SERETIDE COPD CLINICAL

PAPERS

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Meeting the needs of patients with COPD: patients

preference for the Diskus inhaler compared with the
Handihaler.
A.C. MOORE, S. STONE

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Seretide and The Diskus

Top 3 Criteria of an ideal
inhaler accdg to patients:
1. Being quick to use
2. Ease of use
3. Knowing how many
doses are left
p<0.0013

More than twice the

number of patients
preferred the Diskus
(67%) to the Handihaler
(33%)
Study design: Questionnaires were used to assess preference and ease of use of the Diskus and Handihaler in 256
patients with COPD. Patients had used neither device before and were asked to assess each inhaler; to rank the most
important feature of an inhaler; and to elicit an overall preference between the two. Patients considered the Diskus to
be significantly better than the Handihaler on the three most important attributes for an inhaler device (p<0.001).

p<0.0013

3. Moore, AC. et al. Meeting the needs of patients with COPD: patients preference for the Diskus inhaler compared with the Handihaler. 2004,
58, 5, 444450.
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The Prevention of Chronic Obstructive Pulmonary

Disease Exacerbations by Salmeterol/Fluticasone
Propionate or Tiotropium Bromide
Jadwiga A. Wedzicha1, Peter M. A. Calverley2, Terence A. Seemungal3, Gerry
Hagan4, Zainab Ansari4, and Robert A. Stockley5, for the INSPIRE Investigators

INSPIRE STUDY: Seretide vs

Tiotropium
INSPIRE: Investigating New Standards for
Prophylaxis In Reduction of Exacerbations
Duration = 2 years
ITT = 1,323
Scope = 179 centers, 20 countries

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INSPIRE: Study Endpoints

Primary Objective
To study the effect of Seretide vs Tiotropium in reducing the rate of healthcare
utilisation COPD exacerbations over 104 weeks in subjects with severe COPD.

Main Secondary Endpoints

Rate of symptom-defined exacerbations
Time to withdrawal
Post-dose FEV1

Main Other Endpoints

Health Outcomes
total exacerbation rate
SGRQ
DRC data
TDI
Other lung function parameters

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Safety
Adverse events
AEs of special interest
All-cause Mortality

SFC significantly improves quality of

life vs tiotropium (INSPIRE)
SGRQ total scores (units)

55

50

2.1-unit difference
in total SGRQ score
(p=0.038) at wk
104

45
Tiotropium 18 mg
SFC 50/500 mg

40
0
0

-2

SFC vs Tio
Visit 6 (wk 32)
Visit 8 (wk 56)
Visit 10 (wk 80)
Visit 12 (wk 104)

10

22

34
46 58
Time (weeks)

70

82

94

106

Difference (SE)
95% CI
p-value
-1.92 (0.832)
(-3.55, -0.29)
0.021
-2.07 (0.883)
(-3.81, -0.34)
0.019
-2.04 (0.936)
(-3.88, -0.20)
0.030
-2.07 (0.994)
(-4.02,
-0.12)PURPOSES 0.038
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TRAINING

1. Wedzicha JA, et al. AJRCCM 2008; 177: 19-26

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SFC resulted in 52% reduction in

risk of dying vs. Tiotropium
Tiotropium

Probability of Event (%)

7
6

52% reduction
P=0.012

5
4
3
2

SFC

1
Number 0
at Risk

656
664

560
548

531
502

510
475

13

26

39

494
451

477
435

456
416

445
398

160
141

52
65
78
Time to Event (Weeks)

91

104

SFC
TIO

On-treatment Comparison from Coxs Proportional Hazards Model

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Wedzicha et al AJRCCM 2008; 177: 19

Overall study conclusions

First head to head study of two main pharmacological
agents used for COPD.
Novel methodology using two different measures of
exacerbations.
No differences demonstrated for exacerbation rate and
lung function.
Seretide significantly improves Health Status after
optimisation and compared to Tio.
Seretide significantly improves survival compared to tio.

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Salmeterol and Fluticasone Propionate and

Survival in Chronic Obstructive Pulmonary Disease
Peter M.A. Calverley, M.D., Julie A. Anderson, M.A., Bartolome Celli, M.D., Gary T. Ferguson,
M.D., Christine Jenkins, M.D.,Paul W. Jones, M.D., Julie C. Yates, B.S., and Jorgen Vestbo,
M.D., for the TORCH investigators*

The TORCH Survival Study

Affecting Mortality in COPD: Is the Dream Becoming a Reality?

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TORCH Study
TORCH is the first study to specifically investigate
the effect of pharmacotherapy on survival as an
endpoint

The most ambitious study in COPD ever

completed
a first of its kind
large patient population
reliable and robust endpoints
potential to change disease management
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Reliable and robust endpoints

Primary
To study the effect of salmeterol/fluticasone
propionate (SFC) combination vs placebo on
all-cause mortality over 3 years in patients with
moderate to severe COPD
Secondary
To study the effect of SFC on:
moderate and severe exacerbation frequency
Health Status (SGRQ)
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Objectives of TORCH
Others
Compare effect on all-cause mortality:
Combination vs components
Components vs placebo

Compare effect on COPD related mortality:

Between treatments

Compare effect on COPD morbidity:

Lung function
Other exacerbation parameters
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Worldwide participation
TORCH in 42 countries

6112 participants
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TORCH: Study Design

SFC 500/50 bd
FP 500 bd

1,534

2 week
run-in*

Salmeterol 50 bd

Placebo

1,521

1,524

Duration = 3 years
*All ICS and inhaled LABA discontinued before run-in.

ITT population

1,533

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6112 patients

Study population - inclusion

Established history of COPD (ERS definition)

Aged 40-80 yrs inclusive

Smoking history 10 pack years

Reversibility < 10% in predicted FEV1

Pre-bronchodilator FEV1 < 60% predicted
Pre-bronchodilator FEV1/FVC ratio 70%
Able to use Diskus/Accuhaler
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Study population - exclusion

Current diagnosis of asthma or respiratory disorders
other than COPD (lung cancer, sarcoidosis, TB, lung
fibrosis)
X-ray - indicating diagnosis other than COPD
Had a LVRS or lung transplant
Requirement for LTOT (> 12 hrs/day) at start of study

Receiving long term oral corticosteroid therapy

Other disease likely to cause death within 3 yrs
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Outcomes of patients during TORCH

Post withdrawal, patients

allowed to take any medication.
As more patients in placebo
withdrew, it became BIASED
against Seretide

Withdrew

Withdrew

1 yr

RIP

RIP
2 yr

Primary Endpoint of all cause death measured at end of 3 years

Secondary Endpoints measured when on treatment (yellow only)
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3 yr

Premature study drug discontinuation

More placebo patients

withdrawing = more potential
bias against Seretide: sicker
patients tend to discontinue
and replace placebo with
better medication, and the
healthier patients tend to
remain

Vertical bars represent standard errors

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Summary
Seretide significantly improved:
FEV1 compared with components and placebo
Health status compared with components and placebo

Seretide significantly reduced:

FEV1 decline
Exacerbations compared with components or placebo
Hospitalizations compared with placebo

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Mortality conclusions
In the TORCH study:
SFC reduced the risk of dying at any time during 3 years
by 17.5% vs placebo
The absolute risk reduction was 2.6%
FP and SAL mortality was not different to placebo, but
SFC was significantly better than FP
Differences in mortality between SFC and placebo were
driven by cardiovascular, pulmonary and other causes
of death
COPD-related deaths and deaths-on-treatment showed a
similar trend to the all-cause mortality for SFC vs
placebo
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Safety conclusions
SFC was generally well tolerated over three years
The anticipated local side effects of ICS were observed
There was an increase in reporting of pneumonia in the FP
containing arms. However, there was no increase in
pneumonia mortality between SFC and placebo
There was no significant difference in the probability of total
or non-traumatic fractures between groups
In the safety sub-study (n = 658), there were no differences
in BMD or the number of patients developing cataracts
between groups
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Mortality and Safety Summary

SFC 50/500 improves survival vs placebo
and FP
SFC 50/500 is generally well tolerated over
three years

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TORCH: Results Summary

SFC 50/500, in COPD patients with FEV < 60%
Improves survival vs placebo
Significantly improves and maintains health status vs placebo and
components
Significantly reduces the rate of exacerbations vs placebo and
components

Significantly improves lung function vs placebo and components

Has a safety profile generally consistent with previous studies
Led to increased reporting of pneumonia, which did not compromise the
overall benefits of SFC treatment
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Seretide on Exacerbations
TORCH (vs. Placebo and individual
components over 3 years)

1.
2.

25%

Reduction in the rate of

moderate/severe
exacerbations over 3 years
vs control (p<0.001)1

43%

Reduction in the rate of

exacerbations requiring
oral steroids over 3 years
vs control (p<0.001)1

INSPIRE (vs. Tiotropium over 2

years)

There was no significant

difference in the annual
rate of exacerbations with
Seretide vs tiotropium
(1.32 vs 1.28, p=0.656)2

Calverley PM et al. N Engl J Med. 2007; 356: 775-89.

Wedzicha J et al. The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or
tiotropium bromide. American Journal of Respiratory Critical Care Medicine 2008; 177: 19-26
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Seretide on Quality of Life and

Mortality
TORCH (vs. Placebo and individual
components over 3 years)

3.1

17.5%

1.
2.

3.1 unit improvement in

the SGRQ (QoL) score for
patients. Seretide provided
sustained improvements in
QoL score over 3 years 1

Seretide reduced the

risk of mortality at any
time during 3 years by
17.5%1

INSPIRE (vs. Tiotropium over 2

years)

2.1

52%

Seretide was significantly

more effective at
improving health status
of the patients (2.1 unit
difference, p = 0.038) vs.
Tiotropium.2
Seretide provided a 52%
relative risk reduction on
all-cause mortality to
patients compared to
Tiotropium.2

Calverley PM et al. N Engl J Med. 2007; 356: 775-89.

Wedzicha J et al. The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or
tiotropium bromide. American Journal of Respiratory Critical Care Medicine 2008; 177: 19-26
FOR GSK INTERNAL TRAINING PURPOSES

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