
similar for the two disease severities.
Secondary and other efficacy measures supported the findings of the primary efficacy
endpoint by demonstrating a dose response across the doses studied. Serial FEV1
measurements taken on Days 1 and 28 showed that all GW642444M treatment groups
had statistically significantly greater improvements versus placebo in weighted mean
change from baseline FEV1 (0-24 h) except for 6.25 g dose on Day 1. The greatest
improvements in weighted mean change from baseline FEV1 (0-24 h) were seen in the 25
g and 50 g GW642444M groups (193 mL 215 mL on Day 1, and 165 mL - 172 mL
on Day 28). Dose dependent improvements were seen in the proportion of subjects
achieving 200 mL and 12% increase in FEV1, 0-4 h weighted mean FEV1 and 0-4 h
maximum and peak FEV1 , as well as morning and evening PEF the percentage of
symptom-free 24-h periods and rescue-free 24-h periods with the greatest improvements
observed in the 25 g and 50 g groups.
Evidence of sustained bronchodilation with GW642444M was supported by repeated
measures analysis of trough FEV1, serial FEV1, ratio of peak post FEV1 to trough FEV1
and PM PEF assessments. Repeated measures analysis of trough FEV1 showed a dosedependent response with statistically significant improvements in trough FEV1 at 23-24 h
post dose on Day 28 for 12.5 g, 25 g GW642444M compared with placebo; as well as
50 g GW642444M at pre-dose on Day 7, Day 14 and Day 28, and at 23-24-h post-dose
on Day 28. Serial FEV1 profiles both on Day 1 and Day 28 demonstrated
bronchodilation over 24-hours for all GW642444M treatments. The ratio of peak postdose FEV1 to trough FEV1 across all the GW642444M doses was close to 1, suggesting
that the 24-h duration of action is an intrinsic property of the molecule and not a function
of dose. PM PEF, measured pre-evening dose, also showed bronchodilation out to 24hours with increases of >30 L/min in the 25 g and 50 g groups.
A numerically higher percentage of subjects were withdrawn due to lack of efficacy from
the placebo and 3 g GW642444M group (9 and 12% of subjects, respectively)
compared with the 6.25 g, 12.5 g and 25 g treatment groups (5%). No withdrawals
were reported for the 50 g GW642444M group. There was no statistically significant
difference between any of the GW642444M doses and placebo with regards to the
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response to albuterol/salbutamol at any of the time points investigated, suggesting that


tolerance to the bronchodilator response from short-acting -2-agonists with
GW642444M had not developed.
Safety: Overall, GW642444M was well tolerated at all doses in this study. The overall
incidence of AEs was similar across the GW642444M treatment groups (ranging from
23% in the 25 g GW642444M group to 37% in the 3 g group) and was comparable
with the placebo group (36%). There was no dose-related increase in the frequency of
the most commonly reported AEs. Drug-related AEs were reported at very low incidence
(4% to 8% of subjects on any treatment). Tremor and palpitations were infrequent and
similar in frequency to placebo. Two subjects withdrew directly due to AEs (receiving 3
g and 25 g GW642444M respectively). For a further 4 subjects who were withdrawn
due to AEs, the primary reason given for withdrawal from the study was the subject
reaching protocol-defined stopping criteria with related AEs as a sub-reason for
withdrawal. The reported events were ventricular tachycardia (placebo), atrioventricular
block second degree (12.5 g GW642444M), T-wave amplitude decreased (6.25 g
GW642444M), and PR prolongation (6.25 g GW642444M). Asthma exacerbations
were infrequent, with the highest incidence in the placebo and 3 g GW642444M groups
(4% and 7%, respectively), compared with 0% to 3% in other groups.
No safety concerns were noted from the results of haemotology, clinical chemistry
including liver function tests, or urinalysis assessments. No treatment-related changes
were apparent in vital signs assessments. No safety concerns were raised for pulse rate,
and minor increases in pulse rate were found for 25 g and 50 g GW642444M
compared with other active treatments and placebo. However, increases in pulse rate did
not exceed predefined levels of clinically relevant concern. Although a statistically
significant QTc(F) prolongation of 5 msec from placebo was recorded within 10 min of
dosing with 50 g GW642444M on Day 7, there were no clinically relevant increases
from baseline versus placebo in serial, weighted mean or maximum QTc(F) (0-4 h) for any
treatment group, at any time point. Increases in mean serial QTc(B) from baseline versus
placebo of 6 msec to 12.5 msec observed within 1 h of dosing with 50 g GW642444M
on all clinic study days, and within 1 h of dosing with 25 g GW642444M on Days 1 and
14, were above the 5 msec threshold of clinical concern. QTc(F) is acknowledged as the
more robust correction for drugs that are associated with increased heart rate, with QTc(B)
being a poorer correction factor. For potassium and glucose, maximum and weighted
changes from baseline (0-4 h), including changes versus placebo, did not exceed the
predefined levels of clinically relevant concern.
Pharmacokinetics-Pharmacodynamics: GW642444M showed a good therapeutic
margin over the dose range studied. There were limited measurable drug levels above the
quantification limit of 30 pg/mL up to 25 g dose. There was no clear relationship
between systemic exposure (observed Cmax over period 2-30 min post-dose) and any
systemic PD endpoint (pulse rate, QTc, glucose or potassium). The modeled trough
dose-FEV1 response showed a potency (ED50) of 16.1 g [95%CI:12.5-19.7 g] with a
maximum predicted FEV1 (Emax) of 243 mL (95%CI: 149-337 mL).

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Conclusions:

Overall efficacy of GW642444M was demonstrated by a statistically significant


linear trend test in dose response in trough FEV1.

Once-daily treatment with GW642444M resulted in a sustained 24-h improvement in


lung function which was statistically significantly greater than that seen with placebo
at 12.5 g, 25 g and 50 g doses, supporting once-daily dosing.

The Per Protocol and repeated measures analyses confirmed the results from the
primary analysis by demonstrating the superiority of 12.5 g, 25 g and 50 g doses
GW642444M relative to placebo.

Compared with the 3 g, 6.25 g and 12.5 g GW642444M doses, treatment with 25
g and 50 g GW642444M resulted in consistently greater improvements in lung
function (weighted mean 24-h serial FEV1, proportion of subjects achieving 200
mL and 12% increase in FEV1, 0-4 h weighted mean FEV1 and 0-4 h maximum and
peak FEV1), morning and evening PEF as well as symptoms and rescue use
(percentage of symptom- and rescue free 24-h periods).

The sustained 24-h duration of bronchodilatory action for GW642444M and


potential as a once-daily drug was confirmed by repeated measures analysis of the
primary endpoint, repeated measures analysis of serial FEV1 and analysis of PM
PEF. The ratio of peak post-dose FEV1 to trough FEV1 of approximately 1 across all
GW642444M doses suggested that the 24-h duration of action is an intrinsic property
of the molecule and not a function of dose.

A greater withdrawal rate due to lack of efficacy with the lower doses compared to
the higher GW642444M doses are consistent with the findings of the primary and
other efficacy analyses.

There was no evidence of development of tolerance to the bronchodilator response


from short-acting -2-agonist (albuterol/salbutamol) with GW642444M.

Broadly similar dose response effects were found for the lower and upper strata,
suggesting that different doses of GW642444M may not be required for different
severities of asthma.

The review of AEs, vital signs, laboratory parameters (haematology, clinical


chemistry including liver function tests, and urinalysis) and ECG demonstrated that
GW642444M was well tolerated and the observed safety profile was similar across
the GW642444M treatments and placebo. No SAEs were reported.

There were no clinically relevant increases from baseline versus placebo in serial,
weighted mean or maximum QTc(F) (0-4 h) for any treatment group, at any time
point. Although increases in mean serial QTc(B) from baseline versus placebo of 6
msec to 12.5 msec in the 25 g and 50 g GW642444M groups were above the 5
msec threshold of clinical concern, QTc(F) was acknowledged as the more robust
correction for drugs that are associated with increased heart rate, with QTc(B) being a
poorer correction factor.

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Potassium and glucose values did not exceed the predefined levels of clinically
relevant concern. No AEs of hypokalaemia were reported.

PK analysis showed that GW642444 shows a good therapeutic margin over the dose
range studied. There were limited measurable drug levels above the quantification
limit of 30 pg/mL up to 25 g dose, without a clear relationship between systemic
exposure (observed Cmax over period 2-30 min post-dose) and any systemic PD
endpoint (pulse rate, QTc, glucose or potassium).

The combination of good pulmonary potency of GW642444, sustained residency of


the drug in lung biophase and peak to trough ratio close to unity would support the
rationale for once daily potential dosing regimen in asthmatics.

Date of Report: April 2009

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Division: Worldwide Development


Retention Category: GRS019
Information Type: Protocol Amendment
A randomised, double-blind, placebo-controlled parallel group,
dose ranging study evaluating the efficacy and safety of
GW642444M administered once daily compared with placebo
for 28 days in adolescent and adult subjects with persistent
asthma

Title:

Compound Number: GW642444


Effective Date:

21-APR-2004

Protocol Amendment Number: 03


Description: A double-blind placebo-controlled study to evaluate the efficacy (measured
by clinic FEV1, bronchodilator response to salbutamol/albuterol, daily PEF, symptoms,
rescue salbutamol/albuterol use and withdrawals due to lack of efficacy), safety (assessed
by adverse events, clinical laboratory evaluations, ECGs and vital signs) and
pharmacokinetics of five doses (3mcg, 6.25mcg, 12.5mcg, 25mcg and 50mcg) of
GW642444M administered once daily compared with placebo over a 28 day treatment
period in subjects with persistent asthma.
Subject: Asthma, dose ranging, efficacy, safety, pharmacokinetics, placebo
Author:

(Respiratory Medicine Development Centre);


(Respiratory Medicine Development Centre Statistics and Programming);
(Clinical Pharmacology and Discovery Medicine)
(Global Clinical Safety and Pharmacovigilance)
(Division of Pharmacogenetics)

Copyright 2008 the GlaxoSmithKline group of companies. All rights reserved.


Unauthorised copying or use of this information is prohibited.

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Revision Chronology:
GM2006/00690/00

2007-NOV-01

Original

GM2006/00690/01

2007-DEC-17

Amendment No.1: Correction of


inconsistencies within the protocol and
clarification that severe milk protein
allergy is part of exclusion criterion No.
7

GM2006/00690/02

2008-APR-09

Amendment No.2:

GM2006/00690/03

2008-APR-21

To allow subjects to re-screen for


Visit 1 if they fail to meet lung
function criteria and to allow
subjects who have previously
failed screening to be re-screened.

To amend some of the ECG


abnormality randomisation and
withdrawal criteria.

To amend the blood pressure entry


criteria

To clarify the exclusion of subjects


with upper and lower respiratory
tract infections between Visit 1 and
Visit 2 (Randomisation to
Treatment).

To allow the use of long acting


anti-histamines

Amendment 3:
To amend an error to text in
randomisation criterion 7.

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SPONSOR INFORMATION PAGE


Clinical Study Identifier:

B2C109575

GlaxoSmithKline
Ironbridge Road
Stockley Park West
Uxbridge
Middlesex
UB11 1BT
Telephone:
GlaxoSmithKline
Five Moore Drive
P.O. 13398
Research Triangle Park, NC 27709-3398, USA
Telephone:
Sponsor Contact Information:
Sponsor Serious Adverse Events (SAE) Contact Information:
Case Management Group, Global Clinical Safety and Pharmacovigilance (GCSP)
Greenford, UK
Email:
Fax:
United States Medical Monitor:
MD (Director, Respiratory Medicine Development Centre)
Tel:
Mobile:
European and International Medical Monitor:
MA, BM BCh, MFPM (Director, Respiratory Medicine Development
Centre)
Tel:
Mobile:
Regulatory Agency Identifying Number(s):Eudract No. 2007-001713-42
IND No. 74,696

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INVESTIGATOR AGREEMENT PAGE


I confirm agreement to conduct the study in compliance with the protocol, as amended by
this protocol amendment.

Investigator Name: _____________________________

Investigator Signature

Date

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TABLE OF CONTENTS
Page

ABBREVIATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

PROTOCOL SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11

1. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.1. Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.2. Rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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13

2. OBJECTIVE(S) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

14

3. INVESTIGATIONAL PLAN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1. Study Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2. Discussion of Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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4. SUBJECT SELECTION AND WITHDRAWAL CRITERIA. . . . . . . . . . . . . .


4.1. Number of Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2. Inclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3. Exclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.4. Randomisation Criteria. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.5. Withdrawal Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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5. STUDY TREATMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1. Investigational Product and Reference Therapy . . . . . . . . . . . . . . . .
5.2. Treatment Assignment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.3. Blinding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.4. Product Accountability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.5. Treatment Compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.6. Concomitant Medications and Non-Drug Therapies . . . . . . . . . . . . .
5.6.1. Permitted Medications and Non-Drug Therapies . . . . . . . . . . .
5.6.2. Prohibited Medications and Non-Drug Therapies . . . . . . . . . .
5.7. Treatment after the End of the Study . . . . . . . . . . . . . . . . . . . . . . . . .
5.8. Treatment of Investigational Product Overdose . . . . . . . . . . . . . . . . .

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26
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27
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28
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30

6. STUDY ASSESSMENTS AND PROCEDURES . . . . . . . . . . . . . . . . . . . . .


6.1. Critical Baseline Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.2. Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.2.1. Efficacy Endpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.2.2. Efficacy Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.3. Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.3.1. Safety Endpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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6.3.2. Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


6.3.3. Laboratory and Other Safety Assessment Abnormalities
Reported as AEs and SAEs. . . . . . . . . . . . . . . . . . . . . . . . . . .
6.3.4. Time Period and Frequency of Detecting AEs and SAEs . . . .
6.3.5. Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.3.6. Medical Devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.3.7. Prompt Reporting of Serious Adverse Events and Other
Events to GSK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.3.8. Other Safety Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.4. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.4.1. Pharmacokinetic Endpoint(s) . . . . . . . . . . . . . . . . . . . . . . . . . .
6.4.2. Assessment of GW642444, GW630200, GSK932009
GI179710 in plasma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.5. Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.6. Pharmacogenetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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7. DATA MANAGEMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

49

8. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS . . . . . . . . . . .


8.1. Hypotheses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.2. Study Design Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.2.1. Sample Size Assumptions . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.2.2. Sample Size Sensitivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.2.3. Sample Size Re-estimation . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.3. Data Analysis Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.3.1. Analysis Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.3.2. Analysis Data Sets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.3.3. Treatment Comparisons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.3.4. Interim Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.3.5. Key Elements of Analysis Plan . . . . . . . . . . . . . . . . . . . . . . . .

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9. STUDY CONDUCT CONSIDERATIONS . . . . . . . . . . . . . . . . . . . . . . . . . .


9.1. Regulatory and Ethical Considerations, Including the Informed
Consent Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9.2. Quality Control (Study Monitoring) . . . . . . . . . . . . . . . . . . . . . . . . . . .
9.3. Quality Assurance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9.4. Study and Site Closure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9.5. Records Retention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9.6. Provision of Study Results and Information to Investigators . . . . . . .

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10. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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44
44
45
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11. APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.1. Appendix 1: PGx . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11.2. Appendix 2: Laboratory Parameters . . . . . . . . . . . . . . . . . . . . . . . .
11.3. Appendix 3: Country Specific Requirements . . . . . . . . . . . . . . . . . .
11.4. Appendix 4: Protocol Changes . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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ABBREVIATIONS
ABV
AE
ALT
AM
ANCOVA
AST
AUC
AV
CFC
CI
COPD
CPK
CRF
DPI
ECG
EDTA
FEV1
GCSP
GINA
GSK
HFA
IB
IEC
ICS
IRB
ITT
IUD
LABA
LDH
LLQ
LOCF
MAO
mcg
MDI
MedDRA
MSDS
NIH
PD
PEF
PGx
PK
PM
PP
QTc(b)
RAMOS
RAP

Absolute By Volume
Adverse Event
Alanine aminotransferase
Morning
Analysis of Covariance
Aspartate Aminotransferase
Area Under the Curve
Atrioventricular
Chlorofluorocarbon
Confidence Interval
Chronic Obstructive Pulmonary Disease
Creatine Phosphokinase
Case Report Form
Dry Powder Inhaler
Electrocardiogram
Ethylenediaminetetraacetic Acid
Forced Expiratory Volume in 1 second
Global Clinical Safety and Pharmacovigilance
Global Initiative for Asthma
GlaxoSmithKline
Hydrofluoroalkane
Investigator Brochure
Independent Ethics Committee
Inhaled Corticosteroid
Institutional Review Board
Intent To Treat
Intrauterine Device
Long Acting Beta Agonist
Lactate Dehydrogenase
Lower Limit of Quantification
Last Observation Carried Forward
Monoamine Oxidase
Microgram
Metered Dose Inhaler
Medical Dictionary for regulatory Activities
Material Safety Data Sheet
National Institutes of Health
Pharmacodynamics
Peak Expiratory Flow
Pharmacogenetics
Pharmacokinetic
Evening
Per Protocol
QTc corrected for Bazetts formula
Registration and Medication Ordering System
Reporting and Analysis Plan
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SAE
SPM
ULN

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Serious Adverse Event


Study Procedures Manual
Upper Limit of Normal

Trademark Information
Trademarks of the GlaxoSmithKline
group of companies
DISKUS

Trademarks not owned by the


GlaxoSmithKline group of companies
Qvar
Xolair

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PROTOCOL SUMMARY
Rationale
Clinical rationale: The purpose of this study is to evaluate the efficacy and safety of five
doses of GW642444M administered once-daily compared with placebo in subjects with
persistent asthma over a 28-day period. The information obtained will be used to select
the optimum dose for further studies.
Pharmacokinetics Rationale: Pharmacokinetic samples from randomised subjects will be
collected using a population pharmacokinetics (PK) approach. In contrast to traditional
pharmacokinetic methods, the population PK approach allows the identification and
measurement of pharmacokinetic variability in subjects representative of the target
population and the explanation of that variability by identifying factors that may
influence the pharmacokinetic behaviour of the drug. This approach also allows
estimation of the unexplained (random) variability in the patient population, which is
important, since an increase in random variability may result in an underestimate of
efficacy and/or safety. Defining the optimum dose for later stages of development can be
made more efficient by understanding the variability in the pharmacokinetics of a drug.

Objective(s)
Primary Objective
To evaluate the dose response, efficacy and safety of five doses of GW642444M (3mcg,
6.25 mcg, 12.5 mcg, 25mcg and 50 mcg) over a 28 day treatment period in subjects with
persistent asthma
Secondary Objective
To characterise the population pharmacokinetics of GW642444 in subjects with
persistent asthma

Study Design
This will be a multi-centre, randomised, placebo-controlled, double-blind, parallel group
study. Subjects will enter a two week run-in period and those who then fail to meet
eligibility criteria for randomisation will be withdrawn from the study. Those subjects
who meet the eligibility criteria at the end of the run-in period will be stratified in an
approximately 1:1 ratio according to their baseline FEV1 as a percentage of predicted
normal - one stratum for those with FEV1 percent predicted 40% - 65% and one for
those with FEV1 percent predicted > 65%-90%. Once stratified, subjects will be
randomised to one of the following treatments and enter into a 28 day double-blind
treatment period (-4/+2days):

GW642444M 3mcg once daily in the evening

GW642444M 6.25mcg once daily in the evening

GW642444M 12.5mcg once daily in the evening


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GW642444M 25mcg once daily in the evening

GW642444M 50mcg once daily in the evening

Placebo once daily in the evening

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There will be a 7 day follow-up period following the end of the treatment period.
Subjects will remain on their current inhaled corticosteroid therapy (at fixed doses)
throughout the study (screening to follow-up inclusive). At the end of the follow-up
period, subjects will be prescribed appropriate alternative asthma therapy, if required. A
subject will be regarded as having completed the study if they complete all phases of the
study (screening, treatment period and follow-up). Subjects who complete the study will,
therefore, participate in the study for a total of 7 weeks.
Approximately 1200 subjects will be screened to ensure randomisation of 594 subjects
(99 subjects per group) with at least one pre-dose or 23-24 hour post-dose FEV1
assessment on or after nominal Day 7.

Study Endpoints/Assessments
Primary Endpoint
Mean change from baseline in clinic visit trough (pre-bronchodilator and pre-dose) FEV1
at the end of the 28-day treatment period. The trough FEV1 will be defined as the mean of
the FEV1 values obtained 23 and 24 hours after dosing on Day 28.
All other endpoints will be derived from the following assessments:

Clinic measured FEV1

Peak expiratory flow (PEF)

Diary card measures (symptoms, rescue medication usage)

Vital signs (pulse rate and blood pressure)

12-lead ECGs

Clinical laboratory safety tests (including additional potassium and glucose profiling)

Adverse events

Pharmacokinetic sampling

Pharmacogenetic sampling

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1.

INTRODUCTION

1.1.

Background

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GW642444M is a potent, inhaled, long-acting 2-receptor agonist (LABA) currently


under development as the LABA component of an inhaled corticosteroid (ICS)/LABA
combination for use as a once daily treatment in asthma and chronic obstructive
pulmonary disease (COPD) and also as a monotherapy product for the treatment of
COPD.
International guidelines such as those issued by GINA (Global Initiative for Asthma)
[GINA, 2006] and the NHLBI [NIH, 2007] advocate the use of inhaled long-acting 2agonists in combination with inhaled corticosteroids (ICS) as maintenance therapy in
asthma for subjects who remain symptomatic despite low to medium doses of ICS. The
long-acting 2-agonists that are currently available (e.g. salmeterol, formoterol) require
twice-daily administration. There is a significant need for a once-daily inhaled
medication that can help to improve patient compliance and overall disease management
by providing sustained, 24-hour bronchodilation.
Information on the physical, chemical and pharmaceutical properties of GW642444M
and a full summary of all available pre-clinical and clinical data may be found in the
Investigator Brochure [GlaxoSmithKline Document Number SM2003/00028/05] and
supplement [GlaxoSmithKline Document Number RM2007/00094/00].

1.2.

Rationale

Clinical rationale: The purpose of this study is to evaluate the efficacy and safety of five
doses of GW642444M administered once-daily compared with placebo in subjects with
persistent asthma over a 28-day period. The information obtained will be used to select
the optimum dose for further studies.
Pharmacokinetics Rationale: Pharmacokinetic samples from randomised subjects will be
collected using a population pharmacokinetics (PK) approach. In contrast to traditional
pharmacokinetic methods, the population PK approach allows the identification and
measurement of pharmacokinetic variability in subjects representative of the target
population and the explanation of that variability by identifying factors that may
influence the pharmacokinetic behaviour of the drug. This approach also allows
estimation of the unexplained (random) variability in the patient population, which is
important, since an increase in random variability may result in an underestimate of
efficacy and/or safety. Defining the optimum dose for later stages of development can be
made more efficient by understanding the variability in the pharmacokinetics of a drug.

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2.

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OBJECTIVE(S)

Primary Objective
To evaluate the dose response, efficacy and safety of five doses of GW642444M (3mcg,
6.25mcg, 12.5mcg, 25mcg and 50mcg) over a 28 day treatment period in subjects with
persistent asthma

Secondary Objective
To characterise the population pharmacokinetics of GW642444 in subjects with
persistent asthma

3.

INVESTIGATIONAL PLAN

3.1.

Study Design

This will be a multi-centre, randomised, placebo-controlled, double-blind, parallel group


study. Subjects meeting all entry inclusion criteria and none of the exclusion criteria
during the Visit 1 screening period (no longer than 4 days) will enter a two week run-in
period and those who then fail to meet eligibility criteria for randomisation will be
withdrawn from the study. Those subjects who meet the eligibility criteria at the end of
the run-in period will be stratified in an approximately 1:1 ratio according to their
baseline FEV1 as a percentage of predicted normal - one stratum for those with FEV1
percent predicted 40% - 65% and one for those with FEV1 percent predicted > 65%90%. Once stratified, subjects will be randomised to one of the following treatments and
enter into a 28 day double-blind treatment period (-4/+2days):

GW642444M 3mcg once daily in the evening

GW642444M 6.25mcg once daily in the evening

GW642444M 12.5mcg once daily in the evening

GW642444M 25mcg once daily in the evening

GW642444M 50mcg once daily in the evening

Placebo once daily in the evening

There will be a 7 day follow-up period following the end of the treatment period.
Subjects will remain on their current inhaled corticosteroid therapy (at fixed doses)
throughout the study (screening to follow-up inclusive). At the end of the follow-up
period, subjects will be prescribed appropriate alternative asthma therapy, if required. A
subject will be regarded as having completed the study if they complete all phases of the
study (screening, treatment period and follow-up). Subjects who complete the study will,
therefore, participate in the study for a total of 7 weeks.

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The schematic below illustrates the clinic visits required for each phase of the study.

* Visit 1 screening period:


The resting ECG must be performed first. It is then recommended that lung function tests
are performed before any other assessment. If a subject does not meet the inclusion
criteria for FEV1 percent predicted and/or reversibility following inhalation of
albuterol/salbutamol, no other study assessments should be performed at this first visit,
and the subject may return to the site once within 4 days to repeat the lung function tests.
If the subject does meet the lung function entry criteria on the second attempt, then other
Visit 1 assessments must also be performed on this date.
If the subject only becomes eligible at the second screening visit the Investigator must
document that the ECG results and clinical laboratory test results (if taken at first
screening visit) are clinically acceptable within the 4 day screening period. The clinical
laboratory tests and ECG do not need to be repeated at the second screening visit.
However, all other assessments must be repeated on the same day as the qualifying lung
function tests.
The data from the original Visit 1 date will be returned to GSK as well.

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Supplementary study conduct information not mandated to be present in this protocol is


provided in the accompanying Study Procedures Manual (SPM). The SPM will provide
the site personnel with administrative and detailed technical information that does not
impact subject safety.

3.2.

Discussion of Design

Five doses of GW642444M (3mcg, 6.25mcg, 12.5mcg, 25mcg and 50mcg) have been
selected for this phase IIb dose ranging study. The doses have been selected based upon
results from 2 Phase I studies (B2C10001 and B2C108784 [GlaxoSmithKline Document
Number SM2003/00028/05]) and 4 Phase IIa studies (B2C101762, B2C104604,
B2C106093 [GlaxoSmithKline Document Number SM2003/00028/05], and B2C106996
[GlaxoSmithKline Document Number RM2007/00094/00]). The 3mcg dose has been
included as a potential no-effect dose. The 50mcg dose is included as a likely supratherapeutic dose to help establish the therapeutic index for GW642444M and to assess
whether or not a plateau has been achieved. The intervening doses of 6.25mcg, 12.5mcg
and 25mcg represent doubling-dose increments between the lowest and highest doses.
By evaluating a range of doses from 3mcg to 50mcg of GW642444M, it will be possible
to assess the dose response of GW642444M as well as the potential effects of
GW642444M on typical pharmacological class effects (e.g., increased heart rate,
decreased potassium levels, increased glucose levels). The data will provide useful
information in determining the therapeutic index of GW642444M and in selecting the
dose(s) of GW642444M to be carried forward in the Phase III program in the
GW685698X/GW642444M combination product.
The studies performed to date have been conducted with morning dosing. For Phase IIb,
the intention is to dose in the evening to match the corticosteroid dose ranging studies.
However, GSK intends to also explore morning dosing with GW642444 as part of the
ICS/LABA combination development program. Based on observations with salmeterol,
GSK does not expect the efficacy or safety profile to differ based on dosing in the
evening [GlaxoSmithKline Document Number RM2003/00283/00].
Treatment duration of 28 days is considered to be sufficient to demonstrate that the
efficacy of GW642444M is maintained without tolerance

4.

SUBJECT SELECTION AND WITHDRAWAL CRITERIA

4.1.

Number of Subjects

Approximately 1200 subjects will be screened to ensure randomisation of 594 subjects


(99 subjects per group) with at least one pre-dose or 23-24 hour post-dose FEV1
assessment on or after nominal Day 7.

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4.2.

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Inclusion Criteria

Specific information regarding warnings, precautions, contraindications, adverse events,


and other pertinent information on the investigational product that may impact subject
eligibility is provided in the IB [GlaxoSmithKline Document
Number SM2003/00028/05] and IB supplement [GlaxoSmithKline Document
Number RM2007/00094/00]
Subjects eligible for enrolment in the study must meet all of the following criteria:
1

Aged 12 years of age or older at Visit 1


For sites in the following countries, subjects recruited will be 18 years of age:
Germany, Hungary and the Russian Federation and any other countries where local
regulations or the regulatory status of study medication permit enrolment of adults
only.

Male or eligible female subjects


A female is eligible to enter and participate in the study if she is of:
Non-child bearing potential (i.e. physiologically incapable of becoming pregnant),
including any female who is post-menopausal.
Child bearing potential, has a negative pregnancy test at screening, and agrees to one
of the following acceptable contraceptive methods used consistently and correctly
(i.e. in accordance with the approved product label and the instructions of the
physician for the duration of the study screening to follow-up contact):

Complete abstinence from intercourse from screening until 2 weeks after the
follow-up contact; or

Sterilisation of male partner (vasectomy with documentation of azoospermia)


prior to female subject entry into the study, and this male partner is the sole
partner for that subject; or

Implants of levonorgestral inserted for at least 1 month prior to the study


medication administration but not beyond the third successive year following
insertion; or

Injectable progestogen administered for at least 1 month prior to study


medication administration and administered for 1 month following study
completion; or

Oral contraceptive (combined or progestogen only) administered for at least one


monthly cycle prior to study medication administration; or

Double barrier method: condom or occlusive cap (diaphragm or cervical/vault


caps) plus spermicidal agent (foam/gel/film/cream/suppository)
N.B. For German sites female subjects must use a method of birth control other
than the double barrier method

An intrauterine device (IUD), inserted by a qualified physician, with published


data showing that the highest expected failure rate is less than 1% per year; or
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Estrogenic vaginal ring inserted for at least 1 month prior to study medication
administration; or

Percutaneous contraceptive patches in place for at least 1 month prior to study


medication administration
Female subjects should not be enrolled if they are pregnant, or lactating, or plan
to become pregnant during the time of study participation.

Documented clinical history of persistent asthma, as defined by the National


Institutes of Health [NIH, 2007] first diagnosed at least 6 months prior to Visit 1.

Subjects with current reversible airways disease as demonstrated at Visit 1 screening


period by an increase in FEV1 of 12% and 200ml over the presalbutamol/albuterol FEV1 at approximately 30 minutes after the inhalation of
400mcg of salbutamol/albuterol via MDI (spacer permitted for reversibility testing
only if required) or one nebulised salbutamol/albuterol solution.
Re-screening of subjects during the Visit 1 screening period: If a subject does not
meet the inclusion criteria based upon FEV1 percent predicted and/or reversibility,
the subject may return to the site once within 4 days and repeat the lung function
tests.

Subjects must be using an inhaled corticosteroid and have been maintained on a


stable dose for 4 weeks prior to Visit 1 at one of the following doses:
Maximum Allowable Concurrent Inhaled Corticosteroid Doses

Asthma Therapy
fluticasone propionate MDI CFC/HFA
fluticasone propionate DPI
beclomethasone dipropionate
beclomethasone dipropionate HFA (Qvar)
budesonide DPI/MDI
Flunisolide
triamcinolone acetonide
mometasone furoate
Ciclesonide

Maximum Daily Dose (mcg/day)


880mcg1/ 1000mcg2
1000mcg
1680mcg1/ 2000mcg2
640mcg1/ 800mcg2
2000mcg
2000mcg
2000mcg
880mcg
320mcg1/ 400mcg2

CFC=chlorofluorocarbon HFA=hydrofluoroalkane
1. Ex-actuator dose
2. Ex-valve dose

Pre-bronchodilator FEV1 between 40 - 90% predicted at Visit 1.


NHANES III predicted values will be used for subjects aged 12 years and
adjustments to predicted values will be made for African American subjects
[Hankinson, 1999].

Appropriately signed and dated informed consent has been obtained.

Capable of withholding salbutamol/albuterol use for 6 hours prior to clinic visits.

In France, a subject will be eligible for inclusion in this study only if either affiliated
to or a beneficiary of a social security category.
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4.3.

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Exclusion Criteria

Subjects meeting any of the following criteria must not be enrolled in the study:
1

An exacerbation of asthma within 4 weeks of Visit 1, or a culture documented or


suspected bacterial or viral infection of the upper or lower respiratory tract, sinus or
middle ear within 4 weeks of Visit 1 that led to a change in asthma management, or
in the opinion of the Investigator is expected to affect the subjects asthma status or
the subjects ability to participate in the study.

History of life-threatening asthma, defined as an asthma episode that required


intubation and/or was associated with hypercapnoea, respiratory arrest or hypoxia
seizures.

Asthma exacerbation requiring treatment with oral corticosteroids within 3 months


prior to Visit 1.

Hospitalised for an asthma exacerbation within 6 months of Visit 1.


Hospitalisation is defined as an overnight stay in a hospital.

Participated in any study using an investigational drug during the previous 30 days or
will participate simultaneously in another clinical trial.

A subject must not have any clinically significant, uncontrolled condition or disease
state that, in the opinion of the investigator, would put the subject's safety at risk
through study participation or would confound the interpretation of the efficacy
results if the condition/disease exacerbated during the study.
The list of additional excluded conditions/diseases includes, but is not limited to the
following:

congestive heart failure


clinically significant coronary heart disease
stroke within 3 months of Visit 1
poorly controlled peptic ulcer
immunologic compromise
tuberculosis (current or untreated3)
Addison's disease
uncontrolled thyroid disorder
neurological disease
1.
2.
3.
4.

known aortic aneurysm


clinically significant cardiac arrhythmia
uncontrolled hypertension1
haematologic, hepatic, or renal disease
current malignancy2
Cushing's disease
uncontrolled diabetes mellitus
recent history of drug or alcohol abuse
pulmonary disease4

2 or more measurements with systolic blood pressure 160mmHg or diastolic blood pressure
100mmHg[NIH, 2004]
history of malignancy is acceptable only if subject has been in remission for one year prior to Visit 1 (remission =
no current evidence of malignancy and no treatment for the malignancy in the 12 months prior to Visit 1)
Subjects with a history of tuberculosis who have received an approved prophylactic treatment regimen or an
approved active treatment regimen and who have no evidence of active disease for a minimum of 2 years may be
enrolled [American Thoracic Society Documents, 2005; American Thoracic Society, 2003]
Including but not limited to chronic bronchitis, emphysema, bronchiectasis with the need of treatment, cystic
fibrosis, bronchopulmonary dysplasia, and chronic obstructive pulmonary disease.

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Any adverse reaction including immediate or delayed hypersensitivity to any 2agonist or sympathomimetic drug, or known (i.e., patients with a history of severe
milk protein allergy) or suspected sensitivity to the constituents of GW642444M
inhalation powder (e.g., lactose or magnesium stearate).

Subjects who are likely to be non-compliant with study medication and other studyrelated requirements (e.g. attendance at clinic visits or completion of Daily Diary).

Neurological or psychiatric disease or history of drug or alcohol abuse which would


interfere with the subjects proper completion of the protocol requirements.
Abuse of alcohol is defined as an average weekly intake of greater than 21 units or
an average daily intake of greater than 3 units (males) or defined as an average
weekly intake of greater than 14 units or an average daily intake of greater than 2
units (females). The number of units of alcohol in a drink can be determined by
multiplying the volume of the drink (in millilitres) by its percentage ABV and
dividing by 1000

10 Current smoker or a smoking history of 10 pack years or more (e.g. 20 cigarettes/day


for 10 years). A subject may not have used tobacco products within the past one
year (i.e., cigarettes, cigars, or pipe tobacco).
11 Administration of systemic, oral or depot corticosteroids or administration of
anti-IgE (e.g. omalizumab [Xolair]) within 12 weeks of Visit 1.
12 Administration of any of the following asthma medications within 14 days of Visit 1:

Theophyllines

Oral 2-agonists (e.g. bambuterol)

Slow-release bronchodilators

Anticholinergics - short or long-acting

Oral leukotriene receptor antagonists (e.g. montelukast)

Inhaled sodium cromoglicate

Inhaled nedocromil sodium

13 Administration of inhaled long-acting 2-agonists (e.g. salmeterol) within 7 days of


Visit 1
14 Administration of any other prescription or over the counter medication which may
affect the course of asthma, or interact with sympathomimetic amines, such as:
Anticonvulsants (barbiturates, hydantoins, and carbamazepine); Polycyclic
antidepressants; -adrenergic blocking agents; Phenothiazines and Monoamine
oxidase (MAO) inhibitors
15 Administration of a potent P-glycoprotein inhibitor or potent Cytochrome P450 3A4
inhibitor within 4 weeks prior to Visit 1 (e.g. ritonavir and ketoconazole)
16 A subject will not be eligible for this study if he/she is an immediate family member
of the participating Investigator, sub-Investigator, study co-ordinator, or employee of
the participating Investigator

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4.4.

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Randomisation Criteria

At the end of the run-in period subjects must fulfil the following additional criteria in
order to enter the treatment period of the study:
1.

Best baseline pre-dose FEV1 at Visit 2 40% and 90% of their predicted normal.

2.

Any combination of daily asthma symptom scores (day-time plus night-time) of 1


or salbutamol/albuterol use on at least four of the last seven consecutive days of the
run-in period (immediately preceding Visit 2).

3.

No evidence of clinically significant abnormality in the haematological, biochemical


or urinalysis screen at Visit 1, as judged by the investigator.

4.

No diagnosis of chronic hepatitis B and C, as evidenced by positive Hepatitis B


surface antigen (HBsAg) or Hepatitis C antibody screen at Visit 1.

5.

No evidence of significant abnormality in the 12-lead ECG at Visit 1, as judged by


Independent cardiologist.
Selected specific ECG findings that are considered to be significant and will exclude
the subject from study participation include, but are not limited to, the following:

Ventricular rate < 45 beats per minute or > 90 beats per minute

PR interval > 240msec

Evidence of second or third degree atrioventricular (AV) block

Pathological Q waves (defined as wide (> 0.04 seconds) and deep (> 0.4mV (4
mm with 10mm/mV setting) or > 25% of the height of the corresponding R
wave, provided the R wave was > 0.5mV (5 mm with 10mm/mV setting),
appearing in at least two contiguous leads) or other historical or
electrocardiographic evidence of prior myocardial infarction.

Evidence of 2 or more supra-ventricular or ventricular ectopic beats, ie. ANY


couplets, bigeminy, trigeminy or multifocal premature ventricular complexes.
This should be confirmed by 3 readings at least 5 minutes apart.

QTc(B) > 450msec

ST-T wave abnormalities (excluding non-specific ST-T wave abnormalities)

Right or left complete bundle branch block, or a QRS interval >120msec.

Incomplete right bundle branch block (QRS interval > 110msec < 120msec with
right bundle branch block pattern). This should be confirmed by three readings
at least 5 minutes apart.

6.

No changes in asthma medication (excluding rescue salbutamol/albuterol MDI


provided at Visit 1) during the run-in period.

7.

No occurrence of a culture-documented or suspected bacterial or viral infection of


the upper or lower respiratory tract, sinus or middle ear during the run-in period that
led to a change in asthma management, or in the opinion of the Investigator is

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expected to affect the subjects asthma status or the subjects ability to participate in
the study.
8.

Able to correctly use the novel dry powder inhaler.

9.

No asthma exacerbation during the run-in period.


An exacerbation is defined as worsening asthma requiring any treatment other than
rescue salbutamol/albuterol or regular inhaled corticosteroid use. This includes
requiring the use of systemic corticosteroids and/or emergency room visit,
hospitalisation or a change in subjects regular inhaled corticosteroid dose.

10. Compliance with completion of the Daily Diary. Non-compliance with completion
of the Daily Diary, defined as:

Completion of AM and PM symptom scores on less than 4 days out of the last 7
days immediately preceding Visit 2.

Completion of AM and PM rescue use on less than 4 days out of the last 7 days
immediately preceding Visit 2.

Completion of AM and PM PEF measurements on less than 4 days out of the


last 7 days immediately preceding Visit 2.

4.5.

Withdrawal Criteria

A subject will be regarded as having completed the study if they complete all phases of
the study (screening, treatment period and follow-up).
Subjects may be withdrawn from study treatment at anytime by the Investigator if it is
considered to be detrimental for them to continue in the study. Reasons for withdrawal
can include: an adverse event, lost to follow-up, protocol violation, lack of efficacy,
sponsor terminated study, non-compliance, pregnancy, abnormal liver function test,
abnormal laboratory results, or for any other reason. Subjects are also free to withdraw
themselves from the study at anytime, although every effort should be made to persuade
them to return to the clinic for an early withdrawal visit and to return all study related
materials.
Subjects should be withdrawn from the investigational product for any of the following
reasons. Once withdrawn from the investigational product a subject will be considered
withdrawn from the study.
A subject experiences any of the following abnormalities in ECGs. (the decision should
be made following consultation with the medical monitor, unless there is an immediate
safety concern and this is not feasible).

A subject experiences an increase in heart rate from baseline of >40bpm


(relative to the pre-dose Day 1 value) or an absolute heart rate of >110bpm
during the treatment period. This should be confirmed by 3 readings at least 5
minutes apart.

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A subject experiences a prolongation in absolute mean QTC(B) to >500msec or


uncorrected mean QT >600msec during the treatment period. This should be the
mean of three measurements taken at least 5 minutes apart.

Ventricular rate < 37 beats per minute. This should be confirmed by 3 readings
at least 5 minutes apart on 3 or more ECGs.

PR interval > 240msec. This should be confirmed by 3 readings at least 5


minutes apart on 3 or more ECGs.

Evidence of second or third degree atrioventricular (AV) block

Pathological Q waves (defined as wide (> 0.04 seconds) and deep (> 0.4mV (4
mm with 10mm/mV setting) or > 25% of the height of the corresponding R
wave, provided the R wave was > 0.5mV (5 mm with 10mm/mV setting),
appearing in at least two contiguous leads) or other historical or
electrocardiographic evidence of prior myocardial infarction.

Evidence of 2 or more supra-ventricular or ventricular ectopic beats, ie. ANY


couplets, bigeminy, trigeminy or multifocal premature ventricular complexes.
This should be confirmed by 3 readings at least 5 minutes apart.

ST-T wave abnormalities (excluding non-specific ST-T wave abnormalities)

Right or left complete bundle branch block, or a QRS interval >120msec

Incomplete right bundle branch block (QRS interval > 110msec < 120msec with
right bundle branch block pattern). This should be confirmed by three readings
at least 5 minutes apart.

A subject meets any of the lack of efficacy criteria outlined below:

Clinic FEV1 below the FEV1 Stability Limit value calculated at Visit 2 pre-dose
FEV1 at Visit 2 x 80%).
During the 7 days immediately preceding the visit, the subject experienced any
of the following:

> 3 days in which PEF has fallen below the AM PEF Stability Limit calculated
at Visit 2 (Mean AM PEF from the 7 days preceding Visit 2 x 80%)

More than 2 days in which 12 inhalations/day of salbutamol/albuterol were


used

Clinical asthma exacerbation. An exacerbation is defined as worsening asthma


requiring any treatment other than study medication or rescue
salbutamol/albuterol or regular inhaled corticosteroid use. This includes
requiring the use of systemic corticosteroids and/or emergency room visit or
hospitalisation or a change in subjects regular inhaled corticosteroid dose.

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When subjects meet the following liver chemistry threshold criteria, investigational
product must be permanently withdrawn, additional testing performed, and the subject
monitored until liver chemistries resolve, stabilize, or return to baseline values. The
subject must then be permanently withdrawn from the study (see Section 6.3.3 for further
details).

ALT 3xULN and bilirubin 1.5xULN (>35% direct).

ALT 5xULN.

ALT 3xULN if associated with the appearance or worsening of hepatitis symptoms


or rash.

At withdrawal, study related equipment should be returned by the subject and if possible
an Early Withdrawal Visit (See Table 1) should be conducted within 24 hours of the
subjects stopping study medication. In the event a subject withdraws at, or during, a
scheduled visit, an Early Withdrawal Visit is not required. However, all study procedures
scheduled at an Early Withdrawal Visit must be performed at this visit instead. A followup visit should be made 7 days (-4/+2days) after the Early Withdrawal Visit.
Subjects who are withdrawn from the study will not be replaced. The primary reason for
withdrawal will be recorded in the CRF and any data collected up until the point of
withdrawal will be used in the analyses.

5.

STUDY TREATMENTS

5.1.

Investigational Product and Reference Therapy

Compound
Formulation

Dosage Form
Unit Dose Strength(s)

Route of Administration

GW642444M
First strip: GW642444X micronised
drug (as the M salt
triphenylacetate) blended with
lactose and magnesium stearate
Second strip: placebo containing
lactose
Novel dry powder inhaler 30 doses
per device
3 mcg per blister
6.25 mcg per blister
12.5 mcg per blister
25 mcg per blister
50mcg per blister
Inhaled

Placebo
First strip: blend of lactose
and magnesium stearate
Second strip: lactose

Novel dry powder inhaler 30


doses per device

Inhaled

Salbutamol/albuterol MDI for use as rescue medication throughout the study will be
sourced locally or by GSK for sites in the United States of America, for all other sites it
will be sourced locally where possible.
The contents of the label will be in accordance with all applicable regulatory
requirements.
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Under normal conditions of handling and administration, investigational product is not


expected to pose significant safety risks to site staff. A Material Safety Data Sheet
(MSDS) describing the occupational hazards and recommended handling precautions will
be provided to site staff if required by local laws or will otherwise be available from GSK
upon request.
Investigational product must be stored in a secure area under the appropriate physical
conditions for the product. Access to and administration of the investigational product
will be limited to the investigator or designee. Investigational product must be dispensed
or administered only to subjects enrolled in the study and in accordance with the
protocol.
All novel dry powder inhalers containing GW642444M or matching placebo should be
stored, until dispensed, between 2-8C in a secure location.
Once a subject has been confirmed eligible for randomisation (See Section 4.4
Randomisation Criteria) the novel dry powder inhalers should be removed from
refrigerated storage at least 1 hour before administration and allowed to equilibrate to
room temperature under controlled room conditions.
After dispensing, all novel dry powder inhalers containing GW642444M or matching
placebo should be stored below 25C.
All double-blind study medication (used and unused) will be returned to GSK at the end
of the study to be available for inspection. In addition, all supplies of
albuterol/salbutamol inhalation aerosol (used and unused) must be returned to GSK for
local destruction.
Any study inhaler that fails to function properly must be identified to GSK personnel for
return to GSK for testing. Details of the failure will be documented in the eCRF. The
subject should return the device to the clinic as soon as possible and avoid missing any
doses if possible. The site should then call RAMOS and obtain a new treatment pack
number for this subject and dispense a new study medication kit from the site's
investigational product supply as instructed by RAMOS.
Subjects will be randomised in equal numbers to one of the following dose regimens:

GW642444M 3mcg (1 actuation) administered once daily via the novel dry powder
inhaler in the evening

GW642444M 6.25mcg (1 actuation) administered once daily via the novel dry
powder inhaler in the evening

GW642444M 12.5mcg (1 actuation) administered once daily via the novel dry
powder inhaler in the evening

GW642444M 25mcg (1 actuation) administered once daily via the novel dry powder
inhaler in the evening

GW642444M 50mcg (1 actuation) administered once daily via the novel dry powder
inhaler in the evening
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Placebo (1 actuation) administered once daily via the novel dry powder inhaler in the
evening

The duration of treatment for each subject is 28 days. On Days 1 and 2 (Visit 2/2a), Day
7 (Visit 3), Day 14 (Visit 4) and Day 28 (Visit 5) subjects will be required to take their
dose of study medication at the clinic. Study medication will be given at the clinic at
approximately the same time of day ( 1 hour) as Day 1 (Visit 2). On other days, subjects
will be instructed to take their study medication within 1 hour of their dose time on Day
1 (Visit 2). Doses should be taken prior to usage of rescue salbutamol/albuterol. Subjects
will be required to fast for at least 4 hours prior to the planned pre-dose blood sample
until after the 4 hours post-dose assessments on Days 1 and 28 (Visits 2 and 5
respectively)
Inhaled salbutamol/albuterol will be provided for symptomatic relief during the run-in
treatment period and follow-up period.

5.2.

Treatment Assignment

Subjects will be assigned to study treatment in accordance with the randomisation


schedule. Once a randomisation number has been assigned to a subject, it cannot be
reassigned to any other subject in the study.
Subjects will be randomised centrally using RAMOS. This is a telephone based system
which will be used by the Investigator or designee to register the subject, randomise the
subject and receive medication assignment information. Equal numbers of subjects will
be allocated to each treatment. Subjects will be stratified by baseline FEV1 as a
percentage of predicted (FEV1 40% - 65% predicted and FEV1 > 65% - 90%
predicted). Details of how to use RAMOS to register and randomise subjects will be
provided in the SPM.

5.3.

Blinding

This is a double-blind study. Neither the subject nor the Investigator will know which
study medication the subject is receiving. Placebo dry powder formulations will be
provided which are indistinguishable from GW642444M formulation.
The investigator or treating physician may unblind a subjects treatment assignment only
in the case of an emergency, when knowledge of the study treatment is essential for the
appropriate clinical management or welfare of the subject. Whenever possible, the
investigator must first discuss options with the GSK Medical Monitor or appropriate
GSK study personnel before unblinding the subjects treatment assignment. If this is
impractical, the investigator must notify GSK as soon as possible, but without revealing
the treatment assignment of the unblinded subject, unless that information is important
for the safety of subjects currently in the study. The date and reason for the unblinding
must be recorded in the appropriate data collection tool.

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GSKs GCSP staff may unblind the treatment assignment for any subject with an SAE. If
the SAE requires that an expedited regulatory report be sent to one or more regulatory
agencies, a copy of the report, identifying the subjects treatment assignment, may be sent
to clinical investigators in accordance with local regulations and/or GSK policy.
Subjects should be withdrawn from the study if their treatment code becomes unblinded.

5.4.

Product Accountability

In accordance with local regulatory requirements, the investigator, designated site staff,
or head of the medical institution (where applicable) must document the amount of GSK
investigational product dispensed and/or administered to study subjects, the amount
returned by study subjects, and the amount received from and returned to GSK, when
applicable. Product accountability records must be maintained throughout the course of
the study.

5.5.

Treatment Compliance

At Visits 2/2a, 3, 4 and 5 study drug administration will be observed by appropriately


trained site personnel to ensure the proper administration of study drug. Subject
compliance with double-blind study medication will be assessed at Visits 2 through 5 by
reviewing the dose counter on the novel dry powder inhaler. Subjects who are not
compliant with study drug administration should be counselled on appropriate dosing of
the study drug.

5.6.

Concomitant Medications and Non-Drug Therapies

5.6.1.

Permitted Medications and Non-Drug Therapies

All concomitant medications taken during the study will be recorded in the CRF. The
minimum requirement is that drug name and the dates of administration are to be
recorded.
The following asthma medications are permitted:

Short-acting 2-agonists (will be replaced by study issued rescue


salbutamol/albuterol MDI at Visit 1 to be used throughout the Run-In, Treatment
Period and Follow-up Period).

Inhaled corticosteroids are permitted during the study provided the dose remains
constant for at least 4 weeks prior to Visit 1 and remains constant throughout the
study period. The maximum allowable inhaled corticosteroid doses are as follows:

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Asthma Therapy
fluticasone propionate MDI CFC/HFA
fluticasone propionate DPI
beclomethasone dipropionate
beclomethasone dipropionate HFA (Qvar)
budesonide DPI/MDI
flunisolide
triamcinolone acetonide
mometasone furoate
Ciclesonide
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Maximum Daily Dose (mcg/day)


880mcg1/1000mcg2
1000mcg
1680mcg1/2000mcg2
640mcg1/800mcg2
2000mcg
2000mcg
2000mcg
880mcg
320mcg1/400mcg2

Ex-actuator dose
Ex-valve dose

All medications for other disorders (other than those listed in Section 5.6.2) may be
continued throughout the study (including those to treat attention deficit hyperactivity
disorder), provided the dose remains constant and their use would not be expected to
affect the subject's lung function.
Intranasal corticosteroids, intranasal sodium cromoglicate, and topical corticosteroids are
permitted if started prior to Visit 1 and kept at a stable dose throughout the study.
Immunotherapy for treatment of allergies is permitted if started prior to Visit 1 and
remains at a stable dose throughout the study. Hormonal replacement therapy for the
treatment of menopausal symptoms will be permitted if started prior to Visit 1 and
remains at a stable dose throughout the study.
Short-acting and long-acting antihistamines are allowed to control symptoms of allergic
disorders, however, subjects are permitted to use either one oral or one intranasal
antihistamine during the trial. In addition, antihistamine eye drops are allowed during the
trial.
Non-drug therapies for conditions other than asthma may be used during the study if their
use is not considered likely to have an impact on the subject's asthma.
If a subjects current medication is changed as a result of study participation, then
consent will be obtained at this point and the subject will be required to return to the
clinic to complete the screening visit (Visit 1) once the required wash-out has been
completed.
An example of a change as a result of study participation is if subjects treated with
combination therapy consisting of an inhaled corticosteroid and an inhaled long acting
beta2 agonist are switched to the ICS alone (dose to remain constant) in order to allow the
inhaled ICS to be continued (at a stable daily dose) throughout the study.
5.6.2.

Prohibited Medications and Non-Drug Therapies

The following medications are not permitted during the conduct of the study or within
the specified time prior to the study. A more comprehensive list of examples for each of
the classes outlined below can be found in the SPM.
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Within 7 days of Visit 1

Long-acting 2-agonists (e.g. salmeterol)

Inhaled corticosteroid and long acting beta2 agonist combination products

Within 14 days of Visit 1:

Theophyllines

Oral 2-agonists (e.g. bambuterol)

Slow-release bronchodilators

Anticholinergics short or long-acting

Oral leukotriene receptor antagonists (e.g., montelukast)

Inhaled sodium cromoglicate

Inhaled nedocromil sodium

Within 4 weeks of Visit 1:

Potent P-glycoprotein inhibitors (e.g., ketoconazole, ritonavir)

Potent Cytochrome P 3A4 inhibitors (e.g., Cimetidine)

Within 12 weeks of Visit 1:

Systemic, oral, parenteral or depot corticosteroids

Anti-IgE therapy (e.g. omalizumab [Xolair])

In addition, a subject may not concurrently use any other prescription or over-the-counter
medication which may affect the course of asthma, or interact with sympathomimetic
amines throughout the study (Visit 1 to Visit 6 inclusive), such as:

Anticonvulsants (barbiturates, hydantoins, and carbamazepine)

Polycyclic antidepressants

-adrenergic blocking agents

Phenothiazines

Monoamine oxidase (MAO) inhibitors

5.7.

Treatment after the End of the Study

At the end of the follow-up period the investigator should prescribe appropriate
alternative asthma therapy for the subject. There will be no provision to supply
GW642444M after the end of the follow-up period.

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Treatment of Investigational Product Overdose

GSK is not recommending specific treatment guidelines for overdose and toxicity
management relating to GW642444M. The investigator is advised to refer to the relevant
document(s) for detailed information regarding warnings, precautions, contraindications,
adverse events, and other significant data pertaining to the study drug being used in this
study. Such documents may include, but not be limited to, the IB or equivalent document
provided by GSK. Clinical judgment should be used in treating the overdose.

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6.
Table 1
Procedures
Visit
Day

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STUDY ASSESSMENTS AND PROCEDURES


Time and Events Table
Screen/
Run-in
1
-14
(-4/+2)

Written Informed
x
Consent
Subject Demography x
Medical History
x
Asthma History
x
Therapy History
x
Smoking History
x
Physical examination x
Inclusion/Exclusion
x
Criteria
Randomisation
Criteria
Efficacy Assessments
Clinic measured FEV1 x
FEV1 response to
X12
salbutamol/albuterol
x
Issue Diary and PEF
meter9
Review Diary data
Safety Assessments
Concomitant
x
Medication
Vital Signs
x
12-lead ECG
x
Adverse Events
Serious Adverse
x
Events
Laboratory Assessments
Haematology5
x
Chemistry5
x
Urinalysis5
x
PGx Sampling
x
Serum Pregnancy
Test 13
Urine pregnancy
Test13
HBsAg and hepatitis
x
C antibody
Exploratory Lab Assessments
PK sampling6
Serum potassium
and plasma glucose
sampling

Treatment
2/2A1
1

Early
Withdrawal

3
7 (-4/+2)

4
14(-4/+2)

5/5A1
28(-4/+2)

Follow-up
6
D28 + 7
(-4/+2)

x
x2
x3

x2

x2

x2
x3

x4
x4
x
x

x4
x4
x
x

x4
x4
x
x

x4
x4
x
x

x
x
x
x

x
x

x
x

x
x
x

x
x
x

x
x
x5

x
x7

x10

x
X11

x
X11

x
x7
Continued

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Time and Events Table (Continued)


Screen/
Run-in

Treatment

Early
Withdrawal

Followup

Investigational product
Dispense Invest.
x
Product.
Assess Invest.
x
x
x
x
Product compliance
Collect invest.
x
x
product
Issue rescue
x
x8
x8
salbutamol/albuterol
Collect used rescue
x
x
x
salbutamol/albuterol
1. Visit 2/2A and Visit 5/5A will take place over 2 days. In selected centres, subjects will be required to remain in the
clinic overnight (~50% of subjects). In other centres, subjects will return to the clinic approximately mid-morning
on Day 2 and Day 29 (Visit 2A and 5A, respectively) to complete Day 1 and 28 serial FEV1 measurements
2. On Day 1 (Visit 2) and Day 28 (Visit 5) serial measurements of FEV1 to be made at pre-dose, 15, 30 and
60 minutes and 2, 3, 4, 6, 12, 16, 20, 22, 23 and 24 hours post-dose. Measurements at 6 and 12 hours post-dose
will only be made in those subjects remaining at the clinic overnight On Days 7 (Visit 3) and 14 (Visit 4) pre-dose
FEV1 measurements required only
3. To be performed 24 hours after the Day 1 (Visit 2) and Day 28 (Visit 5) administration of investigational product
4. Measurements to be made on Day 1 (Visit 2), Day 7 (Visit 3), Day 14 (Visit 4) and Day 28 (Visit 5): pre-dose,
10minutes and 1, 2 and 4 hours post-dose
5. Samples should be taken pre-dose
6. Samples to be taken as follows:
Day 1 (Visit 2): pre-dose, between 2-10 minutes, between 10-30minutes, between 30minutes -2 hours and
between 2-4 hours post-dose
Day 7 (Visit 3): pre-dose
Day 14 (Visit 4): 2minutes -1hour post-dose
Day 28 (Visit 5): pre-dose, between 2-10 minutes, between 10-30minutes, between 30minutes -2 hours and
between 2-4 hours post-dose
7. Samples will be taken pre-dose and 10 minutes, 1, 2 and 4hours post-dose. Subject will be fasted from at least 4
hours prior to the pre-dose blood sample until after the 4 hour post-dose sample
8. If required
9. Morning and evening PEF, symptoms and rescue medication usage to be recorded every day from Visit 1 through
Visit 6
10. To be taken 24hours post-dose Day 28
11. Serum potassium only. Samples to be taken pre-dose and 10minutes, 1, 2 and 4 hours post-dose. Subjects are
not required to fast for these samples.
12. Subjects not meeting the FEV1 and/or reversibility inclusion criteria may return to the site once within 4 days to
repeat the lung function tests. The Visit 1 screening period ends and the 14 day Run-in period begins when
subjects meet all of the inclusion criteria
13. Required for all females

Where multiple post-dose assessments are scheduled at the same timepoint the sequence
of assessments should be vital signs, 12-lead ECG, blood sampling and FEV1. FEV1
measurements should be made as close to the scheduled timepoint as possible. A time
deviation window of 15minutes is permitted in the 0 and 2 hour post-dose period. For
assessments scheduled between 2 and 12 hours post-dose a time deviation window of
20 minutes is permitted. For assessments scheduled between 16 and 24 hours a time
deviation window of 30minutes is permitted.

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Critical Baseline Assessments

The following baseline characteristics will be collected:

Gender, ethnic origin and date of birth

Asthma history (including duration of asthma and atopic status)

Smoking history

Severity of disease (defined as pre-bronchodilator FEV1 response at Visit 1)

Reversibility to salbutamol

Concurrent medical conditions

A subject who has at least one study procedure performed (in addition to signing a
consent form), and is assigned a subject number, but is not randomised is considered a
screen failure.
Subjects who have previously screen failed for any reason prior to Amendment 02 are
allowed to return to the site once to enter the screening process again.
For all subjects (including previous screen failures prior to Amendment 02) not meeting
the FEV1 and/or reversibility inclusion criteria during the Visit 1 screening period may
return to the site once within 4 days to repeat the lung function tests (refer to the SPM for
further details on screen failures).

6.2.

Efficacy

6.2.1.

Efficacy Endpoints

Primary Endpoint

Mean change from baseline in clinic visit trough (pre-bronchodilator and pre-dose)
FEV1 at the end of the 28-day treatment period. The trough FEV1 will be defined as
the mean of the FEV1 values obtained 23 and 24 hours after dosing on Day 28.

Secondary Endpoints

Change from baseline in weighted mean for 24 hour serial FEV1 on Days 1 and 28
(mean post-dose FEV1 after 15, 30 and 60 minutes and 2, 3, 4, 6, 12, 16, 20, 22, 23
and 24 hours).
Note: this endpoint will be derived for all subjects but the 6 and 12 hour time points
will only be measured in a sub-group of subjects (approximately 50% of subjects).

Mean change from baseline in trough (pre-dose and pre-bronchodilator) daily


evening (PM) peak expiratory flow (PEF) averaged over the 28-day treatment
period.

Mean change from baseline in daily morning (AM) PEF averaged over the 28-day
treatment period.

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Mean change from baseline in the percentage of symptom-free 24 hour periods


during the 28-day treatment period.

Mean change from baseline in the percentage of rescue-free 24 hour periods during
the 28-day treatment period.

Difference in post salbutamol/albuterol FEV1 (FEV1 30minutes after a single dose of


400mcg salbutamol/albuterol) between 24 hours after dosing on Day 1 (Visit 2) and
on Day 28 (Visit 5).

Difference in post salbutamol/albuterol FEV1 (FEV1 30minutes after a single dose of


400mcg salbutamol/albuterol) between screening (Visit 1) and 24 hours after dosing
on Day 1 (Visit 2).

Difference in post salbutamol/albuterol FEV1 (FEV1 30minutes after a single dose of


400mcg salbutamol/albuterol) between screening (Visit 1) and 24 hours after dosing
on Day 28 (Visit 5).

Other Endpoints

Maximum increase in FEV1 (0-4h) on Days 1 and 28 compared with baseline.

Proportion of subjects obtaining 200mL increase from baseline in FEV1 (0-4h) on


Days 1 and 28

Proportion of subjects obtaining 12% increase from baseline in FEV1 (0-4h) on


Days 1 and 28

Mean change from baseline in trough FEV1 at Visits 2/2A, 3 and 4 (i.e. after 23-24
hrs, 7 and 14 days of treatment).

Mean change from baseline in the percentage of symptom-free days during the 28day treatment period.

Mean change from baseline in the percentage of symptom-free nights during the 28day treatment period.

Mean change from baseline in the percentage of rescue-free days during the 28-day
treatment period.

Mean change from baseline in the percentage of rescue-free nights during the 28-day
treatment period.

Mean change from baseline in daily AM PEF during the first 14 days on study
treatment and over weeks 1, 2, 3, 4 and endpoint.

Mean change from baseline in daily PM PEF during the first 14 days on study
treatment and over weeks 1, 2, 3, 4 and endpoint.

Withdrawals due to lack of efficacy as defined in this protocol.

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6.2.2.

Efficacy Assessments

6.2.2.1.

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FEV1 will be measured electronically at clinic visits generated by spirometry using


spirometers provided by a vendor selected by GSK. The highest of three technically
acceptable measurements will be recorded. The FEV1 will be measured at all clinic visits
in the evening prior to study medication dose and any rescue salbutamol/albuterol use;
salbutamol/albuterol should be withheld for at least 6 hours. The FEV1 will be measured
between 5PM and 10 PM at Visit 1 screening period. Pre-dose FEV1 at Visit 2 also needs
to be obtained between 5PM and 8PM. At each subsequent visit, pre-dose FEV1 must be
obtained within 1 hour of the time of the measurement of the pre-dose FEV1 at Visit 2.
At Visits 3 and 4 FEV1 should be measured 23-24 hours after their last dose of study
medication.
At Visit 1 screening period, to check eligibility, reversibility in FEV1 will be assessed.
FEV1 will be measured before and 30 minutes after administration of 400mcg
salbutamol/albuterol via MDI or one nebulised salbutamol/albuterol solution. Subjects
who fail to demonstrate a 12% (and 200ml) increase in FEV1 will not be eligible to
take part in the study.
Re-screening of subjects during the Visit 1 screening period: If a subject does not
meet the inclusion criteria based upon FEV1 percent predicted and/or reversibility, the
subject may return to the site once within 4 days and perform the lung function tests.
If the subject meets the lung function entry criteria on the second attempt, then other Visit
1 procedures should be performed on this date. The data from the original Visit 1 date
will be returned to GSK.
Note: Spacer devices will not be allowed during the study with the exception of use
during reversibility testing.
Percent reversibility will be calculated as follows:
Post-bronchodilator FEV1 - Pre-bronchodilator FEV1 x 100%
Pre-bronchodilator FEV1
At Visit 1, the pre-bronchodilator FEV1 as a percentage of predicted normal will be
calculated as follows:
Pre-bronchodilator FEV1 x 100%
Predicted FEV1
NHANES III predicted values will be used for subjects aged 12 years and adjustments
to these values will be made for African American [Hankinson, 1999].
At Visit 2, the best pre-dose FEV1 must be 40% and 90% of their predicted normal for
the subject to be eligible for the study.

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On Day 1 (Visit 2) and Day 28 (Visit 5), in addition to the pre-dose measurement, serial
FEV1 measurements will be taken as outlined in Table 1. At each time point, the highest
of three technically acceptable measurements will be recorded.
FEV1 Stability Limit
For those subjects who are randomised, a FEV1 Stability Limit will be determined at
Visit 2. This will be calculated as follows:
Best pre-dose FEV1 at Visit 2 x 80%
6.2.2.2.

Response to salbutamol/albuterol

Following completion of the serial 24 hour FEV1 measurements at Visit 2 and Visit 5
(i.e. on Day 2 and Day 29), post salbutamol/albuterol FEV1 will be measured. The
assessment at Visit 2/2a will be made prior to the evening dose of study medication on
Day 2. The subject will be administered a single 400mcg dose of inhaled
salbutamol/albuterol via MDI or one nebulised salbutamol/albuterol solution and FEV1
will be measured 30 minutes after this administration. The highest of three technically
acceptable measurements will be recorded. These assessments will be performed as
follows:

Between 5PM and 10PM

6 hours after the last use of salbutamol/albuterol (compliance with this will be
recorded in the spirometry equipment).

6 hours after the last caffeine consumption

2 hours after exercise (or strenuous activity)

24 hours after the first dose (Visit 2) or last dose (Visit 5) of study medication

For Visit 2/2a only, before the dose of study medication is taken on treatment Day 2.
6.2.2.3.

Diary Parameters

Throughout the study, including the run-in period and 7 day follow-up period, subjects
will record the following parameters in a Daily Diary:

Morning PEF (L/min)

Evening PEF (L/min)

Day-time and night-time asthma symptom scores

Number of inhalations of rescue salbutamol/albuterol usage during the day and night

Whether they have taken their regular inhaled steroid medication

The use of the Daily Diary will be explained to the subject at Visit 1. Subjects will be
asked to return the Diary to the investigator at each clinic visit and the investigator or
his/her designee will review the data recorded. The investigator will ensure that the
subject is completing the Daily Diary correctly and will re-explain proper completion as
appropriate. At Visit 2, if the subject has been unable to complete the Daily Diary
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correctly, or is deemed non-compliant, the subject will be excluded from the study
(see Section 4.3, Exclusion Criteria and Section 4.4, Randomisation Criteria). In the
event there is a technical malfunction of the Daily Diary during the last week of the runin period, the run-in period can be extended for one additional week.
At Visit 3, 4 and 5, the investigator or his/her designee will review all data recorded in
the Daily Diary to confirm that the subject has not met the criteria for withdrawal due to
lack of efficacy (see Section 4.5, Withdrawal Criteria).
Subjects will be issued a paper medical conditions diary to record adverse events during
the study.
6.2.2.4.

Peak Expiratory Flow Measurements

Morning and evening peak expiratory flow will be measured using a peak flow meter that
will be issued to subjects at Visit 1. For each PEF measurement time point, three
measurements will be made (within 30 minutes of each other) and the highest will be
recorded in the Daily Diary. The best measurement at each time point will be used for
subsequent analyses. PEF will be measured each morning prior to any rescue
salbutamol/albuterol use and each evening prior to study medication dose and, if possible,
rescue salbutamol/albuterol use.
PEF Stability Limit
For those subjects who are randomised, a PEF Stability Limit will be calculated by the
Daily Diary. The Stability Limit will be calculated as follows:
Mean AM PEF from the available 7 days preceding Visit 2 x 80%
The AM PEF from the morning of Visit 2 will be included in the calculation of the PEF
stability limit.
The stability limit applies regardless of whether the PEF decrease has occurred in the AM
or PM PEF.
6.2.2.5.

Asthma Symptom Scores

Asthma symptom scores will be recorded twice daily in the Daily Diary before taking any
rescue salbutamol/albuterol or study medication (evening only) and prior to making the
PEF measurements. They will reflect the symptoms for the previous day and night and
will use the following scales:

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Day-time Symptom Score (recorded each evening):


0 = No symptoms during the day
1 = Symptoms for one short period during the day
2 = Symptoms for two or more short periods during the day
3 = Symptoms for most of the day which did not affect my normal daily activities
4 = Symptoms for most of the day which did affect my normal daily activities
5 = Symptoms so severe that I could not go to work or perform normal daily
activities
Night-time Symptom Score (recorded each morning):
0 = No symptoms during the night
1 = Symptoms causing me to wake once (or wake early)
2 = Symptoms causing me to wake twice or more (including waking early)
3 = Symptoms causing me to be awake for most of the night
4 = Symptoms so severe that I did not sleep at all.
6.2.2.6.

Rescue salbutamol/albuterol usage

Subjects will be provided with salbutamol/albuterol MDIs for use as rescue medication
throughout the run-in period, study treatment period and follow-up period. Each morning
and evening, subjects will record in their Daily Diary the number of inhalations of
inhaled salbutamol/albuterol rescue medication used during the previous 12 hours. Use of
spacer devices is not permitted.
6.2.2.7.

Withdrawals Due to Lack of Efficacy

Refer to Section 4.5, Withdrawal criteria for details on withdrawals due to lack of
efficacy.

6.3.

Safety

6.3.1.

Safety Endpoints

Adverse Event reporting throughout the 28-day treatment period.

Haematological and clinical chemistry parameters after 14 days and 28 days of


treatment and dipstick urinalysis parameters after 28 days of treatment.

Vital signs (pulse rate and systolic and diastolic blood pressure) on Days 1, 7, 14 and
28.
The following endpoints will be derived:

Change from baseline in maximum value (0-4 hours) for systolic blood pressure

Change from baseline in minimum value (0-4 hours) for diastolic blood pressure

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Change from baseline in maximum value (0-4 hours) for pulse rate

Weighted mean change from baseline (0-4 hours) for blood pressure and pulse
rate.

12-lead ECG on Days 1, 7, 14 and 28 to derive the following endpoints:

Weighted mean change from baseline (0-4 hours) in the QTc(F) (QT interval
corrected by Fridericia's method)

Weighted mean change from baseline (0-4 hours) in QTc(B) (QT interval
corrected by Bazett's method)

Maximum change from baseline (0-4 hours) for QTc(F) and QTc(B).

Fasting potassium and glucose on Days 1 and 28 and non-fasting potassium only on
Days 7 and 14 to derive the following endpoints:

Maximum decrease from baseline (0-4h) for potassium

Weighted mean change from baseline (0-4h) for potassium

Maximum increase from baseline (0-4h) for glucose

Weighted mean change from baseline (0-4h) for glucose

6.3.2.

Adverse Events

The investigator or site staff will be responsible for detecting, documenting and reporting
events that meet the definition of an AE or SAE.
6.3.2.1.

Definition of an AE

Any untoward medical occurrence in a patient or clinical investigation subject,


temporally associated with the use of a medicinal product, whether or not considered
related to the medicinal product.
Note: An AE can therefore be any unfavourable and unintended sign (including an
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally
associated with the use of a medicinal product. For marketed medicinal products, this
also includes failure to produce expected benefits (i.e. lack of efficacy), abuse or misuse.
Events meeting the definition of an AE include:

Exacerbation of a chronic or intermittent pre-existing condition including either an


increase in frequency and/or intensity of the condition (excluding exacerbations of
the disease/disorder being study).

New conditions detected or diagnosed after investigational product administration


even though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either


investigational product or a concomitant medication (overdose per se will not be
reported as an AE/SAE).
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"Lack of efficacy" or "failure of expected pharmacological action" per se will not be


reported as an AE or SAE. However, the signs and symptoms and/or clinical
sequelae resulting from lack of efficacy will be reported if they fulfil the definition
of an AE or SAE.

Events that do not meet the definition of an AE include:

Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that


leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present


or detected at the start of the study that do not worsen.

The disease/disorder being studied, or expected progression, signs, or symptoms of


the disease/disorder being studied, unless more severe than expected for the subjects
condition.

Exacerbations of the disease/disorder being studied.

6.3.2.2.

Definition of a SAE`

A serious adverse event is any untoward medical occurrence that, at any dose:
a.

Results in death

b.

Is life-threatening
NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in
which the subject was at risk of death at the time of the event. It does not refer to an
event, which hypothetically might have caused death, if it were more severe.

c.

Requires hospitalisation or prolongation of existing hospitalisation


NOTE: In general, hospitalisation signifies that the subject has been detained
(usually involving at least an overnight stay) at the hospital or emergency ward for
observation and/or treatment that would not have been appropriate in the physicians
office or out-patient setting. Complications that occur during hospitalisation are AEs.
If a complication prolongs hospitalisation or fulfils any other serious criteria, the
event is serious. When in doubt as to whether hospitalisation occurred or was
necessary, the AE should be considered serious.
Hospitalisation for elective treatment of a pre-existing condition that did not worsen
from baseline is not considered an AE.

d.

Results in disability/incapacity, or
NOTE: The term disability means a substantial disruption of a persons ability to
conduct normal life functions. This definition is not intended to include experiences
of relatively minor medical significance such as uncomplicated headache, nausea,
vomiting, diarrhoea, influenza, and accidental trauma (e.g. sprained ankle) which
may interfere or prevent everyday life functions but do not constitute a substantial
disruption.
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e.

Is a congenital anomaly/birth defect

f.

Medical or scientific judgement should be exercised in deciding whether reporting is


appropriate in other situations, such as important medical events that may not be
immediately life-threatening or result in death or hospitalization but may jeopardize
the subject or may require medical or surgical intervention to prevent one of the
other outcomes listed in the above definition. These should also be considered
serious. Examples of such events are invasive or malignant cancers, intensive
treatment in an emergency room or at home for allergic bronchospasm, blood
dyscrasias or convulsions that do not result in hospitalization, or development of
drug dependency or drug abuse.

6.3.3.

Laboratory and Other Safety Assessment Abnormalities


Reported as AEs and SAEs

Any abnormal laboratory test results (haematology, clinical chemistry, or urinalysis) or


other safety assessments (e.g., ECGs, radiological scans, vital signs measurements),
including those that worsen from baseline, and felt to be clinically significant in the
medical and scientific judgement of the investigator are to be recorded as AEs or SAEs.
However, any clinically significant safety assessments that are associated with the
underlying disease, unless judged by the investigator to be more severe than expected for
the subjects condition, are not to be reported as AEs or SAEs.
Liver chemistry threshold stopping criteria have been designed to assure subject safety.
When subjects meet the following liver chemistry threshold criteria, investigational
product must be permanently withdrawn, additional testing performed, and the subject
monitored until liver chemistries resolve, stabilize, or return to baseline values. The
subject must then be permanently withdrawn from the study:

ALT 3xULN and bilirubin 1.5xULN (>35% direct).

ALT 5xULN.

ALT 3xULN if associated with the appearance or worsening of hepatitis symptoms


or rash.

Subjects with ALT 3xULN and <5xULN and bilirubin <1.5xULN, who do not exhibit
hepatitis symptoms or rash, can continue investigational product and be monitored
weekly for up to 4 weeks. At any point, if these subjects meet the liver chemistry
threshold stopping criteria (outlined above) or are unable to return for weekly liver
chemistries, investigational product must be permanently stopped, additional testing
performed, and the subject continue safety follow-up until liver chemistries resolve,
stabilize, or return to baseline values. The subject must then be withdrawn from the
study.
Subjects with ALT 3xULN and bilirubin 1.5xULN (>35% direct bilirubin; bilirubin
fractionation required) must be immediately and permanently withdrawn from
investigational product. Every attempt must be made to have the subject return to clinic
(within 24 hours) for repeat liver chemistries and additional testing, and monitored
closely (with specialist or hepatology consultation recommended). This event must be
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reported to GSK within 24 hours of learning of its occurrence. Subjects must be


monitored twice weekly until liver chemistries (ALT, AST, alkaline phosphatase,
bilirubin) resolve, stabilize or return to within baseline values. Upon completion of the
safety follow-up, the subject must then be withdrawn from the study.
Subjects with ALT 5xULN or ALT 3xULN with hepatitis or rash or if increase persists
4 weeks must be immediately withdrawn from investigational product. Every attempt
must be made to have the subject return to clinic within 24-72 hrs for repeat liver
chemistries and additional testing, and monitored weekly until liver chemistries (ALT,
AST, alkaline phosphatase, bilirubin) resolve, stabilize or return to within baseline
values. This event must be reported to GSK within 24 hours of learning of its occurrence.
Subjects with ALT 3xULN and <5xULN and bilirubin <1.5xULN can continue
investigational product, with every attempt made to have the subject return for repeat
liver chemistries within one week, and be monitored weekly for up to 4 weeks. However,
subjects unable to be monitored for 4 weeks must be withdrawn from investigational
product and monitored weekly until liver chemistries resolve, stabilize or return to within
baseline values. These subjects must be withdrawn from the study. This event must be
reported to GSK within 24 hours of learning of its occurrence.
If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <1.5xULN, subjects should
be monitored twice monthly until liver chemistries normalize or return to within baseline
values. Note that investigational product must be withdrawn if bilirubin >1.5xULN or
there are signs/symptoms of hepatitis or hypersensitivity or elevations in ALT 3xULN
and <5xULN persist for more than 4 weeks.
In all the above situations, every attempt must be made to obtain the following:

Viral hepatitis serology including:

Hepatitis A IgM antibody;

Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM);

Hepatitis C RNA;

Cytomegalovirus IgM antibody;

Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain


heterophile antibody or monospot testing);

Hepatitis E IgM antibody (if subject resides outside the USA or Canada, or has
travelled outside USA or Canada in past 3 months)

Blood sample for pharmacokinetic (PK) analysis, obtained within 24 hours of last
dose. Record the date/time of the PK blood sample draw and the date/time of the last
dose of investigational product prior to blood sample draw on the CRF.

Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).

Fractionate bilirubin, if bilirubin 1.5xULN.

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Record the appearance or worsening of clinical symptoms of hepatitis, or


hypersensitivity, fatigue, decreased appetite, nausea, vomiting, abdominal pain,
jaundice, fever, or rash as relevant on the AE report form.

Record use of concomitant medications, acetaminophen, herbal remedies, other over


the counter medications, putative hepatotoxins, or alcohol on the concomitant
medications report form.

The following are required for subjects with ALT 3xULN and bilirubin 1.5xULN but
are optional for other abnormal liver chemistries:

Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney


microsomal antibodies.

Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to


evaluate liver disease.

6.3.4.

Time Period and Frequency of Detecting AEs and SAEs

From the time a subject consents to participate in and completes the study (including any
follow-up period), all SAEs assessed as related to study participation (e.g., protocolmandated procedures, invasive tests, or change in existing therapy) or related to a GSK
concomitant medication, will be reported promptly to GSK. The time period for
collection of AEs will begin from the time of randomisation (first receipt of
investigational product) and will end after the 7 days follow-up period has been
completed.
From Visit 2 onwards (see Table 1), after the subject has had an opportunity to
spontaneously mention any changes in their medical condition, the investigator should
enquire whether the subject has had any AEs by asking the subject standard questions and
reviewing the subjects Daily Diary for evidence of any AEs.
Refer to Section 6.3.7 for reporting requirements for SAEs and other relevant events.
6.3.4.1.

Asthma Exacerbations

For the purposes of this study, a subject will be withdrawn due to lack of efficacy if they
experience a clinical exacerbation, or at the Investigators discretion. An exacerbation is
defined as worsening asthma requiring any treatment other than study medication or
rescue salbutamol/albuterol or the subjects regular inhaled corticosteroid use. This
includes requiring the use of systemic corticosteroids and/or emergency room visit or
hospitalisation or a change in inhaled corticosteroid dose.
Asthma exacerbations should not be recorded as an adverse event, unless they meet the
definition of a Serious Adverse Event (See Section 6.3.2.2). For the purposes of this
study, asthma exacerbations will be collected and recorded on the exacerbations log in
the eCRF. The time period for collection of asthma exacerbations will begin from the
time of randomisation (first receipt of investigational product) and will end after the 7
days follow-up period has been completed.

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Pregnancy

Any pregnancy that occurs during study participation (Visit 2 through to follow-up) must
be reported using a clinical trial pregnancy form. To ensure subject safety, each
pregnancy must be reported to GSK within 2 weeks of learning of its occurrence. The
pregnancy must be followed up to determine outcome (including premature termination)
and status of mother and child. Pregnancy complications, and elective terminations for
medical reasons must be reported as an AE or SAE. Spontaneous abortions must be
reported as an SAE.
Any SAE occurring in association with a pregnancy, brought to the investigators
attention after the subject has completed the study and considered by the investigator as
possibly related to the investigational product, must be promptly reported to GSK.
In the event a subject becomes pregnant during the study they should discontinue taking
the study medication and be withdrawn from the study.
6.3.6.

Medical Devices

Medical devices (peak flow meters) are being provided by GSK for use in this study.

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Prompt Reporting of Serious Adverse Events and Other Events


to GSK

SAEs, pregnancies, medical device incidents and near-incidents, and liver function
abnormalities meeting pre-defined criteria will be reported promptly to GSK as described
in the following table once the investigator determines that the event meets the protocol
definition for that event.
Initial Reports
Type of Event
All SAEs

Time Frame
24 hours

Pregnancy

2 Weeks

Liver chemistry
abnormalities:
ALT3xULN PLUS
Bilirubin1.5xULN)

Documents
SAE data
collection tool
Pregnancy Form

Follow-up Information on a Previous


Report
Time Frame
Documents
24 hours
Updated SAE
data collection tool
2 Weeks
Updated
Pregnancy Form

24 hours

Liver Chemistry
Report Form

24 hours

24 hours
ALT5xULN or
ALT3xULN with
hepatitis or rash or 4
weeks
24 hours
ALT3xULN and
<5xULN and bilirubin
<1.5xULN

Liver Chemistry
Report Form

24 hours

Liver Chemistry
Report Form

24 hours

Updated Liver
Chemistry Report
Form
Updated Liver
Chemistry Report
Form
Updated Liver
Chemistry Report
Form

The method of detecting, recording, evaluating and follow-up of AEs and SAEs plus
procedures for completing and transmitting SA reports to GSK are provided in the SPM.
Procedures for post-study AEs/SAEs are provided in the SPM.
6.3.8.

Other Safety Outcomes

6.3.8.1.

Clinical Laboratory Tests

Clinical laboratory tests (haematology, clinical chemistry and urinalysis) will be


performed as outlined in Table 1. If the clinical laboratory tests have been taken prior to
performing the lung function testing and the subject meets the lung function entry criteria
based on the second lung function attempt the investigator must document the lab results
are clinically acceptable within the 4 day screening period. Additional samples may be
taken for safety reasons at the discretion of the investigator. Details of parameters to be
measured can be found in the SPM.
Serum potassium and plasma glucose will also be monitored to assess the
pharmacodynamic effects of GW642444M (See Table 1). Subjects will be asked to fast
for at least 4 hours prior to the planned blood draw at Screening (Visit 1) and for at least
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4 hours prior to the pre-dose blood samples and until after the 4hour post-dose blood
samples at Visits 2 and 5.
All blood samples will be sent to a central laboratory for analysis. Full details of the
collection and shipping requirements for the central laboratory are provided in the SPM.
A mid-stream urine sample will be collected as outlined in Table 1 for urinalysis tests.
These will be analysed in a central laboratory.
6.3.8.2.

ECG

12-lead ECGs will be measured by the investigator or his/her suitably qualified designee,
as outlined in Table 1. ECGs will be recorded after 5 minutes rest, after measurement of
vital signs and before clinic lung function tests at the specified time.
If the subject fails the lung function criteria at the first attempt, and only becomes eligible
for the study at the second screening visit the investigator must document the ECG results
are clinically acceptable within the 4 day screening period.
Investigators will be provided with ECG machines by GSK through a designated central
laboratory. Paper ECG traces will be recorded at a standard paper speed of 25mm/sec and
gain of 10mm/mV, with a lead II rhythm strip. There will be electronic capture and
storage of the data by a validated method, with subsequent transferral to the central
laboratory for manual reading and calculation of the electrocardiographic parameters.
QTc(F) will be derived by the central laboratory using the manual calculations according
to the following formulae:
RR = (QT/QTc(B))2 and QTc(F) = QT/RR1/3
The manual reading and calculation of the ECG parameters will be used to determine
whether a subject meets the eligibility criteria for enrolment in the study at Visit 2.
The independent cardiologist, at the central laboratory, will be blinded to treatment
assignment and will be responsible for providing an official interpretation of all ECGs
collected in this study. A hard copy of these results will be sent to the study site.
Visit 2 pre-dose ECGs will be interpreted by the independent cardiologist as follows:

within normal limits

abnormal, not clinically significant

abnormal, clinically significant

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If there is a discrepancy between the assessment of the investigator and that of the
independent cardiologist, the assessment of the independent cardiologist will be used in
all analyses and data presentations. If the pre-dose ECG at Visit 2 is judged to be
abnormal and clinically significant, the subject must be withdrawn from the study.
The independent cardiologist will determine whether the Visit 3, 4 and 5 pre-dose ECGs
(or ECG taken at the Early Withdrawal Visit) represents:

no change or insignificant change from the pre-dose ECG performed at Visit 2

significant change (favourable) from the pre-dose ECG performed at Visit 2

significant change (unfavourable) from the pre-dose ECG performed at Visit 2

The independent cardiologist will determine whether the ECGs taken post-dose at Visit 2,
3, 4 and 5 represent:

no change or insignificant change from the pre-dose ECG for the corresponding visit

significant change (favourable) from the pre-dose ECG for the corresponding visit

significant change (unfavourable) from the pre-dose ECG for the corresponding visit

The ECG will be repeated at the Follow-up visit if it is clinically significantly abnormal
at Visit 5.
If any of the abnormalities in ECGs outlined in Section 4.5 (withdrawal criteria) are
observed pre-dose Visit 2 or after randomisation, the subject must be withdrawn from
treatment.
6.3.8.3.

Vital Signs

Sitting pulse rate and blood pressure measurements will be performed by the investigator
or his/her qualified designee, as outlined in Table 1. Measurements will be made with
the subject sitting, having rested in this position for at least 5 minutes before each
reading. They will be taken before measurement of any clinic lung function tests or
ECGs at the specified time point.

6.4.

Pharmacokinetics

6.4.1.

Pharmacokinetic Endpoint(s)

Plasma concentrations of GW642444, the counter-ion and the GW642444 metabolites


GW630200 and GSK932009 and derived population PK parameters for GW642444 in
subjects with persistent asthma following once-daily treatment for 28 days.
Relationship between systemic exposure to GW642444 and systemic pharmacodynamic
endpoints

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Assessment of GW642444, GW630200, GSK932009 GI179710 in


plasma

A sparse sampling approach will be utilised. Blood samples (approximately 4mL) for the
determination of GW642444, the GW642444 metabolites (GW630200 and GSK932009)
and the triphenylacetate counter ion (GI179710) concentrations will be collected from all
subjects over 4 visits (Visits 2, 3, 4 and 5) as follows. The investigator will follow
guidance in the SPM for sample processing, storage and shipment.
Visits 2 and 5 (Days 1 and 28): Subjects will attend the evening clinic without having
taken their study medication. A pre-dose sample will be collected at the beginning of
their clinic visit. Additional samples will then be taken post-dose as indicated in Table 1.
Every attempt should be made to collect samples at times spread throughout the time
window (i.e. avoid collection from all subjects at the same times or extremes of the time
window).
Visit 3 (Day 7): Subjects will attend the evening clinic without having taken their study
medication. A pre-dose sample will be collected at the beginning of their clinic visit.
Visit 4 (Day 14): Subjects will attend the evening clinic without having taken their study
medication. One sample will be taken post-dose as indicated in Table 1. Every attempt
should be made to collect samples at times spread throughout the time window (i.e. avoid
collection from all subjects at the same times or extremes of the time window).
Only samples from subjects receiving GW642444 will be analysed for GW642444. By
first intent only samples from the highest dose group will be analysed for the metabolites
and the triphenylacetate counter-ion; if the majority (>80%) of samples are below the
lower limit of quantification (LLQ), samples from the remaining dose groups will not be
analysed. Personnel (WorldWide Bioanalysis, DMPK) involved in the bioanalysis of PK
samples will be unblinded as per GSK policy. Samples from subjects receiving placebo
will not be analysed.
At each visit, the exact time and date that the investigational product was taken on the
visit day and on the day prior to the visit will be recorded in the eCRF. The exact time
and date of the blood sample collection will also be documented in the eCRF.

6.5.

Pharmacodynamics

See Section 6.3.8.1, Clinical Laboratory Tests.

6.6.

Pharmacogenetics

Information regarding pharmacogenetic research is included in Appendix 1. The IEC/IRB


and, where required, the applicable regulatory agency must approve the PGx assessments
before these can be conducted at the site. The approval(s) must be in writing and will
clearly specify approval of the PGx assessments (i.e., approval of Appendix 1). In some
cases, approval of the PGx assessments can occur after approval is obtained for the rest of
the study. If so, then the written approval will clearly indicate approval of the PGx
assessments is being deferred and in most cases, the study, except for PGx assessments,
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can be initiated. When PGx assessments will not be approved, then the approval for the
rest of the study will clearly indicate this and therefore, PGx assessments will not be
conducted.

7.

DATA MANAGEMENT

Data Management will identify and implement the most effective data acquisition and
management strategy for this clinical trial protocol and deliver datasets which support the
protocol objectives.
For this study subject data will be entered into GSK defined electronic case report forms
(eCRFs), transmitted electronically to GSK and combined with data provided from other
sources (eg Daily Diary data, laboratory data) in a validated data system.
Clinical data management will be performed in accordance with applicable GSK
standards and data cleaning procedures with the objective of removing errors and
inconsistencies in the data which would otherwise impact on the analysis and reporting
objectives, or the credibility of the Clinical Study Report. Adverse events and
concomitant medications terms will be coded using MedDRA and GSKDrug, an internal
validated medication dictionary. An appropriate medical dictionary that covers all
approved drugs in the region will be referenced. Original CRFs will be retained by GSK,
while the investigator will retain a copy. In all cases, subject initials will not be collected
nor transmitted to GSK.

8.

DATA ANALYSIS AND STATISTICAL CONSIDERATIONS

8.1.

Hypotheses

The primary efficacy endpoint is the change from baseline in clinic visit trough FEV1 at
the end of the treatment period and will be derived from the mean of the 23 and 24 hour
post-dose assessments on Day 28. The primary analysis will be a test of linear trend in
dose response to demonstrate overall efficacy of GW642444M relative to placebo. This
will be based on a two-sided hypothesis testing approach whereby the null hypothesis is
that the slope of the dose response relationship is zero. The alternative hypothesis is that
this slope is not zero.
Provided the test of linear trend is statistically significant, two-sided hypothesis tests of
each dose versus placebo will be performed to demonstrate superiority of individual
doses. The null hypothesis is that the effect of each dose regimen of GW642444M and
placebo on trough FEV1 is identical. The alternative hypothesis is that the dose regimens
of GW642444M and placebo have different effects on trough FEV1.

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8.2.

Study Design Considerations

8.2.1.

Sample Size Assumptions

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Approximately 1200 subjects will be screened to ensure randomisation of 594 subjects


(99 subjects per group) with at least one pre-dose or 23-24 hour post-dose FEV1
assessment on or after nominal Day 7. This sample size is based on the primary endpoint
of change from baseline in trough FEV1 and has 97% power to detect a slope of 4ml/mcg
(a dose response effect of 200ml improvement in FEV1 per 50mcg of GW642444M).
This assumes a standard deviation of 430ml (based on previous studies) and significance
declared at the two-sided 5% level.
Similarly, there is >99 % power to detect slopes of 8ml/mcg (200ml improvement per
25mcg dose), 16 ml/mcg (200 ml improvement per 12.5 mcg dose) and 32 ml/mcg (200
ml improvement per 6.25mcg dose). The 3mcg dose is assumed to be a non-effective
dose and the study has approximately 96% power to detect a 200ml effect between this
dose and the 50mcg dose, excluding placebo from the dose response analysis.
Additionally, the study has 90% power to detect a difference of 200ml in pairwise
comparisons of change from baseline in trough FEV1 between any active dose and
placebo.
Any subject whose trough FEV1 measurement at Day 28 is missing will be included in
the analysis of the primary endpoint by imputation using the preceding non-missing
trough FEV1 value (Last Observation Carried Forward [LOCF]). Similarly, subjects
whose FEV1 measurement is missing at Day 28 will be included in a sensitivity analysis
of the primary endpoint by using information obtained from FEV1 measurements at
earlier time points in a Repeated Measures analysis.
8.2.2.

Sample Size Sensitivity

The assumption of a standard deviation of 430ml in trough FEV1 is based on an estimate


from previous studies along with an update using recent study data. The mean of the 23
and 24 hour post-dose assessments will be used to derive the primary endpoint which is
likely to reduce variability further. However, if the actual standard deviation in this study
differs from 430ml, the table below demonstrates the power for both the dose response
test and the pairwise comparisons with the proposed sample size of 99 per group.
Standard Deviation (ml)
400
415
430
440
450
460

Power (%) for Linear Trend


(4ml/mcg slope)
99
98
97
97
96
95

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94
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90
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Sample Size Re-estimation

No sample-size re-estimation is planned for this study.

8.3.

Data Analysis Considerations

8.3.1.

Analysis Populations

Three subject populations will be identified.


Total Population: This population will be comprised of all subjects screened and for
whom a record exists on the study database and will be used for the tabulation and listing
of reasons for withdrawal before randomisation and listing of SAEs for non-randomised
subjects.
Intent-to-Treat (ITT) Population: The ITT Population will be comprised of all subjects
randomised to treatment and who received at least one dose of trial medication.
Randomised subjects will be assumed to have received trial medication unless definitive
evidence to the contrary exists. This will constitute the primary population for all
analyses of efficacy measures and safety measures.
Per Protocol (PP) Population: The PP Population will consist of all subjects in the ITT
Population not identified as major protocol violators. The decision to exclude a subject
from the PP Population will be made prior to breaking the blind. This population will be
used for confirmatory analyses of the primary efficacy endpoint only.
8.3.2.

Analysis Data Sets

Details of the derived data in analysis datasets to be created will be given in the
Reporting and Analysis Plan (RAP).
8.3.3.

Treatment Comparisons

8.3.3.1.

Primary Comparisons of Interest

The primary treatment comparison is a test for linear dose response in trough FEV1
across the five doses of GW642444M and placebo in order to demonstrate overall
efficacy of GW642444M. If this test is statistically significant, each dose of
GW642444M will be compared with placebo to identify effective doses. These
comparisons will be performed by the use of hypothesis tests as described in Section 8.1.
These comparisons are to be performed using the ITT Population.
The primary analysis will be performed using Analysis of Covariance (ANCOVA) with
LOCF to impute missing data. A supporting analysis will also be performed using a
Repeated Measures Mixed Model. Missing data are not implicitly imputed in this
analysis, however, all non-missing data for a subject will be used within the analysis to
estimate the Day 28 treatment effects.

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A 2-sided 5% risk associated with incorrectly rejecting the null hypothesis (significance
level) is considered acceptable for this study. Since the pairwise comparisons with
placebo will only be performed if GW642444M is first shown to be efficacious relative to
placebo by means of the primary dose-response test, no further multiplicity adjustments
will be applied.
8.3.3.2.

Other Comparisons of Interest

The primary comparisons will be supported by the same tests performed using the
PP Population (i.e. pairwise comparisons will only be performed using the PP population
if they are performed for the ITT population). A linear trend test across the five active
doses of GW642444M but excluding placebo will also be performed to further explore
the dose response relationship of GW642444M. Tests of pairwise comparisons will be
performed for all the secondary and other efficacy endpoints.
8.3.4.

Interim Analysis

No interim analysis is planned for this study.


8.3.5.

Key Elements of Analysis Plan

Where possible, data from subjects who withdraw prematurely from the study will be
included in any analyses. Specific details for inclusion will be detailed in the RAP, but in
general the minimum data required will be a baseline evaluation and at least one postbaseline evaluation. Missing trough FEV1 data at Day 28 will be imputed for the primary
analysis using LOCF. The primary endpoint will also be analysed using Repeated
Measures whereby missing data are not directly imputed but the correlation between
visits for all patients is used to adjust the estimate of treatment effect.
For the secondary endpoints relating to serial FEV1, the weighted mean will only be
calculated if there are at least 4 non-missing values in the time period of interest and the
subject has data for at least one time point between 0 and 4 hours, and either Hour 16 or
Hour 20, and either Hour 23 or Hour 24. The AUC will be calculated from the first nonmissing time point to the last non-missing time point. If an observation is missing
between two non-missing observations, the AUC will be interpolated between the two
non-missing values.
Secondary endpoints relating to Diary assessments will be calculated from all available
data over the period of interest. No imputations will be performed for missing data.
All hypothesis tests for main effects will use a 2-sided test at the 5% level of significance.
Any tests for interactions will be 2-sided at the 10% level of significance. We will
explore interactions with treatment as part of the model-checking process. In all cases, if
any assumptions of the proposed method of analyses are not met, alternative methods of
analyses will be used.

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It is anticipated that approximately 100 centres will participate in the study. Therefore, it
is likely that many centres will enrol very small number of subjects. Consequently, all
centres within the same country will be pooled and these amalgamations will be used
wherever pooled centre is incorporated into the analysis. If there are any countries
enrolling very small numbers in total (<12), these countries will be pooled with another
country within a similar geographical region. All amalgamations will be finalised and
documented prior to unblinding the treatment codes.
Baseline values for each endpoint will be those used as appropriate from either Visit 2 for
clinic visit endpoints or from the last 7 days of the Run-in Diary.
8.3.5.1.

Efficacy Analyses

All efficacy data will be summarised using means, standard deviations, medians and
ranges for continuous variables and frequencies and percentages for categorical variables.
Primary Analysis
The primary endpoint of change from baseline in trough FEV1 at the end of treatment
will be derived using the mean of the 23 and 24 hour post-dose FEV1 assessments. The
primary analysis will be performed using an ANCOVA model with effects due to
baseline FEV1, centre grouping, age, sex, baseline percent predicted FEV1 stratum and
treatment group, imputing missing data using LOCF. A linear trend contrast will be
constructed to evaluate the dose response trend. The primary comparisons will also be
performed in a sensitivity analysis using a repeated measures model allowing for effects
due to baseline FEV1, centre grouping, age, sex, baseline percent predicted FEV1 stratum,
visit and treatment group. This model will also contain a visit-by-treatment interaction
term. A linear trend contrast will be constructed for Day 28 to evaluate the dose response
trend.
The estimated slope of the dose response will be presented together with a 95%
confidence interval (CI) for the slope and a p-value for the linear trend test. Estimated
treatment differences for all pairwise comparisons will be presented together with
95% CIs for the difference and p-values, provided the primary dose-response test is
statistically significant.
Secondary Analyses
Trough FEV1 Strata Analyses
The primary endpoint of change from baseline in trough FEV1 at the end of treatment
will also be analysed for each percent predicted FEV1 strata separately in order to
investigate the consistency of the dose response relationship for the different disease
severities. The same ANCOVA model as for the primary analysis will be used to estimate
the dose response slope and its 95% CI for each stratum. Statistical significance testing
will not be performed for the strata analyses.

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0-24 Hour Weighted Mean Serial FEV1


The change from baseline in weighted mean for 24-hour serial FEV1 on Days 1 and 28
will be compared for each GW642444M group versus placebo using an ANCOVA model
with effects due to baseline (pre-dose measurement on Day 1), centre grouping, age, sex,
baseline percent predicted FEV1 stratum and treatment group. This analysis will include
all ITT population patients, including those with the additional timepoint measurements
at 6 and 12 hours after dosing. The weighted mean values will include the 6 and 12 hour
data for those subjects with these assessments. Estimated treatment differences for all
comparisons of GW642444M with placebo will be presented together with 95 % CIs for
the difference and p-values.
Additionally, a sensitivity analysis of the subgroup of subjects (approximately 50%)
having additional measurements at 6 and 12 hours will be performed. Pairwise
comparisons of each GW642444M dose with placebo will be performed.
Trough Evening (PM) PEF
The change from baseline in daily trough (pre-dose and pre-rescue bronchodilator) PM
PEF averaged over the 28-day treatment period will be compared for each GW642444M
dose versus placebo using an ANCOVA model with effects due to baseline PM PEF,
centre grouping, age, sex, baseline percent predicted FEV1 stratum and treatment group.
Estimated treatment differences for all comparisons will be presented together with 95%
CIs for the difference and p-values.
Morning (AM) PEF
The change from baseline in daily AM PEF averaged over the 28-day treatment period
will be compared for each GW642444M dose versus placebo using ANCOVA as
described for trough PM PEF.
Percentage of Symptom-free and Rescue-free 24-hour Periods
The change from baseline in the percentage of symptom-free 24-hour periods and rescuefree 24-hour periods over the 28-day treatment period will be calculated for each subject.
The data will then be analysed appropriately to compare each GW642444M treatment
group with placebo. The analysis methods to be used will be detailed in the RAP.
Response to salbutamol/albuterol
Difference in post salbutamol/albuterol FEV1 (FEV1 30 minutes after a single dose
of 400mcg albuterol/salbutamol) between 24 hours after dosing on Day 1 (Visit 2)
and 24 hours after dosing on Day 28 (Visit 5).

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For the change between 24 hours after dosing on Day 1 (Visit 2) and Day 28 (Visit 5), the
difference between:

Post-salbutamol/albuterol FEV1 24 hours after dosing on Day 1 (Visit 2)

Post-salbutamol/albuterol FEV1 24 hours after dosing on Day 28 (Visit 5)

and

will be derived for each subject and will be compared for each GW642444M group
versus placebo using an ANCOVA model with effects due to baseline, centre grouping,
age, sex, baseline percent predicted FEV1 stratum and treatment. Estimated treatment
differences for all comparisons will be presented together with 95% CIs for the difference
and p-values.
Difference in post salbutamol/albuterol FEV1 (FEV1 30 minutes after a single dose
of 400mcg albuterol/salbutamol) between screening (Visit 1) and 24 hours after
dosing on Day 1 (Visit 2)
For the change between pre-dosing (Visit 1) and 24 hours after dosing on Day 1 (Visit 2),
the difference between:

Post-salbutamol/albuterol FEV1 at Visit 1

Post-salbutamol/albuterol FEV1 24 hours after dosing on Day 1 (Visit 2)

and

will be derived for each subject and will be compared for each GW642444M group
versus placebo using an ANCOVA model as described above for the change between
Day 1 and Day 28.
Difference in post salbutamol/albuterol FEV1 (FEV1 30 minutes after a single dose
of 400mcg albuterol/salbutamol) between screening (Visit 1) and 24 hours after
dosing on Day 28 (Visit 5)
For the change between pre-dosing (Visit 1) and 24 hours after dosing on Day 28
(Visit 5), the difference between:

Post-salbutamol/albuterol FEV1 at Visit 1

Post-salbutamol/albuterol FEV1 24 hours after dosing on Day 28 (Visit 5)

and

will be derived for each subject and will be compared for each GW642444M group
versus placebo using an ANCOVA model as described above for the change between
Day 1 and Day 28.

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Other Analyses
The reporting and analysis of other endpoints as specified in the protocol will be provided
in the RAP.
8.3.5.2.

Safety Analyses

Extent of Exposure
The extent of exposure to study drug will be summarised by treatment group.
Adverse Events (AEs)
AEs will be coded using the standard GSK dictionary, Medical Dictionary for Regulatory
Activities (MedDRA), and grouped by body system. AEs occurring pre-treatment, during
active treatment and post-treatment will be summarised separately. The number and
percentage of subjects experiencing at least one AE of any type, AEs within each body
system and AEs within each preferred term will be presented for each treatment group.
Separate summaries will be provided for all AEs, AEs by maximum severity, drug related
AEs, SAEs, and for AEs leading to withdrawal.
Deaths and SAEs
All SAEs will be tabulated and listed by treatment group. Deaths and SAEs will be
documented in case narrative format.
Clinical Laboratory Evaluations
Clinical laboratory evaluations, including haematology, clinical chemistry and dipstick
urinalysis parameters, will be summarised by treatment group using shift tables and
summary statistics for each visit at which these parameters are collected. Baseline will be
defined as the Visit 1 value. Further details will be provided in the RAP.
Vital Signs Assessments
Vital signs (pulse rate, systolic blood pressure and diastolic blood pressure) will be
summarised by treatment for each clinic visit. Further details will be provided in the
RAP. Additionally, the derived vital signs endpoints of:

Change from baseline in maximum value (0-4 hours) for systolic blood pressure

Change from baseline in minimum value (0-4 hours) for diastolic blood pressure

Change from baseline in maximum value (0-4 hours) for pulse rate

Weighted mean change from baseline (0-4 hours) for blood pressure and pulse
rate.

on Day 1, Day 7, Day 14 and Day 28 will be analysed using ANCOVA with effects due
to baseline value, centre grouping, age, sex, baseline percent predicted FEV1 stratum and
treatment. Baseline will be defined as the Visit 2 pre-dose value. Pairwise comparisons
of each active treatment group versus placebo will be performed.
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12-Lead ECG
12-Lead ECG data will be summarised by treatment using shift tables and summary
tables for Day 1, Day 7, Day 14 and Day 28. Weighted mean change from baseline and
maximum change from baseline in QTc(F) and QTc(B) 0-4 hours post-dose will be derived
on Day 1, Day 7, Day 14 and Day 28, where baseline will be defined as Visit 2 pre-dose,
and will be analysed using ANCOVA as for the derived vital signs endpoints. Pairwise
comparisons of each active treatment group versus placebo will be performed.
Fasting Blood Glucose and Potassium
Fasting plasma glucose and serum potassium data will be summarised by treatment using
shift tables and summary tables for Day 1 and Day 28 and for non-fasting potassium on
Day 7 and 14. Weighted mean change from baseline in glucose and potassium 0-4 hours
post-dosing, maximum decrease from baseline in potassium 0-4hours post-dosing, and
maximum increase from baseline in glucose 0-4hours post-dosing will be derived on Day
1, Day 7, Day 14 and Day 28 (potassium; non fasting potassium on Day 7 and 14) and
Day 1 and Day 28 (glucose), where baseline will be defined as Visit 2 pre-dose, and will
be analysed using ANCOVA as for the derived vital signs endpoints. Pairwise
comparisons of each active treatment group versus placebo will be performed.
8.3.5.3.

Pharmacokinetic Analyses

The GW642444 plasma concentration data will be analysed using nonlinear mixed
effects modeling. The effect of demographic factors and concomitant medications on the
pharmacokinetics will be examined.
GW630200, GSK932009 and counter-ion in plasma concentration data will be analysed
as appropriate.
8.3.5.4.

Pharmacodynamic Analyses

See Section 8.3.5.2.


8.3.5.5.

Pharmacokinetics/Pharmacodynamics Analyses

The relationship between selected endpoints (including heart rate, glucose and potassium)
and systemic exposure to GW642444 will initially be explored graphically. Assessment
of pharmacokinetic/pharmacodynamic relationships may be undertaken via formal
modelling approaches as data permits. A population non linear mixed-effect dose
response analysis may be performed using trough FEV1 data if statistical analysis show
highly non linear trend (such as physiological Emax or variants). Various PD models
including step, step-linear or variant Emax models will be explored.

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9.

STUDY CONDUCT CONSIDERATIONS

9.1.

Regulatory and Ethical Considerations, Including the


Informed Consent Process

Prior to initiation of a study site, GSK will obtain approval from the appropriate
regulatory agency to conduct the study in accordance with applicable country-specific
regulatory requirements, including those required under a US IND.
The study will be conducted in accordance with all applicable regulatory requirements,
including a U.S. IND.
The study will be conducted in accordance with Good Clinical Practice (GCP), all
applicable subject privacy requirements, and the guiding principles of the declaration of
Helsinki, including, but not limited to:

Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and


approval of study protocol and any subsequent amendments.

Subject informed consent.

Investigator reporting requirements.

GSK will provide full details of the above procedures, either verbally, in writing, or
both.

Written informed consent must be obtained from each subject prior to participation
in the study.

9.2.

Quality Control (Study Monitoring)

In accordance with applicable regulations, GCP, and GSK procedures, GSK monitors
will contact the site prior to the start of the study to review with the site staff the protocol,
study requirements, and their responsibilities to satisfy regulatory, ethical, and GSK
requirements. When reviewing data collection procedures, the discussion will include
identification, agreement and documentation of data items for which the CRF will serve
as the source document.
GSK will monitor the study to ensure that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other
study agreements, GCP, and all applicable regulatory requirements.

The investigator and the head of the medical institution (where applicable) agrees to
allow the monitor direct access to all relevant documents

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Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK may
conduct a quality assurance audit of the site records, and the regulatory agencies may
conduct a regulatory inspection at any time during or after completion of the study. In the
event of an audit or inspection, the investigator (and institution) must agree to grant the
auditor(s) and inspector(s) direct access to all relevant documents and to allocate their
time and the time of their staff to discuss any findings/relevant issues.

9.4.

Study and Site Closure

Upon completion or termination of the study, the GSK monitor will conduct site closure
activities with the investigator or site staff (as appropriate), in accordance with applicable
regulations, GCP, and GSK Standard Operating Procedures.
GSK reserves the right to temporarily suspend or terminate the study at any time for
reasons including (but not limited to) safety issues, ethical issues, or severe
noncompliance. If GSK determines that such action is required, GSK will discuss the
reasons for taking such action with the investigator or head of the medical institution
(where applicable). When feasible, GSK will provide advance notice to the investigator
or head of the medical institution of the impending action.
If a study is suspended or terminated for safety reasons, GSK will promptly inform all
investigators, heads of the medical institutions (where applicable),and/or institutions
conducting the study. GSK will also promptly inform the relevant regulatory authorities
of the suspension/termination along with the reasons for such action. Where required by
applicable regulations, the investigator or head of the medical institution must inform the
IRB/IEC promptly and provide the reason(s) for the suspension/termination.

9.5.

Records Retention

Following closure of the study, the investigator or head of the medical institution (where
applicable) must maintain all site study records (except for those required by local
regulations to be maintained elsewhere) in a safe and secure location. The records must
be easily accessible when needed (e.g., for a GSK audit or regulatory inspection) and
must be available for review in conjunction with assessment of the facility, supporting
systems, and relevant site staff.
Where permitted by local laws/regulations or institutional policy, some or all of the
records may be maintained in a format other than hard copy (e.g., microfiche, scanned,
electronic); however, caution must be exercised before such action is taken. The
investigator must ensure that all reproductions are legible and are a true and accurate
copy of the original. In addition, they must meet accessibility and retrieval standards,
including regeneration of a hard copy, if required. The investigator must also ensure that
an acceptable back-up of the reproductions exists and that there is an acceptable quality
control procedure in place for creating the reproductions.

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GSK will inform the investigator of the time period for retaining the site records in order
to comply with all applicable regulatory requirements. The minimum retention time will
meet the strictest standard applicable to a particular site, as dictated by local
laws/regulations, GSK standard operating procedures, and/or institutional requirements.
The investigator must notify GSK of any changes in the archival arrangements, including,
but not limited to archival of records at an off-site facility or transfer of ownership of the
records in the event that the investigator is no longer associated with the site.

9.6.

Provision of Study Results and Information to Investigators

Where required by applicable regulatory requirements, an investigator signatory will be


identified for the approval of the clinical study report. The investigator will be provided
reasonable access to statistical tables, figures, and relevant reports and will have the
opportunity to review the complete study results at a GSK site or other mutuallyagreeable location.
Upon completion of the clinical study report, GSK will ensure public disclosure of the
clinical trial research results via the GSK Clinical Trial Register and provide the
investigator with the full summary of the study results. The investigator is encouraged to
share the summary results with the study subjects, as appropriate. GSK will provide the
investigator with the randomisation codes for their site only after completion of the full
statistical analysis.

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REFERENCES

American Thoracic Society (ATS), Centres for Disease Control and Prevention.
Treatment of Tuberculosis. American Thoracic Society, CDC, and Infectious Diseases
Society of America. Morbidity and Mortality Weekly Report. 2003;52:RR-11 (1-74).
American Thoracic Society Documents. American Thoracic Society/Centers for Disease
Control and Prevention/Infectious Diseases Society of America: Controlling Tuberculosis
in the United States. Am J Respir Crit Care Med. 2005;172:1169-1227.
GlaxoSmithKline Document Number RM2003/00283/00 Study ID GlaxoSmithKline
Document No. A randomized, double-blind, placebo-controlled, parallel group, 12-week
trial evaluating the efficacy and safety of the fluticasone propionate/salmeterol
DISKUS combination product 250/50mcg once daily versus fluticasone
propionate/salmeterol DISKUS combination product 100/50mcg twice daily versus
fluticasone propionate DISKUS 250mcg once daily versus placebo in symptomatic
adolescent and adult subjects with asthma that is not controlled on short-acting beta2agonists alone. Report Date 2004.
GlaxoSmithKline Document Number RM2007/00094/00 Study ID GW642444.
Supplement to GW642444 Investigator's Brochure. Report Date Oct-2007.
GlaxoSmithKline Document Number SM2003/00028/05 Study ID GW642444.
Investigator's brochure for GW642444 a selective beta-2 adrenoceptor agonist. Report
Date 29-Jun-2007.
Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and
Prevention 2006. Global Initiative for Asthma, www.ginasthma.org; 2006.
Hankinson J L, Odencrantz, JR; Feden, KB. Spirometric Reference Values from a
Sample of the General U.S. Population. AM J Respir Crit care Med. 1999;159:179-187.
National Institutes of Health (NIH). The Seventh Report of the Joint National Committee
on Prevention, Detection, and Treatment of High Blood Pressure. National Heart, Lung,
and Blood Institute, U.S. Department of Health and Human Services; 2004. 04-5230.
NIH. Guidelines for the Diagnosis and Management of Asthma (EPR-3) 2007. NHLBI,
August; 2007. NIH publication no. 08-4051.

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11.

APPENDICES

11.1.

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Pharmacogenetic Research
Pharmacogenetics Background
Pharmacogenetics (PGx) is the study of variability in drug response due to hereditary
factors in different populations. There is increasing evidence that an individual's genetic
composition (i.e., genotype) may impact the pharmacokinetics (absorption, distribution,
metabolism, elimination), pharmacodynamics (relationship between concentrations and
pharmacologic effects or the time course of pharmacologic effects) and/or clinical
outcome (in terms of efficacy and/or safety and tolerability). Some reported examples of
PGx analysis include:
Drug
Abacavir
Tranilast

ABT-761

Disease
HIV
[Hetherington, 2002;
Mallal, 2002]
Restenosis
prevention following
coronary bypass
[Roses, 2002]
Asthma
[Drazen, 1999]

Gene
HLA (human
leukocyte
antigen)
UGT1A1

Outcome
Caucasian males with HLA B57 variant were
at increased risk for experiencing
hypersensitivity to abacavir
Drug induced hyperbilirubinemia explained by
high proportion of affected patients having 7/7
TA repeat genotype, consistent with clinically
benign Gilberts Syndrome
ALOX5 Sp1 promoter genotype (x,x)
associated with reduced response to 5lipoxygenase inhibitor ABT-761

ALOX5

A key component to successful PGx research is the collection of samples during the
conduct of clinical studies.
Pharmacogenetics (PGx) is the study of variability in product response due to hereditary
factors in different populations. There is increasing evidence that an individual's genetic
composition (i.e. his or her genotype) may impact product response or clinical outcome
as well as disease susceptibility and the progression of that disease.
If at any time it appears that there is a potential unexpected or unexplained variation in
response to or handling of GW642444M (e.g., pharmacokinetics, efficacy and/or safety)
that may be attributable to genetic variation, then PGx analysis may be conducted. In
these circumstances, the analysis undertaken will be limited to PGx analysis of
GW642444M handling or response and may include the evaluation of specific candidate
genes, the conduct of a whole genome single nucleotide polymorphism (SNP) scan or
other marker scan.
Although a heterogeneous therapeutic response to 2-agonists in asthma is well known,
the relative contribution of genetic (e.g., ADBR2 polymorphisms) and nongenetic (e.g.,
environmental exposures) parameters to this variability remains poorly defined. The 2adrenergic receptor is a 413 amino acid protein encoded for by an intronless gene
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ADRB2) located on chromosome 5q31.32 2. Variation in the activity of this cell surface
receptor is important because it mediates the effects of 2-agonists.
Numerous reports from clinical studies characterizing specific associations between
ADRB2 SNPs and therapeutic outcomes suggest that genetic variation can influence the
response to a variety of 2-agonists, but the clinical significance of these observations is
not yet clear. Screens of ADRB2 have identified polymorphisms which may influence
response to 2-agonists [Israel, 2000; Reishaus, 1983]. In particular, the receptor variant
characterized by substitution of arginine for glycine at position 16 (Gly16Arg) may be an
important determinant of receptor function in vitro and occurs commonly in the
population (minor allele frequency approximately 0.4-0.5). In addition, genome screening
of large asthma and COPD disease populations has identified putative respiratory disease
susceptibility genes and these genes may also influence drug response.
A whole blood sample will be collected (in addition to any blood samples to be taken for
the clinical study) at randomisation or during the study from all consenting subjects.
Pharmacogenetic Research Objectives
The objective of the PGx research (if there is a potential unexpected or unexplained
variation) is to investigate a possible genetic relationship to handling or response to
GW642444M. If at any time it appears there is potential variability in response in this
clinical study or in a series of clinical studies with GW642444M that may be attributable
to genetic variations of subjects, the following objectives may be investigated:

Relationship between genetic variants and the pharmacokinetics of investigational


product

Relationship between genetic variants and safety and/or tolerability of investigational


product

Relationship between genetic variants and efficacy of investigational product

Study Population
Any subject who has given informed consent to participate in the clinical study, has met
all the entry criteria for the clinical study, and receives investigational product may take
part in the PGx research. Any subject who has received an allogeneic bone marrow
transplant must be excluded from the PGx research.
Subject participation in the PGx research is voluntary and refusal to participate will not
indicate withdrawal from the clinical study. Refusal to participate will involve no penalty
or loss of benefits to which the subject would otherwise be entitled.

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Study Assessments and Procedures


In addition to any blood samples take for the clinical study, a whole blood sample
(~10ml) will be collected for the PGx research using a tube containing EDTA. The PGx
sample is labeled (or coded) with a study specific number that can be traced or linked
back to the subject by the investigator or site staff. Coded samples do not carry personal
identifiers (such as name or social security number). The blood sample will be taken on a
single occasion unless a duplicate sample is required due to inability to utilize the original
sample. It is recommended that the blood sample be taken at the first opportunity after a
subject has been randomized and provided informed consent for PGx research, but may
be taken at any time while the subject is participating in the clinical study.
If deoxyribonucleic acid (DNA) is extracted from the blood sample, the DNA may be
subjected to sample quality control analysis. This analysis will involve the genotyping of
several genetic markers to confirm the integrity of individual samples. If inconsistencies
are noted in the analysis, then those samples may be destroyed.
The need to conduct PGx analysis may be identified after a study (or a set of studies) of
GW642444M has been completed and the study data reviewed.
In some cases, the samples may not be studied. e.g., no questions are raised about how
people respond to GW642444M.
Samples will be stored securely and may be kept for up to 15 years after the last subject
completes the study or GSK may destroy the samples sooner. GSK or those working with
GSK (for example, other researchers) will use samples collected from the study for the
purpose stated in this protocol and in the informed consent form.
Subjects can request their sample to be destroyed at any time.
Subject Withdrawal from Study
If a subject who has consented to participate in PGx research and has a sample taken for
PGx research withdraws from the clinical study for any reason other than lost to followup, the subject will be given the following options:

The sample is retained for PGx research

Any PGx sample is destroyed.

If a subject withdraws consent from the PGx research or requests sample destruction for
any reason, the investigator must complete the appropriate documentation to request
sample destruction within the timeframe specified by GSK and maintain the
documentation in the site study records. In either case, GSK will only keep study
information collected/generated up to that point.
Screen and Baseline Failures
If a blood sample for PGx research has been collected and it is determined that the
subject does not meet the entry criteria for participation in the clinical study, then the
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investigator must complete the appropriate documentation to request sample destruction


within the timeframe specified by GSK and maintain the documentation in the site study
records.
Pharmacogenetics Analyses
Generally GSK will utilize two approaches to explore genetic variation in drug response.
1.

Specific sections of DNA may be selected from areas of the genome (e.g., candidate
genes) known to encode the drug target, drug metabolizing enzymes, areas
associated with mechanisms underlying adverse events, and those linked to study
disease and, thus, linked to drug response. The candidate genes that may be
investigated in this study will include the following: the GSK Absorption,
Distribution, Metabolism and Excretion (ADME) panel. Absorption, distribution,
metabolism and excretion (ADME) genes play a central role in drug
pharmacokinetics and pharmacodynamics (PK-PD). The GSK ADME panel
contains genetic markers from one hundred and thirty-five enzymes, transporters and
other genes involved in drug absorption, distribution, metabolism and excretion. The
ADME panel may be used to investigate the relationship between genetic variants on
the panel and pharmacokinetics, safety and efficacy of the investigational product.

The candidate genes that may be investigated include, but may not be limited to the 2adrenoceptor (ADRB2). In addition, continuing research may identify other proteins that
may be involved in the response to GW642444M. The genes that encode these proteins
may also be studied.
In addition, continuing research may identify other enzymes, transporters, proteins, or
receptors that may be involved in response to GW642444M. The genes that may code
for these proteins may also be studied.
1

By evaluating large numbers of polymorphic markers (e.g., single nucleotide


polymorphisms or SNPs) throughout the genome, sets of markers may be identified
that correspond to differential drug response. These will include:

Hardy-Weinberg Equilibrium Testing


The genotypic frequencies of each polymorphism will be evaluated for conformity to
those expected under normal conditions by employing Hardy-Weinberg Equilibrium
testing.
Comparison of Demographic and Baseline Characteristics by Genotype
Differences in baseline clinical characteristics and potential contributing covariates may
be summarized and compared among genotype (or haplotype) subgroups.

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Evaluation of Genotypic Effects


Analyses may be carried out to evaluate the degree of association between subject
genotype (or haplotype) and selected parameters (e.g., pharmacokinetics, efficacy and
safety). Where such genotypic tests are inappropriate (for example, where the number of
marker genotypes is too large and/or the frequency of individual genotypes too small),
allelic tests may be conducted. Allelic tests evaluate whether the frequency of each
marker allele is the same in responders and non-responders.
Evaluation of Treatment by Genotype and Gene-Gene Interaction
In addition to evaluating the main effects of the genotypes (haplotypes or alleles) on the
selected parameters, the possibility of a treatment group by genotype (haplotype or allele)
interaction will also be explored. If appropriate, the joint effects of multiple markers
(gene-gene interactions) may also be evaluated.
Linkage Disequilibrium
For pairs of polymorphisms, the degree to which alleles from the two sites are correlated
(linkage disequilibrium) may also be evaluated. If the genotypes at two polymorphic sites
within a gene are shown to be statistically associated with a response to investigational
product, the degree of linkage disequilibrium will aid interpretation in that it will indicate
the extent to which the two sites are exerting independent effects.
Multiple Comparisons and Multiplicity
An adjustment to observed p-values may be made to limit erroneous conclusions due to
multiple tests when multiple markers are evaluated (especially in the case of a genome
scan for association),
Power and Sample Size Considerations
The ability to detect differential drug response among genotypes at a polymorphic site
depends on the total number of subjects genotyped and the frequency distribution of the
different genotypes. Consequently, genotyping analyses are plausible for those
polymorphic sites where the number of subjects comprising the genotypic groups is
sufficiently large; however, these frequencies will not be known until sufficient samples
have been collected and genotyping is complete.
Estimates of sample sizes required to demonstrate genotype effects vary considerably,
depending on the assumptions made about allele frequency, genetic effect size, and
mechanism of inheritance [Cardon, 2000]. In the work by Palmer and Cookson
[Palmer, 2001], which assumed a genotype relative risk of 1.5, it was estimated that more
than 300 cases and 600 controls would be needed to conduct a genetic association
analysis. In contrast, McCarthy and Hilfiker [McCarthy, 2000] showed that with a
genotype relative risk of 2.16 and a relatively commonly occurring genotype, only 30
cases and 30 controls would be needed to demonstrate an association.

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Published PGx examples include abacavir hypersensitivity reaction [Hetherington, 2002;


Mallal, 2002] and tranilast induced hyperbilirubinemia [Roses, 2002] where genetic
markers have been found to significantly associate with hypersensitivity reaction
(abacavir) and hyperbilirubinemia (tranilast). These examples show that small sample
sizes typically encountered in Phase I and Phase II studies may be sufficient to identify
clinically relevant genetic associations.
Informed Consent
Subjects who do not wish to participate in the PGx research may still participate in the
clinical study. PGx informed consent must be obtained prior to any blood being taken for
PGx research.
Provision of Study Results and Confidentiality of Subjects PGx Data
GSK may summarize the cumulative PGx research results in the clinical study report.
In general, GSK does not inform the investigator, subject, or anyone else (e.g., family
members, study investigators, primary care physicians, insurers, or employers) of the
PGx research results, that are not known to be relevant to the subjects medical care at the
time of the study, because the information generated from PGx studies is preliminary in
nature, and the significance and scientific validity of the results are undetermined at such
an early stage of research, under any circumstances unless required by law.
References
Cardon LR, Idury RM, Harris TJR, Witte JS, Elston RC. Testing drug response in the
presence of genetic information: sampling issues for clinical trials. Pharmacogenetics.
2000; 10:503-10.
Drazen JM, Yandava CN, Dube L, Szcerback N, Hippensteel R, Pillari A, Israel E,
Schork N, Silverman ES, Katz DA, Drajesk J. Pharmacogenetic association between
ALOX5 promoter genotype and the response to anti-asthma treatment. Nature Genet.
1999; 22:168-70.
Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, Lai E,
Davies K, Handley A, Dow DJ, Fling ME, Stocum M, Bowman C, Thurmond LM, Roses
AD. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir.
Lancet. 2002; 359:1121-2.
IsraelE, Drazen JM, Liggett SB, et al. The effect of polymorphisms of the beta (2)adrenergic receptor on the response to regular use of albuterol in asthma. American
Journal of Respiratory & Critical Care Medicine. 2000;162:75.
Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte
C, Maxwell D, James I. Association between presence of HLA-B*5701, HLA-DR7, and
HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir.
Lancet. 2002; 359:727-32.

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McCarthy JJ, Hilfiker R. The use of single-nucleotide polymorphism maps in


pharmacogenomics. Nat Biotechnol. 2000; 18:505-8.
Palmer LJ, Cookson WO. Using single nucleotide polymorphisms as a means to
understanding the pathophysiology of asthma. Respir Res. 2001; 2:102-12.
Reishaus E, Innis M, MacIntyre N, et al. Mutations in the gene encoding for the beta (2)adrenergic receptor in normal and asthmatic subjects. American Journal of Respiratory
Cell & Molecular Biology. 1983;8:334.
Roses AD. Genome-based pharmacogenetics and the pharmaceutical industry. Nat Rev
Drug Discov. 2002; 1:541-9.

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Appendix 2: Laboratory Parameters

Analytes to be included in haematology panel - Haemaglobin, Red Blood Cells, Mean Cell Volume,
Mean Cell Haemoglobin, Mean Cell Haemoglobin Concentration, Haematocrit, Platelets, White
Blood Cells.
Differential white cell count: Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils
Analytes to be included in chemistry panel - Urea, Creatinine, Uric acid, Direct and Indirect
bilirubin, Total bilirubin, Total protein, Albumin, Creatinine kinase, Alkaline Phosphatase, Aspartate
Aminotransferase, Alanine Aminotransferase, Lactate Dehydrogenase, Gamma Glytamyl
Transferase, Glucose, Potassium, Sodium, Calcium, Chloride
Analytes to be included in urinalysis dipstick if abnormal standard panel for microscopy

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Appendix 3: Country Specific Requirements

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Appendix 4: Protocol Changes

Protocol Amendment Number 01


Scope
This amendment applies to all sites.
Protocol changes specified in Amendment No. 1 are summarised below:

Clarification that upper and lower respiratory tract infections are only an exclusion
criterion if they have resulted in a change to subjects asthma management or if they
affect the subjects ability to participate in the study.

Clarification that subjects with severe milk protein allergy should be excluded from
the study as per exclusion criterion No. 7. The protocol has been amended to make
this point explicit.

Clarification that long acting anti-histamines only are prohibited for 14 days prior to
and during the study. This is currently inconsistent within the protocol.

It is no longer necessary for Investigators to consult with the GSK Medical Monitor
prior to withdrawing a subject who has met any of the ECG withdrawal criteria.

Correction of a formatting error that could potentially lead to misinterpretation of the


protocol requirements for prohibited medications.

Clarification that study issued rescue salbutamol/albuterol will be provided for use
during the run-in, treatment period and follow-up period. This is currently
inconsistent within the protocol.

Protocol Changes

Section 4.3. Exclusion Criteria


Original Text
1.

Culture-documented or suspected bacterial or viral infection of the upper or lower


respiratory tract, sinus or middle ear and/or exacerbation of asthma within 4 weeks
of Visit 1.

Revised Text
1.

An exacerbation of asthma within 4 weeks of Visit 1, or a culture documented or


suspected bacterial or viral infection of the upper or lower respiratory tract, sinus or
middle ear within 4 weeks of Visit 1 that led to a change in asthma management, or
in the opinion of the Investigator is expected to affect the subjects asthma status or
the subjects ability to participate in the study.

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Section 4.3. Exclusion Criteria


Original Text
7.

Any adverse reaction including immediate or delayed hypersensitivity to any


2-agonist or sympathomimetic drug, or known or suspected sensitivity to the
constituents of GW642444M inhalation powder (i.e. lactose or magnesium stearate).

Revised text
7.

Any adverse reaction including immediate or delayed hypersensitivity to any 2agonist or sympathomimetic drug, or known (i.e., patients with a history of severe
milk protein allergy) or suspected sensitivity to the constituents of GW642444M
inhalation powder (e.g., lactose or magnesium stearate).

Section 4.3. Exclusion Criteria


Original Text
12. Administration of the following asthma medications within 14 days of Visit 1:

Theophyllines

Oral 2-agonists (e.g. bambuterol)

Slow-release bronchodilators

Anticholinergics - short or long-acting

Oral antihistamines

Oral leukotriene receptor antagonists (e.g. montelukast)

Revised Text
12. Administration of the following asthma medications within 14 days of Visit 1:

Theophyllines

Oral 2-agonists (e.g. bambuterol)

Slow-release bronchodilators

Anticholinergics - short or long-acting

Oral long acting antihistamines

Oral leukotriene receptor antagonists (e.g. montelukast)

Section 4.5. Withdrawal Criteria


Original Text
A subject experiences any of the following abnormalities in ECGs (the decision should
be made following consultation with the medical monitor, unless there is an immediate
safety concern and this is not feasible).

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Revised Text
A subject experiences any of the following abnormalities in ECGs:

Section 5.1. Investigational Product and Reference Therapy


Original Text
Inhaled salbutamol/albuterol will be provided for symptomatic relief during the run-in
and treatment periods.
Revised Text
Inhaled salbutamol/albuterol will be provided for symptomatic relief during the run-in,
treatment period and follow-up period.

Section 5.6.1. Permitted Medications and Non-Drug Therapies


Original Text
The following asthma medications are permitted:

Short-acting 2-agonists (will be replaced by study issued rescue


salbutamol/albuterol MDI at Visit 1 to be used throughout the Run-In and Treatment
Periods)

Revised Text
The following asthma medications are permitted:

Short-acting 2-agonists (will be replaced by study issued rescue


salbutamol/albuterol MDI at Visit 1 to be used throughout the Run-In, Treatment
Period and Follow-up Period)

Section 5.6.2. Prohibited Medications and Non-Drug therapies


Original Text
Within 12 weeks of Visit 1:

Systemic, oral, parenteral or depot corticosteroids

Anti-IgE therapy (e.g. omalizumab [Xolair])

In addition, a subject may not concurrently use any other prescription or over-thecounter medication which may affect the course of asthma, or interact with
sympathomimetic amines, such as:

Anticonvulsants (barbiturates, hydantoins, and carbamazepine)

Polycyclic antidepressants

-adrenergic blocking agents


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Revised Text
Within 12 weeks of Visit 1:

Systemic, oral, parenteral or depot corticosteroids

Anti-IgE therapy (e.g. omalizumab [Xolair])

In addition, a subject may not concurrently use any other prescription or over-the-counter
medication which may affect the course of asthma, or interact with sympathomimetic
amines throughout the study (Visit 1 to Visit 6 inclusive), such as:

Anticonvulsants (barbiturates, hydantoins, and carbamazepine)

Polycyclic antidepressants

-adrenergic blocking agents

Phenothiazines

Monoamine oxidase (MAO) inhibitors

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6. STUDY ASSESSMENTS AND PROCEDURES


Table 1

Time and Events table

Corrected to indicate that rescue salbutamol/albuterol should be collected at the followup visit, not Visit 5/5a
Procedures
Visit
Day

Screen/
Run-in
1
-14(-

Treatment
2/2A1
1

Early
Withdrawal

3
7 (-4/+2)

4
14(-4/+2)

5/5A1
28(-4/+2)

6
D28 + 7(-

4/+2)

Written Informed
x
Consent
Subject Demography x
Medical History
x
Asthma History
x
Therapy History
x
Smoking History
x
Physical examination x
Inclusion/Exclusion
x
Criteria
Randomisation
Criteria
Efficacy Assessments
Clinic measured FEV1 x
FEV1 response to
x
salbutamol/albuterol
x
Issue Diary and PEF
meter9
Review Diary data
Safety Assessments
Concomitant
x
Medication
Vital Signs
x
12-lead ECG
x
Adverse Events
Serious Adverse
x
Events
Laboratory Assessments
Haematology5
x
Chemistry5
x
Urinalysis5
x
PGx Sampling
Serum Pregnancy
x
Test
Urine pregnancy Test
HBsAg and hepatitis
x
C antibody
Exploratory Lab Assessments
PK sampling6
Serum potassium
and plasma glucose
sampling

Follow-up

4/+2)

x
x2
x3

x2

x2

x2
x3

x4
x4
x
x

x4
x4
x
x

x4
x4
x
x

x4
x4
x
x

x
x
x
x

x
x

x
x

x
x
x

x
x
x

x
x
x5

x
x7

x10

x
X11

x
X11

x
x7

Continued

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Time and Events Table (Continued)


Screen/
Run-in

Treatment

Early
Withdrawal

Followup

Investigational product
Dispense Invest.
x
Product.
Assess Invest.
x
x
x
x
Product compliance
Collect invest.
x
x
product
Issue rescue
x
x8
x8
salbutamol/albuterol
Collect used rescue
x
x
x
salbutamol/albuterol
1. Visit 2/2A and Visit 5/5A will take place over 2 days. In selected centres, subjects will be required to remain in the
clinic overnight (~50% of subjects). In other centres, subjects will return to the clinic approximately mid-morning
on Day 2 and Day 29 (Visit 2A and 5A, respectively) to complete Day 1 and 28 serial FEV1 measurements
2. On Day 1 (Visit 2) and Day 28 (Visit 5) serial measurements of FEV1 to be made at pre-dose, 15, 30 and
60 minutes and 2, 3, 4, 6, 12, 16, 20, 22, 23 and 24 hours post-dose. Measurements at 6 and 12 hours post-dose
will only be made in those subjects remaining at the clinic overnight On Days 7 (Visit 3) and 14 (Visit 4) pre-dose
FEV1 measurements required only
3. To be performed 24 hours after the Day 1 (Visit 2) and Day 28 (Visit 5) administration of investigational product
4. Measurements to be made on Day 1 (Visit 2), Day 7 (Visit 3), Day 14 (Visit 4) and Day 28 (Visit 5): pre-dose,
10minutes and 1, 2 and 4 hours post-dose
5. Samples should be taken pre-dose
6. Samples to be taken as follows:
Day 1 (Visit 2): pre-dose, between 2-10 minutes, between 10-30minutes, between 30minutes -2 hours and
between 2-4 hours post-dose
Day 7 (Visit 3): pre-dose
Day 14 (Visit 4): 2minutes -1hour post-dose
Day 28 (Visit 5): pre-dose, between 2-10 minutes, between 10-30minutes, between 30minutes -2 hours and
between 2-4 hours post-dose
7. Samples will be taken pre-dose and 10 minutes, 1, 2 and 4hours post-dose. Subject will be fasted from at least 4
hours prior to the pre-dose blood sample until after the 4 hour post-dose sample
8. If required
9. Morning and evening PEF, symptoms and rescue medication usage to be recorded every day from Visit 1 through
Visit 6
10. To be taken 24hours post-dose Day 28
11. Serum potassium only. Samples to be taken pre-dose and 10minutes, 1, 2 and 4 hours post-dose. Subjects are
not required to fast for these samples.

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Protocol Amendment 02

Protocol Changes
SCOPE: This amendment applies to all sites
Protocol changes specified in Amendment No. 02 are summarised as follows:

To amend the definition of evaluable subjects

To allow subjects to re-screen for Visit 1 if they fail to meet lung function criteria
and to allow subjects who previously failed screening to be re-screened.

To clarify the exclusion of subjects with upper and lower respiratory tract infections
between Visit 1 and Visit 2 (Randomisation to Treatment).

To amend the ECG abnormality randomisation and withdrawal criteria.

To clarify the blood pressure entry criteria.

To clarify that pregnancy tests are required for all females

To allow the use of long acting anti-histamines

To extend the permitted time deviation windows in acknowledgement of the


complexity of the study

Protocol Summary, Study Design


Original wording
Approximately 1200 subjects will be screened to ensure randomisation of 594 subjects
(99 per group) with at least one 23-24 hour post-dose FEV1 assessment.
Revised wording
Approximately 1200 subjects will be screened to ensure randomisation of 594 subjects
(99 subjects per group) with at least one pre-dose or 23-24 hour post-dose FEV1
assessment on or after nominal Day 7.

Section 3.1 Study Design


Original wording
This will be a multi-centre, randomised, placebo-controlled, double-blind, parallel group
study. Subjects will enter a two week run-in period and those who then fail to meet
eligibility criteria for randomisation will be withdrawn from the study.

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Revised wording
This will be a multi-centre, randomised, placebo-controlled, double-blind, parallel group
study. Subjects meeting all entry inclusion criteria and none of the exclusion criteria
during the Visit 1 screening period (no longer than 4 days) will enter a two week run-in
period and those who then fail to meet eligibility criteria for randomisation will be
withdrawn from the study.

Section 3.1 Study Design


Addition of the following text, after the study schematic:
* Visit 1 screening period:
The resting ECG must be performed first. It is then recommended that lung function tests
are performed before any other assessment. If a subject does not meet the inclusion
criteria for FEV1 percent predicted and/or reversibility following inhalation of
albuterol/salbutamol, no other study assessments should be performed at this first visit,
and the subject may return to the site once within 4 days to repeat the lung function tests.
If the subject does meet the lung function entry criteria on the second attempt, then other
Visit 1 assessments must also be performed on this date.
If the subject only becomes eligible at the second screening visit the Investigator must
document that the ECG results and clinical laboratory test results (if taken at first
screening visit) are clinically acceptable within the 4 day screening period. The clinical
laboratory tests and ECG do not need to be repeated at the second screening visit.
However, all other assessments must be repeated on the same day as the qualifying lung
function tests.
The data from the original Visit 1 date will be returned to GSK as well.

Section 4.1 Number of Subjects


Original wording
Approximately 1200 subjects will be screened to ensure randomisation of 594 subjects
(99 per group) with at least one 23-24 hour post-dose FEV1 assessment.
Revised wording
Approximately 1200 subjects will be screened to ensure randomisation of 594 subjects
(99 subjects per group) with at least one pre-dose or 23-24 hour post-dose FEV1
assessment on or after nominal Day 7.

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Section 4.2 Inclusion Criteria


Original wording
4

Subjects with current reversible airways disease as demonstrated at Visit 1 by an


increase in FEV1 of 12% and 200ml over the pre-salbutamol/albuterol FEV1 at
approximately 30 minutes after the inhalation of 400mcg of salbutamol/albuterol via
MDI (spacer permitted for reversibility testing only if required) or one nebulised
salbutamol/albuterol solution.

Revised wording
4. Subjects with current reversible airways disease as demonstrated at Visit 1 screening
period by an increase in FEV1 of 12% and 200ml over the presalbutamol/albuterol FEV1 at approximately 30 minutes after the inhalation of
400mcg of salbutamol/albuterol via MDI (spacer permitted for reversibility testing
only if required) or one nebulised salbutamol/albuterol solution.
Re-screening of subjects during the Visit 1 screening period: If a subject does not
meet the inclusion criteria based upon FEV1 percent predicted and/or reversibility, the
subject may return to the site once within 4 days and repeat the lung function tests.

Section 4.3 Exclusion Criteria


Original wording
5

Previously enrolled in this study, or has participated in any study using an


investigational drug during the previous 30 days or will participate simultaneously in
another clinical trial.

The list of additional excluded conditions/diseases includes, but is not limited to the
following:

congestive heart failure


clinically significant coronary heart disease
stroke within 3 months of Visit 1
poorly controlled peptic ulcer
immunologic compromise
tuberculosis (current or untreated3)
Addison's disease
uncontrolled thyroid disorder
neurological disease
1.
2.
3.
4.

known aortic aneurysm


clinically significant cardiac arrhythmia
uncontrolled hypertension1
haematologic, hepatic, or renal disease
current malignancy2
Cushing's disease
uncontrolled diabetes mellitus
recent history of drug or alcohol abuse
pulmonary disease4

systolic blood pressure 160, or diastolic blood pressure >100


history of malignancy is acceptable only if subject has been in remission for one year prior to Visit 1 (remission =
no current evidence of malignancy and no treatment for the malignancy in the 12 months prior to Visit 1)
Subjects with a history of tuberculosis who have received an approved prophylactic treatment regimen or an
approved active treatment regimen and who have no evidence of active disease for a minimum of 2 years may be
enrolled [American Thoracic Society Documents, 2005; American Thoracic Society, 2003]
Including but not limited to chronic bronchitis, emphysema, bronchiectasis with the need of treatment, cystic
fibrosis, bronchopulmonary dysplasia, and chronic obstructive pulmonary disease.

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12 Administration of any of the following asthma medications within 14 days of Visit 1:

Theophyllines

Oral 2-agonists (e.g. bambuterol)

Slow-release bronchodilators

Anticholinergics - short or long-acting

Oral long-acting antihistamines

Oral leukotriene receptor antagonists (e.g. montelukast)

Inhaled sodium cromoglicate

Inhaled nedocromil sodium

Revised wording
5

Participated in any study using an investigational drug during the previous 30 days or
will participate simultaneously in another clinical trial.

The list of additional excluded conditions/diseases includes, but is not limited to the
following:

congestive heart failure


clinically significant coronary heart disease
stroke within 3 months of Visit 1
poorly controlled peptic ulcer
immunologic compromise
tuberculosis (current or untreated3)
Addison's disease
uncontrolled thyroid disorder
neurological disease
1.
2.
3.
4.

known aortic aneurysm


clinically significant cardiac arrhythmia
uncontrolled hypertension1
haematologic, hepatic, or renal disease
current malignancy2
Cushing's disease
uncontrolled diabetes mellitus
recent history of drug or alcohol abuse
pulmonary disease4

systolic blood pressure 160, or diastolic blood pressure >100 2 or more measurements with systolic blood
pressure 160mmHg or diastolic blood pressure 100mmHg [NIH, 2004]
history of malignancy is acceptable only if subject has been in remission for one year prior to Visit 1 (remission =
no current evidence of malignancy and no treatment for the malignancy in the 12 months prior to Visit 1)
Subjects with a history of tuberculosis who have received an approved prophylactic treatment regimen or an
approved active treatment regimen and who have no evidence of active disease for a minimum of 2 years may be
enrolled [American Thoracic Society Documents, 2005; American Thoracic Society, 2003]
Including but not limited to chronic bronchitis, emphysema, bronchiectasis with the need of treatment, cystic
fibrosis, bronchopulmonary dysplasia, and chronic obstructive pulmonary disease.

12 Administration of any of the following asthma medications within 14 days of Visit 1:

Theophyllines

Oral 2-agonists (e.g. bambuterol)

Slow-release bronchodilators

Anticholinergics - short or long-acting

Oral long acting antihistamines

Oral leukotriene receptor antagonists (e.g. montelukast)


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Section 4.4 Randomisation Criteria


Original Wording
5

No evidence of significant abnormality in the 12-lead ECG at Visit 1


Selected specific ECG findings that are considered to be significant and will exclude
the subject from study participation include, but are not limited to, the following:

Ventricular rate < 45 beats per minute or > 90 beats per minute

PR interval > 240msec

Evidence of second or third degree atrioventricular (AV) block

Pathological Q waves (defined as wide (> 0.04 seconds) and deep (> 0.4mV (4
mm with 10mm/mV setting) or > 25% of the height of the corresponding R
wave, provided the R wave was > 0.5mV (5 mm with 10mm/mV setting),
appearing in at least two contiguous leads) or other historical or
electrocardiographic evidence of prior myocardial infarction.

Evidence of supra-ventricular or ventricular ectopy or arrhythmias

QTc(B) > 450msec

Non-specific intraventricular conduction delay

ST-T wave abnormalities (excluding non-specific ST-T wave abnormalities)

Right or left complete bundle branch block

Incomplete right bundle branch block (QRS interval > 100msec < 120msec with
right bundle branch block pattern)

Revised Wording
5

No evidence of significant abnormality in the 12-lead ECG at Visit 1, as judged by


Independent Cardiologist.
Selected specific ECG findings that are considered to be significant and will exclude
the subject from study participation include, but are not limited to, the following:

Ventricular rate < 45 beats per minute or > 90 beats per minute

PR interval > 240msec

Evidence of second or third degree atrioventricular (AV) block

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Pathological Q waves (defined as wide (> 0.04 seconds) and deep (> 0.4mV (4
mm with 10mm/mV setting) or > 25% of the height of the corresponding R
wave, provided the R wave was > 0.5mV (5 mm with 10mm/mV setting),
appearing in at least two contiguous leads) or other historical or
electrocardiographic evidence of prior myocardial infarction.

Evidence of 2 or more supra-ventricular or ventricular ectopic beats, ie. ANY


couplets, bigeminy, trigeminy or multifocal premature ventricular complexes.
This should be confirmed by 3 readings at least 5 minutes apart.

QTc(B) > 450msec

Non-specific intraventricular conduction delay

ST-T wave abnormalities (excluding non-specific ST-T wave abnormalities)

Right or left complete bundle branch block, or a QRS interval >120msec.

Incomplete right bundle branch block (QRS interval > 110msec < 120msec with
right bundle branch block pattern). This should be confirmed by three readings
at least 5 minutes apart.

Original Wording
7

No occurrence of an upper or lower respiratory tract infection during the run-in


period.

Revised Wording
7

Occurrence of an culture-documented or suspected bacterial or viral infection of the


upper or lower respiratory tract, sinus or middle ear infection during the run-in
period that led to a change in asthma management, or in the opinion of the
Investigator is expected to affect the subjects asthma status or the subjects ability to
participate in the study.

Section 4.5 Withdrawal Criteria


Original text
A subject experiences any of the following abnormalities in ECGs

A subject experiences an increase in heart rate from baseline of >40bpm


(relative to the pre-dose Day 1 value) or an absolute heart rate of >110bpm
during the treatment period. This should be confirmed by 3 readings at least 5
minutes apart.

A subject experiences a prolongation in absolute mean QTC(B) to >500msec or


uncorrected mean QT >600msec during the treatment period. This should be the
mean of three measurements taken at least 5 minutes apart.

Ventricular rate < 37 beats per minute. This should be confirmed by 3 readings
at least 5 minutes apart on 3 or more ECGs.

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PR interval > 240msec. This should be confirmed by 3 readings at least 5


minutes apart on 3 or more ECGs.

Evidence of second or third degree atrioventricular (AV) block

Pathological Q waves (defined as wide (> 0.04 seconds) and deep (> 0.4mV (4
mm with 10mm/mV setting) or > 25% of the height of the corresponding R
wave, provided the R wave was > 0.5mV (5 mm with 10mm/mV setting),
appearing in at least two contiguous leads) or other historical or
electrocardiographic evidence of prior myocardial infarction.

Evidence of supra-ventricular or ventricular ectopy or arrhythmias

Non-specific intraventricular conduction delay

ST-T wave abnormalities (excluding non-specific ST-T wave abnormalities)

Right or left complete bundle branch block

Incomplete right bundle branch block (QRS interval > 100msec < 120msec with
right bundle branch block pattern)

Revised text
A subject experiences any of the following abnormalities in ECGs. (the decision should
be made following consultation with the medical monitor, unless there is an immediate
safety concern and this is not feasible).

A subject experiences an increase in heart rate from baseline of >40bpm


(relative to the pre-dose Day 1 value) or an absolute heart rate of >110bpm
during the treatment period. This should be confirmed by 3 readings at least 5
minutes apart.

A subject experiences a prolongation in absolute mean QTC(B) to >500msec or


uncorrected mean QT >600msec during the treatment period. This should be the
mean of three measurements taken at least 5 minutes apart.

Ventricular rate < 37 beats per minute. This should be confirmed by 3 readings
at least 5 minutes apart on 3 or more ECGs.

PR interval > 240msec. This should be confirmed by 3 readings at least 5


minutes apart on 3 or more ECGs.

Evidence of second or third degree atrioventricular (AV) block

Pathological Q waves (defined as wide (> 0.04 seconds) and deep (> 0.4mV (4
mm with 10mm/mV setting) or > 25% of the height of the corresponding R
wave, provided the R wave was > 0.5mV (5 mm with 10mm/mV setting),
appearing in at least two contiguous leads) or other historical or
electrocardiographic evidence of prior myocardial infarction.

Evidence of 2 or more supra-ventricular or ventricular ectopic beats, ie. ANY


couplets, bigeminy, trigeminy or multifocal premature ventricular complexes.
This should be confirmed by 3 readings at least 5 minutes apart.

Non-specific intraventricular conduction delay


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ST-T wave abnormalities (excluding non-specific ST-T wave abnormalities)

Right or left complete bundle branch block, or a QRS interval >120msec.

Incomplete right bundle branch block (QRS interval > 110msec < 120msec with
right bundle branch block pattern). This should be confirmed by three readings
at least 5 minutes apart.

Section 5.6.1. Permitted Medications and Non-Drug Therapies


Original text
Intranasal corticosteroids, intranasal sodium cromoglicate, short acting anti-histamines
and topical corticosteroids are permitted if started prior to Visit 1 and kept at a stable
dose throughout the study. Immunotherapy for treatment of allergies is permitted if
started prior to Visit 1 and remains at a stable dose throughout the study. Hormonal
replacement therapy for the treatment of menopausal symptoms will be permitted if
started prior to Visit 1 and remains at a stable dose throughout the study.
Revised text
Intranasal corticosteroids, intranasal sodium cromoglicate, short acting anti-histamines
and topical corticosteroids are permitted if started prior to Visit 1 and kept at a stable
dose throughout the study. Immunotherapy for treatment of allergies is permitted if
started prior to Visit 1 and remains at a stable dose throughout the study. Hormonal
replacement therapy for the treatment of menopausal symptoms will be permitted if
started prior to Visit 1 and remains at a stable dose throughout the study.
Short-acting and long-acting antihistamines are allowed to control symptoms of allergic
disorders, however, subjects are permitted to use either one oral or one intranasal
antihistamine during the trial. In addition, antihistamine eye drops are allowed during the
trial.

Section 6 Study assessments and Procedures, Table 1


Addition of the following footnote
12 Subjects not meeting the FEV1 and/or reversibility inclusion criteria may return to
the site once within 4 days to repeat the lung function tests. The Visit 1 screening
period ends and the 14 day Run-in period begins when subjects meet all of the
inclusion criteria

Section 6 Study Assessments and Procedures, Footnote


Addition of footnote 13
13 Required for all females

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Section 6 Study Assessments and Procedures, Text under Table 1


Original text
A time deviation window of 10minutes is permitted in the 0 and 2 hour post-dose
period. For assessments scheduled between 2 and 12 hours post-dose a time deviation
window of 15 minutes is permitted. For assessments scheduled between 16 and 24
hours a time deviation window of 30minutes is permitted.
Revised text
A time deviation window of 15minutes is permitted in the 0 and 2 hour post-dose
period. For assessments scheduled between 2 and 12 hours post-dose a time deviation
window of 20 minutes is permitted. For assessments scheduled between 16 and 24
hours a time deviation window of 30minutes is permitted.

Section 6.1. Critical Baseline Assessments


Original text
Please refer to the SPM for full details on what data should be reported in the eCRF for
screen failures.
Subjects who are screen failures are not permitted to be re-screened for the study.
Revised text
Subjects who have previously screen failed for any reason prior to Amendment 02 are
allowed to return to the site once to enter the screening process again.
For all subjects (including previous screen failures prior to Amendment 02) not meeting
the FEV1 and/or reversibility inclusion criteria during the Visit 1 screening period may
return to the site once within 4 days to repeat the lung function tests (refer to the SPM for
further details on screen failures).
Please refer to the SPM for full details on what data should be reported in the eCRF for
screen failures.
Subjects who are screen failures are not permitted to be re-screened for the study.

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Section 6.2.2.1. Clinic Measurements of FEV1


Original text
FEV1 will be measured electronically at clinic visits generated by spirometry using
spirometers provided by a vendor selected by GSK. The highest of three technically
acceptable measurements will be recorded. The FEV1 will be measured at all clinic visits
in the evening prior to study medication dose and any rescue salbutamol/albuterol use;
salbutamol/albuterol should be withheld for at least 6 hours. The FEV1 will be measured
between 5PM and 10 PM at Visit 1. Pre-dose FEV1 at Visit 2 also needs to be obtained
between 5PM and 8PM. At each subsequent visit, pre-dose FEV1 must be obtained within
1 hour of the time of the measurement of the pre-dose FEV1 at Visit 2. At Visits 3 and 4
FEV1 should be measured 23-24 hours after their last dose of study medication.
At Visit 1, to check eligibility, reversibility in FEV1 will be assessed. FEV1 will be
measured before and 30 minutes after administration of 400mcg salbutamol/albuterol via
MDI or one nebulised salbutamol/albuterol solution. Subjects who fail to demonstrate a
12% (and 200ml) increase in FEV1 will not be eligible to take part in the study
Revised text
FEV1 will be measured electronically at clinic visits generated by spirometry using
spirometers provided by a vendor selected by GSK. The highest of three technically
acceptable measurements will be recorded. The FEV1 will be measured at all clinic visits
in the evening prior to study medication dose and any rescue salbutamol/albuterol use;
salbutamol/albuterol should be withheld for at least 6 hours. The FEV1 will be measured
between 5PM and 10 PM at Visit 1 screening period. Pre-dose FEV1 at Visit 2 also needs
to be obtained between 5PM and 8PM. At each subsequent visit, pre-dose FEV1 must be
obtained within 1 hour of the time of the measurement of the pre-dose FEV1 at Visit 2.
At Visits 3 and 4 FEV1 should be measured 23-24 hours after their last dose of study
medication.
At Visit 1 screening period, to check eligibility, reversibility in FEV1 will be assessed.
FEV1 will be measured before and 30 minutes after administration of 400mcg
salbutamol/albuterol via MDI or one nebulised salbutamol/albuterol solution. Subjects
who fail to demonstrate a 12% (and 200ml) increase in FEV1 will not be eligible to
take part in the study.
Re-screening of subjects during the Visit 1 screening period: If a subject does not
meet the inclusion criteria based upon FEV1 percent predicted and/or reversibility, the
subject may return to the site once within 4 days and perform the lung function tests.
If the subject meets the lung function entry criteria on the second attempt, then other Visit
1 procedures should be performed on this date. The data from the original Visit 1 date
will be returned to GSK.

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Section 6.3.8.1. Clinical Laboratory Tests


Original text
Clinical laboratory tests (haematology, clinical chemistry and urinalysis) will be
performed as outlined in Table 1. Additional samples may be taken for safety reasons at
the discretion of the investigator. Details of parameters to be measured can be found in
the SPM.
Revised text
Clinical laboratory tests (haematology, clinical chemistry and urinalysis) will be
performed as outlined in Table 1. If the clinical laboratory tests have been taken prior to
performing the lung function testing and the subject meets the lung function entry criteria
based on the second lung function attempt the investigator must document the lab results
are clinically acceptable within the 4 day screening period. Additional samples may be
taken for safety reasons at the discretion of the investigator. Details of parameters to be
measured can be found in the SPM.

Section 6.3.8.2. ECG


Addition of the following paragraph
If the subject fails the lung function criteria at the first attempt, and only becomes eligible
for the study at the second screening visit the investigator must document the ECG results
are clinically acceptable within the 4 day screening period

Section 8.2.1 Sample Size Assumptions


Original wording
Approximately 1200 subjects will be screened to ensure randomisation of 594 subjects
(99 per group) with at least one 23-24 hour post-dose FEV1 assessment.
Revised wording
Approximately 1200 subjects will be screened to ensure randomisation of 594 subjects
(99 subjects per group) with at least one pre-dose or 23-24 hour post-dose FEV1
assessment on or after nominal Day 7.

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Section 8.2.2. Sample Size Sensitivity


Original text
Standard Deviation (ml)
400
415
430
440
450
460

Power (%) for Linear Trend


(8ml/mcg slope)
99
98
97
97
96
95

Power for Pairwise Comparisons


(%)
94
92
90
89
88
86

Power (%) for Linear Trend


(4ml/mcg slope)
99
98
97
97
96
95

Power for Pairwise Comparisons


(%)
94
92
90
89
88
86

Revised text
Standard Deviation (ml)
400
415
430
440
450
460
Protocol Amendment 3
This amendment applies to all sites
Scope
Correction of an error in the text of Randomisation Criterion No. 7
Section 4.4. Randomisation Criteria

Original Text
7. Occurrence of a culture-documented or suspected bacterial or viral infection of the
upper or lower respiratory tract, sinus or middle ear during the run-in period that led to a
change in asthma management, or in the opinion of the Investigator is expected to affect
the subjects asthma status or the subjects ability to participate in the study.
Revised text
7. No occurrence of a culture-documented or suspected bacterial or viral infection of the
upper or lower respiratory tract, sinus or middle ear during the run-in period that led to a
change in asthma management, or in the opinion of the Investigator is expected to affect
the subjects asthma status or the subjects ability to participate in the study.

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Division: World Wide Development


Retention Category: GRS019
Information Type: Reporting and Analysis Plan
Title:

Reporting and Analysis Plan for B2C109575. A randomised,


double-blind, placebo-controlled, parallel group,dose ranging
study to evaluate the efficacy and safety of GW642444M
Inhalation Powder administered once daily compared with
placebo for 28 days in adolescent and adult subjects with
persistent asthma.

Compound Number: GW642444


Effective Date:

18-Aug-2008

Description:
This is a Phase IIb multi-centre, randomised, double-blind, parallel-group, placebocontrolled study to evaluate the dose response, efficacy and safety of GW642444M
Inhalation Powder administered once daily in the evening at doses of 3mcg, 6.25mcg,
12.5mcg, 25mcg and 50mcg versus placebo in adolescent and adult subjects 12 years of
age and older with persistent asthma.
Subjects meeting the inclusion criteria at Visit 1 (screening visit, start of run-in) will
complete a 14 day pre-treatment run-in period. The run-in period is provided for
completion of baseline safety evaluations and to obtain baseline measures of asthma
status. Subjects will remain on their current inhaled corticosteroid therapy (at fixed
doses) throughout the study (screening to follow-up inclusive).
Subjects who meet the eligibility criteria for randomisation to study treatment will be
stratified in an approximately 1:1 ratio according to their baseline FEV1 as a percentage
of predicted normal. There will be one stratum for those with FEV1 percent predicted
40% - 65% and one for those with FEV1 percent predicted > 65%-90%. Once
stratified, subjects will be randomised to one of the six treatments and enter into a 28 day
double-blind treatment period. There will be a 7 day follow-up period following the end
of the treatment period. A subject will be regarded as having completed the study if they
complete all phases of the study (screening, treatment period and follow-up). Subjects
who complete the study will, therefore, participate in the study for a total of 7 weeks.
The primary efficacy measure will be the mean change from baseline at the end of the 28
day treatment period in trough (pre-bronchodilator and pre-dose) evening (PM) FEV1
derived from the mean of the 23 and 24 hour post-dose assessments. Secondary efficacy
measures include change from baseline in weighted mean for 24 hour serial FEV1 on
Days 1 and 28, mean change from baseline in daily trough PM PEF, mean change from
baseline in daily morning (AM) PEF, mean change from baseline in the percentage of

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symptom-free 24 hour periods, mean change from baseline in the percentage of rescuefree 24 hour periods, and the difference in post salbutamol/albuterol FEV1.
Safety assessments include adverse events, clinical laboratory evaluations, ECGs and
vital signs. Blood samples will be taken from all subjects for pharmacokinetic analysis
and from those who have consented for pharmacogenetic analysis.
Identifier/Version Number: YM2007/00064/01
Subject: Asthma, GW642444M, dose-ranging, efficacy, safety, pharmacokinetics,
placebo, PM Dosing
Authors Name, Title and Functional Area:
Principal Statistician, Respiratory MDC S&P
Statistician, Respiratory MDC S&P
Approved by:
Date
Senior Statistician
Respiratory MDC S&P
Date
Biostatistics and Programming Manager
Respiratory MDC S&P
Date
Director, Clinical Development
MDC Clinical Respiratory
BM BCh
Director, Clinical Development
MDC Clinical Respiratory

Date

Date
Clinical Pharmacokineticist
CPDM, UK

Copyright 2008 the GlaxoSmithKline group of companies. All rights reserved.


Unauthorised copying or use of this information is prohibited.
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Amendment 1: Summary of Changes


Assessment Windows
The wording around the inclusion of the pre-dose FEV1 measurements in the Per Protocol
analysis based on their timing was clarified.
Protocol Deviations
The reasons for protocol deviations were revised to only include protocol deviations that
relate to the primary efficacy endpoint.
Concomitant Medications
Summaries of asthma concomitant medications will be displayed without regard to ATC
classification.
Primary Efficacy Analysis
The "om" option was added to the SAS proc mixed code for the estimated treatment
differences for the primary endpoint.
Cumulative distribution plots of change from baseline in trough FEV1 were added for the
ITT and PP populations.
The repeated measures model for trough FEV1 was amended to exclude the Day 1 23 and
24 hour post-dose assessments. A figure showing treatment differences from placebo
was added for the repeated measures model.
Strata Analyses of Trough FEV1
Summaries of the as-randomised and actual strata, and summaries by actual stratum of
Day 1 pre-dose percent predicted FEV1 were added.
Baseline Value in ANCOVA Models
The words baseline FEV1 were replaced with baseline value for the ANCOVA
models for the percentage of symptom-free and rescue-free 24-hour periods, days, and
nights, for the derived vital signs endpoints, and for the derived potassium and glucose
endpoints.
FEV1 (0-4 hrs)
Summaries and analysis of weighted mean change from baseline in FEV1 (0-4 hrs) were
added.

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Summaries were added of the cumulative proportion of subjects obtaining both 200mL
and 12% increase from baseline in FEV1 (0-4hr) up to and including each time point.
Summaries of the proportion and cumulative proportion of subjects obtaining 15%
increase from baseline in FEV1 (0-4hr) were added.
Peak FEV1 and Peak to Trough FEV1 Ratio
The calculation and analysis of peak post-dose FEV1 (0-4 hrs) and peak to trough FEV1
ratio have been added.
Baseline Values for ECG and Vital Signs
When determining the baseline value for ECG and vital signs, if the value at Visit 2 predose is missing then the screening value will be used in its place.
Adverse Events
A statement has been added that there will not be a summary of adverse events by
maximum severity.
Vital Signs
Summaries of the derived vital signs endpoints were added, along with summaries of
change from pre-dose.
QTc
Summaries and analyses of post-dose serial QTc(F) and QTc(B) were added.
Scatterplots of serial QTc(F) and QTc(B) versus heart rate from the ECG were added.
Summaries of weighted mean change from pre-dose QTc(F) and QTc(B) were added.
Potassium and Glucose
Summaries were added for change from baseline and change from pre-dose in the derived
potassium and glucose endpoints.
Clinical Pharmacology Data Analyses
Rewording of text in Section 13 to further clarify intent to conduct population
pharmacokinetic, systemic PK/PD, dose-response and K/PD modelling, if appropriate.
Clarification that systemic PK/PD modelling will only be formally investigated if the
treatment differences for the pairwise comparisons for each treatment group vs placebo
for systemic PD endpoints are statistically significant. Update to tables, figures, listings
and file specifications within Attachments to reflect changes in Section 13.

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TABLE OF CONTENTS
PAGE
ABBREVIATIONS ...........................................................................................................8
1.

INTRODUCTION.................................................................................................... 10

2.

STUDY OBJECTIVE(S) AND ENDPOINT(S) ......................................................... 10


2.1.
Study Objective(s) ...................................................................................... 10
2.1.1.
Primary ........................................................................................ 10
2.1.2.
Secondary ................................................................................... 10
2.2.
Study Endpoint(s) ....................................................................................... 10
2.2.1.
Primary Efficacy Endpoint............................................................ 10
2.2.2.
Secondary Efficacy Endpoints ..................................................... 10
2.2.3.
Other Efficacy Endpoints ............................................................. 11
2.2.4.
Exploratory Efficacy Endpoints .................................................... 12
2.2.5.
Safety Endpoints.......................................................................... 12
2.3.
Statistical Hypotheses................................................................................. 13
2.4.
Pharmacokinetic (PK) and PK/Pharmacodynamic (PD) hypotheses ........... 13

3.

STUDY DESIGN .................................................................................................... 13

4.

PLANNED ANALYSES .......................................................................................... 15


4.1.
Interim Analyses ......................................................................................... 15
4.2.
Final Analysis ............................................................................................. 15

5.

SAMPLE SIZE CONSIDERATIONS ....................................................................... 15


5.1.
Sample Size Sensitivity............................................................................... 16

6.

ANALYSIS POPULATIONS ................................................................................... 16


6.1.
Total Population.......................................................................................... 16
6.2.
Intent-to-Treat (ITT) Population................................................................... 16
6.3.
Per Protocol (PP) Population ...................................................................... 16

7.

TREATMENT COMPARISONS.............................................................................. 17
7.1.
Primary Comparisons ................................................................................. 17
7.2.
Other Comparisons of Interest .................................................................... 17
7.3.
Data Display Treatment and Other Sub-group Descriptors ......................... 18

8.

GENERAL CONSIDERATIONS FOR DATA ANALYSES....................................... 18


8.1.
Multicentre Studies ..................................................................................... 19
8.2.
Other Strata and Covariates ....................................................................... 19
8.3.
Examination of Subgroups.......................................................................... 19
8.4.
Multiple Comparisons and Multiplicity ......................................................... 19
8.5.
Statistical Models........................................................................................ 20

9.

DATA HANDLING CONVENTIONS ....................................................................... 20


9.1.
Premature Withdrawal and Missing Data .................................................... 20
9.1.1.
Primary Endpoint ......................................................................... 20
9.1.2.
Secondary Efficacy Endpoints ..................................................... 21
9.1.3.
Other Secondary and Safety Endpoints ....................................... 22
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9.2.

9.3.
9.4.
9.5.

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Derived and Transformed Data................................................................... 22


9.2.1.
Definition of Baseline and Change from Baseline ........................ 22
9.2.2.
Maximum and minimum change from baseline ............................ 22
9.2.3.
Calculation of Weighted Mean Change from Baseline ................. 23
9.2.4.
Calculation of Trough FEV1 for Visits 2/2A, 3 and 4 ..................... 24
9.2.5.
Calculation of Peak FEV1 and Peak to Trough FEV1 Ratio .......... 24
Assessment Windows................................................................................. 24
Values of Clinical Concern.......................................................................... 24
Mis-Stratification ......................................................................................... 24

10. STUDY POPULATION ........................................................................................... 25


10.1. Disposition of Subjects................................................................................ 25
10.2. Protocol Deviations..................................................................................... 25
10.3. Demographic and Baseline Characteristics................................................. 26
10.3.1. Demography and Race ................................................................ 26
10.3.2. History of Asthma and Tobacco Use............................................ 27
10.3.3. Medical Conditions ...................................................................... 28
10.3.4. Concomitant Medications............................................................. 28
10.3.5. Summary of Screening Lung Function Test Results .................... 28
10.4. Treatment Compliance................................................................................ 29
11. EFFICACY ANALYSES.......................................................................................... 29
11.1. Primary Efficacy Analysis............................................................................ 29
11.2. Secondary Efficacy Analyses...................................................................... 32
11.2.1. Strata Analyses of trough FEV1.................................................... 32
11.2.2. Weighted Mean 24 hour Serial FEV1 ........................................... 32
11.2.3. Evening Trough PEF ................................................................... 33
11.2.4. Morning PEF................................................................................ 34
11.2.5. Percentage of Symptom-free and Rescue-free 24-hour
periods......................................................................................... 34
11.2.6. Response to salbutamol/albuterol................................................ 34
11.3. Other Efficacy Analyses.............................................................................. 35
11.3.1. FEV1 (0-4 hours) on Days 1 and 28 ............................................. 35
11.3.2. Percentage of Symptom-free and Rescue-free Days and
Nights .......................................................................................... 35
11.3.3. Withdrawals Due to Lack of Efficacy ............................................ 36
12. SAFETY ANALYSES ............................................................................................. 36
12.1. Extent of Exposure ..................................................................................... 36
12.2. Adverse Events........................................................................................... 36
12.3. Deaths and Serious Adverse Events........................................................... 37
12.4. Adverse Events Leading to Discontinuation of Investigational
Product and/or Withdrawal from the Study and Other Significant
Adverse Events........................................................................................... 37
12.5. Pregnancies (as applicable)........................................................................ 37
12.6. Clinical Laboratory Evaluations................................................................... 37
12.7. Other Safety Measures ............................................................................... 38
12.7.1. Vital Signs Assessments.............................................................. 38
12.7.2. ECG............................................................................................. 38
12.7.2.1. QTc ............................................................................ 39
12.7.3. Potassium and Glucose ............................................................... 40
12.7.4. Exacerbations.............................................................................. 40

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Device Malfunction ...................................................................... 40

13. CLINICAL PHARMACOLOGY DATA ANALYSES.................................................. 41


13.1. Population Pharmacokinetic Analyses ........................................................ 41
13.1.1. General considerations for data analyses .................................... 41
13.1.2. Missing sampling and treatment information ................................ 42
13.1.3. Covariates ................................................................................... 42
13.1.4. Pharmacokinetic Analyses........................................................... 42
13.2. Pharmacokinetic-Pharmacodynamic Analysis............................................. 44
13.2.1. Systemic PK-PD Assessments .................................................... 44
13.2.2. Pharmacokinetic-AE Analysis ...................................................... 44
13.2.3. Dose-response Modelling ............................................................ 45
13.2.4. Dose-Response-Time Modelling (K-PD) ...................................... 45
14. PHARMACOGENETIC DATA ANALYSES............................................................. 45
15. REFERENCES....................................................................................................... 46
16. ATTACHMENTS .................................................................................................... 47
16.1. Table of Contents for Data Display Specifications....................................... 47
16.2. Data Display Specifications ........................................................................ 58

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ABBREVIATIONS
AAUCMB
AE
ALT
AM
ANCOVA
AST
ATC
BMI
CA
CI
CPDM
CSR
DBF
DBR
df
dp
DPI
DS
ECG
eCRF
EVID
FDA
FEV1
GSK
HARP
hr
ICS
IDSL
ITT
L
LFT
LLQ
LOCF
LS
Max.
mcg
MDC
MedDRA
Min.
mL
N
n
NONMEM
NQ
OD
PD

Average Area Under the Curve Minus Baseline


Adverse Event
Alanine aminotransferase
Ante-meridian (morning)
Analysis of covariance
Asparate aminotransferase
Anatomical therapeutic chemical
Body Mass Index
California
Confidence interval
Clinical pharmacology and discovery medicine
Clinical study report
Database freeze
Database release
Degrees of Freedom
Decimal places
Dry Powder Inhaler
Document standard
Electrocardiogram
Electronic case report form
Event identification
US food and drug administration
Forced expiratory volume in 1 second
GlaxoSmithKline
Harmonisation for analysis and reporting program
Hour
Inhaled corticosteroid
International data standards library
Intent-to-treat
Litre
Liver function tests
Lower limit of quantification
Last observation carried forward
Least squares
Maximum
Microgram
Medicine development centre
Medical dictionary for regulatory activities
Minimum
Millilitre
Number of subjects in the treatment group
Number of subjects with non-missing values
A nonlinear mixed effect modeling software
Below quantification limit
Once daily
Pharmacodynamics
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PEF
PGx
PK
PM
PP
QD
RAP
QTc(B)
QTc(F)
RAP
S&P
SD
Std Err
UCSF
UK
US
WWD

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Peak Expiratory Flow


Pharmacogenetics
Pharmacokinetics
Post-meridian (evening)
Per protocol
Quaque diem (once daily)
Reporting and Analysis Plan
QTc calculated using Basset formula
QTc calculated using Frederica formula
Reporting and analysis plan
Statistics and programming
Standard deviation
Standard error
University of California, San Francisco
United Kingdom of Great Britain and Northern Ireland
United States of America
World wide development

Trademark Information
Trademarks not owned by the
GlaxoSmithKline group of companies

Trademarks of the GlaxoSmithKline


group of companies
NONE

NONMEM
SAS

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INTRODUCTION

The analyses described in this document are for inclusion in a Clinical Study Report
(CSR). This Reporting and Analysis Plan (RAP) describes all planned analyses that will
be conducted and presented for B2C109575 and is based upon Section 8 (Data Analysis
and Statistical Considerations) in the B2C109575 protocol [GlaxoSmithKline Document
Number GM2006/00690/03].
This RAP was based on Instructions INS-WWD-4000-v04 effective from 26 June 2008.

2.

STUDY OBJECTIVE(S) AND ENDPOINT(S)

2.1.

Study Objective(s)

2.1.1.

Primary

The primary objective of this 28 day study is to evaluate the dose response, efficacy and
safety of five doses of GW642444M (3mcg, 6.25 mcg, 12.5 mcg, 25mcg and 50 mcg)
administered once daily in the evening in adolescent and adult subjects 12 years of age
and older with persistent asthma to effectively select the appropriate dose of
GW642444M to be evaluated in further clinical studies.
2.1.2.

Secondary

The secondary objective of this study is to characterise the population pharmacokinetics


of GW642444 in subjects with persistent asthma.

2.2.

Study Endpoint(s)

2.2.1.

Primary Efficacy Endpoint

Mean change from baseline to the end of the 28-day treatment period (last
assessment on treatment using last observation carried forward) in trough (PM prebronchodilator and pre-dose) FEV1. The trough FEV1 will be defined as the mean of
the FEV1 values obtained 23 and 24 hours after dosing on Day 28.

2.2.2.

Secondary Efficacy Endpoints

Change from baseline in weighted mean for 24 hour serial FEV1 on Days 1 and 28
(mean post-dose FEV1 after 15, 30 and 60 minutes and 2, 3, 4, 6, 12, 16, 20, 22, 23
and 24 hours);
Note: this endpoint will be derived for all subjects but the 6 and 12 hour time points
will only be measured in a sub-group of subjects (approximately 50% of subjects);

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Mean change from baseline in trough (pre-dose and pre-bronchodilator) daily


evening (PM) peak expiratory flow (PEF) averaged over the 28-day treatment
period;

Mean change from baseline in daily morning (AM) PEF averaged over the 28-day
treatment period;

Mean change from baseline in the percentage of symptom-free 24 hour periods


during the 28-day treatment period;

Mean change from baseline in the percentage of rescue-free 24-hour periods during
the 28-day treatment period;

Difference in post salbutamol/albuterol FEV1 (FEV1 30minutes after a single dose of


400mcg salbutamol/albuterol) between 24 hours after dosing on Day 1 (Visit 2) and
on Day 28 (Visit 5);

Difference in post salbutamol/albuterol FEV1 (FEV1 30minutes after a single dose of


400mcg salbutamol/albuterol) between screening (Visit 1) and 24 hours after dosing
on Day 1 (Visit 2);

Difference in post salbutamol/albuterol FEV1 (FEV1 30minutes after a single dose of


400mcg salbutamol/albuterol) between screening (Visit 1) and 24 hours after dosing
on Day 28 (Visit 5).

2.2.3.

Other Efficacy Endpoints

Maximum increase in FEV1 (0-4hr) on Days 1 and 28 compared with baseline;

Proportion of subjects obtaining 200mL and 12% increase from baseline in


FEV1 (0-4hr) on Days 1 and 28 (note that this is a combination of two separate
endpoints from the protocol, for 200mL and for 12%);

Mean change from baseline in trough FEV1 at Visits 2/2A, 3 and 4 (i.e. after 23-24
hrs, 7 and 14 days of treatment);

Mean change from baseline in the percentage of symptom-free days during the 28day treatment period;

Mean change from baseline in the percentage of symptom-free nights during the 28day treatment period;

Mean change from baseline in the percentage of rescue-free days during the 28-day
treatment period;

Mean change from baseline in the percentage of rescue-free nights during the 28-day
treatment period;

Mean change from baseline in daily AM PEF during the first 14 days on study
treatment and over weeks 1, 2, 3, 4 and endpoint;

Mean change from baseline in daily PM PEF during the first 14 days on study
treatment and over weeks 1, 2, 3, 4 and endpoint;

Withdrawals due to lack of efficacy as defined in the B2C109575 protocol.

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2.2.4.

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Exploratory Efficacy Endpoints

The following endpoints that were not specified in the protocol have been added:

Weighted mean change from baseline (0-4 hours) for FEV1 on Days 1 and 28;

Proportion of subjects obtaining 15% increase from baseline in FEV1 (0-4hr) on


Days 1 and 28;

Mean peak FEV1 (0-4 hours) on Day 28;

Ratio of peak to trough in FEV1 on Day 28. The trough FEV1 will be defined as the
mean of the FEV1 values obtained 23 and 24 hours after dosing on Day 28, with no
imputation.

2.2.5.

Safety Endpoints

The following safety endpoints will be evaluated:

Incidence of adverse events throughout the 28-day treatment period;

Haematological and clinical chemistry parameters after 14 days and 28 days of


treatment and dipstick urinalysis parameters after 28 days of treatment;

Assessment of vital signs (pulse rate and systolic and diastolic blood pressure) on
Days 1, 7, 14 and 28.

The following endpoints will be derived:


Change from baseline in maximum value (0-4 hours) for systolic blood pressure
Change from baseline in minimum value (0-4 hours) for diastolic blood pressure
Change from baseline in maximum value (0-4 hours) for pulse rate
Weighted mean change from baseline (0-4 hours) for blood pressure and pulse rate;

Assessment of 12-lead ECG on Days 1, 7, 14 and 28 to derive the following


endpoints:
Weighted mean change from baseline (0-4 hours) in the QTc(F) (QT interval
corrected by Fridericia's method)
Weighted mean change from baseline (0-4 hours) in QTc(B) (QT interval corrected
by Bazett's method)
Maximum change from baseline (0-4 hours) for QTc(F) and QTc(B);

Fasting potassium and glucose on Days 1 and 28 and non-fasting potassium only on
Days 7 and 14 to derive the following endpoints:
Maximum decrease from baseline (0-4hr) for potassium
Weighted mean change from baseline (0-4hr) for potassium
Maximum increase from baseline (0-4hr) for glucose
Weighted mean change from baseline (0-4hr) for glucose;
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2.3.

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Statistical Hypotheses

The primary efficacy endpoint is the change from baseline in clinic visit trough FEV1 at
the end of the 28-day treatment period and will be derived from the mean of the 23 and
24 hour post-dose assessments on Day 28. The primary analysis will be a test of linear
trend in dose response to demonstrate overall efficacy of GW642444M relative to
placebo. This will be based on a two-sided hypothesis testing approach whereby the null
hypothesis is that the slope of the dose response relationship is zero. The alternative
hypothesis is that this slope is not zero.
H 0 : dose = 0
H 1 : dose 0
Provided the test of linear trend is statistically significant, two-sided hypothesis tests of
each dose versus placebo will be performed to demonstrate superiority of individual
doses over placebo and to aid selection of the optimum dose. The null hypothesis is that
the effect of each dose regimen of GW642444M and placebo on trough FEV1 is
identical. The alternative hypothesis is that the dose regimens of GW642444M and
placebo have different effects on trough FEV1.
H 0 : GW PBO = 0
H 1 : GW PBO 0
Since the pairwise comparisons with placebo will only be performed if the trend test
demonstrates overall efficacy of GW42444M, no further multiplicity adjustments are
required.

2.4.

Pharmacokinetic (PK) and PK/Pharmacodynamic (PD)


hypotheses

The purpose of PK sampling in this study is to characterise the population


pharmacokinetics of GW642444 in asthmatic subjects following once daily GW642444M
treatment for 28 days. A model based evaluation of the relationship between
GW642444M systemic exposure (Cmax) and safety endpoints will be investigated. No
hypothesis will be tested.

3.

STUDY DESIGN

This is a Phase IIb multi-centre, randomised, placebo-controlled, double-blind, parallelgroup study to evaluate the dose response, efficacy and safety of five doses (3mcg, 6.25
mcg, 12.5 mcg, 25mcg and 50 mcg) of GW642444M over a 28 day treatment period in
adolescent and adult subjects with persistent asthma. Approximately 1200 subjects will
be screened to achieve 594 evaluable subjects (with at least one pre-dose or 23-24 hour
post-dose FEV1 assessment on or after nominal Day 7) or 99 subjects per group.

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Subjects will attend the clinic on 6-8 occasions during the study according to the schedule
given in Table 1.
Table 1

Study Schedule Overview

Randomised Treatment
GW642444M 3mcg once daily
GW642444M 6.25mcg once daily

Run-in

Follow-up

GW642444M 12.5mcg once daily


GW642444M 25mcg once daily
GW642444M 50mcg once daily
Placebo

Clinic Visit:

Study Days:

-14

2/2A*
1/2

3
7

4
14

5/5A
28/29

(+7)

* Randomisation

All subjects will be dosed using the Novel Dry Powder Inhaler (DPI).
Subjects meeting all of the inclusion criteria and none of the exclusion criteria at the Visit
1 clinic visit (screening visit, start of run-in) will complete a 14(-4/+2) day pre-treatment
run-in period. The run-in period is provided for completion of baseline safety evaluations
and to obtain baseline measures of asthma status. Subjects will remain on their current
inhaled corticosteroid therapy (ICS) (at fixed doses) throughout the study (screening to
follow-up inclusive). At the end of the follow-up period, subjects will be prescribed
appropriate alternative asthma therapy, if required. Subjects who fail to meet eligibility
criteria for randomisation at visit 2 will be withdrawn from the study. Those subjects who
meet the eligibility criteria at the end of the run-in period will be stratified in an
approximately 1:1 ratio according to their baseline FEV1 as a percentage of predicted
normal. There will be one stratum for those with FEV1 percent predicted 40% - 65%
and one for those with FEV1 percent predicted > 65% - 90%. Once stratified, subjects
will be randomised to one of the six treatments and enter into a 28 day double-blind
treatment period (-4/+2days). Subjects will then attend 3 on-treatment visits at Visits 3, 4
and 5 (days 7, 14 and 28, respectively). The first dose of study medication will be given
in the clinic at the Visit 2 clinic visit.
There will be a 7 day follow-up period following the end of the treatment period. A
subject will be regarded as having completed the study if they complete all phases of the

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study (screening, treatment period and follow-up). Subjects who complete the study will,
therefore, participate in the study for a total of 7 weeks.
Further details of the study design can be found in Section 3 (Investigational Plan) of the
B2C109575 protocol.
The randomisation has been performed in RandAll using an appropriate block size.

4.

PLANNED ANALYSES

4.1.

Interim Analyses

No interim analysis is planned for this study.

4.2.

Final Analysis

All planned analyses (including Clinical, Pharmacokinetic, Pharmacodynamic and


Pharmacogenetic analyses) will be carried out once the clinical study database freeze
(DBF) has taken place. Once this has been achieved unblinding will occur and analyses
be performed.
A data look will be performed when sufficient data are available, but early enough to
leave time for changes prior to database release (DBR).

5.

SAMPLE SIZE CONSIDERATIONS

Approximately 1200 subjects will be screened to achieve 594 evaluable subjects (with at
least one pre-dose or 23-24 hour post-dose FEV1 assessment on or after nominal Day 7)
or 99 subjects per group.
This sample size is based on the primary endpoint of change from baseline in trough
FEV1 and has 97% power to detect a slope of 4ml/mcg (a dose response effect of 200ml
improvement in FEV1 per 50mcg of GW642444M). This assumes a standard deviation of
430ml (based on previous studies) and significance declared at the two-sided 5% level.
Similarly, there is >99 % power to detect slopes of 8ml/mcg (200ml improvement per
25mcg dose), 16 ml/mcg (200 ml improvement per 12.5 mcg dose) and 32 ml/mcg (200
ml improvement per 6.25mcg dose). The 3mcg dose is assumed to be a non-effective
dose and the study has approximately 96% power to detect a 200ml effect between this
dose and the 50mcg dose, excluding placebo from the dose response analysis.
Additionally, the study has 90% power to detect a difference of 200ml in pairwise
comparisons of change from baseline in trough FEV1 between any active dose and
placebo.
Any subject whose FEV1 measurement at Day 28 is missing will be included in the
analysis of the primary endpoint by imputation using the preceding non-missing FEV1
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value (Last Observation Carried Forward [LOCF]). Similarly, subjects whose FEV1
measurement is missing at Day 28 will be included in a sensitivity analysis of the primary
endpoint by using information obtained from FEV1 measurements at earlier time points in
a Repeated Measures analysis.
No sample size review is planned or will be conducted for this study.

5.1.

Sample Size Sensitivity

The assumption of a standard deviation of 430ml in trough FEV1 is based on data from
previous studies. The mean of the 23 and 24 hour post-dose assessments will be used to
derive the primary endpoint which is likely to reduce variability further. However, if the
actual standard deviation in this study differs from 430ml, then Table 2 demonstrates the
power for both the dose response test and the pairwise comparisons with the proposed
sample size of 99 subjects per group.
Table 2

Power for the Pairwise Comparisons

Standard Deviation
(ml)
400
415
430
440
450
460

Power (%) for Linear Trend


(4ml/mcg slope)
99
98
97
97
96
95

6.

ANALYSIS POPULATIONS

6.1.

Total Population

Power for Pairwise


Comparisons (%)
94
92
90
89
88
86

This population will comprise all subjects screened and for whom a record exists on the
study database and will be used for the tabulation of reasons for withdrawal before
randomisation.

6.2.

Intent-to-Treat (ITT) Population

The ITT Population will comprise all subjects randomised to treatment and who have
received at least one dose of trial medication. Randomised subjects will be assumed to
have received trial medication unless definitive evidence to the contrary exists. This will
constitute the primary population for all analyses of efficacy and safety measures.

6.3.

Per Protocol (PP) Population

The PP Population will consist of all subjects in the ITT Population who do not have any
full protocol deviations. Protocol deviations can be either full or partial. Subjects with
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only partial deviations will be considered part of the PP Population but from the date of
their deviation onwards, their data will be excluded.
The decision to exclude a subject or part of their data from the PP Population will be
made prior to breaking the blind. Protocol deviations that will lead to full or partial
exclusion from the PP population are detailed in Section 10.2 (Protocol Deviations). This
population will be used for confirmatory analyses of the primary efficacy endpoint only.

7.

TREATMENT COMPARISONS

7.1.

Primary Comparisons

The primary treatment comparison is a test for linear dose response in trough (prebronchodilator and pre-dose) PM FEV1 derived from the mean of the 23 and 24 hour
post-dose assessments at Day 28 across the five doses of GW642444M and placebo in
order to demonstrate overall efficacy of GW642444M. If this test is statistically
significant, each dose of GW642444M will be compared with placebo to identify
effective doses. These comparisons will be performed by the use of hypothesis tests as
described in Section 2.3. These comparisons are to be performed using the ITT
Population using Analysis of Covariance (ANCOVA) with LOCF to impute missing data.
A supporting analysis will also be performed using a Repeated Measures Mixed Model.
Missing data are not implicitly imputed in this analysis. However, all non-missing data
for a subject will be used within the analysis to estimate the Day 28 treatment effects.
A 2-sided 5% risk associated with incorrectly rejecting the null hypothesis (significance
level) is considered acceptable for this study. Since the pairwise comparisons with
placebo will only be performed if GW642444M is first shown to be efficacious relative to
placebo by means of the primary dose-response test, no further multiplicity adjustments
will be applied.

7.2.

Other Comparisons of Interest

The primary comparisons will be supported by the same tests performed using the PP
Population (i.e. pairwise comparisons will be performed using the PP population only if
they are performed for the ITT population). They will also be supported by the same tests
performed using a Repeated Measures Mixed Model on the ITT population. Missing data
are not implicitly imputed in this analysis; however, all non-missing data for a subject
will be used within the analysis to estimate the day 28 treatment effects.
The dose response across the five active doses of GW642444M will be explored on the
ITT population excluding placebo from the analysis.
Pairwise comparisons will be performed for the other key efficacy endpoints on the ITT
population.

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7.3.

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Data Display Treatment and Other Sub-group Descriptors

In the data displays the randomised treatments will be identified and ordered as shown in
Table 3:
Table 3

Treatment Group Identifiers

Treatment Group

Descriptor

Placebo once daily in the evening


GW642444M 3mcg once daily in the evening
GW642444M 6.25mcg once daily in the evening
GW642444M 12.5mcg once daily in the evening
GW642444M 25mcg once daily in the evening
GW642444M 50mcg once daily in the evening

8.

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg

GENERAL CONSIDERATIONS FOR DATA ANALYSES

All programming will be performed in a HARP environment using SAS Version 8.2 or a
later release.
At a minimum, the following basic descriptive statistics will be used in the summary
tables for continuous variables:
Table 4

Specification of Number of Decimal Places for Descriptive Statistics

Label

Description

No. of decimal places (dp)


more than raw data

N
n
Mean
SD
Median
Min.
Max.

(number of subjects in the treatment group)


(number of subjects with non-missing values)
Arithmetic Mean
Standard Deviation
Median
Minimum
Maximum

Always present to 0 dp
Always present to 0 dp
1 dp more
2 dp more
1 dp more
Same as data
Same as data

In general, the following variables will be used in the presentation of results from
statistical analysis (unless otherwise stated):

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Table 5

Specification of Number of Decimal Places for Statistical Analysis

Label

Description

No. of decimal places


(dp) more than raw
data

Estimate of
Slope
LS Mean
LS Mean
Change
Std Err
Difference
95% CI
p-value

Estimate of slope from the linear trend test of dose


response
Adjusted mean for the treatment group
Adjusted mean change from baseline for the treatment
group
Standard error
Treatment difference from placebo
95% Confidence interval around treatment difference
p-value

Always report in mL/mcg


to 3 dp more
1 dp more
1 dp more

8.1.

2 dp more
1 dp more
1 dp more
Always present to 3 dp
(or <0.001 or >0.999)

Multicentre Studies

It is anticipated that approximately 100 centres (worldwide) will participate in the study.
Therefore, it is likely that many centres will enroll very small numbers of subjects.
Consequently, all centres within the same country will be pooled. If any country has less
than 12 subjects in total then it will be pooled with another country within a similar
geographical region and these amalgamations will be used whenever country is included
in the analysis. All amalgamations will be finalised and documented prior to unblinding
the treatment codes. All summaries and analyses will be of all countries combined
(analysis models will include country as a covariate).

8.2.

Other Strata and Covariates

Unless otherwise stated in Section 11 or Section 12, all models used for the efficacy and
safety analyses will be adjusted for baseline value, country, sex, age, baseline percent
predicted FEV1 stratum and treatment group. Any stratum by treatment interaction will
be explored as part of the model checking process.
Baseline values are defined in Section 9.2.1.

8.3.

Examination of Subgroups

There will be no examination of subgroups.

8.4.

Multiple Comparisons and Multiplicity

There is a single primary endpoint in this study which is the mean change from baseline
at the end of the 28-day treatment period in trough (PM pre-bronchodilator and pre-dose)
FEV1 derived from the mean of the 23 and 24 hour post-dose assessments.

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Since the pairwise comparisons with placebo will only be performed if GW642444M is
first shown to be efficacious relative to placebo by means of the primary dose-response
test, no further multiplicity adjustments will be applied.

8.5.

Statistical Models

Appropriate graphs will be reviewed as part of the model checking process to ensure that
distributional assumptions hold. Interactions with treatment will be explored for all
covariates and tests for interactions will be at the 10% significance level. Any significant
interactions that are found will be thoroughly investigated and where necessary, extra
outputs will be produced.

9.

DATA HANDLING CONVENTIONS

9.1.

Premature Withdrawal and Missing Data

Where possible, data from subjects who withdraw prematurely from the study will be
included in any analyses. In general, the minimum data required will be a baseline
evaluation and at least one post-baseline evaluation.
9.1.1.

Primary Endpoint

Missing trough FEV1 data at Day 28 will be imputed for the primary analysis using last
observation carried forward (LOCF). This means that where the endpoint is missing the
last valid non-missing post-baseline trough assessment will be used instead. Only
measurements from scheduled visits will be used. The exposure treatment start and stop
dates will be used to determine whether a measurement was on-treatment and where
these are missing, all measurements will be assumed to be on-treatment.
For the primary endpoint, trough FEV1 will be derived using the mean of the 23 and 24
hour post-dose FEV1 assessments. If either the 23 or 24 hour post-dose FEV1
assessments on Day 28 is missing, the non-missing of the two values will be used as the
primary endpoint. If both the 23 and 24 hour assessments are missing on Day 28, the
pre-dose Day 28 assessment will be used as the endpoint value. If the Day 28 pre-dose
assessment is also missing then the Day 14 pre-dose assessment will be used as the
endpoint value. If the Day 14 pre-dose assessment is also missing then the Day 7 predose assessment will be used as the endpoint value. If the Day 7 pre-dose assessment is
missing then the endpoint will be set to missing.
The primary endpoint will also be analysed using Repeated Measures whereby missing
data are not directly imputed but the correlation between visits for all subjects is used to
adjust the estimate of treatment effect. All of the available FEV1 measurements from the
scheduled visits will be used in this analysis.
For the Per Protocol analysis, the time of the FEV1 measurements must be within 30
minutes of the planned time relative to dosing for 23-24 hour assessments, or within 1
hour of the time of the corresponding baseline measurement for pre-dose assessments.
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Any FEV1 measurements outside of this time window will be considered missing (note
that the measurements will be considered missing for the sake of the Per Protocol
analysis, but the subject will not be considered a protocol deviator). Similarly any FEV1
measurements that are taken within 6 hours after the use of rescue medication will be
considered missing (note: this only applies to 23-24 hour or pre-dose assessments that
would otherwise be eligible to be included in the analysis of the primary endpoint).
Subjects with only partial protocol deviations will have any data prior to their date of
deviation included in the primary analysis.
9.1.2.

Secondary Efficacy Endpoints

Secondary efficacy endpoints relating to daily diary assessments will be calculated from
all available data over the period of interest - no imputations will be performed on
missing daily diary data. Weekly means and other time periods will be considered
missing if less than 2 days (i.e., 24-hr periods) are recorded.
For analyses of symptoms and rescue use over 24-hour periods, each 24-hour period
incorporates a morning and evening assessment from the same day. A 24-hour period will
be considered symptom-free only if the subjects responses to both morning and evening
assessments indicate no symptoms. Similarly, for rescue use a 24-hour period will be
considered rescue use-free only if the subjects responses to both morning and evening
assessments indicate no use of rescue medication. Data for a 24-hour period will be
considered as missing if both daytime and night time responses are missing. Data will
also be considered missing if one of the daytime or night time responses is missing and
the other response is zero. Table 6 and Table 7 provide examples of how missing data
will be handled.
Table 6

Examples of Assignment of 24-Hour Period Symptom Values

Example

Symptom Scores

1
2
3
4
5

Symptom 24-hr Period

AM

PM

1
0
2
Missing
Missing

0
0
Missing
0
Missing

21

Not Symptom Free


Symptom Free
Not Symptom Free
Missing
Missing

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Table 7

Examples of Assignment of 24-Hour Period Rescue Medication Use


Values

Example

Number of Inhalations of Rescue Medication

1
2
3
4
5
9.1.3.

AM

PM

3
0
5
Missing
Missing

0
0
Missing
0
Missing

Rescue 24-hr Period

Not Rescue Free


Rescue Free
Not Rescue Free
Missing
Missing

Other Secondary and Safety Endpoints

Any missing data in the analyses of the remaining secondary and safety endpoints will
remain missing in the analyses.

9.2.

Derived and Transformed Data

9.2.1.

Definition of Baseline and Change from Baseline

The baseline values for each clinic assessment endpoint will be the Visit 2 pre-dose
assessment. An exception will be the baseline value for the FEV1 response to
salbutamol/albuterol, which will be the Screening pre-salbutamol assessment. The
baseline value for vital signs, ECG, and potassium and glucose analyses will be the Visit
2 pre-dose assessment. For vital signs and ECG, if the Visit 2 pre-dose assessment is
missing then the screening value will be used in its place. For laboratory assessments the
screening measurements will be used as baseline. The baseline values for the symptom,
rescue-use and PEF related endpoints will be derived from the last 7 days of the Daily
Diary prior to the randomisation of the subject.
Change from baseline will be defined as the difference between the value of the endpoint
at the time point of interest and the baseline value as defined above.
9.2.2.

Maximum and minimum change from baseline

For FEV1 (0-4hr) on Days 1 and 28, systolic blood pressure, pulse rate, QTc(B), QTc(F)
and glucose, the maximum change from baseline is defined by ordering all the change
from baseline values and selecting the positive value with the greatest magnitude. If there
are no positive values the negative value with the smallest magnitude will be selected.
For diastolic blood pressure and potassium the minimum change from baseline is defined
by ordering all the change baseline values and selecting the lowest negative value. If
there are no negative values the positive value with the smallest magnitude will be
selected.

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9.2.3.

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Calculation of Weighted Mean Change from Baseline

For endpoints analysed as weighted mean change from baseline, this will be calculated
using the average area under the curve minus baseline (AAUCMB), calculated using the
trapezoidal rule, and dividing by the relevant time interval.
Actual times will be used for the calculation. Pre-dose will be counted as the 0 hr
(baseline) observation in the calculation of the AAUCMB. Allowable time windows for
the calculation of AUC are as follows:

For 0-4 hour endpoints, measurements up to 5 hours (actual time) will be included

For 0-24 hour endpoints, measurements up to 25 hours (actual time) will be included.

The AAUCMB will only be calculated if at there are at least the following non-missing
values in the time period of interest:

For 0-4 hour endpoints, 0 hour (baseline) and a measurement between 3 hours and 5
hours (actual time), and,

For 0-24 hour endpoints, 0 hour (baseline) and at least one post-dose measurement
between 0 and 5 hours (actual time), and at least one measurement between 15 and
21 hours (actual time), and at least one measurement between 22.5 and 25 hours
(actual time).

If these values are missing then the AAUCMB will not be calculated, and the endpoint
treated as missing.
The AAUCMB will be calculated from first non-missing time point to the last nonmissing time point. If one or more observations are missing between two non-missing
observations, the value(s) will be linearly interpolated between the two non-missing
values.
The AAUCMB( t0 tL hrs) will be calculated as follows:
1
AAUCMB( t0 tL hrs) =

2
i=0

(C i + C i +1 )(t i +1 t i )
t L t0

CB

Where,
i = collected measurement
L = last collected measurement
Ci = result of collected measurement i
CB = Baseline
ti = actual time of assessment for collected measurement i
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9.2.4.

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Calculation of Trough FEV1 for Visits 2/2A, 3 and 4

Trough FEV1 at Visit 2/2A will be derived using the mean of the 23 and 24 hour postdose FEV1 assessments on Day 1. If either the 23 or 24 hour post-dose FEV1
assessments on Day 1 is missing, the non-missing of the two values will be used. Trough
FEV1 at Visit 3 will be the pre-dose assessment on Day 7 and the trough FEV1 at Visit 4
will be the pre-dose assessment on Day 14. Missing values will not be imputed.
9.2.5.

Calculation of Peak FEV1 and Peak to Trough FEV1 Ratio

Peak post-dose FEV1 (0-4 hrs) on Day 28 is taken as the maximum post-dose FEV1
recorded over the nominal time points of 15 and 30 minutes, 1, 2, 3, and 4 hours. It will
only be calculated if there is at least one non-missing FEV1 value recorded within the
first hour of dosing. If this is not the case it will be considered missing.
Peak to trough FEV1 ratio on Day 28 is defined as the peak post-dose FEV1 (0-4 hrs) as
defined above, divided by the trough FEV1, for Day 28. The trough FEV1 as used in the
ratio is defined as the mean of the FEV1 values obtained 23 and 24 hours after dosing on
Day 28, with no imputation.

9.3.

Assessment Windows

As explained in Section 9.1.1, only FEV1 measurements that are within 30 minutes of
the time of the planned time relative to dosing for 23-24 hour assessments, or within 1
hour of the time of the corresponding baseline measurement for pre-dose assessments
will be included in the Per Protocol analysis of the primary endpoint. Any FEV1
measurements outside of this time window will be considered missing from the Per
Protocol analysis (note that the measurements will be considered missing for the sake of
the Per Protocol analysis, but the subject will not be considered a protocol deviator).

9.4.

Values of Clinical Concern

Haematological and clinical chemistry data from subjects who have values outside the
normal range will be listed. Plots of liver function test results will be produced and
annotated with the clinical concern levels which are 2 times the upper limit of normal for
ALT, AST and Alkaline Phosphatase and 1.5 times the upper limit of normal for Total
Bilirubin. Plots of minimum potassium and maximum glucose will be produced and
annotated with the clinical concern levels which are 0.9 times the lower limit of normal
for potassium and 1.5 times the upper limit of normal for glucose.

9.5.

Mis-Stratification

If a subject is placed into an incorrect stratification group, according to their baseline


FEV1 as a percentage of predicted (FEV1 40% - 65% predicted and FEV1 > 65% 90% predicted), the site is to leave the stratification as it is. However, the stratification
will be corrected in the analysis.

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10.

STUDY POPULATION

10.1.

Disposition of Subjects

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The number of subjects in each analysis population will be presented (Table 6.1) and the
total number of subjects attending each clinic visit will also be summarised by treatment
group (Table 6.4).
A summary of the number and percentage of subjects who completed the study as well as
subjects who withdrew prematurely from the study will be presented for each treatment
group along with the primary reason for withdrawal and any sub reasons both prior to and
post randomisation (Table 6.2 and Table 6.3). Reasons for premature withdrawal will be
presented in the order they are displayed in the eCRF. A Kaplan-Meier plot showing the
percentage of subjects remaining in the study over time will be produced (Figure 6.1) as
well as a plot showing subject withdrawals due to lack of efficacy over time (Figure 6.2).
A listing of the subject disposition/end of study record for all subjects who discontinued
the study prematurely will be produced (Listing 6.1).
A summary of the number of subjects by centre (Table 6.5) and a listing of the
randomisation data (Listing 6.6) will also be produced.

10.2.

Protocol Deviations

The number and percentage of subjects who were randomised or entered into the trial, but
deviated from the inclusion or exclusion criteria, will be summarised (Table 6.6). A
listing of the inclusion/exclusion criteria deviation record for all subjects with deviations
will be produced (Listing 6.2).
A summary showing the number of subjects within each treatment group with full and
partial protocol deviations will be presented (Table 6.7). A by-subject listing of reasons
for exclusion from the Per Protocol population will also be produced (Listing 6.7).
Reasons for protocol deviations include the following:
1.

Failure of any inclusion, exclusion or randomisation criteria as described in Section 4


of the protocol.

2.

Taking of prohibited medication as described in Section 5.6.2 of the protocol.

3.

Remaining in the study after being ineligible for the study based on the lack of
efficacy withdrawal criteria as described in Section 4.5 of the protocol.

4.

Treatment Compliance of < 80%. (The protocol required subjects to take their study
medication every evening each day. For reporting and analysis purposes, treatment
compliance of 80% is defined here as a lower limit for subjects to remain in the Per
Protocol population.)

5.

Taking the wrong study treatment at any time during the study.

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Apart from any treatment deviations, all full and partial protocol deviations will be
agreed upon prior to unblinding the study.
In addition only FEV1 measurements that are within 30 minutes of the planned time
relative to dosing for 23-24 hour assessments, or within 1 hour of the time of the
corresponding baseline measurement for pre-dose assessments will be included in the Per
Protocol analysis of the primary endpoint. Any FEV1 measurements outside of this time
window will be considered missing (note that the measurements will be considered
missing for the sake of the Per Protocol analysis, but the subject will not be considered a
protocol deviator). Similarly any FEV1 measurements that are taken within 6 hours after
the use of rescue medication will be considered missing for the Per Protocol analysis
(note: this only applies to 23-24 hour or pre-dose assessments that would otherwise be
eligible to be included in the analysis of the primary endpoint).
A listing of subjects for whom the treatment blind was broken during the study will be
produced (Listing 6.3). A listing giving details of any treatment misallocations will also
be produced (Listing 6.8).

10.3.

Demographic and Baseline Characteristics

10.3.1.

Demography and Race

Demographic characteristics (age, ethnicity, sex, height and weight) will be summarised
for the Intent-to-Treat population (Table 6.8) and the Per Protocol population (Table 6.9).
Demographic characteristics will also be listed (Listing 6.4). Age will be calculated from
the date of birth and the date of screening (Visit 1).
The five high level FDA race categories and designated Asian subcategories will be
summarised (Table 6.10) along with all combinations of high level categories which exist
in the data. All five of the high level race categories and the two Asian subcategories
must appear on the display even if there are no subjects in a particular category, but
combinations that do not exist in the data do not need to be represented.
The high level FDA race categories and designated Asian subcategories are:
1. African American/African Heritage
2. American Indian or Alaska Native
3. Asian
a. Central/South Asian Heritage
b. Japanese/East Asian Heritage/South East Asian Heritage
c. Mixed Asian Heritage (only required if data exists)
4. Native Hawaiian or other Pacific Islander
5. White

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Combinations will be represented as the concatenation of the high level category terms,
e.g., White & Asian. The designated Asian subcategories will not be summarised as
combinations with other categories.
A subject will only be represented in a single category. A subject who selects a
combination of races will be counted in the combination of terms, not in each of the
constituent terms. Therefore the counts will add up to the total number of subjects with a
response, and the percentages will add to 100%.
The twelve standard race categories collected on the IDSL eCRF page will be
summarised (Table 6.11) along with categories for mixed race.
The twelve standard race categories and mixed race categories are:
1.

African American/African Heritage

2.

American Indian or Alaska Native

3.

Asian - Central/South Asian Heritage

4.

Asian East Asian Heritage

5.

Asian Japanese Heritage

6.

Asian South East Asian Heritage

7.

Asian Mixed Race

8.

Native Hawaiian or other Pacific Islander

9.

White Arabic/North African Heritage

10. White White/Caucasian/European Heritage


11. White Mixed Race
12. Mixed Race
Asian Mixed Race is only used if more than one Asian category is selected, but no
non-Asian races. Similarly, White Mixed Race is only used if both of the White
categories are selected, and no non-White races. If multiple races of different types are
selected, then the overall Mixed Race category is used.
A subject will only be represented in a single category. A subject who selects a
combination of races will be counted as Asian Mixed Race, White Mixed Race,
or Mixed Race, but not in each of the constituent terms. Therefore the counts will add
up to the total number of subjects with a response, and the percentages will add to 100%.
A by-subject listing of race will be produced (Listing 6.5)
10.3.2.

History of Asthma and Tobacco Use

History of tobacco use is captured at screening and will be summarised (Table 6.12) and
listed (Listing 6.9).

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History of asthma including duration of asthma and history of atopy will also be
summarised (Table 6.13) and listed (Listing 6.10).
10.3.3.

Medical Conditions

A summary of the number and percentage of subjects who report current medical
conditions will be produced (Table 6.14). A by-subject listing will also be produced
(Listing 6.11).
10.3.4.

Concomitant Medications

Concomitant medications will be coded using the GSK Drug coding dictionary, an
internal validated medication dictionary. A summary of the number and percentage of
subjects with concomitant medications will be displayed using a method which presents
multi-ingredient medications according to their combination ATC classification rather
than the classifications of the ingredients. This display will also include single-ingredient
medications. Summaries will be split into asthma and non-asthma concomitant
medications, as well as into those taken pre-, during, and post-treatment (Table 6.15 to
Table 6.20). Asthma concomitant medications will be displayed without regard to ATC
classification.
A medication will be summarised in every period (pre/during/post) in which it was taken,
so a medication that was started in the run-in and stopped during active treatment will
appear in both the pre-treatment and the during treatment tables.
During treatment will be considered to be from the day after the treatment start date until
the treatment stop date.
The methods for dealing with partial drug start and stop dates will be the same for all
medications and will be to include each drug in every period in which it could
conceivably have been taken. For example, if we only have month and year for the drug
start date and it is the same as the month and year of the treatment start date, then the
drug will be considered to have started pre-treatment. Similarly if we only have the year
that the drug was stopped and it is the same as the year that the treatment was stopped
then the drug will be considered to have stopped post-treatment.
A listing of the relationship between ATC level 1, ingredient and verbatim term will be
produced (Listing 6.13) along with a listing of all concomitant medications recorded
(Listing 6.12).
10.3.5.

Summary of Screening Lung Function Test Results

The following lung function test results taken at visit 1 (screening) will be summarised
(Table 6.21):

Pre-bronchodilator FEV1 (L)

Percent predicted FEV1 (%)


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Post-bronchodilator FEV1 (L)

Percent Reversibility FEV1 (%)

Absolute reversibility in FEV1 (mL)

10.4.

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Treatment Compliance

Percentage treatment compliance will be calculated for each subject based on the total
number of inhalations taken from the Novel Dry Powder Inhaler and the expected
number of inhalations to be taken. The expected number of inhalations will be derived as
the expected number of inhalations per day multiplied by the number of days on study
drug based on the subjects treatment start and stop date for the device.
Thus, treatment compliance will be derived as:

Total _ Number _ of _ Inhalations _ Taken


100
Compliance =
Expected
_
Inhalation
s

(
Stop
_
Date

Start
_
Date
+
1

Where Expected _ Inhalations is equal to 1 and Start _ Date and Stop _ Date are the
dates of the first and last doses of study drug, respectively.
The total number of inhalations taken will be based on the dose counter. If there is no
dose counter information at all then the compliance will be missing.
Percentage treatment compliance will be summarised (Table 6.22).

11.

EFFICACY ANALYSES

11.1.

Primary Efficacy Analysis

The primary endpoint of mean change from baseline at Day 28 in trough (PM prebronchodilator and pre-dose) FEV1 will be derived from the mean of the 23 and 24 hour
post-dose assessments and missing data will be imputed using LOCF as described in
Section 9.1.1 and summarised (Table 7.1). The primary analysis will be performed using
an ANCOVA model on the Day 28 data with effects due to baseline FEV1, centre
grouping (country), age, sex, baseline percent predicted FEV1 stratum and dose/treatment
group.
A linear trend contrast will be constructed using the Day 28 data to evaluate the dose
response trend using a SAS procedure with the following syntax:
proc mixed data=start ;
class sex country stratum;
model FEV1 = dose sex country age baseline stratum / ddfm=kr s cl ;
ods output SolutionF=sol ;
run ;
quit ;
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where dose is the dose in mcg for the GW642444M groups and 0 for the Placebo group.
The estimate of slope for the dose term, 95% confidence interval and p-value will be
presented (Table 7.2). This will also be repeated excluding the Placebo group to
investigate the dose response across the five active doses of GW642444M (Table 7.3).
If the primary dose response test is significant (p-value0.05) then estimated treatment
differences for all pairwise comparisons will be presented together with 95% confidence
intervals for the difference and p-values for Day 28 (Table 7.4). This will be
accomplished by using a SAS procedure with the following syntax:
proc mixed data=start ;
class trtcd sex country stratum;
model FEV1 = trtcd sex country age baseline stratum / ddfm=kr ;
lsmeans trtcd / cl diff om;
ods output lsmeans=lsmeans ;
ods output diffs=diffs ;
run ;
quit ;
If the primary dose response test is significant then the following two figures will be
produced. The pairwise treatment differences will be plotted along with the
corresponding 95% confidence intervals (Figure 7.1). The adjusted means for all
treatments will be plotted and a linear regression line overlaid (Figure 7.2). The
regression line is for illustrative purposes only and will be based on the adjusted means of
the Placebo and GW642444M treatment groups. Thus if the number of subjects differ
between the treatment groups the slope may differ slightly from that derived in the
primary dose response test.
A box plot and plot of the cumulative distribution of the change from baseline in trough
FEV1 derived using LOCF will be produced regardless of whether the primary dose
response test is significant (Figure 7.3 and Figure 7.4).
The summary statistics, linear trend test with Placebo, pairwise comparisons and figures
for trough FEV1 derived using LOCF will be repeated on the Per Protocol population
(Table 7.5, Table 7.6, Table 7.7, Figure 7.5, Figure 7.6, Figure 7.7, and Figure 7.8). Note
the analysis without placebo will not be repeated.
The dose response test with placebo for Day 28 will also be performed in a sensitivity
analysis using a repeated measures model which will include data from Day 7 (pre-dose
assessment), Day 14 (pre-dose assessment), and Day 28 (pre-dose assessment, 23 and 24
hour post-dose assessment). The dose response model will allow for effects due to
baseline trough FEV1, centre grouping (country), age, sex, baseline percent predicted
FEV1 stratum and dose (Table 7.8). This model will also contain a visit-by-dose
interaction term. Note the dose-response analysis without placebo will not be repeated.
The pairwise comparisons analysis for Day 28 will be modelled as described for the dose
response test and will allow for effects due to baseline trough FEV1, centre grouping
(country), age, sex, baseline percent predicted FEV1 stratum and treatment group (Table
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7.9). This model will also contain a visit-by-treatment interaction term. This model will
include the following data points: pre-dose Day 7 ("visit 3"), pre-dose Day 14 ("visit 4"),
pre-dose Day 28 ("visit 5"), and trough Day 28 (mean of the 23 and 24 hour post-dose
assessments) ("visit 5A"). The pairwise comparisons at each of these days will all be
displayed and the adjusted means and 95% confidence intervals for these days will be
plotted (Figure 7.9). Treatment differences from placebo will also be plotted (Figure
7.10). The dose response test and pairwise comparisons will use SAS procedures with
the following respective syntaxes:
proc mixed data=start ;
class sex country stratum visit subjid ;
model FEV1 = dose sex country age baseline stratum
visit visit*baseline visit*dose / ddfm=kr ;
repeated visit / subject=subjid type=un;
estimate 'Day 28' dose 1 visit*dose 0 0 0 0.5 0.5 / cl ;
ods output estimates=est ;
run ;
quit ;
Note that the intention of the estimate statement is to obtain the estimate of the mean
response of 23 and 24 hours on Day 28.
proc mixed data=start ;
class trtcd sex country stratum visit subjid ;
model FEV1 = trtcd sex country age baseline stratum
visit visit*baseline visit*trtcd / ddfm=kr ;
repeated visit / subject=subjid type=un ;
lsmeans visit*trtcd / cl diff e om=OMdset at (baseline age)=(&blm. &agem.);
ods output lsmeans=lsmeans ;
ods output diffs=diffs ;
run ;
quit ;
Where OMdset is a dataset with a row for every visit-subject combination that contains
all of the covariates and blm and agem are macro variables containing the means for
baseline and age for the subjects used in the analysis. These are used to derive the
adjusted means using coefficients which are based on the subjects used in the analysis.
The pairwise comparisons for the Per Protocol and repeated measures analysis will only
be produced if primary LOCF dose response test on the ITT population is significant, i.e.
Table 7.7, Table 7.9, Figure 7.5, Figure 7.6 and Figure 7.9 will only be produced if Table
7.4 is produced.
Raw FEV1 and change from baseline values will also be summarised for all treatments at
all visits for pre-dose and 23-24 hour post-dose time points (Table 7.10). All FEV1 data
will be listed (Listing 7.1)

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11.2.

Secondary Efficacy Analyses

11.2.1.

Strata Analyses of trough FEV1

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The change from baseline in trough (23 and 24 hour post-dose assessments) FEV1 at the
end of treatment will be analysed for each percent predicted FEV1 strata separately in
order to investigate the consistency of the dose response relationship for the different
disease severities. An ANCOVA model with effects due to baseline trough FEV1, centre
grouping, age, sex, and dose will be used to estimate the dose response slope presented
together with 95% confidence intervals for each baseline percent predicted FEV1 stratum
(Table 7.12). An ANCOVA model with effects due to baseline trough FEV1, centre
grouping, age, sex, stratum, treatment group, and treatment group by stratum interaction
will be used to estimate the treatment differences for all pairwise comparisons for each
stratum, which will be presented together with 95% confidence intervals (Table 7.13,
Figure 7.11). The adjusted means for all treatments will be plotted and a linear
regression line overlaid for each stratum (Figure 7.12). We are using the interaction
between treatment group and stratum to estimate the treatment effect for each stratum
because this study is not powered for subgroup analyses. Statistical significance testing
will not be performed for the strata analyses. Summary statistics will also be presented
for each stratum (Table 7.11). The as-randomised strata and actual strata will be
summarised (Table 6.23). Summaries of percent predicted FEV1 at Day 1 pre-dose will
be presented by actual stratum (Table 6.24).

11.2.2.

Weighted Mean 24 hour Serial FEV1

The 24-hour serial FEV1 will be measured on Days 1 and 28 at the following time points;
pre-dose, and 15, 30 and 60 minutes and 2, 3, 4, 6, 12, 16, 20, 22, 23 and 24 hours postdose. The 6 and 12 hour time points will only be measured in a subgroup of subjects. The
change from baseline in weighted mean for 24-hour serial FEV1 on Days 1 and 28 will be
compared for each GW642444M group versus placebo using an ANCOVA model with
effects due to baseline (pre-dose measurement on Day 1), centre grouping, age, sex,
baseline percent predicted FEV1 stratum and treatment group. This analysis will include
all ITT population subjects, including those with the additional time point measurements
at 6 and 12 hours after dosing. The weighted mean values will include the 6 and 12 hour
data for those subjects with these assessments. Estimated treatment differences for all
comparisons of GW642444M with placebo will be presented and plotted together with 95
% CIs for the difference and p-values (Table 7.18 and Figure 7.13). The summary
statistics will also be presented for the raw serial measurements for 0-24 hours and for the
weighted means (Table 7.14 and Table 7.17). The summary statistics will also be
presented for the absolute and percentage change from baseline in serial FEV1 for 0-4
hours (Table 7.15 and Table 7.16).
Additionally, a sensitivity analysis will be performed to assess the impact of the 6-12
hour time points. The same ANCOVA model as described above for 0-24 hr weighted
mean FEV1 will be run in three additional ways:

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All subjects. The 6-12 hr time points will be excluded

Subset of subjects who had the 6-12 hr time points measured. All time points
will be included

Subset of subjects who had the 6-12 hr time points measured. The 6-12 hr time
points will be excluded

For each of these subject groups, estimated treatment differences for all comparisons of
GW642444M with placebo will be presented and plotted together with 95 % CIs for the
difference and p-values (Table 7.19, Table 7.20, Table 7.21 and Figure 7.14).
A further sensitivity analysis will be performed to assess the impact of rescue medication
on the weighted mean 24 hour serial FEV1. The same ANCOVA model as described
above for 0-24 hr weighted mean FEV1 will be run after removing the FEV1
measurements that were taken within 6 hours after rescue medication use (Table 7.22).
Plots of mean FEV1 over time will be provided for both Day 1 and Day 28, with 95%
confidence intervals at the 0, 4, 16 and 24 hour time points (Figure 7.15). Plots of the
mean absolute and percentage change from baseline in FEV1 for 0-4 hours will be
provided for both Days 1 and 28 (Figure 7.16 and Figure 7.17).

11.2.3.

Evening Trough PEF

The change from baseline in daily trough (pre-dose and pre-rescue bronchodilator) PM
PEF averaged over the 28-day treatment period will be compared for each GW642444M
dose versus placebo using an ANCOVA model with effects due to baseline PM PEF,
centre grouping, age, sex, baseline percent predicted FEV1 stratum and treatment group.
stimated treatment differences for all comparisons will be presented together with 95%
confidence intervals for the difference and p-values (Table 7.38). Summary statistics will
also be presented (Table 7.31).
In addition summary statistics for the change from baseline in PM PEF over the first 14
days on study treatment and over Weeks 1, 2, 3, 4, endpoint and follow-up will be
presented alongside. A plot showing the mean change from baseline at each day will also
be produced (Figure 7.22).
PEF averaged over the 28 day treatment period will use all available data up to and
including Day 28. Endpoint will be defined as the last 7 days on study medication ending
with the treatment stop date. If the treatment stop date is missing then the date of the last
clinic visit will be used instead. Follow-up will be defined as the 7 days after treatment,
ending with the follow-up visit. Again, if the treatment stop date is missing then the date
of the last clinic visit will be used instead. All other time periods will be exactly as
described, irrespective of when clinic visits occurred e.g. Week 1 will include the first 7
days after randomisation regardless of when visit 3 occurred.

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11.2.4.

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Morning PEF

The change from baseline in daily AM PEF averaged over the 28-day treatment period
will be summarised and analysed as described for Evening Trough PEF (Table 7.39,
Table 7.40 and Figure 7.23).

11.2.5.

Percentage of Symptom-free and Rescue-free 24-hour periods

The change from baseline in the percentage of symptom-free 24-hour periods and rescuefree 24-hour periods over the 28-day treatment period will be calculated for each subject.
Comparisons will then be made of each GW642444M dose versus placebo using an
ANCOVA model with effects due to baseline value, centre grouping, age, sex, baseline
percent predicted FEV1 stratum and treatment group. Estimated treatment differences for
all comparisons will be presented together with 95% confidence intervals for the
difference and p-values (Table 7.42 and Table 7.44). Summary statistics will also be
presented (Table 7.41 and Table 7.43).
If the failure of distributional assumptions prevents the use of an ANCOVA model then
the data will be split into appropriate categories and a proportional odds logistic
regression analysis will be used instead. The categories will be agreed and documented
prior to unblinding.

11.2.6.

Response to salbutamol/albuterol

The post-salbutamol/albuterol FEV1 (FEV1 30 minutes after a single dose of 400mcg


albuterol/salbutamol) will be summarised at screening, Day 1 and Day 28 (Table 7.23).
The differences between screening, Day 1 and Day 28 will also be summarised (Table
7.24).
The difference in post-salbutamol/albuterol FEV1 (FEV1 30 minutes after a single dose of
400mcg albuterol/salbutamol) between 24 hours after dosing on Day 1 (Visit 2) and on
Day 28 (Visit 5) will be derived for each subject and will be compared for each
GW642444M group versus placebo using an ANCOVA model with effects due to
baseline, centre grouping, age, sex, baseline percent predicted FEV1 stratum and
treatment. Estimated treatment differences for all comparisons will be presented together
with 95% CIs for the difference and p-values (Table 7.25 and Figure 7.18).
The difference in post-salbutamol/albuterol FEV1 (FEV1 30 minutes after a single dose of
400mcg albuterol/salbutamol) between screening (Visit 1) and 24 hours after dosing on
Day 1 (Visit 2) will be derived for each subject and will be compared for each
GW642444M group versus placebo using an ANCOVA model as described above for the
change between Day 1 and Day 28. Estimated treatment differences for all comparisons
will be presented together with 95% CIs for the difference and p-values (Table 7.25 and
Figure 7.19).
The difference in post-salbutamol/albuterol FEV1 (FEV1 30 minutes after a single dose of
400mcg albuterol/salbutamol) between screening (Visit 1) and 24 hours after dosing on
Day 28 (Visit 5) will be derived for each subject and will be compared for each
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GW642444M group versus placebo using an ANCOVA model as described above for the
change between Day 1 and Day 28. Estimated treatment differences for all comparisons
will be presented together with 95% CIs for the difference and p-values (Table 7.25 and
Figure 7.20).
Baseline in this analysis is the pre-salbutamol FEV1 value taken at screening.

11.3.

Other Efficacy Analyses

11.3.1.

FEV1 (0-4 hours) on Days 1 and 28

The maximum increase and weighted mean change in FEV1 (0-4hr) on Days 1 and 28
compared with baseline will be calculated for each subject. Comparisons will then be
made of each GW642444M dose versus placebo using an ANCOVA model with effects
due to baseline FEV1, centre grouping, age, sex, baseline percent predicted FEV1 stratum
and treatment group. Estimated treatment differences for all comparisons will be
presented together with 95% confidence intervals for the difference and p-values (Table
7.27 and Table 7.28). Summary statistics will also be presented (Table 7.26 and Table
7.29).
The proportion and cumulative proportion of subjects obtaining both 200mL and
12% increase from baseline in FEV1 (0-4hr) at each planned time point on Days 1 and 28
will be summarised (Table 7.28 and Table 7.31). The proportion and cumulative
proportion of subjects obtaining 15% increase from baseline in FEV1 (0-4hr) at each
planned time point on Days 1 and 28 will be summarised (Table 7.32 and Table 7.33).
Peak post-dose FEV1 (0-4 hrs) on Day 28 will be summarised (Table 7.34) and analysed
as described above for maximum increase in FEV1 (0-4hr) (Table 7.35 and Figure 7.21).
Peak to trough FEV1 ratio on Day 28 will be summarised (Table 7.36).

11.3.2.

Percentage of Symptom-free and Rescue-free Days and Nights

The mean change from baseline in the percentage of symptom-free days, symptom-free
nights, rescue-free days and rescue-free nights over the 28 day treatment period will be
calculated for each subject. Comparisons will then be made of each GW642444M dose
versus placebo using an ANCOVA model with effects due to baseline value, centre
grouping, age, sex, baseline percent predicted FEV1 stratum and treatment group.
Estimated treatment differences for all comparisons will be presented together with 95%
confidence intervals for the difference and p-values (Table 7.46, Table 7.48, Table 7.50
and Table 7.52). Summary statistics will also be presented (Table 7.45, Table 7.47, Table
7.49 and Table 7.51). All available data up to and including the last clinic visit will be
utilised.
If the failure of distributional assumptions prevents the use of an ANCOVA model then
the data will be split into appropriate categories and a proportional odds logistic
regression analysis will be used instead. The categories will be agreed and documented
prior to unblinding.
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11.3.3.

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Withdrawals Due to Lack of Efficacy

Fishers Exact test will be used to compare the number of withdrawals due to lack of
efficacy between each GW642444M treatment group versus placebo (Table 7.53). (See
Section 10.1 for subject disposition tables, listings and figures).

12.

SAFETY ANALYSES

12.1.

Extent of Exposure

The number of days on study drug for each subject will be summarised (Table 8.1) and
will be calculated as (date of last dose date of first dose) + 1. A listing of exposure and
compliance data will also be produced (Listing 8.1).

12.2.

Adverse Events

Adverse events will be coded using the Medical Dictionary for Regulatory Activities
(MedDRA) coding dictionary, to give a preferred term and a system organ class. The
verbatim text will be presented in the listings. AEs will be classified as pre-treatment, ontreatment and post-treatment by comparing the start date of the AE to the dates of the first
and last doses of study medication using the following definitions:

Pre-treatment: AE start date first dose date -1

On-treatment: first dose date AE start date last dose date + 1

Post-treatment: AE start date last dose date + 2

Where AE onset dates are missing or partial than the AE will be considered on-treatment
unless there is evidence to the contrary (e.g. the month of the start date is present and is
less than the month of the first dose of study medication).
The number and percentage of subjects with all adverse events (regardless of causality)
will be summarised for each treatment, sorted by system organ class, preferred term and
total incidence. System organ class will not be presented when the overall incidence for
any adverse event within the particular system is 0. If the total incidence for any two or
more adverse events is equal, the events will be presented in alphabetical order. This will
be done separately for on-treatment and post-treatment AEs (Table 8.2 and Table 8.3). A
further summary of on-treatment adverse events with a total incidence of greater than or
equal to 3% will be produced (Table 8.4).
A summary of any drug related (as recorded by the Investigator) AEs (Table 8.5) and a
summary of any AEs leading to permanent discontinuation of study drug or withdrawal
from the study (Table 8.6) will also be produced.
Summaries of all serious AEs will be produced separately for pre, on and post-treatment
AEs (Table 8.7, Table 8.8 and Table 8.9).

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The association between the adverse event system organ class, preferred terms and the
verbatim text will be also be summarised (Table 8.10).
A listing will be produced of subject numbers for each adverse event (Listing 8.2).
Pre, on and post-treatment adverse events will be listed, sorted by treatment, subject,
onset date and onset time (Listing 8.3, Listing 8.4 and Listing 8.5). In addition listings
will be produced for all AEs leading to permanent discontinuation of study drug or
withdrawal from the study (Listing 8.6), for all non-fatal serious AEs (Listing 8.7) and
for all fatal AEs (Listing 8.8). A listing will also be produced of AEs for subjects not in
the ITT population (Listing 8.9). Adverse events will not be summarised by maximum
severity, which is a change from what is stated in the protocol.

12.3.

Deaths and Serious Adverse Events

Summary tables and listings will be provided for serious and fatal adverse events (See
Section 12.2). In addition, all deaths and serious AE's will be documented in a case
narrative format in the clinical study report.

12.4.

Adverse Events Leading to Discontinuation of


Investigational Product and/or Withdrawal from the Study
and Other Significant Adverse Events

Adverse events leading to discontinuation of investigational product and/or withdrawal


from the study will be listed and summarised as described in Section 12.2 (Adverse
Events).

12.5.

Pregnancies (as applicable)

Any pregnancies reported during the study will be summarised in case narratives.
Pregnancy complications and elective terminations for medical reasons must be reported
as an AE or SAE.

12.6.

Clinical Laboratory Evaluations

Summary statistics for haematological and clinical chemistry parameters will be


produced (Table 8.11 and Table 8.14). Summaries of the data outside the normal range
(Table 8.12 and Table 8.15) and the changes from baseline relative to the normal range
(shift tables) will also be produced (Table 8.13 and Table 8.16). Data from subjects who
have abnormalities outside the normal range will be listed (Listing 8.10 and Listing 8.11).
The normal ranges will also be listed.
The following plots of laboratory results will be produced:

Trellis display of maximum versus baseline LFT (Figure 8.1)

Box plot of maximum liver function tests (Figure 8.2)

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Scatter plot of minimum versus baseline potassium values (Figure 8.3)

Box plot of minimum potassium values (Figure 8.13)

Scatter plot of maximum versus baseline glucose values (Figure 8.14)

Box plot of maximum glucose values (Figure 8.15)

Urinalysis dipstick results will be summarised by treatment (Table 8.17) and listed
(Listing 8.12) at each planned time point when they are collected.

12.7.

Other Safety Measures

12.7.1.

Vital Signs Assessments

Summary statistics of systolic and diastolic blood pressure and pulse rate will be
presented for each treatment group at each time point (Table 8.18). This will be repeated
using the change from baseline values (Table 8.19). All vital signs data will be listed
(Listing 8.13).
Additionally, the following vital signs endpoints will be derived on Days 1, 7, 14 and 28:

Derived Endpoint
Change from baseline in maximum value (0-4 hours)
Change from baseline in minimum value (0-4 hours)
Weighted mean change from baseline (0-4 hours)

Measure(s)
systolic blood pressure
pulse rate
diastolic blood pressure
blood pressure
pulse rate

They will be summarised in Table 8.20, Table 8.23, Table 8.26, Table 8.29, Table 8.32,
and Table 8.35, and will be analysed using ANCOVA with effects due to baseline value,
centre grouping, age, sex, baseline percent predicted FEV1 stratum and treatment group.
Pairwise comparisons of each treatment group versus placebo will be performed and
treatment differences will be presented with 95% confidence intervals (Table 8.22, Table
8.25, Table 8.28, Table 8.31, Table 8.34, and Table 8.37). In addition, change from predose will be summarised in Table 8.21, Table 8.24, Table 8.27, Table 8.30, Table 8.33,
and Table 8.36.
A plot will be produced to compare the LOCF analysis of change from baseline in trough
FEV1 at Day 28 to the weighted mean change from baseline on pulse rate (0-4 hours) at
Day 28 (Figure 8.3). This will take the adjusted differences from placebo and 95%
confidence intervals from Table 7.4 and the adjusted differences from placebo and 95%
confidence intervals from Table 8.37.

12.7.2.

ECG

A summary of ECG parameters will be produced. Each ECG parameter at every assessed
time point will be summarised using summary statistics (Table 8.38).

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A summary of the number and percentage of subjects who had abnormal and/or clinically
significant (as determined by the central cardiologist) ECG findings will be displayed by
treatment (Table 8.39).
A listing of ECG values and findings will also be produced (Listing 8.14 and Listing
8.15).
12.7.2.1.

QTc

QTc(F) and QTc(B) will be summarised using appropriate descriptive statistics by


treatment on Days 1, 7,14 and 28 (Table 8.38).
The maximum QTc(F) and QTc(B) will be categorised and summarised at Days 1, 7, 14
and 28 (Table 8.40 and Table 8.41).
Post-dose serial QTc(F) and QTc(B) will be analysed using ANCOVA as for derived vital
signs endpoints (see Section 12.7.1). Pairwise comparisons of each active treatment
versus placebo will be performed and treatment differences will be presented with 95%
confidence intervals (Table 8.48 and Table 8.49). In addition, the adjusted treatment
differences versus placebo and the corresponding 95% confidence intervals will be
plotted (Figure 8.8 and Figure 8.9).
Scatterplots of serial QTc(F) and QTc(B) versus heart rate from the ECG will be produced
(Figure 8.10 and Figure 8.11).
The following QTc endpoints of change from baseline (pre-dose Visit 2 value) of QTc(F)
and QTc(B) will be derived on Days 1, 7, 14 and 28:

Maximum value (0-4 hours)

Weighted mean (0-4 hours)

Maximum change from baseline will be categorised and the categories summarised
(Table 8.42 and Table 8.43). Weighted mean change from baseline will be summarised
(Table 8.44 and Table 8.46). Weighted mean change from pre-dose will be summarised
(Table 8.45 and Table 8.47). The cumulative distribution of the maximum change from
baseline at 0-4 hours on each day will also be plotted (Figure 8.4 and Figure 8.5).
The change from baseline endpoints will also be analysed using ANCOVA as for derived
vital signs endpoints (see Section 12.7.1). Pairwise comparisons of each active treatment
versus placebo will be performed and treatment differences will be presented with 95%
confidence intervals (Table 8.48 to Table 8.53).
The following plots will also be produced:

Lineplot of change from baseline in QTc(F) over time (Figure 8.6)

Lineplot of change from baseline in QTc(B) over time (Figure 8.7)

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12.7.3.

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Potassium and Glucose

Summary statistics of fasting potassium and glucose will be presented and plotted for
each treatment group on Days 1 and 28 (Table 8.54, Figure 8.16, and Figure 8.17). The
changes from baseline relative to the normal range (shift tables) will also be produced for
fasting potassium and glucose (Table 8.55). Summary statistics of non-fasting potassium
only will be presented for each treatment group on Days 7 and 14 (Table 8.55). The
changes from baseline relative to the normal range (shift tables) will also be produced for
non-fasting potassium (Table 8.57).
Fasting potassium and glucose on Days 1 and 28 and non-fasting potassium only on Days
7 and 14 will be used to derive the following endpoints (where baseline will be defined as
Visit 2 pre-dose):

Derived Endpoint
Maximum decrease from baseline (0-4 hours)
Weighted Mean Change from baseline (0-4 hours)
Maximum increase from baseline (0-4 hours)

Measure(s)
Fasting Potassium
Non-fasting Potassium
Fasting Potassium
Non-fasting Potassium
Glucose
Glucose

and will be analysed using ANCOVA with effects due to baseline value, centre grouping,
age, sex, baseline percent predicted FEV1 stratum and treatment group. Pairwise
comparisons of each treatment group versus placebo will be performed and treatment
differences will be presented with 95% confidence intervals (Table 8.70 to Table 8.72).
Summary statistics of change from baseline and change from pre-dose will also be
presented (Table 8.58 to Table 8.69).
All potassium and glucose data will be listed (Listing 8.16)

12.7.4.

Exacerbations

The number and percentage of subjects who had an asthma exacerbation, who took
corticosteroids for an exacerbation, who were hospitalised due to an exacerbation and
who had an emergency room (ER) visit due to an exacerbation, will be summarised
separately alongside the primary causes of asthma exacerbations (Table 8.76). All asthma
exacerbation data will be listed (Listing 8.17).

12.7.5.

Device Malfunction

Subjects with a Novel Dry Powder Inhaler malfunction will be listed with the primary
reason for malfunction (Listing 8.18).

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13.

CLINICAL PHARMACOLOGY DATA ANALYSES

13.1.

Population Pharmacokinetic Analyses

Pharmacokinetic and Pharmacokinetic/Pharmacodynamic analyses will be performed by,


or under the direct auspice of, Clinical Pharmacology Modelling and Simulation, CPMS,
GlaxoSmithKline.
A parametric modelling framework will be applied to the data for population PK and
population PK-PD analyses. Initially, the sparse PK data will be applied to a predictive
population PK model (using prior model development experience with GW642444).
During model evaluation, the role of influential covariates on the pharmacokinetic
disposition of GW642444 will be investigated. The potential factors include, but not
necessarily limited to, age, race, gender, weight, height, BMI and concomitant
medications.
The systemic pk-pd relating to systemic exposure to GW642444 and maximum and
weighted mean pulse rate (0-4h), maximum and weighted mean glucose (0-4h) and
minimum and weighted mean potassium) (0-4h) (and corresponding change from
baseline values) will be investigated.
A population mixed-effect dose response analysis may be performed using trough FEV1
data. Various PD models including step, step-linear or variant Emax models may be
explored, if data allow.
A population dose-time-response analysis using all serial FEV1 data on day 1, day 7, day
14 and day 28 will be performed to predict the steady state time course of FEV1 as
function of dose. This model can then be applied to estimate the population time to a
200mL and 12% increase from baseline in FEV1 (0-4hr) as well as magnitude of
tachyphylaxis (if relevant).
Model performance will be assessed using standard techniques including goodness of fit
plots, precision of parameter estimates with visual and posterior predictive checks using
Monte-Carlo simulations of the various models.
Concentrations of the triphenylacetate and the metabolites will be listed.

13.1.1.

General considerations for data analyses

Plasma concentrations of GW642444 will be analysed employing population


pharmacokinetic methodology. The PK concentration population (the ITT population
for whom a pharmacokinetic sample was obtained and analysed) will be used for the
population (Pop) PK. The ITT population will be used for PK/PD analyses with
corresponding PK values for the No Treatment group being set to zero.
Concentrations below the lower limit of quantification (LLQ) for the LC-MS-MS assay
(30pg/mL) will be reported as NQ (Below Quantification Limit). Percent of NQ samples
will be calculated overall and by treatment, day and time (window i.e. pre-dose, 2-10
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minutes, 10-30minutes). All NQ values will be set to missing in the PK dataset. Dataset
specifications are detailed in Attachment PK1.

13.1.2.

Missing sampling and treatment information

The sampling times will be relative to the time of the last dose of GW642444. Data from
subjects with inadequate dosing histories (no records for dosing time) or missing sample
information or data (sample not taken, insufficient sample for analysis) will be discarded
from the data file. Concentrations following an obvious missing dosing event will be
excluded from the PK analysis. All excluded observations or discarded data from the data
file along with reasons for exclusion will be listed in the report.
Some concentration results may be inconsistent with the expected PK behaviour of
GW642444. These data may be excluded from the modelling after investigation about
possible sampling/labelling errors. The exclusions will be listed.

13.1.3.

Covariates

The effect of the following covariates on the PK of GW642444M will be investigated:

Demographic data (age, race, gender, weight, body mass index)

Only subjects with a complete set of covariates and a GW642444 concentration will be
included for the first covariate analysis. If some covariates have no influence in this
analysis, then subjects with a missing value for these covariates may be added back into
the dataset in order to improve the final parameter estimates. These subjects, however,
must have values for all of the significant covariates in the model.

13.1.4.

Pharmacokinetic Analyses

GW642444 plasma concentration-time data will be subjected to nonlinear mixed effects


modelling using the program NONMEM to develop a population PK model. The goal of
this analysis will be to determine the systemic exposure following evening dosing to
asthmatic subjects. The effects of subject demographic characteristics including gender,
age, weight, body mass index (BMI) will also be examined. Individual predicted PK
parameters will be summarised descriptively.
Population modelling will be conducted utilising the software NONMEM, version V or
above, (Non-linear mixed effects model, UCSF, CA) which needs specific data formats
and a number of indicator variables identifying each task. A summary of possible
indicator variables and their description is given in the PK attachment. Variables included
in the final dataset will depend upon the best fit population PK model and influential
covariates in this population. Therefore all indicator variables in the PK attachment may
not be included in the final model.
The population PK analysis is based on multiple regression using non-linear mixed effect
models. Mixed effect models describe the influence of both fixed effects and random
effects on a dependent variable, e.g. concentration or a clinical endpoint. Fixed effects,
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THETA () in NONMEM notation, are factors that are either measured or controlled.
Random effects include residual error (ERR), epsilon () in NONMEM notation, and
between subject random effects, ETA () in NONMEM notation.
The population PK mixed effects models include four basic components:

The structural PK model, which predicts the plasma concentration for a typical
patient as a function of time and dose.

The covariate model component, which describes the influence of fixed effects
(demography, disease, concomitant medications) on PK model population
parameters.

The between-subject variance component, which describes the inter-individual


variation in PK parameters (after correction for fixed effects).

The residual error model components, which describes the underlying distribution of
the error in the measured PK variable.

A structural model is built first, including error models. Then significant and clinically
relevant covariates relationships are added, using a predefined strategy (stepwise
inclusion followed by stepwise deletion). The final model should contain no redundant
covariates but the strategy should ensure that no significant covariate was missed.
Initially the simplest structural model will be selected to use as a valid base model. This
assessment will be based on the following evaluations:

Diagnostic plots (observed versus predicted concentrations, residual/weighted


residual versus predicted concentration or time)

Convergence of the minimisation

Number of significant digits > 3

Lack of correlation between parameter estimates

Rate and volume parameter estimates in agreement with physiology

The simplest structural model to use as a valid base model will be based on smallest
objective function and by inspection of the pattern in the residual plots. The best
estimation method, the most appropriate between-subjects variance models, and the
residual error model, will be identified and the resulting model called a BASE model.
Selection of covariates by univariate analyses (reduction of objective function of at least
3.84) will then be made. In building the NONMEM model forwardly, the covariate with
highest correlation will be added to the base model to build the first intermediate
NONMEM model. It will be accepted if the decrease in the objective function () is >
3.841 for a single covariate (p-value<0.05). Likewise, the covariate with second highest
correlation will be added next to the existing intermediate NONMEM model if it meets
the same acceptance criteria. This forward building technique will continue until all the
potential influential covariates are in the model. All selected covariates will be added
together, the model fitted to data, and this will be assigned as the FULL model

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The covariates included in the best NONMEM model built by the forwarding technique
will be confirmed by removing one covariate at a time. Backward deletion will be
applied until no covariate can be removed without significantly increasing the objective
function, resulting in the FINAL model (likelihood ratio test at p<0.005, 1 df, objective
function drop of at least 7.88). If a confidence interval of structural parameters includes
the value zero, the effect is considered not significant and the model is further simplified
until all structural parameters are well estimated.
Acceptable population models should result in successful minimisation, with at least
three significant digits for any parameter, a successful estimation of the covariance, and
the absolute value of last iteration gradients greater than 10-3 but smaller than 100.
Confidence intervals of structural parameters should not include zero; absolute value of
correlation between two structural parameters should not be greater than 0.95.
Acceptable models should not lead to trends in the distribution of weighted residuals
versus model predictions and versus independent variable. They should not be oversensitive to initial estimates. The observations versus predictions data should be evenly
distributed around the unit line, as evidenced by series of diagnostic plots.
If constraints were applied on parameters, no final estimate should be equal to its
boundary.

13.2.

Pharmacokinetic-Pharmacodynamic Analysis

13.2.1.

Systemic PK-PD Assessments

Following determination of a "final" population pharmacokinetic model, the generated


posthoc estimates of Cmax will be used as the pharmacokinetic endpoint. An initial
PK/PD analysis will conducted based on graphical assessments of the relationship
between individual pharmacokinetics and maximum/minimum and weighted mean
systemic PD (maximum and weighted mean pulse rate (0-4h), maximum and weighted
mean glucose (0-4h) and minimum and weighted mean potassium) (0-4h) (and
corresponding change from baseline values)).
The systemic pk-pd relation for systemic exposure to GW642444 and systemic PD
endpoints will only be formally investigated if the treatment differences for the pairwise
comparisons for each treatment group vs placebo for HR, glucose, potassium & QTC are
statistically significant.
Dataset specifications are detailed in Attachment PK1.

13.2.2.

Pharmacokinetic-AE Analysis

Relationships between GW642444 pharmacokinetics and adverse events (selected from


database listings based on frequency of occurrence or on clinical interest) will also be
undertaken as appropriate.

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13.2.3.

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Dose-response Modelling

This will be a supporting analysis using the absolute trough FEV1 (mean of 23to 24h post
dose) and change from baseline FEV1. The objective of this population dose-response
modelling using non linear mixed effects is to derive a predictive population doseresponse relationship based on trough FEV1 (primary efficacy variable), if data allow.
The following parameters for GW642444 can be estimated including potency (ED50),
shape and maximum response (Emax) and associated inter- and intra-subject variability
in the model parameters. Any time dependency in drug effect (tachyphylaxis) as well as
patient factors (covariate) on pharmacodynamic effect can also be formally evaluated.
The modelling strategy will involve testing the population linear and non linear mixedeffect dose response analysis using the longitudinal trough FEV1 data using all treatment
groups including placebo. This type of model assumes a parametric form for dose versus
response (including linear or Emax model) and normally distributed random effects for
individuals and for treatment response within individuals. Various PD models including
step, step-linear or variant Emax models may be explored. The shape of the dose
response curve will be informally tested by expanding the model in a logical manner with
progressively more parameters. Once a full model is developed , the significance of its
parameters will be formally tested by independently removing each one from the full
model and performing a likelihood ratio test that compares the difference in goodness of
fit (-2 ln likelihood) between the reduced model and the full model to its reference, chisquare distribution. Confidence intervals on parameter estimates will be obtained from
either the usual approximate asymptotic covariance matrix of the estimates or by using
non parametric bootstrapping method.

13.2.4.

Dose-Response-Time Modelling (K-PD)

The time course of FEV1 profile (absolute and/or % change from baseline) on day 1, 14
and day 28 will be simultaneously characterised (if possible) using a K-PD model
paradigm which extracts information about kinetic parameters that contributes towards
pharmacodynamic response using the full pulmonary pharmacodynamic profiles over a
wide dose range (Gabrielsson et al , 2000 - Biopharm Drug Dispos 21, 41-52). This
longitudinal non linear mixed effect modelling would allow estimation of the parameters
describing turnover of response (time to a 200mL and 12% increase from baseline in
FEV1 (0-4hr), time dependency in FEVl change) and pharmacodynamic characteristics
(potency and intrinsic efficacy). Confidence intervals on all derived parameter estimates
will be obtained from either the usual approximate asymptotic covariance matrix of the
estimates or by using non parametric bootstrapping method.

14.

PHARMACOGENETIC DATA ANALYSES

If PGx analyses are required, they will be detailed in a separate analysis plan.

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REFERENCES

GlaxoSmithKline Document Number GM2006/00690/03. Study B2C109575. A doubleblind placebo-controlled study to evaluate the efficacy (measured by clinic FEV1,
bronchodilator response to salbutamol/albuterol, daily PEF, symptoms, rescue
salbutamol/albuterol use and withdrawals due to lack of efficacy), safety (assessed by
adverse events, clinical laboratory evaluations, ECGs and vital signs) and
pharmacokinetics of five doses (3mcg, 6.25mcg, 12.5mcg, 25mcg and 50mcg) of
GW642444M administered once daily compared with placebo over a 28 day treatment
period in subjects with persistent asthma.

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16.

ATTACHMENTS

16.1.

Table of Contents for Data Display Specifications

Study Population
Tables
Table 6.1 Summary of Subject Populations
Table 6.2 Summary of Reasons For Withdrawal Prior to Randomisation
Table 6.3 Summary of End of Study Record
Table 6.4 Summary of Attendance at Each Clinic Visit
Table 6.5 Summary of Number of Subjects by Centre
Table 6.6 Summary of Inclusion/Exclusion Criteria Deviations
Table 6.7 Summary of Protocol Deviations
Table 6.8 Summary of Demographic Characteristics
Table 6.9 Summary of Demographic Characteristics Per Protocol Population
Table 6.10 Summary of Race and Racial Combinations
Table 6.11 Summary of Race and Racial Combination Details
Table 6.12 Summary of History of Tobacco Use at Visit 1 (Screening)
Table 6.13 Summary of Duration of Asthma and Asthma History
Table 6.14 Summary of Current Medical Conditions
Table 6.15 Summary of Asthma Concomitant Medications Taken Pre-Treatment
Table 6.16 Summary of Asthma Concomitant Medications Taken During Treatment
Table 6.17 Summary of Asthma Concomitant Medications Taken Post Treatment
Table 6.18 Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment
Table 6.19 Summary of Non-Asthma Concomitant Medications Taken During Treatment
Table 6.20 Summary of Non-Asthma Concomitant Medications Taken Post Treatment
Table 6.21 Summary of Screening Lung Function Test Results
Table 6.22 Summary of Treatment Compliance (%)
Table 6.23 Summary of Percent Predicted FEV1 Strata: As Randomised and Actual
Table 6.24 Summary of Percent Predicted FEV1 (%) Day 1 Pre-Dose by Actual Stratum

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Figures
Figure 6.1 Subject Withdrawals Over Time
Figure 6.2 Subject Withdrawals due to Lack of Efficacy Over Time

ICH Required Listings


Listing 6.1 Listing of Reasons for Premature Withdrawal
Listing 6.2 Listing of Subjects with Inclusion/Exclusion Criteria Deviations
Listing 6.3 Listing of Subjects for Whom the Treatment Blind was Broken During the
Study
Listing 6.4 Listing of Demographic Characteristics
Listing 6.5 Listing of Race

Non ICH Required Listings


Listing 6.6 Listing of Randomisation Data
Listing 6.7 Listing of Reasons for Protocol Deviation
Listing 6.8 Listing of Subjects who Received Incorrect Medication
Listing 6.9 Listing of History of Tobacco Use
Listing 6.10 Listing of Duration of Asthma and Asthma History
Listing 6.11 Listing of Current Medical Conditions
Listing 6.12 Listing of Concomitant Medications
Listing 6.13 Listing of Relationship Between ATC Level 1, Ingredient and Verbatim
Text

Efficacy
Tables
Table 7.1 Summary of Trough FEV1 (L) (LOCF) Intent-to-Treat
Table 7.2 Linear Trend Test of Change from Baseline in Trough FEV1 (L) (LOCF)
Intent-to-Treat
Table 7.3 Linear Trend Test of Change from Baseline in Trough FEV1 (L) (LOCF)
Excluding Placebo - Intent-to-Treat
Table 7.4 Statistical Analysis of Change from Baseline in Trough FEV1 (L) (LOCF) Intent-to-Treat
Table 7.5 Summary of Trough FEV1 (L) (LOCF) Per Protocol
Table 7.6 Linear Trend Test of Change from Baseline in Trough FEV1 (L) (LOCF) Per
Protocol

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Table 7.7 Statistical Analysis of Change from Baseline in Trough FEV1 (L) (LOCF) Per Protocol
Table 7.8 Linear Trend Test of Change from Baseline in Trough FEV1 (L) (Repeated
Measures)
Table 7.9 Statistical Analysis of Change from Baseline in Trough FEV1 (L) (Repeated
Measures)
Table 7.10 Summary of Pre-Dose and Trough FEV1 (L) (No Imputation)
Table 7.11 Summary of Change from Baseline in Trough FEV1 (L) at Day 28 by Stratum
Table 7.12 Slope Estimate of Change from Baseline in Trough FEV1 (L) (LOCF) by
Stratum
Table 7.13 Statistical Analysis of Change from Baseline in Trough FEV1 (L) (LOCF) by
Stratum
Table 7.14 Summary of Raw Serial FEV1 (L)
Table 7.15 Summary of Absolute Change from Baseline in Serial FEV1 (L) (0-4 hours)
Table 7.16 Summary of Percentage Change from Baseline in Serial FEV1 (L) (0-4 hours)
Table 7.17 Summary of Weighted Mean Change from Baseline in 24 Hour Serial Clinic
FEV1 (L)
Table 7.18 Statistical Analysis of Weighted Mean Change from Baseline in 24 Hour
Serial Clinic FEV1 (L). All Subjects, including 6-12 hour time points
Table 7.19 Sensitivity Analysis of Weighted Mean Change from Baseline in 24 Hour
Serial Clinic FEV1 (L). All Subjects excluding 6-12 hour time points
Table 7.20 Sensitivity Analysis of Weighted Mean Change from Baseline in 24 Hour
Serial Clinic FEV1 (L). Subset of Subjects who had the 6-12 hour time points
measured. All time points included
Table 7.21 Sensitivity Analysis of Weighted Mean Change from Baseline in 24 Hour
Serial Clinic FEV1 (L). Subset of Subjects who had 6-12 hour time points
measured, excluding 6-12 hour time points
Table 7.22 Sensitivity Analysis of Weighted Mean Change from Baseline in 24 Hour
Serial Clinic FEV1 (L). Observations without rescue medication
Table 7.23 Summary of Post-salbutamol/albuterol FEV1 (L)
Table 7.24 Summary of Post-salbutamol/albuterol FEV1 (L) Differences
Table 7.25 Statistical Analysis of difference in post-salbutamol/albuterol FEV1
Table 7.26 Summary of Maximum Increase from Baseline in FEV1 (L) (0-4hr)
Table 7.27 Statistical Analysis of Maximum Increase from Baseline in FEV1 (L) (0-4
hours)
Table 7.28 Summary of Weighted Mean Change from Baseline in FEV1 (L) (0-4hr)
Table 7.29 Statistical Analysis of Weighted Mean Change from Baseline in FEV1 (L) (04 hours)
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Table 7.30 Summary of the Proportion of Subjects Obtaining 200mL and 12%
increase from Baseline FEV1 (L) (0-4hr)
Table 7.31 Summary of the Cumulative Proportion of Subjects Obtaining 200mL and
12% increase from Baseline FEV1 (L) (0-4hr)
Table 7.32 Summary of the Proportion of Subjects Obtaining 15% increase from
Baseline FEV1 (L) (0-4hr)
Table 7.33 Summary of the Cumulative Proportion of Subjects Obtaining 15% increase
from Baseline FEV1 (L) (0-4hr)
Table 7.34 Summary of Peak Post-Dose FEV1 (L) (0-4 hours)
Table 7.35 Statistical Analysis of Peak Post-Dose FEV1 (L) (0-4 hours)
Table 7.36 Summary of Ratio of Peak Post-Dose FEV1 to Trough FEV1
Table 7.37 Change from Baseline in PM PEF (L/min)
Table 7.38 Statistical Analysis of Change from Baseline in PM PEF (L/min)
Table 7.39 Change from Baseline in AM PEF (L/min)
Table 7.40 Statistical Analysis of Change from Baseline in AM PEF (L/min)
Table 7.41 Change from Baseline in Percentage of Symptom Free 24 Hour Periods
Table 7.42 Statistical Analysis of Change from Baseline in Percentage of Symptom Free
24 Hour Periods
Table 7.43 Change from Baseline in Percentage of Rescue Free 24 Hour Periods
Table 7.44 Statistical Analysis of Change from Baseline in Percentage of Rescue Free 24
Hour Periods
Table 7.45 Change from Baseline in Percentage of Symptom Free Days
Table 7.46 Statistical Analysis of Change from Baseline in Percentage of Symptom Free
Days
Table 7.47 Change from Baseline in Percentage of Symptom Free Nights
Table 7.48 Statistical Analysis of Change from Baseline in Percentage of Symptom Free
Nights
Table 7.49 Change from Baseline in Percentage of Rescue Free Days
Table 7.50 Statistical Analysis of Change from Baseline in Percentage of Rescue Free
Days
Table 7.51 Change from Baseline in Percentage of Rescue Free Nights
Table 7.52 Statistical Analysis of Change from Baseline in Percentage of Rescue Free
Nights
Table 7.53 Statistical Analysis of Withdrawals Due to Lack of Efficacy

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Figures
Figure 7.1 Adjusted Treatment Differences of Change from Baseline in Trough FEV1 (L)
(LOCF) at Day 28 Intent-to-Treat
Figure 7.2 Adjusted Means of Change from Baseline in Trough FEV1 (L) (LOCF) at Day
28 Intent-to-Treat
Figure 7.3 Box Plot of Change from Baseline in Trough FEV1 (L) (LOCF) at Day 28
Intent-to-Treat
Figure 7.4 Empirical Distribution Function for Change from Baseline in Trough FEV1
(L) (LOCF) at Day 28 Intent-to-Treat
Figure 7.5 Adjusted Treatment Differences of Change from Baseline in Trough FEV1 (L)
(LOCF) at Day 28 Per Protocol
Figure 7.6 Adjusted Means of Change from Baseline in Trough FEV1 (L) (LOCF) at Day
28 Per Protocol
Figure 7.7 Box Plot of Change from Baseline in Trough FEV1 (L) (LOCF) at Day 28
Per Protocol
Figure 7.8 Empirical Distribution Function for Change from Baseline in Trough FEV1
(L) (LOCF) at Day 28 Per Protocol
Figure 7.9 Repeated Measures Analysis of Change from Baseline in Trough FEV1 (L)
Figure 7.10 Repeated Measures Analysis of Change from Baseline in Trough FEV1 (L)
Differences from Placebo
Figure 7.11 Adjusted Treatment Differences of Change from Baseline in Trough FEV1
(L) (LOCF) at Day 28, by Stratum
Figure 7.12 Adjusted Means of Change from Baseline in Trough FEV1 (L) (LOCF) at
Day 28, by Stratum
Figure 7.13 Adjusted Treatment Differences of Weighted Mean 24 hour Serial FEV1 (L)
Figure 7.14 Adjusted Treatment Differences from Sensitivity Analysis of Weighted Mean
24 hour Serial FEV1 (L)
Figure 7.15 Plot of Mean Clinic FEV1 (L) Over Time
Figure 7.16 Plot of Absolute Change from Baseline in Serial FEV1 (L) 0-4 hours
Figure 7.17 Plot of Percentage Change from Baseline in Serial FEV1 (L) 0-4 hours
Figure 7.18 Adjusted Treatment Differences of post-salbutamol/albuterol FEV1 (L)
Day 28 Day 1
Figure 7.19 Adjusted Treatment Differences of post-salbutamol/albuterol FEV1 (L)
Day 1 Screening
Figure 7.20 Adjusted Treatment Differences of post-salbutamol/albuterol FEV1 (L)
Day 28 Screening
Figure 7.21 Adjusted Treatment Differences of Peak Post-Dose FEV1 (L) (0-4 hours)
Figure 7.22 Mean Change from Baseline in PM PEF (L/min)
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Figure 7.23 Mean Change from Baseline in AM PEF (L/min)

ICH Required Listings


Listing 7.1 Listing of Clinic Lung Function Data

Safety
Tables
Table 8.1 Summary of Exposure
Table 8.2 Summary of On-Treatment Adverse Events
Table 8.3 Summary of Post-Treatment Adverse Events
Table 8.4 Summary of Most Frequent On-Treatment Adverse Events
Table 8.5 Summary of Drug-Related Adverse Events
Table 8.6 Summary of Adverse Events Leading to Permanent Discontinuation of Study
Drug or Withdrawal From the Study
Table 8.7 Summary of Pre-Treatment Serious Adverse Events
Table 8.8 Summary of On-Treatment Serious Adverse Events
Table 8.9 Summary of Post-Treatment Serious Adverse Events
Table 8.10 Relationship of Adverse Event System Organ Class, Preferred Term and
Verbatim Text
Table 8.11 Summary of Chemistry Data
Table 8.12 Summary of Chemistry Data Outside the Normal Range
Table 8.13 Summary of Chemistry Changes from Baseline Relative to the Normal Range
Table 8.14 Summary of Haematology Data
Table 8.15 Summary of Haematology Data Outside the Normal Range
Table 8.16 Summary of Haematology Changes from Baseline Relative to the Normal
Range
Table 8.17 Summary of Urine Dipstick Results
Table 8.18 Summary of Vital Signs
Table 8.19 Summary of Change from Baseline in Vital Signs
Table 8.20 Summary of Maximum Increase from Baseline in Systolic Blood Pressure (04 hrs)
Table 8.21 Summary of Maximum Increase from Pre-Dose in Systolic Blood Pressure (04 hrs)
Table 8.22 Statistical Analysis of Maximum Increase from Baseline in Systolic Blood
Pressure (0-4 hrs)

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Table 8.23 Summary of Maximum Decrease from Baseline in Diastolic Blood Pressure
(0-4 hrs)
Table 8.24 Summary of Maximum Decrease from Pre-Dose in Diastolic Blood Pressure
(0-4 hrs)
Table 8.25 Statistical Analysis of Maximum Decrease from Baseline in Diastolic Blood
Pressure (0-4 hrs)
Table 8.26 Summary of Maximum Increase from Baseline in Pulse Rate (0-4 hrs)
Table 8.27 Summary of Maximum Increase from Pre-Dose in Pulse Rate (0-4 hrs)
Table 8.28 Statistical Analysis of Maximum Increase from Baseline in Pulse Rate (0-4
hrs)
Table 8.29 Summary of Weighted Mean Change from Baseline in Systolic Blood
Pressure (0-4 hours)
Table 8.30 Summary of Weighted Mean Change from Pre-Dose in Systolic Blood
Pressure (0-4 hours)
Table 8.31 Statistical Analysis of Weighted Mean Change from Baseline in Systolic
Blood Pressure (0-4 hours)
Table 8.32 Summary of Weighted Mean Change from Baseline in Diastolic Blood
Pressure (0-4 hours)
Table 8.33 Summary of Weighted Mean Change from Pre-Dose in Diastolic Blood
Pressure (0-4 hours)
Table 8.34 Statistical Analysis of Weighted Mean Change from Baseline in Diastolic
Blood Pressure (0-4 hours)
Table 8.35 Summary of Weighted Mean Change from Baseline in Pulse Rate (0-4 hours)
Table 8.36 Summary of Weighted Mean Change from Pre-Dose in Pulse Rate (0-4
hours)
Table 8.37 Statistical Analysis of Weighted mean change from baseline in Pulse Rate (04 hours)
Table 8.38 Summary of ECG Values
Table 8.39 Summary of ECG Findings
Table 8.40 Summary of Maximum Post-Dose QTc (F) Interval (msec)
Table 8.41 Summary of Maximum Post-Dose QTc (B) Interval (msec)
Table 8.42 Summary of Maximum Change from Baseline (0-4 hours) in QTc (F) Interval
(msec)
Table 8.43 Summary of Maximum Change from Baseline (0-4 hours) in QTc (B) Interval
(msec)
Table 8.44 Summary of Weighted Mean Change From Baseline (0-4 hours) in QTc (F)
Interval (msec)

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Table 8.45 Summary of Weighted Mean Change From Pre-Dose (0-4 hours) in QTc (F)
Interval (msec)
Table 8.46 Summary of Weighted Mean Change From Baseline (0-4 hours) in QTc (B)
Interval (msec)
Table 8.47 Summary of Weighted Mean Change From Pre-Dose (0-4 hours) in QTc (B)
Interval (msec)
Table 8.48 Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(F)
(msec)
Table 8.49 Statistical Analysis of Change from Baseline in Post-Dose Serial QTc(B)
(msec)
Table 8.50 Statistical Analysis of Change from Baseline in Maximum Value (0-4 hrs)
QTc (F) (msec)
Table 8.51 Statistical Analysis of Change from Baseline in Maximum Value (0-4 hrs)
QTc (B)
Table 8.52 Statistical Analysis of Weighted Mean Change from Baseline (0-4 hrs) QTc
(F)
Table 8.53 Statistical Analysis of Weighted Mean Change from Baseline (0-4 hrs) QTc
(B)
Table 8.54 Summary of Fasting Potassium and Glucose
Table 8.55 Summary of Non-fasting Potassium
Table 8.56 Summary of Fasting Potassium and Glucose Changes from Baseline Relative
to the Normal Range
Table 8.57 Summary of Non-fasting Potassium Changes from Baseline Relative to the
Normal Range
Table 8.58 Summary of Maximum Decrease from Baseline in Fasting Potassium (0-4
hrs)
Table 8.59 Summary of Maximum Decrease from Pre-Dose in Fasting Potassium (0-4
hrs)
Table 8.60 Summary of Maximum Decrease from Baseline in Non-Fasting Potassium (04 hrs)
Table 8.61 Summary of Maximum Decrease from Pre-Dose in Non-Fasting Potassium
(0-4 hrs)
Table 8.62 Summary of Maximum Increase from Baseline in Glucose (0-4 hrs)
Table 8.63 Summary of Maximum Increase from Pre-Dose in Glucose (0-4 hrs)
Table 8.64 Summary of Weighted Mean Change from Baseline in Fasting Potassium (0-4
hrs)
Table 8.65 Summary of Weighted Mean Change from Pre-Dose in Fasting Potassium (04 hrs)

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Table 8.66 Summary of Weighted Mean Change from Baseline in Non- Fasting
Potassium (0-4 hrs)
Table 8.67 Summary of Weighted Mean Change from Pre-Dose in Non- Fasting
Potassium (0-4 hrs)
Table 8.68 Summary of Weighted Mean Change from Baseline in Glucose (0-4 hrs)
Table 8.69 Summary of Weighted Mean Change from Pre-Dose in Glucose (0-4 hrs)
Table 8.70 Statistical Analysis of Maximum Decrease from Baseline in Fasting
Potassium (0-4 hrs)
Table 8.71 Statistical Analysis of Maximum Decrease from Baseline in Non-Fasting
Potassium (0-4 hrs)
Table 8.72 Statistical Analysis of Maximum Increase from Baseline in Glucose (0-4 hrs)
Table 8.73 Statistical Analysis of Weighted Mean Change from Baseline in Fasting
Potassium (0-4 hrs)
Table 8.74 Statistical Analysis of Weighted Mean Change from Baseline in Non- Fasting
Potassium (0-4 hrs)
Table 8.75 Statistical Analysis of Weighted Mean Change from Baseline in Glucose (0-4
hrs)
Table 8.76 Summary of Subjects with Asthma Exacerbations

Figures
Figure 8.1 Trellis Display of Maximum Post-Baseline LFT Values Versus Baseline LFT
Values
Figure 8.2 Box Plot of Maximum Post-Baseline Liver Function Tests
Figure 8.3 Trough FEV1 (L) (LOCF) Versus Change from Baseline in Weighted Mean
Pulse Rate at Day 28
Figure 8.4 Empirical Distribution Function for Maximum Change (0-4 hours) in QTc (F)
Interval (msec)
Figure 8.5 Empirical Distribution Function for Maximum Change in QTc (B) Interval
Figure 8.6 Mean (95% CI) Change from Baseline in QTc (F) Interval by Time and
Treatment
Figure 8.7 Mean (95% CI) Change from Baseline in QTc (B) Interval by Time and
Treatment
Figure 8.8 Adjusted Treatment Differences (95% CI) of Change from Baseline in PostDose Serial QTc(F) (msec)
Figure 8.9 Adjusted Treatment Differences (95% CI) of Change from Baseline in PostDose Serial QTc(B) (msec)
Figure 8.10 Serial QTc(F) (msec) versus Heart Rate (beats/min)
Figure 8.11 Serial QTc(F) (msec) versus Heart Rate (beats/min)
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Figure 8.12 Minimum Post-Baseline Potassium Values Versus Baseline Potassium


Values
Figure 8.13 Box Plot of Minimum Post-Baseline Potassium Values
Figure 8.14 Maximum Post-Baseline Glucose Values Versus Baseline Glucose Values
Figure 8.15 Box Plot of Maximum Post-Baseline Glucose Values
Figure 8.16 Mean Fasting Potassium by Time and Treatment
Figure 8.17 Mean Fasting Glucose by Time and Treatment

ICH Required Listings


Listing 8.1 Listing of Exposure and Compliance Data
Listing 8.2 Listing of Subject Numbers for Individual Adverse Events
Listing 8.3 Listing of Pre-Treatment Adverse Events
Listing 8.4 Listing of On-Treatment Adverse Events
Listing 8.5 Listing of Post-Treatment Adverse Events
Listing 8.6 Listing of Adverse Events Leading to Permanent Discontinuation of Study
Drug or Withdrawal From the Study
Listing 8.7 Listing of Non-Fatal Serious Adverse Events
Listing 8.8 Listing of Fatal Adverse Events
Listing 8.9 Listing of Adverse Events for Subjects not in Intent-to-Treat Population
Listing 8.10 Listing of Chemistry Data for Subjects With at Least One Normal Range
Abnormality
Listing 8.11 Listing of Haematology Data for Subjects With at Least One Normal Range
Abnormality
Listing 8.12 Listing of Urinalysis Data for Subjects with Positive Dipstick Results

Non ICH Required Listings


Listing 8.13 Listing of Vital Signs
Listing 8.14 Listing of ECG Values
Listing 8.15 Listing of ECG Findings
Listing 8.16 Listing of Potassium and Glucose
Listing 8.17 Listing of Asthma Exacerbations
Listing 8.18 Listing of Device Malfunctions

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Pharmacokinetics
Tables
Table 9.1 Summary of % of NQ values by treatment, day & time for GW642444,
triphenyacetate, GW630200 & GSK932009
Table 9.2 Estimated Population PK Parameter means and their 95% Confidence
Intervals BASE PK model
Table 9.3 Summary of Covariate Analysis
Table 9.4 Estimated PK Parameter means and their 95% Confidence Intervals FINAL
PK Model
Table 9.5 Estimated Population PK Parameter means and their 95% Confidence Intervals
Systemic PK/PD model
Table 9.6 Estimated Population PK Parameter means and their 95% Confidence Intervals
DR model
Table 9.7 Estimated Population PK Parameter means and their 95% Confidence Intervals
K/PD model

Figures
Figure 9.1 Goodness of fit plots for base PK model
Figure 9.2 Plots of base model PK parameter estimates versus influential covariates, if
applicable
Figure 9.3 Goodness of fit plots for final PK model
Figure 9.4 Scatter Plot of PD endpoints versus GW62444 Cmax
Figure 9.5 Goodness of fit plots for PK/PD models
Figure 9.6 Goodness of fit plots for DR and K/PD models

Listings
Listing 9.1 Concentration time for GW642444
Listing 9.2 Concentration time for triphenylacetate
Listing 9.3 Concentration time for GW630200
Listing 9.4 Concentration time for GSK9322009
Listing 9.5 NONMEM PK data file for GW642444
Listing 9.6 NONMEM output files from the Base & Final Models PK
Listing 9.7 NONMEM control files from Base & Final Models PK
Listing 9.8 NONMMEM systemic PK/PD data file for GW642444
Listing 9.9 NONMEM output files from systemic PK/PD modelling

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Listing 9.10 NONMEM control files from systemic PK/PD modelling


Listing 9.11 NONMEM output files from DR modelling
Listing 9.12 NONMEM control files from DR modelling
Listing 9.13 NONMMEM K/PD data file for GW642444
Listing 9.14 NONMEM output files from K/PD modelling
Listing 9.15 NONMEM control files from K/PD modelling

16.2.

Data Display Specifications

The data display shells are contained in separate documents which are available on
request.

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Attachment PK1: Population PK and PK/PD dataset specification


Introduction
The purpose of this Attachment is to prospectively define and document the structure of
the datasets required for the population PK, PK/PD and K_PD analyses for the clinical
study report for protocol B2C109575.

General considerations for dataset generation


The PK concentration population will be used for the population (Pop) PK. The ITT
population will be used for PK/PD analyses with corresponding PK values for the No
Treatment group being set to zero.For pharmacokinetic analysis, concentrations below
the lower limit of quantification (LLQ) will be reported as NQ (Below Quantification
Limit). All NQ values will be set to missing in the PK datasets. The dataset described
below will be provided within 15 days of DBF. Data from subjects with inadequate
dosing histories (no records for dosing time) or missing sample information or data (i.e.
sample not taken (NS), insufficient sample for analysis (IS)) will be excluded from the
data file. Concentrations following an obvious missing dosing event will also be
excluded. All excluded observations along with reasons for exclusion will be listed in a
separate file.
The data for PK/PD and K-PD evaluation will be provided within 15working days of
generation as comma delimited files (*.csv). Missing values will be assigned .
The K-PD data the dataset will include:
SUBJID, PERD, DAY, DGRP, AMT, TRLD, FEV1, MDV, EVID, CMT, SS, II, BL,
AGE, WT, HT, SEX, ETHN, BMI, STRATUM

where:
FEV1 = FEV1 value
BL = baseline FEV1 value

Missing Sampling and Covariates in PK Analysis


The sampling times are relative to the time of the last active dose of GW642444. Data
from subjects with inadequate dosing histories (no records for dosing time) or missing
sample information will be discarded from the data file. Concentrations following an
obvious missing dosing event will be excluded from the PK analysis. All excluded
observations or discarded data from the data file along with reasons for exclusion will be
listed in the report.

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Population PK Dataset File Structure

The file structure is a space-delimited file with each row containing the following
columns of information.
Order
in File
1
2
3

Variable
short name
STUD
POP
ID

Assessment
description
Study identifier
Study population
NONMEM
Identifier
Patient identifier in
study

Format

Unit

Valid Values / Format

Integer
Interger
Interger

109575
0=Asthmatics
500 to n

SUBJ

Varchar

PERD

Study Visit

Varchar

DAY

Study day

Varchar

DRUG

Name of drug

Varchar

8
9
10
11

DEV
FORM
DGRP
AMT

Device
Formulation
Treatment
Dose given

Interger
Interger
Decimal
Decimal

Mcg
Mcg

12

TRLD

Decimal

13

TIME

Decimal

14

CONC

The time elapsed


between the time of
measurement and the
time of dosing
The time elapsed
between the time of
concentration
measurement and the
time of 1st active dose
The result for
concentration

Maximum 10 characters (numeric or


text). Different identifier for each
subject.
Maximum 10 characters (numeric or
text)
Maximum 10 characters (numeric or
text)
Maximum 12 characters (numeric or
text)
GW642444
2=Novel dry powder inhaler
3=M-salt Magnesium Stereate
float (12.4). Dose group
float (12.4)
Only in dosing records with LABL
DOSE.
3 = GW642444 3mcg QD
6.25 = GW642444 6.25mcg QD
12.5 = GW642444 12.5mcg QD
25 = GW642444 25mcg QD
50 = GW642444 50mcg QD
In all other records (records with
CONC measurements) use .
float (12.4)
When LABL = DOSE, TIME = 0
To calculate elapsed time use the last
active dose as detailed below
float (12.4)
When LABL = DOSE, TIME = 0
To calculate elapsed time use the first
active dose (Day 1 active dose pm)

Decimal

pg/mL

15

MDV

Missing data variable

Integer

16

EVID

Event identifier.

Integer

60

float (15.5)
Missing values are represented by .
At dosing times (when AMT is
positive), CONC should be .
Either 0 if drug concentration value
present or 1 if missing value or
EVID=1
Flag indicating whether LABL
contains dosing admin info or drug
concentration data.
Valid values are 1 each dosing record for subject

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Order
in File

Variable
short name

Assessment
description

Format

Unit

17

LABL

Record label

Varchar

18

ROUT

Character

19

RATE

Route of
administration
Rate of infusion for
intravenous study

Decimal

g/h

20

AGE

Age

Decimal

yrs

21

WT

Weight

Decimal

kg

22

HT

Height

Decimal

cm

23

SEX

Subject gender

Enum

24
25
26

ETHN
RACE
BMI

Subject ethnicity
Subject race
Body mass index

Enum
Enum
Decimal

kg/m^2

27
28

SMOK
II

Smoking habits
Interdose interval

I Integer
decimal

29

ADDL

Additional dose

integer

30
31

AMPM
DATETIME

Time of day of dosing


Date and time of Dose
or PK sample

Interger
YYYY-MMDD
HH:MM:SS

32

STRATA

FEV1 stratum

Enum
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Valid Values / Format


0 - for all other records
Maximum 32 characters (numeric or
text),
Record identifier:
In dosing records: LABL will be
DOSE
In records with concentration
measurements: CONC
Maximum 2 letters:
IH = inhaled
float (12.4)
In records with concentration
measurements, RATE is .,
In dosing records, if ROUT equals IH,
the value of RATE is -2.
float (8.3). Age in years at time of
screening rounded down to give age
at last birthday.
float (8.3). Weight in kilograms at time
of screening.
float (8.3). Height in centimetres at
time of screening.
Integer. One of the following
1 = male
2 = female
Integer, As CRF numerical category
Integer. As CRF numerical category
body mass index calculated as weight
divided by height squared
Integers represent different categories
float (12.4).
II gives the time between additional
doses. II should be a positive number
if and only if the AMT and ADDL data
items are positive numbers.
For CONC records, II should be
zero.
Integer, maximum 4 positions.
ADDL describes how many additional
doses, exactly like the present dose,
will be given. ADDL should be a
positive number if and only if the AMT
and II data items are positive
numbers.
ADDL = (Treatment duration / II) ,
where treatment duration is under
assumption of total compliance.
For CONC records, ADDL should be
zero.
2=pm
Date and time of dosing or CONC
measurement. The supported range is
'1000-01-01 00:00:00' to '9999-12-31
23:59:59'
One stratum : FEV1 predicted >40%-

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Order
in File

33

Variable
short name

Assessment
description

Format

CONMED

CYP 3A4 conmeds

Interger

CENT

Study centre number

Enum

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Unit

Valid Values / Format

<65% and one for FEV! Predicted


>65% -<90%
'0' - identifying patients who have not
taken any CYP3A4 inhibitors
'1' - identifying patients who have
taken strong CYP3A4 inhibitors
'2' - identifying patients who have
taken moderate CYP3A4 inhibitors
Integer, Centre grouping (Country)

NOTE only active doses to be included in the dataset as identified below for calculation
of TIME

* Calculation of TRLD
Visit 2 (Day 1), samples 2-5 - pm dose on Visit day (Day 1)
Visit 3 (Day 7), sample 1 pm dose on previous day to Visit (Day 6)
Visit 4 (Day 14), sample 1 pm dose on Visit day (Day 14)
Visit 5 (Day 28), sample 1 pm dose on previous day to Visit (Day 27)
Visit 5 (Day 28), samples 2-5 pm dose on Visit day (Day 28)

An example Dataset is provided on the following page.

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Population PK Dataset File Example


ST
UD

P
O
P

I
D

SU
BJ

PE
RD

D
A
Y

DRU
G

D
E
V

FO
RM

DG
RP

A
M
T

TR
LD

TI
M
E

CO
NC

M
D
V

E
VI
D

LAB
L

RO
UT

RA
TE

A
G
E

W
T

H
T

S
E
X

ET
HN

B
M
I

II

AD
DL

AM
PM

DATE
TIME

CE
NT

This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect
patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For
further information please see the Patient Level Data section of the GSK Clincal Study Register.

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PK/PD and DR Dataset File Structure

The file structure is a space-delimited file with each row containing the following columns of information.
Order in
File

Format

Unit

Valid Values / Format

STUD
SUBJ

Study identifier
Patient identifier in study

Integer
Varchar

2
3
4
5
6
7
8

PERD
DAY
DRUG
DEV
FORM
DGRP
AMT
LABL

Study Visit
Study day
Name of Drug
Device
Formulation
Treatment
Dose given
Record label

Varchar
Varchar
Varchar
Interger
Interger
Decimal
Decimal
Varchar

Mcg
Mcg
-

9
10

POP
AGE

Study Population
Age

Interger
Decimal

Yrs

11
12
13

WT
HT
SEX

Weight
Height
Patient gender

Decimal
Decimal
Enum

Kg
Cm
-

14
15
16
17
18

EtTHN
RACE
BHR
MR4
MR4C

Enum
Enum
XX.X
XX.X
XX.X

Bpm
Bpm
Bpm

19
20

WMR4
WR4C

Patient ethnicity
Patient race
Baseline heart rate
Maximum heart rate (0-4h)
Maximum change from baseline heart
rate (0-4h)
Weighted mean heart rate (0-4h)
Weighted mean change from baseline

109575
Maximum 10 characters (numeric or text). Different identifier for each
subject
Maximum 10 characters (numeric or text
Maximum 10 characters (numeric or text
Maximum 10 characters (numeric or text). GW642444
2=Novel dry powder inhaler
3=M-salt Magnesiun Sterearte
Dose group
AMT = 0 400
Maximum 32 characters (numeric or text),
Record identifier: LABL will be OBSERVATION
0=Asthmatics
Integer. Age in years at time of screening rounded down to give age
at last birthday.
Weight in kilograms at time of screening.
Height in centimetres at time of screening.
Integer. One of the following 1 = male
2 = female
Integer.
Integer.
Mean pre-dose HR
Max HR (0-4h)
Max change from baseline in HR (0-4h

XX.X
XX.X

Bpm
Bpm

Weighted mean HR (0-4h)


Max change from baseline in HR (0-4h

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Variable short name

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Variable short name

21
22
23

BP
MP4
MP4C

24
25

WP4
WP4C

26
27

BG
MG4
MG4C

28
29

WG4
WG4C

30
31
32
33
34

BQTB
MQTB4
MQTBC4
WQTB4
WQTBC4

35
36
37
38
39

BQTF
MQTF4
MQTFC4
WQTF4
WQTFC4

40

CENT

heart rate (0-4h)


Baseline potassium
Min. Potassium (0-4h)
Min Potassium Change from baseline (04h)
Weighted mean potassium (0-4h)
Weighted mean potassium Change from
baseline (0-4h)
Baseline glucose
Max Glucose (0-4h)
Max Glucose Change from baseline (04h)
Weighted mean Glucose (0-4h)
Weighted mean Glucose Change from
baseline (0-4h)
Baseline QTc(B)
Max QTC(B) (0-4h)
Max QTC(B) Change from baseline (0-4h)
Weighted mean QTC(B) (0-4h)
Weighted mean QTC(B) Change from
baseline (0-4h)
Baseline QTc(F)
Max QTc(F) (0-4h)
Max QTc(F)Change from baseline (0-4h)
Weighted mean QTc(F) (0-4h)
Weighted mean QTc(F) Change from
baseline (0-4h)
Baseline FEV1
Trough FEV1 on Day
Change from baseline trough FEV1 on
Day
Centre

Format

Unit

Valid Values / Format

XX.X
X.XX
XXX

Mmol/L
Mmol/L
Mmol/L

Mean pre-dose potassium


Min potassium (0-4h) (fasted)
Min potassium (0-4h) change from baseline (fasted)

X.XX
X.XX

Mmol/L
Mmol/L

Weighted mean potassium (0-4h) (fasted)


Weighted mean potassium Change from baseline (0-4h) (fasted)

XX.X
X.XX
X.XX

Mmol/L
Mmol/L
Mmol/L

Mean Pre-dose Glucose


Max glucose (0-4) (fasted)
Max glucose (0-4) change from baseline (fasted)

X.XX
X.XX

Mmol/L
Mmol/L

Weighted mean glucose (0-4h) (fasted)


Weighted mean glucose (0-4h) change from baseline (fasted)

X.XX
X.XX
X.XX
X.XX
X.XX

msec
msec
msec
msec
msec

Mean pre-dose QTc(B)


Max QTC(B) (0-4h)
Max QTC(B) (0-4h) change from baseline
Weighted mean QTC(B) (0-4h)
Weighted mean QTC(B) (0-4h) Change from baseline

X.XX
X.XX
X.XX
X.XX
X.XX

msec
msec
msec
msec
msec

Mean pre-dose QTc(F)


Max QTc(F) (0-4h)
Max QTc(F) (0-4h) change from baseline
Weighted mean QTc(F) (0-4h)
Weighted mean QTc(F) (0-4h) Change from baseline

X.XX
X.XX

Trough FEV1 on Day 1, 7, 14 and 28


Change from baseline trough FEV1 on Day 1, 7, 14, and 28

XX

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FEV1B
FEV1
FEV1C

Assessment description

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K_PD Dataset File Structure


STU

SUB
J

PER
D

DA
Y

DGR
P

AM
T

LABL

TLR
D

FEV
1

MD
V

EVI
D

CM
T

S
S

I
I

BAS
E

AG
E

WT

HT

SE
X

ETH
N

BMI

STRATU
M

This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient
privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further
information please see the Patient Level Data section of the GSK Clincal Study Register.

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LIST OF INVESTIGATORS AND IECS/IRBS FOR B2C109575 (YM2008/00019/00)


Investigator

Investigator/ Site no.

Hospital/ Institution and Address

IEC/IRB Committee Chair and Name of


Committee

Argentina
Argentina
Argentina

ChairpersonArgentina
Chairperson-

Argentina

Chairperson-

1
Argentina
ChairpersonArgentina

CONFIDENTIAL

Argentina

Argentina
ChairpersonArgentina

Argentina
Chairperson-

YM2008/00019/00
B2C109575

Chairperson-

CONFIDENTIAL
B2C109575

Investigator

Investigator/ Site no.

Hospital/ Institution and Address

IEC/IRB Committee Chair and Name of


Committer.

Argentina

Argentina
ChairpersonArgentina
ChairpersonArgentina

Argentina

Chairperson-

CONFIDENTIAL

Chairperson-

Argentina

2
Chairperson-

Argentina

BELGIUM
Belgium
Belgium.

ChairpersonBelgium
Chairperson-

CANADA
Canada
Canada

ChairpersonCanada

Canada

YM2008/00019/00
B2C109575

Belgium.

CONFIDENTIAL
B2C109575

Investigator

Investigator/ Site no.

Hospital/ Institution and Address

IEC/IRB Committee Chair and Name of


Committee
ChairpersonCanada

Canada

ChairpersonCanada

Canada

ChairpersonCanada
Chairperson-

Canada

Canada

Chairperson-

Canada
Canada

ChairpersonCanada

Chairperson-

CONFIDENTIAL

Canada

Canada

CHILE
Chile,

Chile
Chairperson-

Chile,
Chile,

Chairperson-

YM2008/00019/00
B2C109575

Chile,
Chairperson-

CONFIDENTIAL
B2C109575

Investigator

Investigator/ Site no.

Hospital/ Institution and Address

IEC/IRB Committee Chair and Name of


Committee

FRANCE
France
France

Chairperson- France
Chairperson-

France
France
ChairpersonDr. med.

Germany
Dr. med.

ChairpersonChairperson-

Germany
Germany

Germany
Dr.

med
Germany
Dr. Med.

MD

Germany
ChairpersonChairperson-

Germany

Dr. med.
Germany

Chairperson-

Germany

Dr. med.
Germany

Chairperson-

Germany

YM2008/00019/00
B2C109575

Germany

CONFIDENTIAL

France
GERMANY

CONFIDENTIAL
B2C109575

Investigator

Investigator/ Site no.

Hospital/ Institution and Address


Dr. Med

IEC/IRB Committee Chair and Name of


Committee

Germany

Germany
Chairperson-

Dr. med.

Drs.
Germany
Chairperson-

Germany
KOREA
Korea

Korea
ChairpersonKorea

ChairpersonNETHERLAND
The

Netherlands
The Netherlands

The Netherlands
ChairpersonThe Netherlands
ChairpersonThe Netherlands
Chairperson-

The Netherlands
Peru

ChairpersonChairperson-

Peru
Peru

YM2008/00019/00
B2C109575

PERU

Peru

CONFIDENTIAL

Korea

CONFIDENTIAL
B2C109575

Investigator

Investigator/ Site no.

Hospital/ Institution and Address

IEC/IRB Committee Chair and Name of


Committee

Peru

Peru
Chairperson-

PHILIPPINES
Philippines
Philippines
Chairperson
Chairperson

Philippines
Chairperson
Chairperson

POLAND
Poland

Poland

Chairperson-

Poland
Poland

Chairperson-

Poland
Poland
ChairpersonPoland

YM2008/00019/00
B2C109575

Poland
Chairperson-

Poland

CONFIDENTIAL

Philippines

CONFIDENTIAL
B2C109575

Investigator

Investigator/ Site no.

Hospital/ Institution and Address

IEC/IRB Committee Chair and Name of


Committee
Chairperson-

Poland
RUSSIAN FEDERATION

Russia
Chairperson-

Russian Federation

Russian Federation
Chairperson-

Chairperson-

Russia

Russian Federation
Chairperson-

Russia

Russia
ChairpersonRussia
ChairpersonRussian Federation
Chairperson-

YM2008/00019/00
B2C109575

Russian Federation

CONFIDENTIAL

Russian Federation

CONFIDENTIAL
B2C109575

Investigator

Investigator/ Site no.

Hospital/ Institution and Address

IEC/IRB Committee Chair and Name of


Committee

Russian Federation

Russia
ChairpersonRussia
Russia

ChairpersonRussia
Chairperson-

Chairperson-

8
Russian

Federation
ChairpersonSOUTH AFRICA

CONFIDENTIAL

Russia
Russian Federation

South Africa
South

Africa

Chairperson-

South Africa
Chairperson-

South Africa

South Africa
Chairperson-

YM2008/00019/00
B2C109575

South Africa

CONFIDENTIAL
B2C109575

Investigator

Investigator/ Site no.

Hospital/ Institution and Address

IEC/IRB Committee Chair and Name of


Committee
South Africa

South Africa

Chairperson-

South Africa,

South Africa
Chairperson-

SWEDEN
Sweden
Sweden

ChairpersonSweden

Sweden
THAILAND

9
Thailand
Chairperson-

Thailand

Chairperson-

CONFIDENTIAL

Chairperson-

Thailand

Thailand
UNITED STATES

Chairperson-

YM2008/00019/00
B2C109575

Chairperson-

CONFIDENTIAL
B2C109575

Investigator

Investigator/ Site no.

Hospital/ Institution and Address

IEC/IRB Committee Chair and Name of


Committee

MD
ChairpersonChairpersonMD
ChairpersonChairperson-

10
ChairpersonChairperson-

CONFIDENTIAL

Chairperson-

Chairperson-

ChairpersonChairperson-

10

YM2008/00019/00
B2C109575

Chairperson-

CONFIDENTIAL
B2C109575

Investigator

Investigator/ Site no.

Hospital/ Institution and Address

IEC/IRB Committee Chair and Name of


Committee
ChairpersonChairpersonChairpersonChairperson-

ChairpersonMD,

CONFIDENTIAL

11

Chairperson-

ChairpersonChairpersonChairperson-

Co-ChairpersonCo-Chairperson-

11

YM2008/00019/00
B2C109575

M.D.,

CONFIDENTIAL
B2C109575

Investigator

Investigator/ Site no.

Hospital/ Institution and Address

IEC/IRB Committee Chair and Name of


Committee
ChairpersonChairpersonChairpersonChairperson-

12
ChairpersonChairperson-

CONFIDENTIAL

Chairperson-

Chairperson-

12

YM2008/00019/00
B2C109575

Chairperson*No Patients Enrolled

This section contained Principal Investigators Curriculum Vitae and has been excluded to
protect Principal Investigator privacy.

CONFIDENTIAL

YM2008/00019/00
B2C109575

CONFIDENTIAL

Assent Form B2C109575


for Genetic Research Using Coded Sample and Data
Effective Date: 6 November 2007
GlaxoSmithKline Protocol Title:
A Study to Evaluate the Efficacy and Safety of GW642444M Once a Day compared with
Placebo for 28 days in Patients 12 years of age and older with Asthma
Subject Number: __________________

If the subject is unable to sign #1 below, then #2 must be completed (this can be done
by the parent/legal representative or medical staff).
(#1)
This study will look at genes in my blood. The study has been explained to me
and my questions answered. I would like to be in the study. The tube with my blood has
a number on it. If I decide later that I dont want to be in the study, my blood will be
thrown away. I can ask the study staff questions at any time.
Date: ________________ Signature: ________________________________
Day / Month / Year

(#2)

In my opinion, this child is unable to give written assent.

Date: ________________ Signature: ________________________________


Day / Month / Year
Parent/Legal Representative

A copy of this Assent Form (signed and dated) must be given to the subjects
parent or legal representative.

PGx Assent Form


B2C109575

Version No.: 01
Dated: 6 Nov 2007

Page 1 of 1

CONFIDENTIAL

YM2008/00019/00
B2C109575

CONFIDENTIAL

Informed Consent Form and


Information Sheet for Pharmacogenetic Research

GlaxoSmithKline Protocol Title:


A randomised, double-blind, placebo-controlled, parallel group, dose ranging study
evaluating the efficacy and safety of GW642444M administered once daily compared
with placebo for 28 days in adolescent and adult subjects with persistent asthma

GlaxoSmithKline Protocol Number:


Study Doctor:
Site Address:

B2C109575

To be completed per site


To be completed per site

Site Phone Number: To be completed per site


Subject Identification: ____________________
This consent form is in addition to the informed consent form you signed for the
B2C109575 clinical study.
PURPOSE and DESCRIPTION OF THE RESEARCH
The purpose of this consent form is to explain what pharmacogenetic research is and to
ask you to give a blood sample that may be used in this research. The sponsor of the
research is the GlaxoSmithKline group of companies [referred to as GSK in this
consent]. The study doctor and institution are paid by GSK to conduct this research.
This study may have about 600 subjects at about 200 sites around the world.
WHAT IS PHRMACOGENETIC RESEARCH?
Genes, which we inherit from our parents, may control the way we react to or handle a
medicine. Pharmacogenetics is the study of differences in how our bodies respond to
or handle medicines. This pharmacogenetic research is looking at genetic differences
to better understand why people react differently when they get the same medicine. If it
appears that there is a difference in the way people respond to or handle GW642444M,
GSK may study these differences using your genes or genetic material taken from your
blood sample.
WHAT ARE THE BENEFITS of PARTICIPATING IN THIS RESEARCH STUDY?
You may help scientists understand why people react to or handle GW642444M
differently. This may help identify who is more likely to respond to GW642444M and
who may experience side effects.

PGx Consent Form


B2C109575
Page 1 of 5

Subject Initials _______Date____________


Version NO.: 02
Date: 10 DEC 2007

CONFIDENTIAL

YM2008/00019/00
B2C109575

CONFIDENTIAL

WHAT EXACTLY WILL PARTICIPATION IN THE RESEARCH INVOLVE?


If you choose to take part in this research, a qualified medical worker will take about
10mLs (or 2 teaspoons) of your blood. In the unlikely case that there is a problem
processing your sample, then we may ask you to give a second sample.
IS PARTICIPATION IN THIS STUDY VOLUNTARY?
Participation in this pharmacogenetic research is voluntary. You may decline to take
part now or you may decide to take part and then change your mind. GSK may store
your sample for up to 15 years after the last subject completes the study or GSK may
destroy your sample at an earlier time. If you decide not to participate or to withdraw
your consent after starting the study, you do not have to give a reason and there will be
no change to your medical treatment or to your participation in the B2C109575 study. If
you withdraw from this research, your sample will be destroyed and GSK will only keep
and study information collected/generated up to that point.
In special cases, your sample may not be used. This might happen if there are not
enough subjects, if the study is stopped for other reasons, or if no questions are raised
about how people respond to or handle GW642444M.
WHAT ARE THE RISKS INVOLVED WITH BLOOD SAMPLING?
The physical risks of giving a blood sample are the same as those for any blood sample
taken from a vein. You may feel faint, experience mild pain, bruising, irritation or
redness at the site of puncture. In rare cases an infection could develop.
COMPENSATION FOR STUDY-RELATED INJURY
[US Language]
If you are physically injured by the properly performed blood draw and you have
followed the directions of the study staff, the sponsor will cover the reasonable medical
expenses necessary to treat the injury. No other compensation is offered by GSK, but
you do not waive any legal rights by signing this consent form.
[ROW - Use language approved by operating company].
WHAT OTHER OPTIONS ARE THERE?
You have the choice not to take part in this research.
HOW ARE PRIVACY, DATA PROTECTION AND CONFIDENTIALITY PROTECTED?
As part of the study, medical information about you will be collected and analyzed along
with your sample. This medical information can include your asthma history.
To protect your privacy, your sample and medical information will be labeled (or
coded) with a study subject number, not your name. Only your study doctor and his or
her staff will keep the link between your subject number and your name.
PGx Consent Form
B2C109575
Page 2 of 5

Subject Initials _______Date____________


Version NO.: 02
Date: 10 DEC 2007

CONFIDENTIAL

YM2008/00019/00
B2C109575

CONFIDENTIAL

GSK will control access to its files that hold your coded information and results. Your
name will not appear in any publications or reports about this research.
GSK or those working with GSK (for example, other researchers) will only work with
your sample for the use stated in this consent. Samples will be stored securely. GSK
will require anyone who works with your sample to agree to hold the research
information and any individual results in confidence.
Medical information about you may be produced as part of the research or study
procedures. If at the time of the study, this information is known to be relevant to your
medical care it will be given to the study doctor who will be encouraged to share it with
you or your doctor. You will be told if any of this medical information requires
confirmation using a clinical test. This is important because some research results are
for research purposes and may have only limited relevance for clinical diagnosis or
treatment GSK will not release individual results to anyone else (e.g., family members,
primary care physicians, insurers, or employers) under any circumstance, unless
required by law.
GSK has taken appropriate measures to ensure the confidentiality of the researchrelated information. However, if you pass on your individual results (if obtained by you),
there is a possibility that this could have an affect on your insurance or employment.
This risk is similar as if you were to disclose any type of personal medical information to
a third party.
Medical information, samples and research results from you and other research
participants may be studied by GSK to make medicines or tests to determine the bodys
response to or handling of medicine. Your information and any results will be put in a
computer and stored in electronic databases. International regulations for information
on computers and relevant laws on processing personal information will be strictly
adhered to. Your information, sample, and results could be sent to other researchers
working with GSK and to other GSK sites.
By agreeing to take part in this research, you will allow your medical information,
sample, and pharmacogenetic results to be reviewed as part of collecting and analyzing
study results. The people who may check this research include GSK, people working
with GSK on this research, ethics committees and regulatory authorities (such as the
EMEA). These persons are required to maintain the confidentiality of the information.
WILL THERE BE COMPENSATION FOR PARTICIPATION IN THE RESEARCH?
You will not receive any payment for taking part in this pharmacogenetic research.
COMMERCIAL ISSUES
GSK and/or others intend to claim sole ownership of any research results consistent
with this consent. The results of this research may have commercial or intellectual
property value. By signing this consent, you agree that GSK can apply for patents and
PGx Consent Form
B2C109575
Page 3 of 5

Subject Initials _______Date____________


Version NO.: 02
Date: 10 DEC 2007

CONFIDENTIAL

YM2008/00019/00
B2C109575

CONFIDENTIAL

you understand that you will not receive any financial benefit that might come from the
research.
WHO CAN YOU CALL FOR MORE INFORMATION ABOUT THIS RESEARCH
STUDY?
You may contact __________ at telephone number __________ at any time if you have
questions about this study, an injury related to the blood draw for this research, or wish
to withdraw from this research. If you have questions about your rights as a research
subject, you may contact __________ of the Independent Ethics Committee at
telephone number________.

PGx Consent Form


B2C109575
Page 4 of 5

Subject Initials _______Date____________


Version NO.: 02
Date: 10 DEC 2007

CONFIDENTIAL

YM2008/00019/00
B2C109575

CONFIDENTIAL

CONSENT
A copy of this Consent Form (signed and dated) must be given to the subject
or legal representative.
GSK study code: B2C109575
My signature below indicates that:
1. I have read this form and the research has been explained to me.
2. I have been able to discuss the research and ask questions. I am satisfied with the
answers.
3. I have been given the time to consider whether or not to take part in this research.
4. I have freely decided to take part in the research study described in this form.

Subjects Name (Please Print): __________________________________


Subjects Signature: _______________________________________
Date:
____________
(or that of Legal Representative)
(Day/Month/Year)
Name and Signature of Individual Obtaining the Subjects Consent:
Name (Please Print): _________________________________
Signature: ________________________________________________ Date:
____________
(Day/Month/Year)

PGx Consent Form


B2C109575
Page 5 of 5

Subject Initials _______Date____________


Version NO.: 02
Date: 10 DEC 2007

CONFIDENTIAL

YM2008/00019/00
B2C109575

CONFIDENTIAL

WRITTEN ASSENT FORM

Study Title

A Study to Evaluate the Efficacy and Safety of GW642444M Once a Day


compared with Placebo for 28days in Patients 12 years of age and older
with Asthma

Study Identifier:

B2C109575

Sponsor:

GlaxoSmithKline (GSK)
Five Moore Drive
P.O. Box 13398
Research Triangle Park, NC 27709

Subject
Identification: __________________
Study Doctor: ___________________

WHY IS THE STUDY BEING DONE?


Doctor [Investigator Name] is doing a study to see if a new medicine for asthma works.
This study will compare different doses of the new medicine to see which one works the
best. The medicines come in a powder form, but you use it the same way as your inhaler.
You can only be in this study if you have asthma. About 600 people, 12 years of age and
older with asthma, will take part in this study.

WHAT MEDICINES WILL I TAKE?


If you are in the study, you will be given an inhaler device. All inhaler devices have
powder in them; some of inhalers have powder in them that contains medicine, but some
do not contain any medicine at all. You and your doctor will not be able to tell if your
inhaler devices have medicine in them or not, but your doctor can find out if he/she needs
to.
The doctor will review all your current medication and tell you which medicines you can
and cannot take during the study. You will continue to use your steroid inhaler whilst you
are in the study. You will be given a fast acting, quick relief inhaler (albuterol/salbutamol)
to take home so you can use it for your asthma symptoms when you have them.

WHAT DO I HAVE TO DO?


This study will last for up to 7 weeks. You will come to your doctors office up to 9 times
altogether. Some subjects need to stay in the clinic overnight for 2 of the visits. Your
doctor will discuss this with you and your parent/guardian to see if you want to or are able
to.
Informed Assent Form
B2C109575

Childs Initials________Date_________
Version No.: 03
-1-

14Apr08

CONFIDENTIAL

YM2008/00019/00
B2C109575

CONFIDENTIAL

For some of the visits you will need to fast (nothing to eat or drink, except water) before
and during the visit. Your study doctor will explain this to you in more detail.
When you come to your doctors office, you will usually need to blow into a machine that
will tell the doctor how well you can breathe. On two of the visits you will need to do this
quite a few times throughout the day. You may occasionally feel lightheaded when
blowing into the machine. You will be asked questions about how you are feeling during
the study.
Your doctor will check your pulse and blood pressure and make tracings of your heart
rhythm throughout the morning on most of the visits. These are painless procedures.
At anytime during the study, tell your Mom or Dad [use country region descriptions] or
your guardian or the doctor if you feel sick.
Your doctor will give you a special device to take home with you to blow in every day that
will keep track of how well you are breathing. Your doctor will tell you how to use this
device. You will blow into the device in the morning and the evening before you take your
medication. You will also keep track of whether or not you used your medicine each day
and what your asthma symptoms are like each day. You will need to bring the device with
you to every visit. You need to tell your parents/guardian if your asthma gets worse or call
your doctor.
Your doctor or study staff will also give you a paper diary to keep track of how well you are
feeling. You will write down if you dont feel well and write down any medicines you take
when you dont feel well during the study. You will need to bring the card with you to every
visit.
When you come to your study doctors office you will have some blood taken for tests to
check your health. If you are a female this will include a pregnancy test at one of the
visits. The doctor will insert a small plastic tube into your vein to make taking blood
easier. This may be uncomfortable and will occasionally hurt, but only for a short time.
When you come into the doctors office at the start, and then again at the end of the study,
you will also be asked to give a small amount of urine (pee) [use country regional
description] in a cup for some tests to check your health. If you are a female this will
include a pregnancy test.
You do not have to be in the study if you don't want to. If you say yes now, you can still
say no at any time and stop later if you change your mind. No one will mind or be angry
with you if you say no. The doctor will still take care of you in exactly the same way. The
doctor will give you other medicine for your asthma.

CAN BAD THINGS HAPPEN TO ME BY BEING IN THE STUDY?


Your asthma could get worse during the study. The doctor may decide to stop you from
continuing in the study if your asthma gets worse or if your doctor feels there are other
reasons that it is not safe for you to continue in the study. Also, the sponsor of the study
may decide to stop the study at any time.
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If you have any questions, you should ask your study doctor or his staff.
Sign your name below if you want to be in the study. Do not sign below if you do not want
to be in the study.

Childs Signature

Date

Parent/Guardians Signature

Date

Assent Form administered and explained in person by:

Signature and Title

Date

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Written Informed Consent Form

Study Title

A randomised, double-blind, placebo-controlled, parallel group, dose


ranging study evaluating the efficacy and safety of GW642444M
administered once daily compared with placebo for 28 days in
adolescent and adult subjects with persistent asthma

Study Identifier:

B2C109575

Sponsor:

GlaxoSmithKline (GSK)

Subject
Identification: __________________
Study Doctor:
Written Information Sheet

WHAT DOES GIVING CONSENT MEAN?


The information in this consent form will help you decide if you would like to take part in
this study. The consent is an agreement from you that you wish to take part in this
study. Before you decide, it is important for you to know why the research is being done,
what will happen during the study and your rights if you decide you want to take part in
the study. Please read the following information carefully and talk about it if you wish
with friends, family and your doctor. This form may have words or information that you
do not understand. Please ask the study doctor or study nurse to explain any words or
information that you do not understand. Take your time to decide whether or not you
wish to take part.
WHY IS THE STUDY BEING DONE AND ARE THERE ANY OTHER TREATMENTS?
You are invited to take part in a study testing the experimental drug GW642444M, which
is being studied as a new treatment for people with asthma. Experimental study drugs
are drugs which have not been approved for general use in a country by the regulatory
authorities in that country. This experimental study drug belongs to a family of drugs
called beta2 agonists. It works by acting on muscles around the airways in the lungs,
causing them to relax, which helps open up the airways and make breathing easier. The
study drug, which is a fine dry powder, will be given by inhalation and breathed in
through your mouth, using an inhaler.
This study compares how well different doses of the experimental study drug,
(GW642444M) compared to placebo (which has no active ingredients) control asthma.
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Placebo is a powder that looks like the study drug but contains no medicine. Different
doses of the study drug are included to see which dose works best.
Some other drugs (taken by mouth or breathed in) are available for the treatment of
asthma. These include drugs which help to open the airways in the lungs (such as quick
relief medicines like albuterol/salbutamol [use country specific names]), and drugs which
help reduce inflammation (redness and swelling) in the airways of the lungs (inhaled
corticosteroids). If you decide not to be in this study, your study doctor will advise you
on which asthma drug or drugs you need to take and other things you need to do for
your asthma.
HOW MANY VISITS ARE REQUIRED?
You may be in this study up to 7 weeks and will need to visit with your study doctor
between 6 to 9 times.
The following visits will take place:
Approximate Time
required to spend
Visit No.
Time
at the Clinic
Screening
2-3hrs (between
Visit 1
Study Start
5PM and 10PM)
Screening
Rescreening (if required)
2-3hrs (between
Period
5PM and 10PM)
Randomisation
6 hours if not staying
overnight
27 hours if staying
Visit 2
2 Weeks after Visit 1
overnight
Visit 2a*
Treatment
9 hours
Visit 3
Treatment
1 Week after Visit 2
5 hours
Visit 4
Treatment
1 Week after Visit 3
5 hours
End of Treatment
6 hours if not staying
overnight
27 hours if staying
Visit 5
2 Week after Visit 4
overnight
Visit 5a*
Treatment
9 hours
Visit 6
Follow-up
1 Week after Visit 5
1 hour
* About half of all subjects will be required to remain at the clinic overnight at Visit 2 and
Visit 5. Your study doctor will discuss with you if this is a possible option or not. If you
do not stay overnight you will still need to return to the clinic the next day for Visits 2a
and 5a.
Visit Type

Visits 1 Screening Period: If you qualify for the study, you will keep taking your own
steroid inhaler and will be given a quick relief or rescue inhaler (albuterol/salbutamol
inhalation aerosol) to use for the relief of any asthma symptoms. Study procedures and
tests, described below, will be done to check your asthma. You will be asked to
describe any medical problems you have now and medical problems you have had in
the past (before this visit). You will also need to tell your doctor about any drugs you are
taking.
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At Visit 2: If you still qualify to be in the study you will be randomised to study drug.
Randomisation means that you are randomly (by chance, like flipping a coin) assigned to
one of the six study treatments. The group you are assigned to is chosen by a computer
program, without using any information about you. You will take your first dose of study
drug in the clinic at this visit.
You will receive one of the following six study drugs to be taken in the evening every day
for 4 weeks:
EVENING
3mcg GW642444M Inhaler
6.25mcg GW642444M Inhaler
12.5mcg GW642444M Inhaler
25mcg GW642444M Inhaler
50mcg GW642444M Inhaler
Placebo Inhaler
mcg = microgram
You will have a 1 out of 6 (17%) chance of receiving placebo.
Because this is a blinded study, neither you, your doctor, nor your study nurse, will
know what study drug (or placebo) you have been given. Your study doctor can find out
what drug you are on at any time if it is necessary to know this for your safety.
If you are not staying at the clinic overnight you will need to return to the clinic the
following day in the mid-morning for visit 2a.
Visits 3 and 4: During the 4 weeks of taking this drug, you will visit the clinic twice.
Study tests, listed below, will be done to check your asthma. The study doctor will
decide at each visit if you may continue to be in the study.
Visit 5/5a: This is the visit when you will stop taking the study drug. You will need to
return all study medication that has been provided to you for this study.
If you are not staying at the clinic overnight you will need to return to the clinic the
following day in the mid-morning for visit 5a.
Visit 6: This is the follow-up clinic visit and will happen 1 week after finishing the study
drug to see how you are feeling or if you have any questions about your asthma. You
will need to return all study related equipment and your rescue inhaler at this visit. Your
doctor will tell you what asthma drugs and other care you need for your asthma.

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WHAT WILL BE DONE DURING THE STUDY?


Visit 1 (Screening Period):
At your first visit we will obtain your informed consent before proceeding with any
assessments. You will need to fast (nothing to eat and drink except water) for at least 4
hours before you are due to have your blood taken until after you have had your blood
taken for testing.
Medical, Therapy and Smoking History: You will be asked to describe the medical
problems you have now and any medical problems you have had before this visit.
It is important you tell your doctor if you have any allergies, such as severe milk protein
allergy, as this may affect your ability to take part in this study.
You will also need to tell your doctor about your smoking history and any drugs you may
be taking (such as aspirin or vitamins).
Blood and Urine Lab Tests:
About 3 teaspoons (16mLs) of blood will be taken from a vein in your arm to check your
health. This will also be checked at Visits 4 and 5 (or if you have to stop taking the study
drug at another visit). If you are a female your pregnancy status will also be checked at
this Visit (blood sample) and again at Visit 2 and Visit 5/5a (urine samples) (or if you
have to stop taking the study drug at another visit). More about the blood tests will be
explained to you by your study doctor.
You will also need to give a urine sample to check your health.
Physical Examination and Medical Tests:
Your study doctor will perform a physical exam, check your pulse rate and blood
pressure and perform medical tests including an ECG (trace of heart activity), lung
function tests (to measure how well your lungs are working by asking you to blow at
different times into a machine). You will have to do the lung function tests before and
after you have taken a quick relief inhaler). If your lung function test results mean that
you are not eligible to take part in the study on the first attempt, you may be given the
option to return to the clinic within 4 days to try again.
Peak Expiratory Flow:
Before you leave the clinic we will give you your quick relief inhaler and an electronic
peak flow meter. The peak flow meter is a small device that you use at home to
measure your lung function (how fast you can blow air from your lungs). You will be
taught how to use the peak flow meter. You will need to use this meter twice a day,
morning and evening, to measure your peak flow. You will need to do this every day
until you complete the study (Visit 6).

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Electronic Daily Diary:


The electronic diary is an instrument that combines a peak flow meter and a symptom
diary. Every day in the morning and evening, you will need to answer the following
questions on the electronic diary:

If you took your regular steroid inhaler medicine.


How you rate your day-time and night-time asthma symptoms on a scale (this scale
will be explained to you by your study doctor or study staff).
The number of inhalations (puffs) of the quick relief or rescue inhaler you used
during the day and during the night.

You should refrain from using your quick reliever medication for 6 hours before
each visit (excluding follow-up Visit 6).
Please take your regular inhaled steroid as usual before you attend the clinic
visits.
You will need to fast (nothing to eat or drink except water) for at least 4 hours
before Visit 2 And Visit 5 until 4 hours after you take your dose of study drug at
the clinic.
Visit 2/2a and 5/5a:

Administration of study drug, and a check to see how well you are using your
inhaler.

Review of your daily diary.

Ask if you are experiencing any problems or side effects.

Lung Function Tests (42 in total if you are staying in overnight, 36 in total if you are
not staying in overnight).

ECG measurements (5 in total).

Heart rate and blood pressure tests: (5 in total).

Blood Tests: Because blood will be taken a number of times during the visit a small
plastic tube (cannula) will be inserted into one of the veins in your arm. We will take
approximately 50mLs of blood (10 teaspoons full).

Urine sample to check health at Visit 5 only and pregnancy status (females only) at
Visit 2 and 5/5a.

Reversibility Test: You will be given a lung function test to measure your breathing
before and after you have been given a quick relief or rescue inhaler
(albuterol/salbutamol inhalation aerosol).

Once you have been randomised to receive study medication you should measure your
peak flow as follows:
Morning: before you take your steroid inhaler or any rescue medication
Evening: before your evening dose of study medication and before you take
your steroid inhaler or any rescue medication
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You will also be asked to write down on a specific piece of paper the times when you
feel sick, any drugs not related to this study that you may have started to take, or if you
have changed the amount of any drugs you are already taking.
Study Drug: You must take your study drug once every day in the evening (as your
doctor has told you), and bring all of the used and unused study drug with you to each
visit.
Visit 3 and 4:

Administration of study drug, and a check to see how well you are using your
inhaler.

Lung Function Tests (3 in total).

ECG measurements (5 in total).

Heart rate and Blood pressure tests: (5 in total)

Blood Tests: As we will take blood a number of times during the visit a small plastic
tube (cannula) may be inserted into one of the veins in your arm. We will take
approximately 30mLs of blood (6 teaspoons full).

Visit 6 (Follow-up Visit):

Review of your electronic diary and return all study related equipment and
medication

Review of your therapy and any problems or side effects

Early Withdrawal Visit:


If you withdraw from the study early for any reason you will need to attend an Early
Withdrawal Visit at the clinic. The following assessments will be performed:
Physical examination
Lung function tests
Heart rate and blood pressure test
ECG measurement
A blood test to check your health, and pregnancy status (females only for
pregnancy test)
A urine sample to check your health
Review your diary, and ask if you have experienced any side effects or health
problems
You will need to return all study related medications and equipment at this visit.
HOW MANY OTHER SUBJECTS ARE THERE IN THE STUDY?
About 600 male and female subjects with asthma who are 12 years of age and older will
be in this study at about 200 clinics around the world. Once the number of subjects
needed for the study is in the study, no more subjects will be allowed to enter the study.
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DO YOU HAVE TO STAY IN THE STUDY?


Your participation is entirely voluntary. You may decide you do not want to take part in
this study. Should you decide to take part, you will be given this information to take
home, you will be asked to read this information, and you will be asked to sign a consent
form. You may decide at any time that you no longer want to take part in this study after
it has started. Should you decide this, you must inform your study doctor as soon as you
can. Your decision not to take part in the study or to leave the study after it has started
will not affect your current or future medical care, or any benefits to which you may
otherwise be entitled.
If you have a very bad asthma attack or your asthma gets worse (asthma exacerbation),
you will not be allowed to stay in the study if any of the following happens:

You are admitted to a hospital


You visit an emergency room or urgent care facility for your asthma
You need other drugs for your asthma besides study medication, rescue
medication and your usual dose of inhaled steroid
You need a lot more study rescue medication (quick relief) than usual

If this happens, you will be asked to complete the Early Withdrawal Visit, your study drug
will be collected, and your study doctor will recommend other drugs and care for your
asthma. If the study doctor is not your regular doctor, you will be asked to go back to
your regular doctor.
You should contact your study doctor if you decide to stop being in the study for any
reason. Your study doctor will tell you the best way for you to stop being in the study.
Although not expected, the company doing this study or the study doctor may decide
you should stop being in this study at any time for any of the following reasons:

It is not in the best interest of your health to continue the study medication
Something serious happens to you, which may need treatment
You do not follow your doctors instructions
The study is stopped or cancelled
You become pregnant.

Sometimes during the course of a research project, new information becomes available
about the drug that is being studied. If this happens, your doctor will tell you about the
new information and you can talk to your study doctor to decide if you want to stay in the
study. Any information and study data collected before you withdraw from the study will
be used at GSK, the company doing this study.
WHAT IF I AM TAKING AN INHALED CORTICOSTEROID AND LONG-ACTING beta2AGONIST COMBINATION TO CONTROL MY ASTHMA NOW?
If you are currently taking an inhaled corticosteroid (ICS) and long-acting beta2-agonist
(LABA) combination (e.g., Advair/Seretide, Symbicort) before you sign this consent form,
you may still be in this study if you and your doctor decide, but you will need to stop
taking your combination treatment 1 week before Visit 1. You will need to take an ICS
that has been prescribed to you throughout the study (Until Visit 6) but must stop taking
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the long-acting beta2-agonist (LABA) 1 week before Visit 1. You may take a quick relief
inhaler such as albuterol/salbutamol, in the 1 week before Visit 1, and during the study.
The study doctor will decide if your ICS and LABA combination can be changed to the
ICS by itself based on your current and past asthma history. If you stop or change any
medications to be in this study, there is a danger that your asthma may get worse.
Before changing any medication for this study, you will be told about all of the possible
risks and benefits of changing your medication and you must agree that you have been
told about these risks and benefits by signing this consent form. Changing your asthma
medication may cause your asthma symptoms to get worse. Risks include asthma that
gets worse, including immediate asthma attacks, more wheezing and breathing
problems than usual, using more quick relief medication (albuterol/salbutamol) than
usual, waking up more at night because of asthma, and having asthma symptoms on
more days than usual.
After talking about any possible changes in your medications with the study doctor and
the possible risks and benefits of these changes, it is your choice whether you want to
change your asthma medication to qualify to participate in this study. The study doctor
must agree your medicine can be switched based on your current and past asthma
history. If you decide you do not want to change asthma medications, then you will not
be able to take part in this study.

WHAT ARE THE EXPECTED RISKS FOR TAKING PART IN THE STUDY?
All drugs may cause side effects in some people. There are known side effects for the
study medications. Only you should take the study medication, and it must be kept out
of the reach of children and persons not able to read or understand.
WHAT ARE THE MOST COMMON SIDE EFFECTS FOR THE STUDY MEDICATION I
MAY RECEIVE DURING THIS TRIAL?
The drug being tested in this study may involve risks to you that are currently
unforeseeable. As with any new medicine that only a limited number of people have
taken, we dont yet know all its side effects. In any clinical trial, there is a risk of an unexpected, serious reaction to the study medicine, which could be life threatening.
Descriptions of all known possible side effects are listed below.
GW642444M
GW642444M is a long acting beta2 agonists. Long acting beta2 agonists have been
associated with the following side effects:

Increases in heart rate


Changes in blood pressure
Decreases of potassium levels (a chemical) in blood stream
Increases in glucose levels (i.e. sugar) in the blood stream
Awareness of heart beating
Tremors (shakiness of hands)

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Headaches
Muscle cramps (pain in the muscles)
Cardiac arrhythmias (abnormal heart rhythms when the heart beats too slow or too
fast or not on a regular rhythm) (rarely)

Inhaling any medicine can occasionally cause the airways to narrow for a short time,
leading to wheezing, shortness of breath and chest tightness. If that happens to you,
you will be given a quick relief inhaler to relieve your symptoms.
Data from a large clinical study in the United States has shown that subjects taking
salmeterol (insert trade name), which is also a long acting beta2 agonist, were at an
increased risk of serious respiratory-related events, including a small but significant
increase in deaths, from asthma problems when compared with those subjects taking
placebo. Further analyses suggest that this risk may be greater in African Americans.
Reproductive Risks
Pregnant or breast feeding women, or women planning to become pregnant cannot
participate in this study.
Aside from abstinence, even when you use one of the allowed contraceptive methods,
there may still be a small risk that you could become pregnant and your unborn baby
may have been exposed to one of the study drugs, which may involve unknown risks to
your baby, even if you stop taking the drug right away. So, if you think you are pregnant
or may become pregnant, you must tell your study doctor as soon as possible. If you do
become pregnant you will be required to withdraw from the study.
There are no studies with GW642444 in pregnant women. The safety of GW642444 in
pregnancy has been studied in several different types of animals. In the developing
offspring from these pregnant animals treated with GW642444, cleft palate, problems
with how bones form and join together, and eye lid changes were sometimes seen.
.
All females aged 12 years and older, except those who are pregnant, nursing or
planning to get pregnant during the time of the study, may be in this study.
If you choose to be in this study, you must use one of the allowed birth control methods
(a way to keep you from becoming pregnant) for the specified period of time before and
after you are in the study. Ask your doctor if you have any questions about these
choices and which might be best for you. The kinds of birth control methods allowed in
the study are:
Male partner who is sterile prior to the female subject entering into the study and is
the only sexual partner for that female subject
Implants of levonorgestrel (NORPLANT)
Injectable progestogen (DEPO-PROVERA)
Birth control pills (either combined estrogen/progestin or progestin only)
Any intrauterine device (IUD) with a documented failure rate of less than 1% per year
Females of childbearing potential who are not sexually active must commit to
complete abstinence from intercourse throughout the clinical trial, and for a period
after the trial to account for elimination of the drug (minimum of six days).

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Double barrier method spermacide plus a mechanical barrier (e.g., spermacide


plus a male condom or a spermacide and female diaphragm) Not applicable for
German subjects.
The contraceptive transdermal patch, ORTHO EVRA (if the subject is less than 198
pounds or 90kg)
Estrogenic vaginal ring

All females will have a blood pregnancy test at Visit 1 and a urine pregnancy test Visit 2
and Visit 5/5a. The test at Visit 1 and Visit 2 must be negative for you to continue in the
study. Any female subject who becomes pregnant during the study will have to stop
being in the study right away.
Placebo
If you are randomised to receive placebo (which is a powder that looks like the study
drug but contains no medicine) the only active medicine you will receive as part of the
study is the quick relief or rescue inhaler. You will however need to keep taking your
own steroid inhaler. Your asthma may get worse, so your asthma symptoms, breathing
(lung function) and quick relief or rescue inhaler use will be checked closely to see if
your asthma is getting worse. Your study doctor will stop you from staying in the study if
your asthma is getting worse, before the condition of your asthma becomes unsafe. Let
your study doctor know if you feel your asthma is getting worse.
Study Rescue Medication (albuterol/salbutamol)
The quick relief or rescue inhaler (albuterol/salbutamol) is available by prescription.
Common side effects reported by people taking albuterol/salbutamol include:

Skin rashes, swelling in the face or mouth and throat, shortness of breath and/or
wheezing with or without a low blood pressure
Decrease of potassium (a chemical) in the blood stream
Tremor (shakiness of hands)
Headache
Hyperactivity
Tachycardia (fast heart beat)
Awareness of heart beating
Cardiac arrhythmias (abnormal heart rhythms when the heart beats too slow or too
fast or not on a regular rhythm)
Peripheral vasodilation (flushing of the skin)
Wheezing or trouble breathing after using an inhaler
Mouth and throat irritation
Muscle cramps (pain in the muscles)

WHAT OTHER POSSIBLE RISKS ARE THERE FOR BEING IN THIS STUDY?
During the breathing (lung function) tests, you may have shortness of breath, coughing,
feel light-headed or faint and/or have chest tightness. If any of these things should
happen to you, you will receive medical treatment.

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You will be asked to stop taking your quick reliever for a certain period of time prior to a
breathing test.
Although the study drug in this clinical trial is not known to cause liver problems, study
drug(s) can uncommonly cause liver injury, which is identified by blood tests, or the
appearance of or worsening of fatigue (feeling tired), nausea (feeling sick in your
stomach), vomiting, abdominal pain (pain in the stomach area), jaundice (yellow eyes
and/or skin), fever, or rash. Should you develop these signs, you must tell your doctor
right away. If your blood tests suggest a possible liver injury, you will be asked to return
to the clinic right away to assure your continued safety, and to do more testing to see if
your liver disease was caused by a virus, a gallbladder problem or some other liver
disease. This testing will include additional blood tests (approximately 1 teaspoon per
test), and may include a liver ultrasound (picture) or other liver tests. If this happens,
your study doctor will ask you to stop taking the study medication. Your safety will be
checked until your blood tests return to normal.
During the study at any time, but especially during the 4-week treatment phase of the
study, your asthma may get worse, stay the same, or get better. Even though the quick
relief inhaler may make you feel better, there is a chance that your asthma may get
worse. If you feel that your asthma is getting worse, use the quick relief inhaler given to
you. If your asthma does not get better after using this inhaler, call the study doctor at
the phone number listed on this form or go to the emergency room for medical attention
right away.
When blood is taken for lab tests, you may feel slight pain or discomfort from the needle
stick in your vein and occasionally you may get a bruise or feel faint. Rarely, infection or
bleeding may develop where the needle entered the skin or vein.
You may experience slight skin irritation from the ECG pads, but this is generally mild
and resolves within a few days.
It is very important that you are able to make it to the clinic for all study visits, so you
need to think about the time needed and whether you can do this before you agree to be
in the study.
ARE THERE ANY BENEFITS FROM BEING IN THE STUDY?
A possible benefit of this study is having your asthma get better but this benefit cannot
be guaranteed. Although this study may not be of direct benefit to you, you may receive
helpful information about asthma and its treatment from being in this study. Also,
discovery of new medicines may provide benefits to other people with asthma and new
ways to manage asthma.
WHAT PAYMENTS WILL BE MADE FOR THE STUDY?
There will be no cost to you for study medications or clinic visits. You will not be paid for
participating in the study; however, GSK has made provisions with the study doctor to
compensate you for the reasonable travel costs to and from study visits and for other
miscellaneous costs (such as expense for a meal).
You will be paid $
per visit, for a total of $
to compensate you for the travel
costs to and from study visits and for other miscellaneous costs if you complete this
study. If you have to stop being in the study before completing this study, or if the study
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ends early, you will receive a partial payment based upon the number of visits
completed.
WHO SHOULD YOU CONTACT TO ANSWER ANY QUESTIONS ON THE STUDY?
If you have any questions concerning this study, or if at any time you feel you have
experienced a research-related injury or a reaction to the study medication, you may
contact Dr.
at
or after hours at
.
If you have any questions about your rights as a study subject, you may call:
[Insert Independent Ethics Committee]
[and address]
[and phone number]
An independent ethics committee or institutional review board (IEC/IRB) is an
independent group of people who have reviewed this research study with the welfare of
the subject in mind.

IN THE EVENT YOU ARE INJURED IN THE STUDY, WHAT COMPENSATION WILL
BE AVAILABLE?
US required language:
If you are injured by the investigational medicine being studied or by any procedure that
is done to you as specified by the study, GSK will pay for reasonable and necessary
medical expenses to treat the injury that are not covered by your medical insurance.
GSK is not offering to compensate you for any other expenses; you do not give up any
of your legal rights by signing this form.
Required language for UK and other countries with local requirements:
If you are injured by a medicine or clinical procedure that you would not have been given
outside this study, you will be compensated. Your study doctor can give you a copy of
the compensation guidelines for this kind of injury.
WHO WILL HAVE ACCESS TO MEDICAL AND PERSONAL INFORMATION ABOUT
YOU THAT IS COLLECTED IN THIS STUDY?
If you decide to participate in the study, the study doctor and staff will collect medical
and personal information about you as part of doing the study. People who work for or
with GlaxoSmithKline, and others like the independent ethics committee or the
institutional review board (IEC/IRB) for the study or regulatory authorities responsible for
approving medicines, will have access to this information at the site in order to check
that the study is done properly. GlaxoSmithKline staff who see this information at the
site will keep it confidential.
The study site will also transfer to GSK some of the information it collects, in a coded
form. The information transferred will not include your name, initials, address, or other
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direct identifiers. It will be assigned a code number that only the site can connect back
to your name.
Your permission to the study doctor and staff to use this information and share it with
GlaxoSmithKline and others as described below for the study doesnt automatically end
at a particular time.
You may decide not to sign this authorization (by signing this consent form), or you may
revoke this authorization in writing at any time. However, you can only participate in the
study if you authorize the use and disclosure of the information as described above. If
you decide not to sign this authorization/consent form, you will not be enrolled in the
study. If you sign this authorization and decide later to revoke this authorization, you will
be dropped from the study at that time. Information collected up to the time you revoke
this authorization will continue to be used as study data if it is scientifically appropriate to
do so.
While you are in the study, the study site will not share certain new medical information
about you that is created as part of the study (such as whether or not you are getting
study drug, or the results of certain tests) unless the study doctor decides it is medically
important to do so. This is done to stop the study results from being distorted. Once the
study is over, you will be given access to medical information about you that you are
entitled to see. At any time, you may ask your study doctor to let you see your personal
information, e.g., name and address and to correct it if necessary.
WHAT WILL GLAXOSMITHKLINE (GSK) DO WITH THE INFORMATION IT GETS?
GSK may use the information that the study doctor gives it (i.e. the coded information):

By storing and analyzing it electronically to find out what this study is telling us.

By sharing it with regulatory authorities that approve new medicines, or with groups
that check that research is done properly

By publishing the results of the study (this will not include any information that
directly identifies you)

By sharing it as part of research with other companies or universities for the purpose
of further understanding or developing this drug and with other GSK offices in this
country and in other countries. If the information is sent to another country, GSK will
apply the same level of protection to your information, to the extent permitted by
local law

By using it to plan new studies or other types of research or other medical purposes
related to the development of the drug.

WHAT WILL HAPPEN TO TISSUE SAMPLES (BLOOD and URINE) FROM THIS
STUDY?
Blood samples will be taken during the study to confirm subject eligibility and to assess
the effects of GW642444M. Blood samples collected will be coded to protect your
confidentiality and will be transferred to GSK or other researchers working with GSK.
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Samples will not be stored for longer than 15 years from the date the last subject has
completed the study.
HOW IS GLAXOSMITHKLINE INVOLVED?
This study is sponsored by GlaxoSmithKline (GSK). The study doctors and/or the
institutions are paid by GSK to conduct this research study.
SUBECTSs STATEMENT OF CONSENT
I have read the statements in this informed consent form for this study. The study
information and procedures have been explained to me by [insert name(s)] on [insert
date] during the consent process for this study.
I have had the opportunity to ask questions about this study, and answers and
explanations have been provided.
I have been given time and opportunity to read the information carefully, to discuss it
with others and to decide whether or not to take part in this study.
I authorize the use and disclosure of my personal information as described in this
document.
I agree to take part in this study.

Subjects Signature

Date

Printed name of Subject

Signature of Legally
Acceptable Representative (LAR)

Date

Print name of Legally


Acceptable Representative (LAR)

Description of LAR authority,


i.e. parent/guardian, etc.:

Signature of Witness

Date

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Printed name of Witness

Signature of Person Conducting Consent

Date

Printed name of Person Conducting Consent

Informed Consent Form


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ICH Data Listings


Page

Listing - ICH 6.1 Listing of Reasons for Premature Withdrawal (Intent-to-Treat


Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Listing - ICH 6.2 Listing of Subjects with Inclusion / Exclusion Criteria Deviations
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11

Listing - ICH 6.3 Listing of Subjects for Whom the Treatment Blind was Broken
during the Study (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . .

12

Listing - ICH 6.4 Listing of Demographic Characteristics (Intent-to-Treat


Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13

Listing - ICH 6.5 Listing of Race (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . .

41

Listing - ICH 7.1 Listing of Clinic Lung Function Data (Intent-to-Treat Population) . .

69

Listing - ICH 8.1 Listing of Exposure and Compliance Data (Intent-to-Treat


Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

794

Listing - ICH 8.2 Listing of Subject Numbers for Individual Adverse Events
(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

855

Listing - ICH 8.3 Listing of Pre-Treatment Adverse Events (Intent-to-Treat


Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

889

Listing - ICH 8.4 Listing of On-Treatment Adverse Events (Intent-to-Treat


Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

892

Listing - ICH 8.5 Listing of Post-Treatment Adverse Events (Intent-to-Treat


Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

970

Listing - ICH 8.6 Listing of Adverse Events Leading to Permanent Discontinuation


of Study Drug or Withdrawal from the Study (Intent-to-Treat Population) . . . . . .

979

Listing - ICH 8.7 Listing of Non-Fatal Serious Adverse Events (Intent-to-Treat


Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

984

Listing - ICH 8.8 Listing of Fatal Adverse Events (Intent-to-Treat Population) . . . . . .

985

Listing - ICH 8.9 Listing of Adverse Events for Subjects not in Intent-to-Treat
Population (Not in Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . .

986

Listing - ICH 8.10 Listing of Chemistry Data for Subjects With at Least One Normal
Range Abnormality (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . .

987

Listing - ICH 8.11 Listing of Haematology Data for Subjects With at Least One
Normal Range Abnormality (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . .

2848

Listing - ICH 8.12 Listing of Urinalysis Data for Subjects with Positive Dipstick
Results (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4148

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Listing - ICH 8.20 Listing of Exposure and Compliance Data Subjects Who
Received Treatment but Were Not Randomised (Total Population) . . . . . . . . . .

4282

Listing - ICH 8.21 Listing of Chemistry Data for Subjects With at Least One Normal
Range Abnormality Subjects Who Received Treatment but Were Not
Randomised (Total Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4283

Listing - ICH 8.22 Listing of Haematology Data for Subjects With at Least One
Normal Range Abnormality Subjects Who Received Treatment but Were Not
Randomised (Total Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4287

This section contained data from each individual patient, rather than in aggregate. They have
been excluded to protect patient privacy. Anonymized data from each patient may be made
available subject to an approved research proposal. For further information please see the
Patient Level Data section of the GSK Clinical Study Register.

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Other Data Listings


Page

Listing - Other 6.6 Listing of Randomisation Data (Intent-to-Treat Population) . . . . .

Listing - Other 6.7 Listing of Reasons for Protocol Deviation (Intent-to-Treat


Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

25

Listing - Other 6.8 Listing of Subjects who Received Incorrect Medication


(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

30

Listing - Other 6.9 Listing of History of Tobacco Use (Intent-to-Treat Population) . . .

31

Listing - Other 6.10 Listing of Duration of Asthma and Asthma History


(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

59

Listing - Other 6.11 Listing of Current Medical Conditions (Intent-to-Treat


Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

88

Listing - Other 6.12 Listing of Concomitant Medications (Intent-to-Treat Population)

141

Listing - Other 6.13 Listing of Relationship Between ATC Level 1, Ingredient and
Verbatim Text (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1076

Listing - Other 6.101 Listing of Subjects with Compliance Greater than 110
Percent (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1129

Listing - Other 8.13 Listing of Vital Signs (Intent-to-Treat Population) . . . . . . . . . . . .

1130

Listing - Other 8.14 Listing of ECG Values (Intent-to-Treat Population) . . . . . . . . . .

1738

Listing - Other 8.15 Listing of ECG Findings (Intent-to-Treat Population) . . . . . . . . .

2667

Listing - Other 8.16 Listing of Potassium and Glucose (Intent-to-Treat Population) .

4738

Listing - Other 8.17 Listing of Asthma Exacerbations (Intent-to-Treat Population) . .

5338

Listing - Other 8.18 Listing of Device Malfunctions (Intent-to-Treat Population) . . . .

5340

Listing - Other 8.19 Listing of Viral Data (Intent-to-Treat Population) . . . . . . . . . . . .

5359

Listing - Other 8.23 Listing of Vital Signs Subjects Who Received Treatment but
Were Not Randomised (Total Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5360

Listing - Other 9.1 Listing of Individual Plasma PK Concentration-Time Data for


GW642444 (PK Concentration Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5361

Listing - Other 9.2 Listing of Individual Plasma PK Concentration-Time Data for


Triphenylacetate (PK Concentration Population) . . . . . . . . . . . . . . . . . . . . . . . .

5600

Listing - Other 9.3 Listing of Individual Plasma PK Concentration-Time Data for


GW630200 (PK Concentration Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5837

Listing - Other 9.4 Listing of Individual Plasma PK Concentration-Time Data for


GSK932009 (PK Concentration Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6076

CONFIDENTIAL

YM2008/00019/00
B2C109575

Listing - Other 9.5 Observed GW642444 Cmax and tmax (estimated over period
2-30 mins post-dose) by Subject, Treatment and Visit . . . . . . . . . . . . . . . . . . . .

6315

Listing - Other 9.6 Pharmacokinetic and Pharmacodynamic Model Outputs . . . . . . .

6338

This section contained data from each individual patient, rather than in aggregate. They have
been excluded to protect patient privacy. Anonymized data from each patient may be made
available subject to an approved research proposal. For further information please see the
Patient Level Data section of the GSK Clinical Study Register.

CONFIDENTIAL

Table 1

Protocol Level Administration

Study Number: B2C109575

Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the efficacy and
safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult subjects with
persistent asthma.

Data Management
Group
Randomisation
Company and
Address
Address
GlaxoSmithKline
BDS (Biomedical
Registration and
Data Sciences)
Medication
GlaxoSmithKline
Ordering System
R&D Ltd
(RAMOS)
Stockley Park West New Frontiers
Uxbridge
Science Park
Middlesex
Third Avenue
UB11 1BU
Harlow
Essex
CM19 5AW

Site of
Medical Writing:
Manufacture & Clinical Report
Assembly
Authorship
Names of authors
Address
and their Address
GlaxoSmithKlin
e GMS Ware
GlaxoSmithKline
Priority Street
R&D Ltd
Ware
Stockley Park
Hertfordshire
West
SG12 0DJ
Uxbridge
Middlesex
UB11 1BU

Site of
EU
release

Location of
Study Master
File

Address
GlaxoSmi
thKline
New
Frontiers
Science
Park,
Third
Avenue,
Harlow,
Essex,
CM19
5AW

Address
GlaxoSmithKline
New Frontiers
Science Park,
Third Avenue,
Harlow, Essex,
CM19 5AW

GCP
Regulatory
inspection
Name of
Agency
ANMAT
(Argentinian
Regulatory
Authority)

CONFIDENTIAL

Statistics Group
Medical Writing:
Study
Protocol
Sponsor
Authorship
Names of authors
Address
and their Address Address
GlaxoSmithKlin
S&P
e R&D Ltd
GlaxoSmithKline (Stats &
Stockley Park R&D Ltd
Programming)
West
Stockley Park
GlaxoSmithKline
Uxbridge
West
R&D Ltd
Middlesex
Uxbridge
Stockley Park West
UB11 1BU
Middlesex
Uxbridge
UB11 1BU
Middlesex
UB11 1BU

YM2008/00019/00
B2C109575

CONFIDENTIAL

Table 2

Country Level Administration

Study Number: B2C109575

Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.

Participating
Countries

Responsible for
which sites

Address of resource

(CSS)
GlaxoSmithKline
Argentina S.A.
Carlos Casares 3690
(1644) Victoria
Buenos Aires B1644 BCD

Centre Numbers

Address
GlaxoSmithKline
New Frontiers
Science Park, Third
Avenue, Harlow,
Essex, CM19 5AW

Were Audits
done?

Centre Number
of Site(s)

yes/no
No

Centre numbers

Conducted by:
Name and
address of audit
group

YM2008/00019/00
B2C109575

Laboratory name
and address
Quest Diagnostics
Ltd, Unit B1,
Parkway West,
Cranford lane,
Heston, TW5 9QA,
UK
Quest Diagnostics
Clinical Trials, 7600
Tyrone Avenue,
Van Nuys, CA
91405, USA
Quest Diagnostics
Clinical
Laboratories.
10200 CommerceParkway, Miramar,
FL 33025 USA
Tan Toc Seng
hospital, I I Jalan
Tan Toc Seng,
Singapoie, 308433,

Audits

CONFIDENTIAL

Country Name
Argentina

Monitoring

Sites of
distribution in
Europe

Laboratory
Assessments

CONFIDENTIAL

Study Number: B2C109575

Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.

Participating
Countries

Responsible for
which sites

Monitoring

Sites of
distribution in
Europe

Laboratory
Assessments

Audits
Were Audits
done?

YM2008/00019/00
B2C109575

Conducted by:

CONFIDENTIAL

Singapore
Cardinal Health 234
GmbH, Clinical
Services,
Leibnizstrasse 7,
97204 Hoechberg,
Germany
GlaxoSmithKline
R&D, New Frontiers
Science park North,
Third Ave, Harlow,
UK, CM19 5AW
Laboratorio de
Analisis
lnfectologicos y
ClinicosMonteagudo 218(4000) San Miguel
de TucumanArgentina
Laboratorio del
Hospital
Aeronautico
Central, Ventura de
la Vega 3697 Piso
3" (C1437HPA),
Ciudad Autonoma

Centre Number
of Site(s)

CONFIDENTIAL

Study Number: B2C109575

Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.

Participating
Countries

Responsible for
which sites

Monitoring

Sites of
distribution in
Europe

Laboratory
Assessments

Audits
Were Audits
done?

GlaxoSmithKline
Rue du Tilleul 13
1332 GENVAL, Belgium

Quest Diagnostics
Ltd, Unit B1,
Parkway West,
Cranford lane,
Heston, TW5 9QA,
UK
4

GlaxoSmithKline
New Frontiers
Science Park, Third
Avenue, Harlow,
Essex, CM19 5AW

No

YM2008/00019/00
B2C109575

Belgium

Conducted by:

CONFIDENTIAL

de Buenos Aires.
Argentina
Laboratorio
INSARES,
Rondeau 335,
(5500) Mendoza,
Argentina
Laboratorio del
Instituto Central de
Medicina, Calle 43
N585 (1900) La
Plata Buenos
Aires, Argentina
Laboratorio
Diagnostico Medico
S.R.L., Junin 1023
(C1113AAE)
Ciudad Autonoma
de Buenos Aires,
Argentina

Centre Number
of Site(s)

CONFIDENTIAL

Study Number: B2C109575

Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.

Participating
Countries

Responsible for
which sites

Monitoring

Sites of
distribution in
Europe

Laboratory
Assessments

Audits
Were Audits
done?

YM2008/00019/00
B2C109575

Conducted by:

CONFIDENTIAL

Quest Diagnostics
Clinical Trials, 7600
Tyrone Avenue,
Van Nuys, CA
91405, USA
Quest Diagnostics
Clinical
Laboratories.
10200 CommerceParkway, Miramar,
FL 33025 USA
Tan Toc Seng
hospital, I I Jalan
Tan Toc Seng,
Singapoie, 308433,
Singapore
Cardinal Health 234
GmbH, Clinical
Services,
Leibnizstrasse 7,
97204 Hoechberg,
Germany
GlaxoSmithKline
R&D, New Frontiers
Science park North,
Third Ave, Harlow,
UK, CM19 5AW

Centre Number
of Site(s)

CONFIDENTIAL

Study Number: B2C109575

Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.

Participating
Countries

Responsible for
which sites

Monitoring

Sites of
distribution in
Europe

Laboratory
Assessments

Audits
Were Audits
done?

Canada

Dr

No

YM2008/00019/00
B2C109575

GlaxoSmithKline,
5 Moore Drive,
PO Box 13398,
Research Triangle
Park, NC 27709.

Conducted by:

CONFIDENTIAL

GlaxoSmithKline Canada
7333 Mississauga Road
Mississauga, Ontario
Canada
L5N 6L4

Quest Diagnostics
Ltd, Unit B1,
Parkway West,
Cranford lane,
Heston, TW5 9QA,
UK
Quest Diagnostics
Clinical Trials, 7600
Tyrone Avenue,
Van Nuys, CA
91405, USA
Quest Diagnostics
Clinical
Laboratories.
10200 CommerceParkway, Miramar,
FL 33025 USA
Tan Toc Seng
hospital, I I Jalan
Tan Toc Seng,
Singapoie, 308433,
Singapore
Cardinal Health 234
GmbH, Clinical
Services,
Leibnizstrasse 7,

Centre Number
of Site(s)

CONFIDENTIAL

Study Number: B2C109575

Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.

Participating
Countries

Responsible for
which sites

Monitoring

Sites of
distribution in
Europe

Laboratory
Assessments

Audits
Were Audits
done?

Chile
GlaxoSmithKline
Av. Andres Bello 2687
Piso 21, Las Condes
Santiago, 7550611

GlaxoSmithKline
New Frontiers
Science Park, Third
Avenue, Harlow,
Essex, CM19 5AW

No

YM2008/00019/00
B2C109575

Quest Diagnostics
Ltd, Unit B1,
Parkway West,
Cranford lane,
Heston, TW5 9QA,
UK
Quest Diagnostics
Clinical Trials, 7600
Tyrone Avenue,
Van Nuys, CA
91405, USA
Quest Diagnostics
Clinical
Laboratories.
10200 CommerceParkway, Miramar,
FL 33025 USA
Tan Toc Seng
hospital, I I Jalan

Conducted by:

CONFIDENTIAL

97204 Hoechberg,
Germany
GlaxoSmithKline
R&D, New Frontiers
Science park North,
Third Ave, Harlow,
UK, CM19 5AW

Centre Number
of Site(s)

CONFIDENTIAL

Study Number: B2C109575

Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.

Participating
Countries

Responsible for
which sites

Monitoring

Sites of
distribution in
Europe

Laboratory
Assessments

Audits
Were Audits
done?

France

GlaxoSmithKline
New Frontiers
Science Park, Third
Avenue, Harlow,
Essex, CM19 5AW

No

YM2008/00019/00
B2C109575

GlaxoSmithKline, 100
Route De Versailles,
78163 Marly Le Roi,
Cedex, France

Quest Diagnostics
Ltd, Unit B1,
Parkway West,
Cranford lane,
Heston, TW5 9QA,
UK
Quest Diagnostics
Clinical Trials, 7600
Tyrone Avenue,
Van Nuys, CA
91405, USA
Quest Diagnostics

Conducted by:

CONFIDENTIAL

Tan Toc Seng,


Singapoie, 308433,
Singapore
Cardinal Health 234
GmbH, Clinical
Services,
Leibnizstrasse 7,
97204 Hoechberg,
Germany
GlaxoSmithKline
R&D, New Frontiers
Science park North,
Third Ave, Harlow,
UK, CM19 5AW

Centre Number
of Site(s)

CONFIDENTIAL

Study Number: B2C109575

Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.

Participating
Countries

Responsible for
which sites

Monitoring

Sites of
distribution in
Europe

Laboratory
Assessments

Audits
Were Audits
done?

GlaxoSmithKline GmbH &


Co. KG, Alsterufer 1
20354 Hamburg

Quest Diagnostics
Ltd, Unit B1,
Parkway West,
Cranford lane,
Heston, TW5 9QA,
9

GlaxoSmithKline
New Frontiers
Science Park, Third
Avenue, Harlow,
Essex, CM19 5AW

No

YM2008/00019/00
B2C109575

Germany

Conducted by:

CONFIDENTIAL

Clinical
Laboratories.
10200 CommerceParkway, Miramar,
FL 33025 USA
Tan Toc Seng
hospital, I I Jalan
Tan Toc Seng,
Singapoie, 308433,
Singapore
Cardinal Health 234
GmbH, Clinical
Services,
Leibnizstrasse 7,
97204 Hoechberg,
Germany
GlaxoSmithKline
R&D, New Frontiers
Science park North,
Third Ave, Harlow,
UK, CM19 5AW

Centre Number
of Site(s)

CONFIDENTIAL

Study Number: B2C109575

Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.

Participating
Countries

Responsible for
which sites

Monitoring

Sites of
distribution in
Europe

Laboratory
Assessments

Audits
Were Audits
done?

YM2008/00019/00
B2C109575

10

Conducted by:

CONFIDENTIAL

10

UK
Quest Diagnostics
Clinical Trials, 7600
Tyrone Avenue,
Van Nuys, CA
91405, USA
Quest Diagnostics
Clinical
Laboratories.
10200 CommerceParkway, Miramar,
FL 33025 USA
Tan Toc Seng
hospital, I I Jalan
Tan Toc Seng,
Singapoie, 308433,
Singapore
Cardinal Health 234
GmbH, Clinical
Services,
Leibnizstrasse 7,
97204 Hoechberg,
Germany
GlaxoSmithKline
R&D, New Frontiers
Science park North,
Third Ave, Harlow,

Centre Number
of Site(s)

CONFIDENTIAL

Study Number: B2C109575

Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.

Participating
Countries

Responsible for
which sites

Monitoring

Sites of
distribution in
Europe

Laboratory
Assessments

Audits
Were Audits
done?

Centre Number
of Site(s)

Conducted by:

UK, CM19 5AW


Netherlands

11

11

GlaxoSmithKline
New Frontiers
Science Park, Third
Avenue, Harlow,
Essex, CM19 5AW

No

YM2008/00019/00
B2C109575

Quest Diagnostics
Ltd, Unit B1,
Parkway West,
Cranford lane,
Heston, TW5 9QA,
UK
Quest Diagnostics
Clinical Trials, 7600
Tyrone Avenue,
Van Nuys, CA
91405, USA
Quest Diagnostics
Clinical
Laboratories.
10200 CommerceParkway, Miramar,
FL 33025 USA
Tan Toc Seng
hospital, I I Jalan
Tan Toc Seng,
Singapoie, 308433,
Singapore
Cardinal Health 234
GmbH, Clinical
Services,

CONFIDENTIAL

GlaxoSmithKline BV,
Huis ter Heideweg 62
3705 LZ Zeist,
Netherlands

CONFIDENTIAL

Study Number: B2C109575

Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.

Participating
Countries

Responsible for
which sites

Monitoring

Sites of
distribution in
Europe

Laboratory
Assessments

Audits
Were Audits
done?

12

Peru

GlaxoSmithKline Peru,
Ave. Javier Prado Oeste
995
San Isidro,
Lima 27
Peru

12

GlaxoSmithKline
New Frontiers
Science Park, Third
Avenue, Harlow,
Essex, CM19 5AW

No

YM2008/00019/00
B2C109575

Quest Diagnostics
Ltd, Unit B1,
Parkway West,
Cranford lane,
Heston, TW5 9QA,
UK
Quest Diagnostics
Clinical Trials, 7600
Tyrone Avenue,
Van Nuys, CA
91405, USA
Quest Diagnostics
Clinical
Laboratories.
10200 CommerceParkway, Miramar,
FL 33025 USA
Tan Toc Seng

Conducted by:

CONFIDENTIAL

Leibnizstrasse 7,
97204 Hoechberg,
Germany
GlaxoSmithKline
R&D, New Frontiers
Science park North,
Third Ave, Harlow,
UK, CM19 5AW

Centre Number
of Site(s)

CONFIDENTIAL

Study Number: B2C109575

Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.

Participating
Countries

Responsible for
which sites

Monitoring

Sites of
distribution in
Europe

Laboratory
Assessments

Audits
Were Audits
done?

Philippines

Quest Diagnostics
Ltd, Unit B1,
Parkway West,
Cranford lane,
Heston, TW5 9QA,
UK
Quest Diagnostics
Clinical Trials, 7600
Tyrone Avenue,
Van Nuys, CA
91405, USA
13

GlaxoSmithKline
New Frontiers
Science Park, Third
Avenue, Harlow,
Essex, CM19 5AW

No

YM2008/00019/00
B2C109575

2266 Don Chino Roces


Ave,
Makati City 1231, Metro
Manila, Philippines

Conducted by:

CONFIDENTIAL

13

hospital, I I Jalan
Tan Toc Seng,
Singapoie, 308433,
Singapore
Cardinal Health 234
GmbH, Clinical
Services,
Leibnizstrasse 7,
97204 Hoechberg,
Germany
GlaxoSmithKline
R&D, New Frontiers
Science park North,
Third Ave, Harlow,
UK, CM19 5AW

Centre Number
of Site(s)

CONFIDENTIAL

Study Number: B2C109575

Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.

Participating
Countries

Responsible for
which sites

Monitoring

Sites of
distribution in
Europe

Laboratory
Assessments

Audits
Were Audits
done?

Centre Number
of Site(s)

Conducted by:

GlaxoSmithKline
Commercial Sp
53 Rzymowskiego Street

Quest Diagnostics
Ltd, Unit B1,
Parkway West,
Cranford lane,
14

GlaxoSmithKline
New Frontiers
Science Park, Third
Avenue, Harlow,

Yes

GSK - Worldwide
Regulatory
Compliance - UK

YM2008/00019/00
B2C109575

Poland

CONFIDENTIAL

14

Quest Diagnostics
Clinical
Laboratories.
10200 CommerceParkway, Miramar,
FL 33025 USA
Tan Toc Seng
hospital, I I Jalan
Tan Toc Seng,
Singapoie, 308433,
Singapore
Cardinal Health 234
GmbH, Clinical
Services,
Leibnizstrasse 7,
97204 Hoechberg,
Germany
GlaxoSmithKline
R&D, New Frontiers
Science park North,
Third Ave, Harlow,
UK, CM19 5AW

CONFIDENTIAL

Study Number: B2C109575

Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.

Participating
Countries

Responsible for
which sites

Monitoring

Sites of
distribution in
Europe

Laboratory
Assessments

Audits
Were Audits
done?

02-697 Warsaw, Poland

YM2008/00019/00
B2C109575

15

Conducted by:

Essex, CM19 5AW

CONFIDENTIAL

15

Heston, TW5 9QA,


UK
Quest Diagnostics
Clinical Trials, 7600
Tyrone Avenue,
Van Nuys, CA
91405, USA
Quest Diagnostics
Clinical
Laboratories.
10200 CommerceParkway, Miramar,
FL 33025 USA
Tan Toc Seng
hospital, I I Jalan
Tan Toc Seng,
Singapoie, 308433,
Singapore
Cardinal Health 234
GmbH, Clinical
Services,
Leibnizstrasse 7,
97204 Hoechberg,
Germany
GlaxoSmithKline
R&D, New Frontiers
Science park North,

Centre Number
of Site(s)

CONFIDENTIAL

Study Number: B2C109575

Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.

Participating
Countries

Responsible for
which sites

Monitoring

Sites of
distribution in
Europe

Laboratory
Assessments

Audits
Were Audits
done?

Centre Number
of Site(s)

Conducted by:

Third Ave, Harlow,


UK, CM19 5AW
Russian Federation

16

16

GlaxoSmithKline
New Frontiers
Science Park, Third
Avenue, Harlow,
Essex, CM19 5AW

No

YM2008/00019/00
B2C109575

Quest Diagnostics
Ltd, Unit B1,
Parkway West,
Cranford lane,
Heston, TW5 9QA,
UK
Quest Diagnostics
Clinical Trials, 7600
Tyrone Avenue,
Van Nuys, CA
91405, USA
Quest Diagnostics
Clinical
Laboratories.
10200 CommerceParkway, Miramar,
FL 33025 USA
Tan Toc Seng
hospital, I I Jalan
Tan Toc Seng,
Singapoie, 308433,
Singapore
Cardinal Health 234
GmbH, Clinical

CONFIDENTIAL

GlaxoSmithKline Russia
Krylatskaya street 17,
build 3
121614 Moscow, Russia

CONFIDENTIAL

Study Number: B2C109575

Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.

Participating
Countries

Responsible for
which sites

Monitoring

Sites of
distribution in
Europe

Laboratory
Assessments

Audits
Were Audits
done?

South Africa
GlaxoSmithKline
SouthAfrica
Carisbrook Building,
The Campus,
57 Sloane Street
Bryanston 2021
Guateng, SouthAfrica

17

GlaxoSmithKline
New Frontiers
Science Park, Third
Avenue, Harlow,
Essex, CM19 5AW

No

YM2008/00019/00
B2C109575

Quest Diagnostics
Ltd, Unit B1,
Parkway West,
Cranford lane,
Heston, TW5 9QA,
UK
Quest Diagnostics
Clinical Trials, 7600
Tyrone Avenue,
Van Nuys, CA
91405, USA
Quest Diagnostics
Clinical
Laboratories.
10200 CommerceParkway, Miramar,
FL 33025 USA

Conducted by:

CONFIDENTIAL

17

Services,
Leibnizstrasse 7,
97204 Hoechberg,
Germany
GlaxoSmithKline
R&D, New Frontiers
Science park North,
Third Ave, Harlow,
UK, CM19 5AW

Centre Number
of Site(s)

CONFIDENTIAL

Study Number: B2C109575

Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.

Participating
Countries

Responsible for
which sites

Monitoring

Sites of
distribution in
Europe

Laboratory
Assessments

Audits
Were Audits
done?

South Korea

Quest Diagnostics
Ltd, Unit B1,
Parkway West,
Cranford lane,
Heston, TW5 9QA,
UK
Quest Diagnostics
Clinical Trials, 7600
Tyrone Avenue,
Van Nuys, CA
18

GlaxoSmithKline
New Frontiers
Science Park, Third
Avenue, Harlow,
Essex, CM19 5AW

No

YM2008/00019/00
B2C109575

GlaxoSmithKline Korea
Ltd
9th Floor Kukje Centre
Bldg
191 Hangang-ro 2-ga,
Yongsangu
Seoul 140-702, Korea

Conducted by:

CONFIDENTIAL

18

Tan Toc Seng


hospital, I I Jalan
Tan Toc Seng,
Singapoie, 308433,
Singapore
Cardinal Health 234
GmbH, Clinical
Services,
Leibnizstrasse 7,
97204 Hoechberg,
Germany
GlaxoSmithKline
R&D, New Frontiers
Science park North,
Third Ave, Harlow,
UK, CM19 5AW

Centre Number
of Site(s)

CONFIDENTIAL

Study Number: B2C109575

Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.

Participating
Countries

Responsible for
which sites

Monitoring

Sites of
distribution in
Europe

Laboratory
Assessments

Audits
Were Audits
done?

GlaxoSmithKline AB
Box 516, Rasundavagen

Quest Diagnostics
Ltd, Unit B1,
Parkway West,
19

GlaxoSmithKline
New Frontiers
Science Park, Third

No

YM2008/00019/00
B2C109575

Sweden

Conducted by:

CONFIDENTIAL

19

91405, USA
Quest Diagnostics
Clinical
Laboratories.
10200 CommerceParkway, Miramar,
FL 33025 USA
Tan Toc Seng
hospital, I I Jalan
Tan Toc Seng,
Singapoie, 308433,
Singapore
Cardinal Health 234
GmbH, Clinical
Services,
Leibnizstrasse 7,
97204 Hoechberg,
Germany
GlaxoSmithKline
R&D, New Frontiers
Science park North,
Third Ave, Harlow,
UK, CM19 5AW

Centre Number
of Site(s)

CONFIDENTIAL

Study Number: B2C109575

Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.

Participating
Countries

Responsible for
which sites

Monitoring

Sites of
distribution in
Europe

Laboratory
Assessments

Audits
Were Audits
done?

12
169 29 SOLNA, Sweden

YM2008/00019/00
B2C109575

20

Conducted by:

Avenue, Harlow,
Essex, CM19 5AW

CONFIDENTIAL

20

Cranford lane,
Heston, TW5 9QA,
UK
Quest Diagnostics
Clinical Trials, 7600
Tyrone Avenue,
Van Nuys, CA
91405, USA
Quest Diagnostics
Clinical
Laboratories.
10200 CommerceParkway, Miramar,
FL 33025 USA
Tan Toc Seng
hospital, I I Jalan
Tan Toc Seng,
Singapoie, 308433,
Singapore
Cardinal Health 234
GmbH, Clinical
Services,
Leibnizstrasse 7,
97204 Hoechberg,
Germany
GlaxoSmithKline
R&D, New Frontiers

Centre Number
of Site(s)

CONFIDENTIAL

Study Number: B2C109575

Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.

Participating
Countries

Responsible for
which sites

Monitoring

Sites of
distribution in
Europe

Laboratory
Assessments

Audits
Were Audits
done?

Centre Number
of Site(s)

Conducted by:

Science park North,


Third Ave, Harlow,
UK, CM19 5AW

21

GlaxoSmithKline Thailand
Ltd
12th Floor,
Wave Place,
55 Wireless Road,
Lumpini,
Patumwan, Bangkok
10330

21

GlaxoSmithKline
New Frontiers
Science Park, Third
Avenue, Harlow,
Essex, CM19 5AW

No

YM2008/00019/00
B2C109575

Quest Diagnostics
Ltd, Unit B1,
Parkway West,
Cranford lane,
Heston, TW5 9QA,
UK
Quest Diagnostics
Clinical Trials, 7600
Tyrone Avenue,
Van Nuys, CA
91405, USA
Quest Diagnostics
Clinical
Laboratories.
10200 CommerceParkway, Miramar,
FL 33025 USA
Tan Toc Seng
hospital, I I Jalan
Tan Toc Seng,
Singapoie, 308433,
Singapore
Cardinal Health 234

CONFIDENTIAL

Thailand

CONFIDENTIAL

Study Number: B2C109575

Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.

Participating
Countries

Responsible for
which sites

Monitoring

Sites of
distribution in
Europe

Laboratory
Assessments

Audits
Were Audits
done?

Centre Number
of Site(s)

Conducted by:

United States

Dr
GlaxoSmithKline,
5 Moore Drive,
PO Box 13398, Research
Triangle Park, NC 27709.

22

GlaxoSmithKline,
5 Moore Drive,
PO Box 13398,
Research Triangle
Park, NC 27709.

Yes

GSK - Worldwide
Regulatory
Compliance
USA
GSK - Worldwide
Regulatory
Compliance Canada

YM2008/00019/00
B2C109575

Quest Diagnostics
Ltd, Unit B1,
Parkway West,
Cranford lane,
Heston, TW5 9QA,
UK
Quest Diagnostics
Clinical Trials, 7600
Tyrone Avenue,
Van Nuys, CA
91405, USA
Quest Diagnostics
Clinical
Laboratories.
10200 CommerceParkway, Miramar,

CONFIDENTIAL

22

GmbH, Clinical
Services,
Leibnizstrasse 7,
97204 Hoechberg,
Germany
GlaxoSmithKline
R&D, New Frontiers
Science park North,
Third Ave, Harlow,
UK, CM19 5AW

CONFIDENTIAL

Study Number: B2C109575

Study Title: A Randomized, double-blind, placebo controlled, parallel group, dose ranging study evaluating the
efficacy and safety of GW642444M administered once daily compared with placebo for 28 days in adolescent and adult
subjects with persistent asthma.

Participating
Countries

Responsible for
which sites

Monitoring

Sites of
distribution in
Europe

Laboratory
Assessments

Audits
Were Audits
done?

Conducted by:

CONFIDENTIAL

23

FL 33025 USA
Tan Toc Seng
hospital, I I Jalan
Tan Toc Seng,
Singapoie, 308433,
Singapore
Cardinal Health 234
GmbH, Clinical
Services,
Leibnizstrasse 7,
97204 Hoechberg,
Germany
GlaxoSmithKline
R&D, New Frontiers
Science park North,
Third Ave, Harlow,
UK, CM19 5AW

Centre Number
of Site(s)

YM2008/00019/00
B2C109575

23

CONFIDENTIAL
B2C109575

Statistical Appendix

TABLE OF CONTENTS
PAGE

EXTRA OUTPUTS TO INVESTIGATE INTERACTIONS ...................................................................................................................534


2.1.
Interaction Investigation for Primary Efficacy Endpoint ...........................................................................................................534

3.

BAYESIAN ANALYSES ......................................................................................................................................................................554


3.1.
Tables .....................................................................................................................................................................................554
3.2.
Figures ....................................................................................................................................................................................560

-1-

CONFIDENTIAL

2.

YM2008/00019/00
B2C109575

SAS OUTPUT .........................................................................................................................................................................................2


1.1.
Primary Linear Trend Test Table 7.2: Linear Trend Test of Change from Baseline in Trough FEV1 (mL/mcg)
(LOCF) Intent-to-Treat ................................................................................................................................................................2
1.2.
Primary Pairwise Comparisons Table 7.4: Statistical Analysis of Change from Baseline in Trough FEV1 (L)
(LOCF) Intent-to-Treat ..............................................................................................................................................................13
1.3.
Supporting Pairwise Comparisons Table 7.7: Statistical Analysis of Change from Baseline in Trough FEV1 (L)
(LOCF) Per Protocol .................................................................................................................................................................27
1.4.
Supporting Pairwise Comparisons Table 7.9: Statistical Analysis of Change from Baseline in Trough FEV1 (L)
(Repeated Measures) ...............................................................................................................................................................42
1.5.
Secondary Efficacy Comparisons Table 7.13: Statistical Analysis of Change from Baseline in Trough FEV1 (L)
(LOCF) at Day 28 by % Predicted FEV1 Stratum ...................................................................................................................122
1.6.
Secondary Efficacy Comparisons Table 7.20: Statistical Analysis of Weighted Mean Change from Baseline in 24
Hour Serial Clinic FEV1 (L) All Subjects, including 6-12 hour time points ..............................................................................139
1.7.
Safety Comparisons Table 8.37: Statistical Analysis of Weighted Mean Change from Baseline in Pulse Rate
(beats/min) (0-4 hrs)................................................................................................................................................................217
1.8.
Safety Comparisons Table 8.70: Statistical Analysis of Maximum Decrease from Baseline in Fasting Potassium (04 hrs) .......................................................................................................................................................................................377
1.9.
Safety Comparisons Table 8.72: Statistical Analysis of Maximum Increase from Baseline in Glucose (0-4 hrs) ................455

1.

CONFIDENTIAL
B2C109575

1.

SAS OUTPUT

1.1.

Primary Linear Trend Test Table 7.2: Linear Trend Test of Change from Baseline in Trough FEV1
(mL/mcg) (LOCF) Intent-to-Treat

YM2008/00019/00
B2C109575

-2-

CONFIDENTIAL

LinearTrendTestActualAnalysis14:25Friday,November7,20081

TheMixedProcedure

This section contained data from each individual patient, rather than in

aggregate. They have been excluded to protect patient privacy.

Anonymized
data from each patient may be made available subject to

an approved research proposal. For further information please see the

Patient Level Data section of the GSK Clincal Study Register.

CONFIDENTIAL
B2C109575

1.2.

Primary Pairwise Comparisons Table 7.4: Statistical Analysis of Change from Baseline in Trough
FEV1 (L) (LOCF) Intent-to-Treat

YM2008/00019/00
B2C109575

- 13 -

CONFIDENTIAL

13

ChangefromBaselineActualAnalysis14:25Friday,November7,20081

TheMixedProcedure

This section contained data from each individual patient, rather than in

aggregate. They have been excluded to protect patient privacy. Anonymized

data from each patient may be made available subject to an approved research
proposal. For further information please see the Patient Level Data section of the

GSK Clincal Study Register.

CONFIDENTIAL
B2C109575

1.3.

Supporting Pairwise Comparisons Table 7.7: Statistical Analysis of Change from Baseline in
Trough FEV1 (L) (LOCF) Per Protocol

YM2008/00019/00
B2C109575

- 27 -

CONFIDENTIAL

27

ChangefromBaselineActualAnalysis14:26Friday,November7,20081

TheMixedProcedure

This section contained data from each individual patient, rather than in

aggregate.
They have been excluded to protect patient privacy. Anonymized data

from each patient may be made available subject to an approved research

proposal. For further information please see the Patient Level Data section of the

GSK Clincal Study Register.

CONFIDENTIAL
B2C109575

1.4.

Supporting Pairwise Comparisons Table 7.9: Statistical Analysis of Change from Baseline in
Trough FEV1 (L) (Repeated Measures)

YM2008/00019/00
B2C109575

- 42 -

CONFIDENTIAL

42

ChangefromBaselineActualAnalysis14:24Friday,November7,20081

TheMixedProcedure

This section contained data from each individual patient, rather

than in aggregate. They have been excluded to protect patient

privacy. Anonymized data from each patient may be made

available subject to an approved research proposal. For further

information please see the Patient Level Data section of the GSK

Clincal Study Register.

CONFIDENTIAL
B2C109575

1.5.

Secondary Efficacy Comparisons Table 7.13: Statistical Analysis of Change from Baseline in
Trough FEV1 (L) (LOCF) at Day 28 by % Predicted FEV1 Stratum

YM2008/00019/00
B2C109575

- 122 -

CONFIDENTIAL

122

ChangefromBaselineActualAnalysis14:26Friday,November7,20081

TheMixedProcedure

This section contained data from each individual patient, rather than in

aggregate.
They have been excluded to protect patient privacy. Anonymized

data from each patient may be made available subject to an approved

research proposal. For further information please see the Patient Level Data

section of the GSK Clincal Study Register.

CONFIDENTIAL
B2C109575

1.6.

Secondary Efficacy Comparisons Table 7.20: Statistical Analysis of Weighted Mean Change
from Baseline in 24 Hour Serial Clinic FEV1 (L) All Subjects, including 6-12 hour time points

YM2008/00019/00
B2C109575

- 139 -

CONFIDENTIAL

139

Day1ofTreatmentPeriod14:25Friday,November7,20081
ActualModelChangeFromBaseline

TheMixedProcedure

This section contained data from each individual patient, rather than in

aggregate. They have been excluded to protect patient privacy.

Anonymized data from each patient may be made available subject to an

approved research proposal. For further information please see the

Patient Level Data section of the GSK Clincal Study Register.

CONFIDENTIAL
B2C109575

1.7.

Safety Comparisons Table 8.37: Statistical Analysis of Weighted Mean Change from Baseline in
Pulse Rate (beats/min) (0-4 hrs)

YM2008/00019/00
B2C109575

- 217 -

CONFIDENTIAL

217

Day1ofTreatmentPeriod14:33Friday,November7,20081
ActualModelChangeFromBaseline

TheMixedProcedure

This section contained data from each individual patient, rather than in

aggregate. They have been excluded to protect patient privacy. Anonymized

data from each patient may be made available subject to an approved

research proposal. For further information please see the Patient Level Data

section of the GSK Clincal Study Register.

CONFIDENTIAL
B2C109575

1.8.

Safety Comparisons Table 8.70: Statistical Analysis of Maximum Decrease from Baseline in
Fasting Potassium (0-4 hrs)

YM2008/00019/00
B2C109575

- 377 -

CONFIDENTIAL

377

Day1ofTreatmentPeriod14:32Friday,November7,20081
StatisticalAnalysisofChangeFromBaselineinmaxdecrK_PLC(04hrs)

TheMixedProcedure

This section contained data from each individual patient, rather than in

aggregate. They have been excluded to protect patient privacy.

Anonymized data from each patient may be made available subject to

an approved research proposal. For further information please see the

Patient Level Data section of the GSK Clincal Study Register.

CONFIDENTIAL
B2C109575

1.9.

Safety Comparisons Table 8.72: Statistical Analysis of Maximum Increase from Baseline in
Glucose (0-4 hrs)

YM2008/00019/00
B2C109575

- 455 -

CONFIDENTIAL

455

Day1ofTreatmentPeriod14:30Friday,November7,20081
StatisticalAnalysisofChangeFromBaselineinmaxincrGLUCP_PLC(04hrs)

TheMixedProcedure

This section contained data from each individual patient, rather than in

aggregate. They have been excluded to protect patient privacy.

Anonymized data from each patient may be made available subject to

an approved research proposal. For further information please see the

Patient Level Data section of the GSK Clincal Study Register.

CONFIDENTIAL
B2C109575

2.

EXTRA OUTPUTS TO INVESTIGATE INTERACTIONS

2.1.

Interaction Investigation for Primary Efficacy Endpoint

CONFIDENTIAL

534

YM2008/00019/00
B2C109575

- 534 -

CONFIDENTIAL

B2C109575

CONFIDENTIAL

535

YM2008/00019/00
B2C109575

- 535 -

CONFIDENTIAL
B2C109575

536

YM2008/00019/00
B2C109575

- 536 -

CONFIDENTIAL

B2C109575:ModelCheckingforStatisticalAnalysisofChangefromBaselineinTroughFEV1(L)(LOCF)(IntenttoTreat)1
16:00Friday,October31,2008

TheFREQProcedure

Tableofage2grpbyTRTCD

age2grpTRTCD(Randomizedtreatmentcode)

Frequency|
ColPct|Placebo|3mcg|6.25mcg|12.5mcg|25mcg|50mcg|Total
+++++++
1235|34|23|33|33|30|32|185
|35.79|23.47|33.33|34.02|30.30|32.00|
+++++++
3680|61|75|66|64|69|68|403
|64.21|76.53|66.67|65.98|69.70|68.00|
+++++++
Total9598999799100588

CONFIDENTIAL
B2C109575

537

YM2008/00019/00
B2C109575

- 537 -

CONFIDENTIAL

B2C109575:ModelCheckingforStatisticalAnalysisofChangefromBaselineinTroughFEV1(L)(LOCF)(IntenttoTreat)2
LSMeanChangeestimates,addingintreatment*ageinteraction16:00Friday,October31,2008

_TRTCDage2grpEstimateStdErrProbtupplow

3mcg12350.12610.095300.18650.313230.06113
36800.065090.060700.28400.184310.05413

6.25mcg12350.030440.085540.72210.137570.19845
36800.11790.062010.05770.239720.00388

12.5mcg12350.0097930.085680.90900.178080.15850
36800.18780.062980.00300.311460.06405

25mcg12350.011050.087260.89930.160350.18245
36800.19220.061550.00190.313090.07128

50mcg12350.036600.086190.67120.205890.13268
36800.20610.062500.00100.328880.08337

CONFIDENTIAL
B2C109575

538

YM2008/00019/00
B2C109575

- 538 -

CONFIDENTIAL

B2C109575:ModelCheckingforStatisticalAnalysisofChangefromBaselineinTroughFEV1(L)(LOCF)(IntenttoTreat)3
LSMeanChangeestimates,addingintreatment*ageinteraction,removing7subjectswithhighestCookDvalues
16:00Friday,October31,2008

_TRTCDage2grpEstimateStdErrProbtupplow

3mcg12350.16990.090410.06080.347470.00770
36800.067750.056320.22950.178380.04288

6.25mcg12350.047330.081870.56340.208150.11348
36800.11890.057540.03920.231960.00591

12.5mcg12350.048880.081240.54760.208460.11069
36800.19030.058440.00120.305100.07550

25mcg12350.070810.082120.38890.232120.09049
36800.20660.057270.00030.319060.09407

50mcg12350.11090.081110.17190.270250.04838
36800.21230.058020.00030.326250.09833

CONFIDENTIAL
B2C109575
B2C109575:ModelCheckingforStatisticalAnalysisofChangefromBaselineinTroughFEV1(L)(LOCF)(IntenttoTreat)4
LSMeanChangeestimates,removing7subjectswithhighestCookDvalues
16:00Friday,October31,2008

TRTCDEstimateStdErrProbtLowerUpper

3mcg0.081490.047510.08690.011830.1748
6.25mcg0.095730.047120.04270.0031790.1883
12.5mcg0.14610.047400.00220.052970.2392
25mcg0.16000.046840.00070.067990.2520
50mcg0.18930.04707<.00010.096890.2818

CONFIDENTIAL

539

YM2008/00019/00
B2C109575

- 539 -

CONFIDENTIAL
B2C109575
B2C109575:ModelCheckingforStatisticalAnalysisofChangefromBaselineinTroughFEV1(L)(LOCF)(IntenttoTreat)5
checkageasacontinuousinteraction,removing7subjectswithhighestCookDvalues
16:00Friday,October31,2008

NumDen
EffectDFDFFValueProbF

TRTCD55551.580.1629
SEX15558.820.0031
AMALG115553.390.0001
AGE155527.47<.0001
FEVBL15554.890.0274
ASTRATUM15550.970.3242
AGE*TRTCD55552.440.0335

CONFIDENTIAL

540

YM2008/00019/00
B2C109575

- 540 -

CONFIDENTIAL
B2C109575

541

YM2008/00019/00
B2C109575

- 541 -

CONFIDENTIAL

B2C109575:ModelCheckingforStatisticalAnalysisofChangefromBaselineinTroughFEV1(L)(LOCF)(IntenttoTreat)6
LSMeanChangeestimates,addingintreatment*sexinteraction16:00Friday,October31,2008

_TRTCDSEXEstimateStdErrProbtupplow

3mcgF0.070830.067660.29560.203720.06207
M0.062380.077700.42240.215000.09023

6.25mcgF0.0020090.067860.97640.135290.13128
M0.14570.076410.05710.295770.00442

12.5mcgF0.11250.066460.09090.243080.01799
M0.15550.078800.04900.310250.00068

25mcgF0.11130.064630.08570.238190.01568
M0.13530.081310.09680.294990.02445

50mcgF0.15260.066630.02240.283500.02174
M0.17640.078300.02470.330160.02257

CONFIDENTIAL
B2C109575

YM2008/00019/00
B2C109575

- 542 -

CONFIDENTIAL

542

B2C109575:ModelCheckingforStatisticalAnalysisofChangefromBaselineinTroughFEV1(L)(LOCF)(IntenttoTreat)7
FEVBaselinebyCentre16:00Friday,October31,2008

TheMEANSProcedure

AnalysisVariable:FEVBLBaselineFEV1

Std
CentreIDNMeanDevMinMax

33.220.922.324.16

11.98.1.981.98

22.790.352.543.04

11.72.1.721.72

11.79.1.791.79

12.22.2.222.22

22.570.142.472.68

22.110.112.032.19

23.150.282.953.35

31.700.501.302.27

11.75.1.751.75

12.97.2.972.97

11.53.1.531.53

11.24.1.241.24

22.800.212.652.95

12.42.2.422.42

11.63.1.631.63

12.06.2.062.06

CONFIDENTIAL
B2C109575

42.220.561.402.62
12.77.2.772.77
11.98.1.981.98
21.460.041.431.49
21.620.321.401.85
21.630.281.431.83
12.68.2.682.68

CONFIDENTIAL

543

YM2008/00019/00
B2C109575

- 543 -

CONFIDENTIAL
B2C109575

YM2008/00019/00
B2C109575

- 544 -

CONFIDENTIAL

544

B2C109575:ModelCheckingforStatisticalAnalysisofChangefromBaselineinTroughFEV1(L)(LOCF)(IntenttoTreat)8
FEVBaselinebyCentre16:00Friday,October31,2008

TheMEANSProcedure

AnalysisVariable:FEVBLBaselineFEV1

Std
CentreIDNMeanDevMinMax

22.880.012.872.88

12.91.2.912.91

11.65.1.651.65

12.82.2.822.82

12.39.2.392.39

12.55.2.552.55

22.041.141.232.85

12.40.2.402.40

12.56.2.562.56

22.070.082.022.13

32.120.231.912.37

21.990.131.902.08

12.35.2.352.35

12.24.2.242.24

32.610.941.933.68

21.850.241.682.01

11.79.1.791.79

11.43.1.431.43

CONFIDENTIAL
B2C109575

11.95.1.951.95
31.480.191.271.61
21.370.590.951.79
102.790.841.664.47
11.79.1.791.79
61.700.420.932.11
31.630.321.271.82

CONFIDENTIAL

545

YM2008/00019/00
B2C109575

- 545 -

CONFIDENTIAL
B2C109575
B2C109575:ModelCheckingforStatisticalAnalysisofChangefromBaselineinTroughFEV1(L)(LOCF)(IntenttoTreat)9
FEVBaselinebyCentre16:00Friday,October31,2008

TheMEANSProcedure

AnalysisVariable:FEVBLBaselineFEV1

Std
CentreIDNMeanDevMinMax

21.650.751.122.18

CONFIDENTIAL

546

YM2008/00019/00
B2C109575

- 546 -

CONFIDENTIAL
B2C109575

YM2008/00019/00
B2C109575

- 547 -

CONFIDENTIAL

547

B2C109575:ModelCheckingforStatisticalAnalysisofChangefromBaselineinTroughFEV1(L)(LOCF)(IntenttoTreat)10
TroughFEVChangefromBaselinebyCentre16:00Friday,October31,2008

TheMEANSProcedure

AnalysisVariable:FEVTRLCHChangefrombaselinetroughFEV1(LOCF)

CentreIDNMeanStdDevMinimumMaximum

30.210.490.770.17

10.17.0.170.17

20.140.140.040.23

10.11.0.110.11

10.20.0.200.20

10.08.0.080.08

20.040.000.040.04

20.100.860.520.71

20.520.130.430.61

30.150.030.180.12

10.00.0.000.00

10.11.0.110.11

10.22.0.220.22

10.07.0.070.07

20.000.010.010.01

10.36.0.360.36

10.25.0.250.25

10.05.0.050.05

40.210.230.030.51

CONFIDENTIAL
B2C109575

10.45.0.450.45
10.06.0.060.06
20.190.220.030.35
20.380.020.360.39
20.120.300.100.33
10.14.0.140.14

CONFIDENTIAL

548

YM2008/00019/00
B2C109575

- 548 -

CONFIDENTIAL
B2C109575

YM2008/00019/00
B2C109575

- 549 -

CONFIDENTIAL

549

B2C109575:ModelCheckingforStatisticalAnalysisofChangefromBaselineinTroughFEV1(L)(LOCF)(IntenttoTreat)11
TroughFEVChangefromBaselinebyCentre16:00Friday,October31,2008

TheMEANSProcedure

AnalysisVariable:FEVTRLCHChangefrombaselinetroughFEV1(LOCF)

CentreIDNMeanStdDevMinimumMaximum

20.110.280.090.31

10.24.0.240.24

10.38.0.380.38

10.53.0.530.53

10.94.0.940.94

10.70.0.700.70

20.010.140.110.09

10.13.0.130.13

10.28.0.280.28

20.440.200.300.58

30.010.290.260.33

20.200.150.090.31

10.93.0.930.93

10.22.0.220.22

30.120.170.020.31

20.891.280.021.79

10.16.0.160.16

10.07.0.070.07

10.24.0.240.24

CONFIDENTIAL
B2C109575

30.470.190.320.68
20.560.130.470.65
100.530.580.061.73
10.07.0.070.07
60.000.060.050.10
30.190.460.150.71

CONFIDENTIAL

550

YM2008/00019/00
B2C109575

- 550 -

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B2C109575
B2C109575:ModelCheckingforStatisticalAnalysisofChangefromBaselineinTroughFEV1(L)(LOCF)(IntenttoTreat)12
TroughFEVChangefromBaselinebyCentre16:00Friday,October31,2008

TheMEANSProcedure

AnalysisVariable:FEVTRLCHChangefrombaselinetroughFEV1(LOCF)

CentreIDNMeanStdDevMinimumMaximum

20.030.130.070.12

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B2C109575:ModelCheckingforStatisticalAnalysisofChangefromBaselineinTroughFEV1(L)(LOCF)(IntenttoTreat)13
AnyBronchodilatorUseDuringAnyClinicVisit16:00Friday,October31,2008

TheFREQProcedure

TableofAnyBronchbyTRTCD

AnyBronchTRTCD(Randomizedtreatmentcode)

Frequency|
ColPct|Placebo|3mcg|6.25mcg|12.5mcg|25mcg|50mcg|Total
+++++++
N|60|78|83|81|86|90|478
|63.16|79.59|83.84|83.51|86.87|90.00|
+++++++
Y|35|20|16|16|13|10|110
|36.84|20.41|16.16|16.49|13.13|10.00|
+++++++
Total9598999799100588

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B2C109575:ModelCheckingforStatisticalAnalysisofChangefromBaselineinTroughFEV1(L)(LOCF)(IntenttoTreat)14
AnyBronchodilatorUseDuringLastClinicVisit(Day7orlater)16:00Friday,October31,2008

TheFREQProcedure

TableofBronchAtLastVisbyTRTCD

BronchAtLastVis
TRTCD(Randomizedtreatmentcode)

Frequency|
ColPct|Placebo|3mcg|6.25mcg|12.5mcg|25mcg|50mcg|Total
+++++++
N|71|87|93|93|97|93|534
|74.74|88.78|93.94|95.88|97.98|93.00|
+++++++
Y|24|11|6|4|2|7|54
|25.26|11.22|6.06|4.12|2.02|7.00|
+++++++
Total9598999799100588

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3.

BAYESIAN ANALYSES

3.1.

Tables

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Population:IntenttoTreat
Table30.1
BayesianAnalysisofChangefromBaselineinTroughFEV1(L)(LOCF)onDay28

3mcg6.25mcg12.5mcg25mcg50mcg
ColumnvsPlacebo(N=101)(N=101)(N=100)(N=101)(N=102)

BayesianAnalysisAssuming
NoninformativePrior
n98999799100
PosteriorMeanDifference(SD)0.0630.0690.1300.1210.161
(0.0509)(0.0505)(0.0508)(0.0500)(0.0502)
95%CredibleInterval(0.037,(0.029,(0.031,(0.023,(0.062,
0.164)0.169)0.229)0.219)0.259)

P(Diff>0)0.8940.9160.9950.992>0.999
P(Diff>0.15)0.0440.0550.3450.2800.588
P(Diff>0.2)0.0040.0050.0830.0560.221

Note:Placebo(N=102):n=95
Note:Analysisadjustedforbaseline(predoseonday1),country,sex,age,stratumandtreatment.

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Table30.2
BayesianAnalysisofWeightedMeanChangefromBaselineinPulseRate(beats/min)(04hours)onDay28

3mcg6.25mcg12.5mcg25mcg50mcg
ColumnvsPlacebo(N=101)(N=101)(N=100)(N=101)(N=102)

BayesianAnalysisAssuming
NoninformativePrior
n8491889397
PosteriorMeanDifference(SD)0.1(1.13)0.9(1.10)1.0(1.11)0.4(1.10)2.2(1.10)
95%CredibleInterval(2.1,2.3)(3.1,1.2)(3.1,1.2)(1.7,2.6)(0.0,4.3)

P(Diff>6)<0.001<0.001<0.001<0.001<0.001

Note:Placebo(N=102):n=87
Note:Analysisadjustedforbaseline(predoseonday1),country,sex,age,stratumandtreatment.

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Table30.3
BayesianAnalysisofMaximumIncreasefromBaselineinPulseRate(beats/min)(04hours)onDay28

3mcg6.25mcg12.5mcg25mcg50mcg
ColumnvsPlacebo(N=101)(N=101)(N=100)(N=101)(N=102)

BayesianAnalysisAssuming
NoninformativePrior
n8591889398
PosteriorMeanDifference(SD)0.1(1.27)0.3(1.24)0.1(1.25)1.0(1.23)2.7(1.23)
95%CredibleInterval(2.4,2.6)(2.7,2.1)(2.6,2.3)(1.4,3.4)(0.3,5.1)

P(Diff>10)<0.001<0.001<0.001<0.001<0.001

Note:Placebo(N=102):n=87
Note:Analysisadjustedforbaseline(predoseonday1),country,sex,age,stratumandtreatment.

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Table30.4
BayesianAnalysisofMaximumIncreasefromBaselineinGlucose(mmol/L)(04hours)onDay28

3mcg6.25mcg12.5mcg25mcg50mcg
ColumnvsPlacebo(N=101)(N=101)(N=100)(N=101)(N=102)

BayesianAnalysisAssuming
NoninformativePrior
n8390879394
PosteriorMeanDifference(SD)0.06(0.163)0.05(0.159)0.06(0.160)0.20(0.157)0.20(0.157)
95%CredibleInterval(0.38,0.26)(0.27,0.36)(0.26,0.37)(0.11,0.50)(0.11,0.50)

P(Diff>1.5)<0.001<0.001<0.001<0.001<0.001

Note:Placebo(N=102):n=85
Note:Analysisadjustedforbaseline(predosemeasurementonDay1),country,sex,age,stratumandtreatment.

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Population:IntenttoTreat
Table30.5
BayesianAnalysisofMaximumDecreasefromBaselineinFastingPotassium(mmol/L)(04hours)onDay28

3mcg6.25mcg12.5mcg25mcg50mcg
ColumnvsPlacebo(N=101)(N=101)(N=100)(N=101)(N=102)

BayesianAnalysisAssuming
NoninformativePrior
n7884848690
PosteriorMeanDifference(SD)0.05(0.053)0.14(0.052)0.09(0.052)0.07(0.052)0.14(0.052)
95%CredibleInterval(0.16,0.05)(0.25,0.04)(0.19,0.01)(0.17,0.03)(0.25,0.04)

P(Diff<0.3)<0.0010.001<0.001<0.0010.002

Note:Placebo(N=102):n=77
Note:Analysisadjustedforbaseline(predosemeasurementonDay1),country,sex,age,stratumandtreatment.

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3.2.

Figures

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Post-Hoc Analyses Data Source Figures and Tables


Page

Figure 6.101 Subject Withdrawals Due to Lack of Efficacy Over Time, by Stratum .

Figure 7.101 Adjusted Treatment Differences of Change from Baseline in PM PEF


(L/min) Days 1-28, by %Predicted FEV1 Stratum . . . . . . . . . . . . . . . . . . . . . . . .

Figure 7.102 Adjusted Treatment Differences of Change from Baseline in AM PEF


(L/min) Days 1-28, by %Predicted FEV1 Stratum . . . . . . . . . . . . . . . . . . . . . . . .

Figure 7.103 Mean Number of Puffs of Rescue Medication Per Day . . . . . . . . . . . .

Figure 7.104 PM Minus AM PEF (L/min) Over the Screening and Treatment
Periods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 7.105 Mean Number of Puffs of Rescue Medication Per Day, by Stratum . . .

Figure 7.106 Box Plot of Trough % Predicted FEV1 (LOCF) at Day 28, by %
Predicted FEV1 Stratum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11

Figure 7.107 Adjusted Treatment Differences of Change from Baseline in


Percentage of Symptom Free 24 Hour Periods Days 1-28, by %Predicted
FEV1 Stratum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13

Figure 7.108 Adjusted Treatment Differences of Change from Baseline in


Percentage of Rescue Free 24 Hour Periods Days 1-28, by %Predicted FEV1
Stratum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

14

Figure 7.110 Adjusted Means of Change from Baseline in Trough FEV1 (L)
(LOCF) at Day 28 - Intent-to-Treat Without Regression Line . . . . . . . . . . . . . . .

15

Table 6.101 Summary of Investigator Performance (Total Population) . . . . . . . . . . .

16

Table 6.102 Summary of Reversibility at Screening by Actual Stratum


(Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

21

Table 6.104 Summary of Adolescent Subjects (Intent-to-Treat Population) . . . . . . .

23

Table 7.101 Statistical Analysis of Change from Baseline in PM PEF (L/min) by %


Predicted FEV1 Stratum (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . .

24

Table 7.102 Statistical Analysis of Change from Baseline in AM PEF (L/min) by %


Predicted FEV1 Stratum (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . .

25

Table 7.103 Statistical Analysis of Change from Baseline in Day 1 Trough FEV1
(L) Intent-to-Treat (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . .

26

Table 7.104 Summary of Number of Puffs of Rescue Medication, Day 1 and Last
Clinic Visit (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

27

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Table 7.106 %nrstr(Summary of the Proportion of Subjects Obtaining >= 200mL


and >= 12%%) Increase from Baseline FEV1 (L) (Day 28, 22-24hrs) by %
Predicted FEV1 Stratum (Intent-to-Treat Population) . . . . . . . . . . . . . . . . . . . . .

29

Table 7.107 Statistical Analysis of Change from Baseline in Trough FEV1 (L)
(LOCF) Subset of Subjects who had the 6-12 hour time points measured Per
Protocol (Per Protocol Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

30

Table 7.108 Statistical Analysis of Change from Baseline in Percentage of


Symptom Free 24 Hour Periods by % Predicted FEV1 Stratum (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

31

Table 7.109 Statistical Analysis of Change from Baseline in Percentage of Rescue


Free 24 Hour Periods by % Predicted FEV1 Stratum (Intent-to-Treat
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

32

Page 1 of 2

Protocol: B2C109575
Population: Intent-to-Treat
Figure 6.101
Subject Withdrawals Due to Lack of Efficacy Over Time, by Stratum
Stratum=1: >=40% - <=65%
30

20

CONFIDENTIAL

Percentage of Subjects Withdrawn

25

15

10

1 Week

2 Weeks

3 Weeks

4 Weeks

Time Since Randomisation


Treatment

Placebo
3mcg

6.25mcg
12.5mcg

25mcg
50mcg

Note: Subjects are represented from their date of randomisation to their date of study drug discontinuation due to lack of efficacy

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0
Randomisation

Page 2 of 2

Protocol: B2C109575
Population: Intent-to-Treat
Figure 6.101
Subject Withdrawals Due to Lack of Efficacy Over Time, by Stratum
Stratum=2: >65% - <=90%
30

20

CONFIDENTIAL

Percentage of Subjects Withdrawn

25

15

10

1 Week

2 Weeks

3 Weeks

4 Weeks

Time Since Randomisation


Treatment

Placebo
3mcg

6.25mcg
12.5mcg

25mcg
50mcg

Note: Subjects are represented from their date of randomisation to their date of study drug discontinuation due to lack of efficacy

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Randomisation

Protocol: B2C109575
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Page 1 of 1
Figure 7.101
Adjusted Treatment Differences of Change from Baseline in PM PEF (L/min)
Days 1-28, by %Predicted FEV1 Stratum

60

55

45

40

35

CONFIDENTIAL

Mean Difference from Placebo and 95% Confidence Interval

50

30

25

20

15

10

-5
3mcg

6.25mcg
Stratum

12.5mcg
>=40% - <=65%

25mcg
>65% - <=90%

Note: Analysis performed using ANCOVA with covariates of baseline, country, sex, age, stratum, treatment,
and treatment by stratum interaction
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject

50mcg

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Population: Intent-to-Treat

Page 1 of 1
Figure 7.102
Adjusted Treatment Differences of Change from Baseline in AM PEF (L/min)
Days 1-28, by %Predicted FEV1 Stratum

60

55

45

40

35

CONFIDENTIAL

Mean Difference from Placebo and 95% Confidence Interval

50

30

25

20

15

10

-5
3mcg

6.25mcg
Stratum

12.5mcg
>=40% - <=65%

25mcg
>65% - <=90%

Note: Analysis performed using ANCOVA with covariates of baseline, country, sex, age, stratum, treatment,
and treatment by stratum interaction
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject

50mcg

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Page 1 of 1

Protocol: B2C109575
Population: Intent-to-Treat
Figure 7.103
Mean Number of Puffs of Rescue Medication Per Day
5

CONFIDENTIAL

Mean Number of Puffs

0
-7

14

21

Days
Treatment

Placebo
3mcg

6.25mcg
12.5mcg

25mcg
50mcg

28

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Page 1 of 1

Protocol: B2C109575
Population: Intent-to-Treat
Figure 7.104
PM Minus AM PEF (L/min) Over the Screening and Treatment Periods
60

50

30

CONFIDENTIAL

Mean PM minus AM PEF (L/min)

40

20

10

-10
-7

14

21

Days
Treatment

Placebo
3mcg

6.25mcg
12.5mcg

25mcg
50mcg

28

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Protocol: B2C109575
Population: Intent-to-Treat
Figure 7.105
Mean Number of Puffs of Rescue Medication Per Day, by Stratum
Stratum=1: >=40% - <=65%
5

CONFIDENTIAL

Mean Number of Puffs

0
-7

14

21

Days
Treatment

Placebo
3mcg

6.25mcg
12.5mcg

25mcg
50mcg

28

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Protocol: B2C109575
Population: Intent-to-Treat
Figure 7.105
Mean Number of Puffs of Rescue Medication Per Day, by Stratum
Stratum=2: >65% - <=90%
5

CONFIDENTIAL

10

Mean Number of Puffs

0
-7

14

21

Days
Treatment

Placebo
3mcg

6.25mcg
12.5mcg

25mcg
50mcg

28

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Protocol: B2C109575
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Page 1 of 2
Figure 7.106
Box Plot of Trough % Predicted FEV1 (LOCF) at Day 28, by % Predicted FEV1 Stratum
Stratum=1: >=40% - <=65%

This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect
patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal.
For further information please see the Patient Level Data section of the GSK Clincal Study Register.

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Page 1 of 1
Figure 7.107
Adjusted Treatment Differences of Change from Baseline in Percentage of Symptom Free 24 Hour Periods
Days 1-28, by %Predicted FEV1 Stratum

40

35

25

CONFIDENTIAL

13

Mean Difference from Placebo and 95% Confidence Interval

30

20

15

10

-5

3mcg

6.25mcg
Stratum

12.5mcg
>=40% - <=65%

25mcg
>65% - <=90%

Note: Analysis performed using ANCOVA with covariates of baseline, country, sex, age, stratum, treatment,
and treatment by stratum interaction
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject

50mcg

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Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Figure 7.108
Adjusted Treatment Differences of Change from Baseline in Percentage of Rescue Free 24 Hour Periods
Days 1-28, by %Predicted FEV1 Stratum

50

45

35

30

CONFIDENTIAL

14

Mean Difference from Placebo and 95% Confidence Interval

40

25

20

15

10

-10
3mcg

6.25mcg
Stratum

12.5mcg
>=40% - <=65%

25mcg
>65% - <=90%

Note: Analysis performed using ANCOVA with covariates of baseline, country, sex, age, stratum, treatment,
and treatment by stratum interaction
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject

50mcg

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-5

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Figure 7.110
Adjusted Means of Change from Baseline in Trough FEV1 (L) (LOCF) at Day 28 - Intent-to-Treat
Without Regression Line

0.4

CONFIDENTIAL

15

LS Mean Change from Baseline in Trough FEV1 (L)

0.3

0.2

0.1

Placebo 3mcg 6.25mcg

12.5mcg

25mcg
Treatment

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age, stratum and treatment.

50mcg

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0.0

Protocol: B2C109575
Population: Total

Page 1 of 5
Table 6.101
Summary of Investigator Performance

Screen Screen
Country
Scr RandNo. in
No. in
No.
Period* Rate per
Investigator (ID)
#
omised
ITT Pop
PP Pop
With PVs
Completed (Weeks) Week
-----------------------------------------------------------------------------------------------------------Argentina
Any Investigator

16
Canada
Any Investigator

(67%)
(88%)
(56%)
(60%)
(56%)
(57%)

36
15
5
3
9
4

(67%)
(88%)
(56%)
(60%)
(56%)
(57%)

34
14
4
3
9
4

(63%)
(82%)
(44%)
(60%)
(56%)
(57%)

4
3
1
0
0
0

17
12
5

7
6
1

(41%)
(50%)
(20%)

7
6
1

(41%)
(50%)
(20%)

7
6
1

(41%)
(50%)
(20%)

0
0
0

92
13
4
27
2
5
10
3
28

25
3
1
12
1
2
2
1
3

(27%)
(23%)
(25%)
(44%)
(50%)
(40%)
(20%)
(33%)
(11%)

25
3
1
12
1
2
2
1
3

(27%)
(23%)
(25%)
(44%)
(50%)
(40%)
(20%)
(33%)
(11%)

25
3
1
12
1
2
2
1
3

(27%)
(23%)
(25%)
(44%)
(50%)
(40%)
(20%)
(33%)
(11%)

1
0
0
0
0
0
0
0
1

11
2
9

7
0
7

(64%)

7
0
7

(64%)

7
0
7

(64%)

0
0
0

(78%)

(78%)

(78%)

(7%)
(18%)
(11%)

29
12
5
3
6
3

5.9
5
4.9
2.6
4.1
3.7

9.2
3.4
1.9
1.9
3.9
1.9

(29%) 11.9
(33%) 9.7
(20%) 6.1

1.4
1.2
0.8

22
3
1
10
1
1
2
1
3

(24%)
(23%)
(25%)
(37%)
(50%)
(20%)
(20%)
(33%)
(11%)

24
16.1
9
21.1
0.6
13.9
16.6
4
19.1

3.8
0.8
0.4
1.3
3.5
0.4
0.6
0.8
1.5

7
0
7

(64%)

2.3
1
2.3

4.8
2
3.9

5
4
1
(1%)

(4%)

(54%)
(71%)
(56%)
(60%)
(38%)
(43%)

(78%)

# Number of subjects screened. All percentages are calculated using this number as the denominator.
* Screen Period is from the first screening date to the last.

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Chile
Any Investigator

36
15
5
3
9
4

CONFIDENTIAL

Belgium
Any Investigator

54
17
9
5
16
7

Protocol: B2C109575
Population: Total

Page 2 of 5
Table 6.101
Summary of Investigator Performance

Screen Screen
Country
Scr RandNo. in
No. in
No.
Period* Rate per
Investigator (ID)
#
omised
ITT Pop
PP Pop
With PVs
Completed (Weeks) Week
-----------------------------------------------------------------------------------------------------------France
Any Investigator

17
Korea
Any Investigator

(52%)
(45%)
(71%)

14
0
4
10

(48%)

97
12
18
17
27
3
4
5
11

65 (67%)
9 (75%)
15 (83%)
17 (100%)
12 (44%)
0
2 (50%)
2 (40%)
8 (73%)

63
8
15
16
12
0
2
2
8

(65%)
(67%)
(83%)
(94%)
(44%)

41
26
15

23
11
12

(56%)
(42%)
(80%)

55
9
30
16

21
8
4
9

(38%)
(89%)
(13%)
(56%)

(36%)
(71%)

13
0
4
9

(45%)
(36%)
(64%)
(61%)
(67%)
(78%)
(94%)
(44%)

(50%)
(40%)
(73%)

59
8
14
16
12
0
2
1
6

23
11
12

(56%)
(42%)
(80%)

19
7
3
9

(35%)
(78%)
(10%)
(56%)

1
0
0
1

(3%)
(7%)
(8%)
(8%)
(11%)

13
0
4
9

(45%) 13.3
5.4
(36%) 5.3
(64%) 13.3
(58%)
(58%)
(83%)
(82%)
(41%)

(50%)
(20%)
(55%)

8
1
2
0
2
0
0
1
2

(20%)
(18%)

56
7
15
14
11
0
2
0
7

21
9
12

(51%)
(35%)
(80%)

3
2
1

(7%)
(8%)
(7%)

22
11
11

(54%)
(42%)
(73%)

9.7
8.6
9

4.2
3
1.7

19
7
3
9

(35%)
(78%)
(10%)
(56%)

1
1
0
0

(2%)
(11%)

18
6
3
9

(33%) 20.4
(67%) 7.1
(10%) 20.4
(56%) 11.1

2.7
1.3
1.5
1.4

(7%)

19
10
14.1
18
1.9
0.4
(50%) 6.4
11.1
(64%) 13.1

2.2
0.7
2.1
1.1

Peru
# Number of subjects screened. All percentages are calculated using this number as the denominator.
* Screen Period is from the first screening date to the last.

5.1
1.2
1.3
0.9
14.5
7
0.6
0.4
0.8

YM2008/00019/00
B2C109575

Netherlands
Any Investigator

15
0
5
10

CONFIDENTIAL

Germany
Any Investigator

29
4
11
14

Protocol: B2C109575
Population: Total

Page 3 of 5
Table 6.101
Summary of Investigator Performance

Screen Screen
Country
Scr RandNo. in
No. in
No.
Period* Rate per
Investigator (ID)
#
omised
ITT Pop
PP Pop
With PVs
Completed (Weeks) Week
-----------------------------------------------------------------------------------------------------------Any Investigator

18

Poland
Any Investigator

Russian Federation
Any Investigator

21
1
7
13

(58%)
(20%)
(70%)
(62%)

21
1
7
13

(58%)
(20%)
(70%)
(62%)

21
1
7
13

(58%)
(20%)
(70%)
(62%)

1
0
1
0

23
12
11

8
6
2

(35%)
(50%)
(18%)

8
6
2

(35%)
(50%)
(18%)

7
6
1

(30%)
(50%)
(9%)

1
0
1

102
7
15
2
43
35

(10%)

(4%)
(9%)

81 (79%)
2 (29%)
12 (80%)
2 (100%)
33 (77%)
32 (91%)

81 (79%)
2 (29%)
12 (80%)
2 (100%)
33 (77%)
32 (91%)

81 (79%)
2 (29%)
12 (80%)
2 (100%)
33 (77%)
32 (91%)

5
1
1
0
1
2

(5%)
(14%)
(7%)

41
8
3
6
1
4
16
3

41
8
3
6
1
4
16
3

40
8
2
6
1
4
16
3

3
1
1
1
0
0
0
0

(4%)
(10%)
(14%)
(7%)

(55%)
(80%)
(43%)
(43%)
(13%)
(36%)
(94%)
(43%)

(55%)
(80%)
(43%)
(43%)
(13%)
(36%)
(94%)
(43%)

(54%)
(80%)
(29%)
(43%)
(13%)
(36%)
(94%)
(43%)

(2%)
(6%)

18
1
6
11

(50%)
(20%)
(60%)
(52%)

5.1
4.9
2.4
4.7

7
1
4.1
4.5

6
5
1

(26%)
(42%)
(9%)

5.3
2.3
5.3

4.4
5.3
2.1

72 (71%) 16.4
1 (14%) 0.1
9 (60%) 14.3
2 (100%) 4.4
29 (67%) 13
31 (89%) 4

6.2
49
1.1
0.5
3.3
8.8

38
7
3
5
1
4
15
3

(51%) 11.1
(70%) 5.9
(43%) 4.9
(36%) 3
(13%) 8.9
(36%) 8.3
(88%) 3.6
(43%) 5.4

South Africa
# Number of subjects screened. All percentages are calculated using this number as the denominator.
* Screen Period is from the first screening date to the last.

6.6
1.7
1.4
4.7
0.9
1.3
4.8
1.3

YM2008/00019/00
B2C109575

74
10
7
14
8
11
17
7

(3%)

CONFIDENTIAL

Philippines
Any Investigator

36
5
10
21

Protocol: B2C109575
Population: Total

Page 4 of 5
Table 6.101
Summary of Investigator Performance

Screen Screen
Country
Scr RandNo. in
No. in
No.
Period* Rate per
Investigator (ID)
#
omised
ITT Pop
PP Pop
With PVs
Completed (Weeks) Week
-----------------------------------------------------------------------------------------------------------Any Investigator

19

Thailand
Any Investigator

United States
Any Investigator

10
1
7
0
2

(32%)
(25%)
(41%)

27
16
11

(32%)
(25%)
(41%)

(50%)

10
1
7
0
2

15
7
8

(56%)
(44%)
(73%)

31
22
9

18
14
4

(58%)
(64%)
(44%)

420
7
15
5
6
8
5
4
4
5
11
14

221
6
8
1
3
2
3
2
1
3
5
10

15
7
8

(56%)
(44%)
(73%)

18
14
4

(58%)
(64%)
(44%)

(53%) 219
(86%)
6
(53%)
8
(20%)
1
(50%)
3
(25%)
2
(60%)
3
(50%)
2
(25%)
1
(60%)
3
(45%)
5
(71%) 10

(50%)

0
0
0
0
0

8
1
6
0
1

15
7
8

(56%)
(44%)
(73%)

0
0
0

17
13
4

(55%)
(59%)
(44%)

2
2
0

(49%) 15
(86%) 0
(53%) 0
(20%) 0
(50%) 0
(25%) 0
(60%) 0
2
1
(40%) 1
(45%) 0
(71%) 1

(52%) 207
(86%)
6
(53%)
8
(20%)
1
(50%)
3
(25%)
2
(60%)
3
(50%)
0
(25%)
0
(60%)
2
(45%)
5
(71%) 10

3.3
1.3
3.3
1.1
0.4

9.4
3.1
5.2
5.3
9.3

15
7
8

(56%) 14.3
(44%) 13.3
(73%) 10.4

1.9
1.2
1.1

(6%)
(9%)

16
12
4

(52%)
(55%)
(44%)

7
5
9

(4%)

194
6
6
1
3
2
3
2
0
2
4
10

(46%)
(86%)
(40%)
(20%)
(50%)
(25%)
(60%)
(50%)

(50%)
(25%)
(20%)
(7%)

(26%)
(25%)
(35%)
(25%)

4.4
4.4
1

26
5.7
13.6
8.9
21
16.9
14.3
4.1
14.9
(40%) 8
(36%) 15.6
(71%) 21.4

# Number of subjects screened. All percentages are calculated using this number as the denominator.
* Screen Period is from the first screening date to the last.

16.2
1.2
1.1
0.6
0.3
0.5
0.4
1
0.3
0.6
0.7
0.7

YM2008/00019/00
B2C109575

(32%)
(25%)
(41%)

(50%)

10
1
7
0
2

CONFIDENTIAL

Sweden
Any Investigator

31
4
17
6
4

Protocol: B2C109575
Population: Total

Page 5 of 5
Table 6.101
Summary of Investigator Performance

Screen Screen
Country
Scr RandNo. in
No. in
No.
Period* Rate per
Investigator (ID)
#
omised
ITT Pop
PP Pop
With PVs
Completed (Weeks) Week
-----------------------------------------------------------------------------------------------------------8
9
7
2
2
2
17
13
14
17
4
7
6
22
9
1
8
17
12

(35%)
(53%)
(78%)
(25%)
(14%)
(20%)
(74%)
(72%)
(70%)
(77%)
(44%)
(28%)
(43%)
(65%)
(75%)
(14%)
(62%)
(57%)
(43%)

8
9
7
2
2
2
17
13
14
17
4
7
6
22
9
1
7
16
12

(35%)
(53%)
(78%)
(25%)
(14%)
(20%)
(74%)
(72%)
(70%)
(77%)
(44%)
(28%)
(43%)
(65%)
(75%)
(14%)
(54%)
(53%)
(43%)

8
9
7
2
2
2
16
11
13
17
4
5
6
22
9
1
7
15
11

(35%)
(53%)
(78%)
(25%)
(14%)
(20%)
(70%)
(61%)
(65%)
(77%)
(44%)
(20%)
(43%)
(65%)
(75%)
(14%)
(54%)
(50%)
(39%)

0
0
0
0
0
0
1
2
1
1
0
2
0
0
0
0
0
1
2

(4%)
(11%)
(5%)
(5%)
(8%)

(3%)
(7%)

7
9
7
2
2
2
15
12
13
16
4
6
5
18
9
0
5
15
8

(30%)
(53%)
(78%)
(25%)
(14%)
(20%)
(65%)
(67%)
(65%)
(73%)
(44%)
(24%)
(36%)
(53%)
(75%)

16.3
17.6
6.4
12.6
11
13
14.1
17.4
23.7
24
5.3
22.4
11.7
12.9
8.7
2.4
(38%) 17.4
(50%) 21.6
(29%) 18.3

YM2008/00019/00
B2C109575

# Number of subjects screened. All percentages are calculated using this number as the denominator.
* Screen Period is from the first screening date to the last.

1.4
1
1.4
0.6
1.3
0.8
1.6
1
0.8
0.9
1.7
1.1
1.2
2.6
1.4
2.9
0.7
1.4
1.5

CONFIDENTIAL

20

23
17
9
8
14
10
23
18
20
22
9
25
14
34
12
7
13
30
28

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 2

Table 6.102
Summary of Reversibility at Screening by Actual Stratum

Stratum: Stratum 1: >=40% - <=65%

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------Percent Reversibility
n
44
46
43
42
47
46
FEV1 (%)
Mean
31.1
26.4
27.6
27.4
28.6
29.7
SD
17.49
15.32
14.55
13.29
23.08
19.32
Median
24.7
21.2
26.4
23.7
20.1
26.2
Min.
12
2
10
12
12
-12
Max.
86
76
82
74
123
102

21

n
44
Mean
542.8
SD
319.85
Median 433.5
Min.
202
Max.
1552

46
447.4
270.44
338.0
29
1317

43
489.9
213.72
432.0
207
936

42
522.3
258.56
478.0
201
1501

47
520.4
408.61
383.0
200
2207

46
530.4
305.66
439.0
-229
1427

CONFIDENTIAL

Absolute Reversibility
FEV1 (mL)

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 2

Table 6.102
Summary of Reversibility at Screening by Actual Stratum

Stratum: Stratum 2: >65% - <=90%

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------Percent Reversibility
n
58
55
58
58
54
56
FEV1 (%)
Mean
23.3
22.4
25.4
23.7
26.4
23.6
SD
12.70
11.49
16.04
17.96
18.63
10.78
Median
18.7
17.7
21.1
16.8
19.4
20.4
Min.
7
12
6
12
12
13
Max.
67
70
100
125
114
72

22

n
58
Mean
565.2
SD
286.98
Median 457.0
Min.
164
Max.
1697

55
576.7
259.80
521.0
215
1305

58
616.7
328.62
520.0
148
1564

58
547.7
296.61
464.0
209
1499

54
557.4
267.15
465.0
243
1277

56
542.3
203.73
497.5
257
1028

CONFIDENTIAL

Absolute Reversibility
FEV1 (mL)

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1
Table 6.104
Summary of Adolescent Subjects

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Total
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
(N=607)
-----------------------------------------------------------------------------------------------------------Age (y)
n
7
2
2
7
5
4
27
12-13 years
1 (14%)
0
0
3 (43%)
1 (20%)
1 (25%)
6 (22%)
14-15 years
6 (86%)
1 (50%)
0
3 (43%)
1 (20%)
2 (50%)
13 (48%)
16-17 years
0
1 (50%)
2 (100%)
1 (14%)
3 (60%)
1 (25%)
8 (30%)

CONFIDENTIAL

23

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.101
Statistical Analysis of Change from Baseline in PM PEF (L/min) by % Predicted FEV1 Stratum

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Days 1-28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Stratum 1: >=40% <=65%
n
44
45
43
40
47
46
LS Mean
374.7
391.8
402.4
414.5
414.0
417.2
LS Mean Change
-3.1(5.92)
13.9(5.88)
24.6(5.96)
36.7(6.15)
36.1(5.70)
39.4(5.87)
(SE)

24

Stratum 2: >65% <=90%


n
LS Mean
LS Mean Change
(SE)
Column vs Placebo
Difference
95% C.I.

17.0
(0.9,33.2)

55
380.9
3.1(5.20)

54
392.1
14.2(5.39)

11.2
(-3.4,25.7)

27.7
(11.5,43.9)

58
402.3
24.4(5.18)

21.4
(7.1,35.7)

39.8
(23.1,56.5)

58
401.3
23.4(5.13)

20.4
(6.2,34.6)

39.2
(23.3,55.1)

54
410.1
32.2(5.33)

29.1
(14.7,43.6)

42.5
(26.4,58.6)

56
415.4
37.6(5.15)

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.

34.5
(20.2,48.9)

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline, country, sex, age, stratum, treatment,
and treatment by stratum interaction
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.102
Statistical Analysis of Change from Baseline in AM PEF (L/min) by % Predicted FEV1 Stratum

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Days 1-28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Stratum 1: >=40% <=65%
n
43
45
43
40
47
46
LS Mean
365.0
379.9
389.5
397.7
402.2
403.2
LS Mean Change
2.3(5.72)
17.1(5.58)
26.7(5.67)
34.9(5.84)
39.4(5.42)
40.5(5.57)
(SE)

25

Stratum 2: >65% <=90%


n
LS Mean
LS Mean Change
(SE)
Column vs Placebo
Difference
95% C.I.

14.8
(-0.6,30.3)

55
364.3
1.6(4.95)

54
382.7
20.0(5.11)

18.4
(4.6,32.2)

24.4
(8.9,40.0)

58
389.6
26.9(4.94)

25.3
(11.7,38.9)

32.7
(16.7,48.6)

58
396.5
33.7(4.88)

32.2
(18.7,45.6)

37.1
(21.9,52.4)

54
399.7
37.0(5.07)

35.4
(21.7,49.1)

38.2
(22.8,53.6)

56
409.5
46.8(4.90)

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.

45.2
(31.5,58.8)

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline, country, sex, age, stratum, treatment,
and treatment by stratum interaction
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.103
Statistical Analysis of Change from Baseline in Day 1 Trough FEV1 (L)
Intent-to-Treat

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 1
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------n
101
101
101
99
100
101
LS Mean
2.415
2.499
2.448
2.503
2.551
2.556
LS Mean Change
0.173(0.032)
0.257(0.032)
0.207(0.031)
0.262(0.032)
0.310(0.032)
0.314(0.031)
(SE)
0.084
0.034
0.088
(-0.004,0.172) (-0.054,0.121) (0.000,0.176)
0.062
0.449
0.049

0.136
(0.049,0.224)
0.002

0.141
(0.053,0.229)
0.002

26

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.
p-value

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 2

Table 7.104
Summary of Number of Puffs of Rescue Medication, Day 1 and Last Clinic Visit

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Time
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Day 1
Nighttime
No puffs
44 (43%)
39 (39%)
38 (38%)
40 (40%)
37 (37%)
39 (38%)
1 or more puffs
57 (56%)
61 (60%)
61 (60%)
58 (58%)
62 (61%)
63 (62%)
Missing
1 (<1%)
1 (<1%)
2 (2%)
2 (2%)
2 (2%)
0
36 (35%)
50 (49%)
16 (16%)

41 (41%)
44 (44%)
16 (16%)

33 (33%)
47 (47%)
21 (21%)

36 (36%)
51 (51%)
13 (13%)

33 (33%)
47 (47%)
21 (21%)

41 (40%)
45 (44%)
16 (16%)

24 Hour

No puffs
1 or more puffs
Missing

22 (22%)
71 (70%)
9 (9%)

20 (20%)
76 (75%)
5 (5%)

18 (18%)
77 (76%)
6 (6%)

16 (16%)
79 (79%)
5 (5%)

15 (15%)
79 (78%)
7 (7%)

19 (19%)
77 (75%)
6 (6%)

No puffs
1 or more puffs
Missing

39 (38%)
30 (29%)
33 (32%)

47 (47%)
16 (16%)
38 (38%)

56 (55%)
15 (15%)
30 (30%)

42 (42%)
18 (18%)
40 (40%)

62 (61%)
14 (14%)
25 (25%)

57 (56%)
19 (19%)
26 (25%)

Daytime

No puffs
1 or more puffs
Missing

26 (25%)
39 (38%)
37 (36%)

25 (25%)
35 (35%)
41 (41%)

28 (28%)
31 (31%)
42 (42%)

18 (18%)
37 (37%)
45 (45%)

29 (29%)
30 (30%)
42 (42%)

30 (29%)
31 (30%)
41 (40%)

24 Hour

No puffs
1 or more puffs
Missing

18 (18%)
51 (50%)
33 (32%)

20 (20%)
40 (40%)
41 (41%)

20 (20%)
37 (37%)
44 (44%)

10 (10%)
45 (45%)
45 (45%)

26 (26%)
35 (35%)
40 (40%)

22 (22%)
42 (41%)
38 (37%)

No puffs
1 or more puffs
Missing

37 (36%)
24 (24%)
41 (40%)

39 (39%)
25 (25%)
37 (37%)

49 (49%)
9 (9%)
43 (43%)

45 (45%)
12 (12%)
43 (43%)

49 (49%)
14 (14%)
38 (38%)

50 (49%)
12 (12%)
40 (39%)

Day 2
Nighttime

Last Clinic Visit Day 1


Nighttime

Last Clinic Visit Day 1 is nominal Day 7 or Day 14 or Day 28


Last Clinic Visit Day 2 is nominal Day 8 or Day 15 or Day 29

YM2008/00019/00
B2C109575

No puffs
1 or more puffs
Missing

CONFIDENTIAL

27

Daytime

Protocol: B2C109575
Population: Intent-to-Treat

Page 2 of 2

Table 7.104
Summary of Number of Puffs of Rescue Medication, Day 1 and Last Clinic Visit

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Time
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
----------------------------------------------------------------------------------------------------------Daytime
No puffs
30 (29%)
28 (28%)
24 (24%)
25 (25%)
33 (33%)
29 (28%)
1 or more puffs
26 (25%)
35 (35%)
20 (20%)
32 (32%)
21 (21%)
20 (20%)
Missing
46 (45%)
38 (38%)
57 (56%)
43 (43%)
47 (47%)
53 (52%)
24 Hour

18 (18%)
39 (38%)
45 (44%)

17 (17%)
40 (40%)
44 (44%)

16 (16%)
25 (25%)
60 (59%)

20 (20%)
38 (38%)
42 (42%)

28 (28%)
27 (27%)
46 (46%)

16 (16%)
29 (28%)
57 (56%)

No puffs
1 or more puffs
Missing

37 (36%)
25 (25%)
40 (39%)

45 (45%)
25 (25%)
31 (31%)

38 (38%)
25 (25%)
38 (38%)

51 (51%)
25 (25%)
24 (24%)

55 (54%)
17 (17%)
29 (29%)

44 (43%)
28 (27%)
30 (29%)

Daytime

No puffs
1 or more puffs
Missing

27 (26%)
38 (37%)
37 (36%)

33 (33%)
40 (40%)
28 (28%)

31 (31%)
34 (34%)
36 (36%)

40 (40%)
41 (41%)
19 (19%)

46 (46%)
28 (28%)
27 (27%)

46 (45%)
33 (32%)
23 (23%)

24 Hour

No puffs
1 or more puffs
Missing

21 (21%)
43 (42%)
38 (37%)

26 (26%)
43 (43%)
32 (32%)

24 (24%)
41 (41%)
36 (36%)

35 (35%)
44 (44%)
21 (21%)

38 (38%)
34 (34%)
29 (29%)

33 (32%)
40 (39%)
29 (28%)

Last Clinic Visit Day 2


Nighttime

28

YM2008/00019/00
B2C109575

Last Clinic Visit Day 1 is nominal Day 7 or Day 14 or Day 28


Last Clinic Visit Day 2 is nominal Day 8 or Day 15 or Day 29

CONFIDENTIAL

No puffs
1 or more puffs
Missing

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.106
Summary of the Proportion of Subjects Obtaining >= 200mL and >= 12%
Increase from Baseline FEV1 (L) (Day 28, 22-24hrs)
by % Predicted FEV1 Stratum

Planned
Relative Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Stratum
Time
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-------------------------------------------------------------------------------------------------------->=40%-<=65% 22 hours 18 / 39 (46%) 17 / 35 (49%) 17 / 34 (50%) 17 / 35 (49%) 27 / 43 (63%) 29 / 39 (74%)
23 hours 15 / 39 (38%) 15 / 35 (43%) 16 / 34 (47%) 18 / 35 (51%) 30 / 43 (70%) 29 / 42 (69%)
24 hours 14 / 38 (37%) 13 / 35 (37%) 19 / 35 (54%) 21 / 36 (58%) 32 / 43 (74%) 28 / 42 (67%)
>65%-<=90%

11 / 48 (23%) 19 / 49 (39%) 19 / 56 (34%) 14 / 50 (28%) 26 / 50 (52%) 19 / 55 (35%)


12 / 47 (26%) 13 / 49 (27%) 17 / 56 (30%) 17 / 52 (33%) 22 / 50 (44%) 19 / 55 (35%)
12 / 48 (25%) 13 / 48 (27%) 16 / 56 (29%) 12 / 51 (24%) 22 / 50 (44%) 22 / 54 (41%)

29

CONFIDENTIAL

22 hours
23 hours
24 hours

YM2008/00019/00
B2C109575

Protocol: B2C109575
Population: Per Protocol

Page 1 of 1

Table 7.107
Statistical Analysis of Change from Baseline in Trough FEV1 (L) (LOCF)
Subset of Subjects who had the 6-12 hour time points measured
Per Protocol

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Day 28
(N=98)
(N=97)
(N=98)
(N=98)
(N=93)
(N=99)
-----------------------------------------------------------------------------------------------------------n
61
61
63
69
57
56
LS Mean
2.428
2.529
2.519
2.533
2.608
2.552
LS Mean Change
0.161(0.044)
0.262(0.045)
0.252(0.044)
0.266(0.042)
0.341(0.046)
0.285(0.047)
(SE)
0.100
0.091
0.105
0.180
(-0.025,0.226) (-0.032,0.213) (-0.016,0.225) (0.054,0.305)

0.124
(-0.003,0.251)

30

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline (pre-dose on day 1), country, sex, age,
stratum and treatment

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.108
Statistical Analysis of Change from Baseline in Percentage of Symptom Free 24 Hour Periods
by % Predicted FEV1 Stratum

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Days 1-28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Stratum 1: >=40% <=65%
n
43
45
43
40
47
46
LS Mean
23.0
32.1
30.9
40.8
45.2
38.8
LS Mean Change
12.6(5.04)
21.7(4.89)
20.5(5.02)
30.4(5.15)
34.8(4.78)
28.5(4.83)
(SE)

31

Stratum 2: >65% <=90%


n
LS Mean
LS Mean Change
(SE)
Column vs Placebo
Difference
95% C.I.

9.1
(-4.6,22.8)

55

25.7
15.3(4.39)

54

33.7
23.4(4.44)

8.1
(-4.1,20.2)

7.9
(-5.8,21.7)

58

36.3
25.9(4.31)

10.6
(-1.4,22.6)

17.8
(3.6,31.9)

58

34.9
24.5(4.30)

9.2
(-2.7,21.1)

22.2
(8.7,35.7)

54

48.1
37.7(4.46)

22.4
(10.2,34.5)

15.8
(2.2,29.5)

56

45.7
35.4(4.33)

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.

20.0
(7.9,32.2)

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline, country, sex, age, stratum, treatment,
and treatment by stratum interaction
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject

Protocol: B2C109575
Population: Intent-to-Treat

Page 1 of 1

Table 7.109
Statistical Analysis of Change from Baseline in Percentage of Rescue Free 24 Hour Periods
by % Predicted FEV1 Stratum

Placebo
3mcg
6.25mcg
12.5mcg
25mcg
50mcg
Days 1-28
(N=102)
(N=101)
(N=101)
(N=100)
(N=101)
(N=102)
-----------------------------------------------------------------------------------------------------------Stratum 1: >=40% <=65%
n
44
45
43
40
47
46
LS Mean
24.3
33.8
33.1
40.1
57.0
41.6
LS Mean Change
11.2(5.10)
20.7(5.01)
20.1(5.12)
27.1(5.27)
43.9(4.89)
28.5(4.94)
(SE)

32

Stratum 2: >65% <=90%


n
LS Mean
LS Mean Change
(SE)
Column vs Placebo
Difference
95% C.I.

9.5
(-4.4,23.4)

55

30.9
17.9(4.51)

54

42.9
29.9(4.56)

12.0
(-0.5,24.4)

8.9
(-5.2,22.9)

58

45.9
32.8(4.40)

15.0
(2.7,27.3)

15.9
(1.5,30.3)

58

44.8
31.8(4.40)

13.9
(1.6,26.1)

32.7
(19.0,46.5)

54

55.6
42.6(4.56)

24.7
(12.3,37.1)

17.3
(3.4,31.2)

56

51.5
38.4(4.44)

CONFIDENTIAL

Column vs Placebo
Difference
95% C.I.

20.6
(8.2,32.9)

YM2008/00019/00
B2C109575

Note: Analysis performed using ANCOVA with covariates of baseline, country, sex, age, stratum, treatment,
and treatment by stratum interaction
Note: Baseline is defined as the last 7 days prior to the randomisation of the subject

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