Treating COPD:

Reaching for GOLD

NOVARTIS

GRANTS AS PRINCIPAL INVESTIGATOR FOR INTERNATIONAL PHASE II & III TRIALS
A randomised, 24-week, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy, safety and
tolerability of Ariflo (15 mg twice daily) in patients with Chronic Obstructive Pulmonary Disease (COPD).
Protocol number: SB 207499/042
Trial period: 13/04/1999 till 26/10/1999
Phase: II

A multidose comparison of Tiotropium inhalation capsules, Salmeterol inhalation aerosol and placebo in a six-month,
double-blind, double-dummy, safety and efficacy study in patients with Chronic Obstructive Pulmonary Disease (COPD).
Protocol number: BI205.137 (ZA100)
Trial period: 10/05/1999 till 20/04/2000
Phase: III

A multicentre, open-label extension study to evaluate the safety, tolerability and efficacy of oral SB 207499 (15mg twice
daily) in patients with Chronic Obstructive Pulmonary Disease (COPD).
Protocol number: SB 207499/040
Trial period: 26/10/1999 till 06/08/2002
Phase: III

A randomised, double-blind, double-dummy, placebo- and active controlled, parallel-group efficacy and safety
comparison of 12-week treatment of two doses [5g (2 actuations of 2.5 g) and 10 g (2 actuations of 5 g)] of
Tiotropium inhalation solution delivered by Respimat inhaler, placebo and Ipratropium Bromide inhalation aerosol (MDI)
in patients with Chronic Obstructive Pulmonary Disease (COPD).
Protocol number: BI205.251
Trial period: 04/02/2003 22/06/2004
Phase: III

DECLARATION
Effect of roflumilast on exacerbation rate in patients with COPD. A 52 weeks, double-blind study with 500 mcg roflumilast
once daily versus placebo. The HERMES study.
Protocol number: BY217/M2-125
Commenced: 24/05/2006
Phase: III

Effect of roflumilast in COPD patients treated with salmeterol. A 12 week, double blind study with 500 mcg roflumilast
once daily versus placebo. (EOS-study)
Protocol number: BY217/M2-127
Commenced: 28/06/2006
Phase: III

A 52-week randomized, double-blind, parallel group, placebo controlled, multicenter clinical trial, to assess the efficacy
and safety of 200g of the anti-cholinergic LAS 34273 compared to placebo, both administered once-daily by inhalation,
in the maintenance treatment of patients with moderate to severe stable chronic obstructive pulmonary disease
(ALMIRAL)
Protocol number: M/34273/31
Commenced: 13/11/2006
Phase: IV

Effect of Roflumilast on exacerbation rate in patients with Chronic Obstructive Pulmonary disease. A 52 week s double-
blind study with 500ug Roflumilast once daily versus placebo. (OPUS)
Protocol Title: BY217/M2-111
Trial period: 01/12/2003 16/09/2005
Phase: III

A double-blind, randomised, placebo controlled study to investigate chronic intermittent pulse therapy of moxifloxacin as
a prevention of acute exacerbation in out-patients with chronic bronchitis.
Protocol number: BAY 12-8039 / 11229 / PULSE
Trial period: 11/10/2004 10/05/2007
Phase: III


COPD
COPD is a gradually progressive
disease
Dyspnoea (persistent & progressive)
is the hallmark symptom and is the
most frequent reason that patients
seek medical attention.
COPD
Cough is often the first symptom to develop and is
frequently discounted by the patient as an expected
consequence of smoking.
Initially, the cough may be intermittent, but later is
present every day.
Chronic cough associated with COPD can be
unproductive. Notably, some patients can develop
considerable airflow limitation without the presence of a
cough.
Stage I-III COPD prevalence: BOLD study

11
19
26
24
18
13
22
19
19
20
14
19
0
7
14
21
28
P
r
e
v
a
l
e
n
c
e

o
f

C
O
P
D

(

4
0

y
e
a
r
s

o
f

a
g
e
)

Buist al. Lancet 2007;370:741
COPD is under-diagnosed BOLD
0
8
15
23
30
GOLD Stage I+
GOLD Stage II+
Doctor-diagnosed COPD
Buist, et al. Lancet 2007
Risk Factors for COPD
Genes
Infections
Socio-economic
status
Aging Populations
CAUSES OF COPD
50 to 60 fold higher incidence of COPD in HIV independent of
other risk factors
Cannabis: 1 joint = 2.5 - 5 cigarettes thus higher risk of COPD
Passive or environmental tobacco smoke may contribute to
COPD: same risk on average as a smoker (15 - 20% of passive
smokers develop disabling airflow limitation)
Pregnancy: smoking may predispose foetus to later COPD
Hubbly bubbly or hookah pipe worse than cigarette smoke - a
session of 20 min equals smoking 200 cigarettes (WHO) and in
an average shared session you would inhale 20 cigarettes
nicotine
There are 4500 chemicals in a cigarette
50% of people who smoke will die from the habit with an average
reduction of 8 - 20y of lifespan
P
L
V
P
L
V
X
Trapped
air
Normal COPD
MECHANISM OF COPD
Expiratory Airflow Obstruction
. .
P
L
= translung pressure; V = ventilation

Reduced recoil
Reduced tethering
Increased airways resistance
Differential Diagnosis
Asthma
CHF
Bronchiectasis
Tuberculosis
Obliterative bronchiolitis
onset younger age, nonsmokers, h/o RA or fume exposure
Diffuse panbronchiolitis
Male nonsmokers, chronic sinusitis, centrilobular nodular opacities and
hyperinflation
COPD
Symptoms differ from asthma
COPD Asthma
Onset Midlife Early in life (often childhood)
Symptoms Slowly progressive
Dyspnoea during activity
Vary from day to day
More common at night/early
morning
Airflow limitation Largely irreversible Largely reversible
Main risk factors for
development
Tobacco smoke and
airborne pollutants
Exposure to allergens, infections,
diet, tobacco smoke,
socioeconomic
Additional features Chronic cough & sputum
Family history of COPD
Allergy, rhinitis and eczema also
present
Family history of asthma
GOLD. Global strategy for diagnosis, management, and prevention of COPD. 2013

Assess COPD Comorbidities
COPD patients are at increased risk for:
Cardiovascular diseases
Osteoporosis
Respiratory infections
Anxiety and Depression
Diabetes
Lung cancer
These comorbid conditions may influence mortality and
hospitalizations and should be looked for routinely, and
treated appropriately.
Investigations
Chest X-ray: Seldom diagnostic but valuable to exclude alternative
diagnoses and establish presence of significant comorbidities.
Lung Volumes and Diffusing Capacity / Spirometry: Help to
characterize severity, but not essential to patient management.
Oximetry and Arterial Blood Gases: Pulse oximetry can be used to
evaluate a patients oxygen saturation and need for supplemental
oxygen therapy.
Alpha-1 Antitrypsin Deficiency Screening: Perform when COPD
develops in patients of Caucasian descent under 45 years or with a
strong family history of COPD.
Exercise Testing: Objectively measured exercise impairment,
assessed by a reduction in self-paced walking distance (such as
the 6 min walking test) or during incremental exercise testing in
a laboratory, is a powerful indicator of health status impairment
and predictor of prognosis.
Composite Scores: Several variables (FEV
1
, exercise tolerance
assessed by walking distance or peak oxygen consumption,
weight loss and reduction in the arterial oxygen tension) identify
patients at increased risk for mortality.



Additional Investigations
Spirometry
What is a spirometer?
A spirometer is a device used to
measure respiratory movements
as a function of time
Spirometry can be used to
measure
forced expiratory volume in
one second (FEV
1
)
forced vital capacity (FVC)
Respiratory values
Respiratory parameters
Tidal volume (TV) The amount of air that is either inhaled or exhaled during one bbrespiratory
cycle
Inspiratory reserve volume
(IRV)
The maximal amount of air that can be inhaled from the end-inspiratory position
Expiratory reserve volume
(ERV)
The maximal amount of air that can be exhaled from the resting end-expiratory
level
Forced expiratory volume at
one second (FEV
1
)
The volume of air forcefully and rapidly expelled in one second following
maximal inspiration
Residual volume (RV) The volume of air remaining in the lungs after maximal expiration
Lung capacities
Total lung capacity (TLC) The volume of air contained in the lungs after maximal inspiration
Vital capacity (VC) The volume of air that can be expelled from the lungs from a position of full
inhalation, with no limit to the duration of exhalation; it is equal to the
inspiratory capacity plus the expiratory reserve volume
Inspiratory capacity (IC) The volume of air that can be taken into the lungs on a full inhalation, starting
from the functional residual capacity; it is equal to the tidal volume plus
inspiratory reserve volume
Functional residual capacity
(FRC)
The volume of air remaining at the end of a normal quiet exhalation
Forced vital capacity (FVC) Vital capacity measured when the patient is exhaling with maximum speed and
effort
Normal
COPD
1 sec
FVC
8
7
6
5
4
3
2
1
0
-2
-3
-4
-5
IC
F
l
o
w

(
L
/
s
)

6 5 4 3 2
Volume (L)
1 sec
8
6
4
2
0
-2
-4
-6
Predicted
Actual
IC
8 7 6 5 4 3 2
Volume (L)
F
l
o
w

(
L
/
s
)

Spirometry Loops
Patients with COPD have less elastic airways and consequently it takes longer to expel
a similar proportion of air:
This graph shows how the FEV
1
:FVC ratio is affected by COPD.
A diagnosis of COPD is made when FEV1 is less than 70% of FVC.
FVC
Bronchodilator medications are central to
symptom management in COPD
GOLD Strategy: COPD Management
V
.

BD
Air flow
Deflation
Improvement in flow FEV
1
Improvement in volumes FVC and IC
BD = bronchodilator; FEV
1
= forced expiratory volume in 1 second
FVC = forced vital capacity
Bronchodilator therapy deflates the lung
The MRC breathlessness scale
Stenton C Occup Med (Lond) 2008;58:226-227
GOLD Strategy:
Pharmacologic management of COPD*

(C) (D)
LABA+ICS or LAMA LABA+ICS or LAMA
LABA and LAMA

LABA+ICS and LAMA or
LABA+ICS and PDE4-inh or
LABA and LAMA or
LAMA and ICS or
LAMA and PDE4-inh
SABA or SAMA prn LABA or LAMA

LABA or LAMA or
SABA and SAMA
LABA and LAMA
(A) (B)
GOLD 1
GOLD 2
GOLD 3
GOLD 4
mMRC 2
CAT 10
mMRC 01
CAT <10
Exacerbations per year
2
*Medications in each box are mentioned in alphabetical order, and therefore not necessarily in order of preference

SABA: short-acting
2
-agonist; SAMA: short-acting muscarinic antagonist; p.r.n.: as needed (pro re nata); LABA: long-acting
2
-agonist;
LAMA: long-acting muscarinic antagonist; ICS: inhaled corticosteroid; PDE4-inh: phosphodiesterase-4 inhibitor
First choice;
Second choice
0
1
GOLD. Global strategy for diagnosis, management, and prevention of COPD, 2014
Or 1 leading
to hospital
admission
(not leading
to hospital
admission)
***p<0.001 vs placebo;

p<0.01,

p<0.05 vs salmeterol
Data are LSM.
Difference of 1 = clinically important improvement in the
Transition Dyspnoea Index (TDI) total score (dotted line)
Indacaterol vs Salmetarol
improved dyspnoea over 12 weeks
2.0
1.5
1.0
0.5
0
0.90
1.45

***

INLIGHT 2
TDI total score versus placebo Patients (%) with clinically important
change (1 point) in TDI total score
***
80
60
40
20
0
***
39.5%
60.1%
51.4%

***
Placebo Indacaterol 150 g o.d. Salmeterol 50 g b.d.
Kornmann et al. Eur Respir J 2010;
Kornmann et al. ACCP 2009

50
90
110
120 120
150
140
160
130
160
180
190
Tiotropium 18 g o.d. Indacaterol 150 g o.d. Indacaterol 300 g o.d.
Indacaterol vs Tiotropium
has a faster onset of bronchodilator effect on Day 1
Time post-dose (minutes)
***
***
***
***
***
***
***
***
***
***
***
**


200
180
160
140
120
100
80
60
40
20
0
F
E
V
1

d
i
f
f
e
r
e
n
c
e

v
e
r
s
u
s

p
l
a
c
e
b
o

(
m
L
)

5 15 30 60




MCID
INTIME
Vogelmeier et al. Respir Res 2010
**p<0.01, ***p<0.001 vs placebo; p<0.05 vs tiotropium
Data are least squares means
The dotted line represents the 120 mL MCID vs placebo
Indacaterol vs Tiotropium
significant improves dyspnea score at 12 weeks
0
1
1
2
2
3
TDI total score
Difference
0.58 (p<0.001)
40
45
50
55
60
Patients (%) with clinically important
change (1 point) in TDI total score
TDI = Transition
Dyspnea Index
1.43
2.01
50.1%
57.9%
I
M
P
R
O
V
E
M
E
N
T

Dunn et al. ACCP 2010; Buhl ERJ 2011
INTENSITY
Odds ratio 1.49 (p<0.001)
Indacaterol 150 g o.d.
Tiotropium 18 g o.d.
GOLD Strategy:
Pharmacologic management of COPD*

(C) (D)
LABA+ICS or LAMA LABA+ICS or LAMA
LABA and LAMA

LABA+ICS and LAMA or
LABA+ICS and PDE4-inh or
LABA and LAMA or
LAMA and ICS or
LAMA and PDE4-inh
SABA or SAMA prn LABA or LAMA

LABA or LAMA or
SABA and SAMA
LABA and LAMA
(A) (B)
GOLD 1
GOLD 2
GOLD 3
GOLD 4
mMRC 2
CAT 10
mMRC 01
CAT <10
Exacerbations per year
2
*Medications in each box are mentioned in alphabetical order, and therefore not necessarily in order of preference

SABA: short-acting
2
-agonist; SAMA: short-acting muscarinic antagonist; p.r.n.: as needed (pro re nata); LABA: long-acting
2
-agonist;
LAMA: long-acting muscarinic antagonist; ICS: inhaled corticosteroid; PDE4-inh: phosphodiesterase-4 inhibitor
First choice;
Second choice
0
1
GOLD. Global strategy for diagnosis, management, and prevention of COPD, 2014
Or 1 leading
to hospital
admission
(not leading
to hospital
admission)
Use of ICS in COPD
GOLD Strategy:
Pharmacologic management of COPD*

(C) (D)
LABA+ICS or LAMA LABA+ICS or LAMA
LABA and LAMA

LABA+ICS and LAMA or
LABA+ICS and PDE4-inh or
LABA and LAMA or
LAMA and ICS or
LAMA and PDE4-inh
SABA or SAMA prn LABA or LAMA

LABA or LAMA or
SABA and SAMA
LABA and LAMA
(A) (B)
GOLD 1
GOLD 2
GOLD 3
GOLD 4
mMRC 2
CAT 10
mMRC 01
CAT <10
Exacerbations per year
2
*Medications in each box are mentioned in alphabetical order, and therefore not necessarily in order of preference

SABA: short-acting
2
-agonist; SAMA: short-acting muscarinic antagonist; p.r.n.: as needed (pro re nata); LABA: long-acting
2
-agonist;
LAMA: long-acting muscarinic antagonist; ICS: inhaled corticosteroid; PDE4-inh: phosphodiesterase-4 inhibitor
First choice;
Second choice
0
1
GOLD. Global strategy for diagnosis, management, and prevention of COPD, 2014
Or 1 leading
to hospital
admission
(not leading
to hospital
admission)
Pharmacologic Therapy
ICS - Benefits and harms
In severe COPD, twice daily combination therapy with ICS in
combination with LABA vs. placebo + LABA (TORCH STUDY)
resulted in:
No effect on quality of life, total mortality or COPD related-deaths
Reduced frequency of moderate to severe exacerbations, exacerbations
requiring steroids or hospitalization
Effect size very small (0.03 0.34 exacerbations per year difference)
Increased risk of pneumonia (number needed to harm [NNH] = 14)
ICS alone increased mortality (NNH = 30) and COPD-related deaths
(NNH = 46) compared with combination therapy
Calverley, 2007
The role of inhaled corticosteroids in COPD is
limited to specific indications
Long-term ICS treatment is recommended for patients with
severe/very severe COPD and frequent exacerbations (GOLD groups
C and D) (patients with 2 exacerbations per year)
Long-term ICS monotherapy is not recommended because it is less
effective than combination of LABA and ICS
Oral steroids no longer recommended for maintenance treatment of
COPD Cochrane database 2005
A therapeutic trial of oral steroids to distinguish responders from non
responders is no longer recommended. There is no reason ever for a
trial of steroids in COPD - it does not predict prognosis or the future
response to inhaled steroids
Global Initiative for Chronic Obstructive
Lung Disease (GOLD) 2013
(www.goldcopd.org)
O2 in COPD
Home O2 for patients with secondary effects of
hypoxia: Cor Pulmonale with decompensation,
pulmonary hypertension or polycythaemia
Long term continuous O2 PaO2 < 55mmHg at rest or <
59mmHg with PHTS, RVFailure or polycythaemia
Intermittent O2 for air travel
PaO2 decreases by 4mmHg /1000ft - Commercial
aircraft pressurised to 6000 - 7000ft so potential drop in
PaO2 of 24 - 28mmHg
All pts with PaO2 < 70mmHg should have
supplemental O2 on aircraft
Conclusions
COPD is a progressive disease that leads to a downward
spiral of airflow limitation, breathlessness and inactivity.
GOLD strategy recommends long acting bronchodilators
in all subcategories
The appropriate use of ICS should be for patients who
have had frequent exacerbations (>2/year) and oral ICS
have no role in treatment
Use O2 appropriately
50% of COPD pts are undiagnosed
COPD evident by age 50 years
At time of diagnosis FEV1 < 50%
50% 5y survival