Dual bronchodilation in COPD

Prof. Gamal Rabie Agmy , MD, FCCP
Dual Bronchodilation in COPD

Patients with COPD have the symptoms of
chronic bronchitis and emphysema. Which
of the following morphologic patterns of
emphysema is typically most severe in the
upper lobes?
1-Centriacinar emphysema
2-Panacinar emphysema
3-Distal acinar emphysema
4-Paraseptal emphysema

Which of the following is
independently associated with an
increased risk for all-cause mortality
in patients with COPD?
1-Asthma
2-Bronchiectasis
3-Underweight status
4-Depression

Which of the following is generally
recognized as the most significant
symptom of COPD?
1-Productive cough
2-Pulmonary hypertension
3-Cor pulmonale
4-Breathlessness

Which of the following studies provides
the best clues to the acuteness and
severity of disease exacerbation?
1-Serum chemistry evaluation
2-Alpha1-antitrypsin measurement
3-Arterial blood gas (ABG) analysis
4-Sputum evaluation

Which of the following is accurate
regarding the treatment of patients with
COPD?
1-Pneumococcal vaccines are contraindicated in
patients with COPD
2-Intravenous alpha1-antitrypsin levels should be kept
at 8-10 mmol/L
3-Long-term oxygen therapy is recommended for
patients with a partial pressure of oxygen in arterial
blood <55 mm Hg or oxygen saturation <86%
4-Because cardiovascular disease is common in
patients with COPD, beta-blockers are indicated in all
patients

COPD is caused by inhaled noxious agents, with
lung damage leading to airflow limitation
Inhaled noxious agents
(e.g. cigarette smoking, pollutants)
Obstruction and airflow limitation
Lung damage
Small airway disease:
Airway narrowing
and fibrosis
Mucus hyper
secretion
(chronic bronchitis)
Parenchymal
destruction:
Loss of alveolar
attachments, decrease
in elastic recoil
(emphysema)
GOLD 2014

Tissue Repair
Inflammation
Oxidative stress
Impaired Quality of Life
InactivityDeconditioning
Hyperinflation
Death
Dyspnea
Decreased
Exercise Capacity
Exacerbations
Expiratory Flow Limitation
BRONCHODILATOR
(pivotal)

THE PRIMARY PHYSIOLOGIC
IMPAIRMENT IN COPD IS
AIRFLOW LIMITATION
Rabe K et al. PATS 2006;3:270–5.

Expiratory airflow obstruction
Reduced recoil
Reduced tethering
Increased airways resistance
PL = translung pressure; V = ventilation

Airflow limitation includes irreversible and partially
reversible components
Irreversible components include1,2
Alveolar destruction
- loss of elastic recoil
Destruction of alveolar attachments
- maintain patency of small airways
Small airway fibrosis
Partially reversible components include1,2
- Accumulation of mucus
- Smooth muscle bronchoconstriction2
- Inflammatory infiltrate in airway mucosa
1. GOLD 2009; 2. Brusasco Eur Respir Rev 2006

Airflow limitation in COPD
reduced elastic recoil leads to hyperinflation
Normal COPD
Reduced
IC
Impaired chest wall and diaphragm mechanics

Relationship between static lung volumes and
disease severity.
Air trapping and lung
hyperinflation were
shown to occur even in
the earliest stages of
COPD and increased
exponentially with
severity of airway
obstruction
Expert Rev. Respir. Med. 6(6), 651–662 (2012)
RV: Residual volume

Breathlessness exists in all GOLD stages
Proportionofsubjects(%)
Agusti et al Respir Res 2010
GOLD II
GOLD III
GOLD IV
mMRC Score

Decreased exercise tolerance in all GOLD stages
Spruit et al Respir Med 2010
Percent
Distance walked (meters)
GOLD II
GOLD III
GOLD IV

Patients avoid dyspnoea by becoming less active,
leading to a dyspnea/inactivity downward spiral
Adapted from Reardon et al. Am J Med 2006
ZuWallack R. COPD 2007
Becomes more
sedentary to avoid
dyspnoea-producing
activity
(decreases activity)
Dyspnoea
with activities
Deconditioning
aggravates dyspnoea;
patients adjust by
reducing activity further
The dyspnea inactivity downward spiral

V
BD
 Air flowDeflation
 Improvement in flow – FEV1
 Improvement in volumes – FVC and IC
Bronchodilator therapy deflates the lung
BD = bronchodilator; V = ventilation; FEV1= forced expiratory volume in 1 second;
FVC= forced vital capacity; IC = inspiratory capacity

Rationale for combination
LAMA + LABA
• Further benefits expected in
—Lung function
—Symptoms
—Exercise tolerance
• Similar safety profile as individual therapies anticipated
• Increased convenience: patient only needs 1 inhaler
LAMA monotherapy LABA monotherapy

Proskocil BJ et al. Proc Am Thorac Soc. 2005;2(4):305-310.
SMC relaxationSMC contraction
M3- muscarinic
receptors
Beta Agonists
(LABA)Antocholinergics
(LAMA)
β2-adrenergic
receptors
Mechanisms of action of bronchodilators on
airway smooth muscle

Serching for Maximal Bronchodilation
1.5
1.4
1.3
1.2
1.1
0.9
1.0
0 2 4 6 8 10 12 14 16 18 20 22 24
09:00 h 15:00 h 21:00 h 03:00 h 09:00 h
FEV1(L)
Time (hours)
-2
*
*
*
*
**
**
*
**
*
*
*
AUC
FEV1 Peak
FEV1 trough
¿ceilling effect?

Ipratropium + Albuterol
Combination of short-actingBD’s
40
50
60
70
80
90
100
0 15 30 45 60 75 90 105 120
%Responding
Albuterol Ipratropium
Minutes post-drug administration
Dorinsky PM, et al. Chest. 1999;115:966–971.

The present and future
LAMAs
• Tiotropium
• Glycopyrronium (NVA237)
• Umeclidinium bromide
• Aclidinium bromide
LABAs
• Olodaterol
• Indacaterol
• Vilanterol
• Carmoterol
• Formoterol
• Salmeterol
Fixed - Combinations
- Olodaterol/tiotropium
- Indacaterol/ glycopyrronium
- Umeclidinium/ vilanterol
- Formoterol/aclidinium
- Formoterol/glycopyrrolate

Glycopyrronium + Indecaterol fixed combination

-
-
COPD:Therapeutic Approach
LABA + LAMA
ICS
COPD
Escalating Therapy
Long Active Bronchodilators
LAMA or LABA
+
+
+
Reflumilast, Theo.
Antibiotics
De-Escalating Therapy

INSTEAD study design
b.i.d. = twice daily; FEV1 = forced expiratory volume in 1 second
TDI = transition dyspnea index; SGRQ = St George’s Respiratory
Questionnaire; q.d. = once daily; SFC = salmeterol/fluticasone
propionate Rossi et al. Eur Respir J 2014
SFC 50/500 µg b.i.d.
Indacaterol 150 µg q.d.
Randomization (1:1)
Continue on SFC or
switch to indacaterol
SFC 50/500 µg
b.i.d.
Run-in/screening
SFC 50/500 µg
b.i.d.
2 weeks≥3 months
Visits: Weeks 4, 8
Primary endpoint
• Trough FEV1 at Week 12 (non-inferiority)
Secondary endpoints include:
• Lung function
• Breathlessness (TDI)
• Health status (SGRQ)
26-week blinded treatment

INSTEAD: switch from SFC 50/500 µg b.i.d. to indacaterol
150 µg q.d. had no clinically relevant effect on lung function
PPS (all patients in FAS without major protocol deviations) was used for primary efficacy analysis.
FAS included all randomised patients who received at least one dose of study drug, and was used
for all secondary analyses. Non-inferiority demonstrated if 95% CI for difference between
indacaterol and SFC was above –0.06 (i.e. to right of dashed rule)
b.i.d. = twice daily; CI = confidence interval; FAS = full analysis set; LSM = least-squares mean
q.d. = once daily; FEV1 = forced expiratory; volume in 1 second; PPS = per-protocol set (primary
analysis); SFC = salmeterol/fluticasone propionate Rossi et al. Eur Respir J 2014
LSM treatment difference in trough FEV1 after 12 weeks
Indacaterol 150 µg q.d. versus SFC 50/500 µg b.i.d. treatment difference (L)
Trough FEV1
Primary analysis
(PPS)
Secondary analysis
(FAS)
Difference (95% Cl)
–0.009
(–0.045, 0.026)
–0.014
(–0.046, 0.019)
–0.09 –0.06 –0.03 0.00 0.03

Time to first moderate or severe COPD exacerbation to Week 26
Hazard ratio: 0.80, p=0.258
Indacaterol 150 µg q.d.
100
80
60
40
20
0
1 2 3 4 5
Time to first exacerbation (months)
Patientsexacerbation-free(%)
6
INSTEAD: switch from SFC to indacaterol did not increase
risk of moderate-to-severe exacerbations
b.i.d. = twice daily; q.d. = once daily
SFC = salmeterol/fluticasone propionate Rossi et al. Eur Respir J 2014
0

WISDOM study design
b.i.d. = twice daily; ICS = inhaled corticosteroid
q.d. = once daily Magnussen et al. N Engl J Med 2014
Salmeterol 50 µg b.i.d.
+ fluticasone 500 µg b.i.d.
Tiotropium 18 µg q.d. +
salmeterol 50 µg b.i.d.
Randomization (1:1)
Continue on triple or
withdraw ICS in a stepwise manner
Run-in/screening
Tiotropium 18 ug q.d.
+ salmeterol 50 ug b.i.d.
+ fluticasone 500 µg b.i.d.
6 weeks
52-week blinded treatment
Reduced
to 500 µg
Reduced
to 200 µg
Reduced
to 0 µg (placebo)
Daily fluticasone dose in ICS withdrawal group
0‒6 6–12 12–52 weeks

Daily fluticasone dose in ICS withdrawal group
Reduced
to 500 µg
Reduced
to 200 µg
Reduced
to 0 µg (placebo)
ICS continuation
ICS withdrawal
0
–20
–40
–60
–80
0 6 12 18 52
p<0.001
p=0.001
Adjustedmeanchange
inFEV1(mL)
Week
Number at risk:
ICS continuation 1,223 1,135 1,114 1,077 970
ICS withdrawal 1,218 1,135 1,092 1,058 935
WISDOM: ICS withdrawal led to a small but significant
reduction in FEV1 versus ICS continuation in patients
with severe COPD
b.i.d. = twice daily; COPD = chronic obstructive pulmonary disease
FEV1 = forced expiratory volume in 1 second
ICS = inhaled corticosteroid; q.d. = once daily Magnussen et al. N Engl J Med 2014

Number at risk:
ICS continuation 1,243 1,059 927 827 763 694 646 615 581 14
ICS withdrawal 1,242 1,090 965 825 740 688 646 607 570 19
WISDOM: withdrawal of ICS did not increase the risk of
moderate or severe exacerbations in patients with severe
COPD
b.i.d. = twice daily; CI = confidence interval; COPD = chronic obstructive pulmonary
disease; FEV1 = forced expiratory volume in 1 second; ICS = inhaled corticosteroid Magnussen et al. N Engl J Med 2014
Moderate or severe COPD exacerbation
Hazard ratio, 1.06 (95% CI 0.94, 1.19)
p=0.35 by Wald’s chi-square test
ICS continuation
ICS withdrawal
1.0
0
0
Estimatedprobability
Weeks to event
0.2
0.4
0.6
0.8
6 12 18 24 30 36 42 48 54

OPTIMO study design
 Prospective, real-life study: physicians prescribed treatment as they saw fit
• Aim: to investigate whether withdrawal of ICS in COPD patients at low risk of
exacerbation is linked to a deterioration in lung function and symptoms and to a
higher frequency of exacerbations.
COPD = chronic obstructive pulmonary disease
ICS = inhaled corticosteroid; LABA = long-acting β2-
agonist Rossi et al. Respir Res 2014
914 patients on
LABA + ICS
Remained on ICS:
n=482 (59.1%)
No ICS
n=334 (40.9%)
Remained on ICS:
n=546 (59.7%)
Changed to no ICS
n=368 (40.3%)
Treatment decision at
initial visit
Treatment received
at Month 6 visit
Tiotropium (27%)
Indacaterol (29%)
Formoterol or salmeterol (15%)
Tiotropium/indacaterol (20%)
Other (9%)

OPTIMO: lung function was similar for a bronchodilator-only
regimen versus remaining on LABA/ICS therapy at
6 months
 914 patients at low risk of an exacerbation treated with a LABA/ICS
• Of these, 59.7% of patients continued with LABA/ICS; the remaining 40.3% had their
ICS withdrawn and treatment with bronchodilator monotherapy or dual therapy was
instituted*
*LABA; LAMA; LABA/LAMA; short-acting bronchodilators and/or theophylline
FEV1 = forced expiratory volume in 1 second
ICS = inhaled corticosteroid; LABA = long-acting β2-agonist
LAMA = long-acting muscarinic antagonist Rossi et al. Respir Res 2014
p=0.752
100
0
No ICS
FEV1%predicted
80
60
40
20
ICS
72.5 72.1

OPTIMO: withdrawal of ICS in COPD did not increase risk of
exacerbations versus a bronchodilator-only regimen
*Patients with moderate airflow limitation (forced expiratory volume in 1 second >50%
predicted); †LABA; LAMA; LABA/LAMA; short-acting bronchodilators and/or theophylline
ICS = inhaled corticosteroid; LABA = long-acting β2-agonist
LAMA = long-acting muscarinic antagonist Rossi et al. Respir Res 2014
Withdrawal of ICS can be safe in COPD patients at low risk of exacerbation*,
provided maintenance treatment with bronchodilators† is continued
p=0.347
100
0
No ICS
Patientsexacerbation-freeafter
6months(%)
80
60
40
20
ICS
74.0 71.0

Inhaled corticosteroids in COPD: the clinical
evidence:Pierre Ernst, Nathalie Saad, Samy Suissa
ERS J Published 1 February 2015
In this article, we focus on the scientific evidence from
randomised trials supporting treatment with inhaled
corticosteroids (ICS) in chronic obstructive pulmonary
disease (COPD), including treatment with combinations of
long-acting β-agonist (LABA) bronchodilators and ICS. Our
emphasis is on the methodological strengths and limitations
that guide the conclusions that may be drawn.

evidence:Pierre Ernst, Nathalie Saad, Samy Suissa
The evidence of benefit of ICS and, therefore, of the
LABA/ICS combinations in COPD is limited by major
methodological problems. From the data reviewed herein,
we conclude that there is no survival benefit independent of
the effect of long-acting bronchodilation and no effect on
FEV1 decline, and that the possible benefit on reducing
severe exacerbations is unclear. Our interpretation of the
data is that there are substantial adverse effects from the
use of ICS in patients with COPD, most notably severe
pneumonia resulting in excess deaths.

evidence: Pierre Ernst, Nathalie Saad, Samy Suissa
Currently, the most reliable predictor of response to ICS in
COPD is the presence of eosinophilic inflammation in the
sputum. There is an urgent need for better markers of
benefit and risk that can be tested in randomised trials for
use in routine specialist practice. Given the overall safety
and effectiveness of long-acting bronchodilators in subjects
without an asthma component to their COPD, we believe
use of such agents without an associated ICS should be
favoured.

When I will be using fixed
LAMA + LABA combination ?
 First-line therapy for patients that are symptomatic with
preserve lung function (GOLD B – Stage II)
 Patients with worsening lung function relative few
symptoms (GOLD C – Stage III)
 Adjunctive therapy in Patients with more severe disease
(GOLD D)
.1Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011.
Accessed at http://www.goldcopd.org/uploads/users/files/GOLD_Report_2011_Feb21.pdf

LAMA or
LABA or
SABA+SAMA
ICS+LABA+LAMA or
ICS+LABA+PDE4l or
LAMA+LABA or
LAMA+PDE4l
LAMA+LABA
LAMA+LABA or
LAMA+PDE4I or
LABA+PDE4l
CAT, COPD Assessment Test; GOLD, Global initiative for chronic Obstructive Lung
Disease; ICS, inhaled corticosteroid; LABA, long-acting 2-agonist; LAMA, long-
acting muscarinic antagonist; mMRC, modified Medical Research Council; PDE4,
phosphodiesterase-4 inhibitor; SABA, short-acting 2-agonist; SAMA, short-acting
muscarinic antagonist
Global Strategy for the Diagnosis, Management and Prevention
of COPD, Global Initiative for Chronic Obstructive Lung Disease
(GOLD) 2013. Available from: http://www.goldcopd.org/.
A B
DC
Exacerbationsper
year
>2
1
0
mMRC 0-1 CAT <10
GOLD 4
mMRC ≥2 CAT ≥10
GOLD 3
GOLD 2
GOLD 1
Pharmacological management of stable
COPD: FUTURE

IND/GLY BREEZHALER
Start a new chapter in COPD

• IND/GLY Breezhaler is the first inhaled once-
daily fixed-dose combination of a LABA
(indacaterol) and a LAMA (glycopyrronium
bromide) in a single inhaler, developed for use
in COPD.
• The recommended dose is the inhalation of the
content of one capsule once daily using the
IND/GLY Breezhaler inhaler.
• IND/GLY Breezhaler is recommended to be
administered at the same time of the day each
day.
• If a dose is missed, it should be taken as soon as
possible on the same day.
IND/GLYBREEZHALER
5
4IND/GLY insert leaflet. Approved on 22/6/2015

5
5IND/GLY insert leaflet. Approved on 22/6/2015
IND/GLYBREEZHALER MECHANISM OF ACTION
• When indacaterol and glycopyrronium are administered
together in IND/GLY Breezhaler, they provide additive efficacy
due to their different mode of action targeting different
receptors and pathways to achieve smooth muscle relaxation.
• The combination of indacaterol and glycopyrronium in IND/GLY
Breezhaler showed a rapid onset of action within 5 minutes
after dosing.
• The effect remains constant over the whole 24-h dosing
interval.

3. Tarsin et al. J Aerosol Med 2004 4. Chodosh et al. J Aersol Med 2001
BREEZHALER: A LOW AIRFLOW RESISTANCE DEVICE
The Breezhaler device has low airflow resistance suitable for use
by patients with chronic obstructive pulmonary disease, even
those with severe disease.1
The majority of patients were able to achieve flow rates of >60
L/min1
In separate studies, airflow resistance has been determined for the
following devices:
Breezhaler*1 2.2 10‒2 kPa½L/min
Diskus*2 2.7 10‒2 kPa½L/min
Turbohaler*3 3.4 10‒2 kPa½L/min
HandiHaler*45.1 10‒2 kPa½L/min
DPI = dry powder
inhaler
1. Pavkov et al. Curr
Med Res Opin 2010
2. Janssens et al. Eur Respir J 2008

Modified from Hodder, Price. Int J Chron Obstruct Pulmon Dis 2011
DEVICE CHARACTERISTICS: IMPORTANCE TO PATIENTS
Device factors*
Perceived efficacy
Ease of use
Convenience
Feelings of stigmatization due to need for device use in public
Physician device preference
Availability of drug/device preparations
Brand loyalty
Cost
Time to learn; clear instructions
Device appearance and characteristics
Cleaning issues
Disposability/environmental issues
*listed in no particular order ofpreference
Several factors affect patients’ attitudes to devices used for COPD therapy

THE BREEZHALER DEVICE ALLOWS PATIENTS TO
HEAR, FEEL AND SEE THAT THEY HAVE TAKEN THE DOSE
CORRECTLY
 The Breezhaler device was
designed to provide
dose delivery feedback
mechanisms1
 The Breezhaler device is also
a low-resistance inhaler, which
delivers a consistent dose
across a wide range of COPD
severities2
The click whenthe
capsule is piercedand
the whirring sound
during inhalation
The product upon
inhalation due to the
presence of lactosein
the formulation
The clear and empty orange
transparent capsule after
inhalation to confirm that
the full dose was taken
Adapted from QVA149 Breezhaler Summary of product characteristics, 2013
.1QVA149 Breezhaler Summary of product characteristics,2013
.2Colthorpe. J Drug Assess 2013

.1Chapman et al. Int J Chron Obstruct Pulmon Dis 2011
.2Pavkov R, et al. Curr Med Res Opin 2010 ; 3. Indacaterol Breezhaler SmPC 2014
4. Glycopyrronium Breezhaler SmPC 2014 ; 5. QVA149 Breezhaler SmPC 2014
BREEZHALER: CLARITY FOR COPD PATIENTS, CONFIDENCE FOR
PHYSICIANS
Correct use Comfortable inhalation &
consistent performance
Confirmed dose
 Correct use from Day 1,
even with minimal
instruction1
 Low internal resistance1,2
 Sufficient peak inspiratory flow
across all COPD severities2
 Transparent capsule
for dose
confirmation3–5

IND/GLYBREEZHALER IGNITE PROGRAM
• IGNITE is a large program studying the efficacy and safety of QVA149
– Includes 11 studies in total (n=11,198*), of which nine were
completed by 2014
• Studies in the IGNITE program examine a range of clinically relevant
endpoints, comparing QVA149 with:
– monocomponents
• indacaterol 150 µg
• glycopyrronium 50 µg
– established current standards of care
• tiotropium 18 µg (open label and blinded)
• Tiotropium + Formoterol.
• SFC 50/500 µg.
*target enrolment
SFC =salmeterol/fluticasonepropionate

Long-termsafety
(vs placebo)
Exercise tolerance
(vs tiotropium and
placebo)
(vs glycopyrronium and tiotropium)
FEV1, TDI, SGRQ
(vs fluticasone/salmeterol)
FEV1, TDI,SGRQ
(vs glycopyrronium, indacaterol,
tiotropium and placebo)
BDI, TDI
(vs tiotropium)
Long-termexacerbations
China safety and efficacy
Long-termsafety
(vs tiotropium and placebo)
Japan pivotal safety
(vs tiotropium)

 Non-inferiority vs free combination





Exacerbations

IND/GLYBREEZHALER IGNITE PROGRAM
MORE THAN 6,500 PATIENTS

New

A NEW CHAPTER FOR
SYMPTOMATIC COPD PATIENTS
62
SIGNIFICANT IMPROVEMENT IN LUNG FUNCTION
SIGNIFICANT IMPROVEMENT IN SYMPTOMS
SIGNIFICANT IMPROVEMENT IN QUALITY OF LIFE
SIGNIFICANT REDUCTION IN RESCUE MEDICATION
SIGNIFICANT REDUCTION IN EXACERBATIONS

A NEW CHAPTER FOR
63
SIGNIFICANT IMPROVEMENT IN
LUNG FUNCTION

Trough FEV1* over the entire 26-week treatment period SIGNIFICANT
400mL
IMPROVEMENT
over placebo
at week 26 peak
FEV1
# (P<0.001)
* Forced expiratory volume in 1 s
# 2 hrs. post dose
IND/GLYBREEZHALER SIGNIFICANTLY IMPROVED
LUNG FUNCTION VS. PLACEBO OVER 26 WEEK TREATMENT
A multicenter, randomized, double-blind, placebo- and active-controlled, 26-week trial. Patients with moderate-to-
severe stable COPD (n=2144) were randomized (2:2:2:2:1) to receive once-daily IND/GLYBreezhaler (Indacaterol 110
mg/Glycopyrronium 50 mg), Indacaterol 150 mg, Glycopyrronium 50 mg, open-label tiotropium 18 mg or placebo.
The primary end-point was trough forced expiratory volume in 1 s (FEV1) at week 26 for IND/GLYBreezhaler versus its
monocomponents.
Bateman E et al, Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE
study; Eur Respir J 2013; 42:1484–1494

Pre-dose FEV1* at week 12 (LSM)
tiotropium 18 µg+
formoterol 12 µg (n=421)
IND/GLY
BREEZHALER
(n=432)
SIGNIFICANT
72mL
IMPROVEMENT
vs.
tiotropium +
formoterol
0 1.2FEV1 (L) 1.4 1.6
P<0.001
IND/GLYBREEZHALERSIGNIFICANTLY IMPROVEDLUNG
FUNCTION VS. TIOTROPIUM + FORMOTEROL
Least square mean(LSM)
A 26-week multicenter, randomized, blinded, triple-dummy, parallel-group, non-inferiority trial 934 patients aged ≥40
years with moderate-to-severe COPD were randomized to IND/GLYBREEZHALER 110/50 mg o.d. or TIO 18 mg o.d.+
FOR 12 mg twice daily (1:1) for 26weeks.
The primary endpoint was to demonstrate non-inferiority in HRQoL assessed using St George’s Respiratory
Questionnaire-COPD(SGRQ-C).
Buhl R et al. Efficacy and safety of once-daily QVA149 compared with the free combination of once-daily
tiotropium plus twice-daily formoterol in patients with moderate-to-severe COPD (QUANTIFY): a
randomized, non-inferiority study. Thorax. 2015:70(4):311-319.

Onset of action in terms of FEV1(L)* at 5 minutes post dose at week 26
(LSM)
randomized, double-blind, parallel-group study. Lancet Respir Med. 2013; 1:51-60.
1.52
1.67
P<0.0001
FEV1 (L)
1.60 1.5 1.7
SIGNIFICANT
150mL
IMPROVEMENT
in FEV1 5 min post-
dose
vs.
fluticasone/salmeterol
IND/GLYBREEZHALER PROVIDED RAPID BRONCHODILATION
WITHIN 5 MINUTES
A multicenter, randomized, double-blind, double dummy, parallel-group, 26-week study in patients with moderate-to-
severe COPD. 523 patients were randomly assigned to once-daily IND/GLYBreezhaler 110/50 μg or twice-daily
salmeterol–fluticasone 50/500 μg for 26 weeks.
The primary endpoint was to demonstrate the superiority of IND/GLYBreezhaler compared with SFC for the standardized
area under the curve from 0 to 12 h post dose for forced expiratory volume in 1 second (FEV1 AUC0–12h) after 26 weeks
oftreatment
Vogelmeier CF, et al. Efficacy and safety of once-daily QVA149 compared with twice-daily
salmeterol/fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a
fluticasone/
salmeterol
(n=264)
IND/GLY
BREEZHALER
(n=258)

2.11 2.42
1.8
2
2.2
2.4
2.6
Tiotropium
∆=140mL, p=0.002∆=320mL,p<0.001
Beeh, et al. Respir Med 2014
IND/GLYBREEZHALER IMPROVES DYNAMIC HYPERINFLATION
VS. TIOTROPIUM
Dynamic IC is measured while patient is pedaling at isotime;
values are LS mean ± SE
Dynamicinspiratorycapacity(L)
Placebo IND/GLY BREEZHALER
2.29
Day 21

A NEW CHAPTER FOR
16
SYMPTOMS

Improvement in TDI* focal score after 26 weeks of treatment (LSM)5
oftreatment
SIGNIFICANT
47%
IMPROVEMENT
vs.
fluticasone/
salmeterol
(n=213)
IND/GLY
BREEZHALER
(n=212)
1.60
2.36
P=0.003
1
TDI focal
score
2.00 0.5 1.0 1.5 2.5
* Transition Dyspnea index
IND/GLYBREEZHALER SIGNIFICANTLY IMPROVES BREATHLESSNESS
VS. FLUTICASONE/SALMETEROL

10 20 30 40 50 60 70
Patients achieving clinical important increase ≥1 in TDI score at week 26
SIGNIFICANT
19%
RELATIVE RISK REDUCTION
IN PATIENTS WHO ACHIEVED
A CLINICALLY RELEVANT
IMPROVEMENT
vs.
fluticasone/
salmeterol
(n=213)
IND/GLY
BREEZHALER
(n=212)
56·8%
67·5%
p=0·046
Patients %0
DYSPNEA VS. FLUTICASONE/SALMETEROL
oftreatment

0 0.2 0.4 0.6 0.8 1 1.2
DYSPNEA VS. TIOTROPIUM
Improvement in TDI* focal score at week 26
P=0.0071.09
TDI focal score
aboveplacebo
open-label
tiotropium
18 µg vs
placebo
(n=480)
IND/GLY
BREEZHALER
vs placebo
(n=474)
SIGNIFICANT
88%
RELATIVE
IMPROVEMENT
Vs.
Tiotropium
WHEN BOTH COMPAREDTO
PLACEBO
*TDI: Transition dyspnea index
P=0.0170.58
monocomponents.

Percentage of patients achieving MCID* ≥1 in TDI** at week 26
tiotropium 18 µg+
formoterol 12µg
(n=158)
IND/GLY
BREEZHALER
(n=195)
SIGNIFICANT
22.7%
IN PATIENTS WHO
ACHIEVED A CLINICALLY
RELEVANT
IMPROVEMENT
VS.
tiotropium + formoterol
0 42 60
Patients(%)
44 46
P<0.01
48
*Minimum clinically important difference (≥1 unit).
** TDI: Transition dyspneaindex
# In per protocol setanalysis
DYSPNEA VS. TIOTROPIUM + FORMOTEROL

IND/GLYBREEZHALER SIGNIFICANTLY IMPROVES
DYSPNEA VS. TIOTROPIUM
SIGNIFICANT
126%
IMPROVEMENT
vs.
tiotropium
-0.49
0.88
0.39
-0.6
-0.4
-0.2
0
0.2
0.4
0.6
0.8
1
Placebo
SAC# TDI* total score
UltibroBreezhaler
110/50µg
(N=223)
Tiotropium
18 µg
(N=220)
(N=218)
*p<0.001 **p=0.021
Data are presented as least squaresmean¡SE.
TDI: Transition DyspneaIndex
Patient-reported dyspnea scores after 6 weeks of treatment (LSM)
*p<0.001
COPD: the BLAZE study Eur Respir J 2014; 43: 1599–1609
#SAC: Self-administered computerized
A multicenter, blinded, double-dummy, three-period crossover study, 247 patients were randomized to once-daily
IND/GLYBreezhaler 110/50 mg, placebo or tiotropium 18 mg. Superiority of IND/GLYBreezhaler versus placebo
(primary objective) and tiotropium (secondary objective) was assessed for improvement in dyspnea via the self-
administered computerized (SAC) version of the Baseline and Transition Dyspnea Index after 6 weeks.
Mahler DA et al, Dual bronchodilation with QVA149 reduces patient-reported dyspnea in

A NEW CHAPTER FOR
22
QUALITY OF LIFE

Improvement from baseline in health status SGRQ* totalscore
open-label
tiotropium 18µg
(n=737)
IND/GLY
BREEZHALER
(n=729)
SIGNIFICANT
60%
IMPROVEMENT
vs.
tiotropiumChange inSGRQ
score
frombaseline
8
double-blind, parallel-group study. Lancet Respir Med. 2013 May;1(3):199-209
5
-1 1 3 5 7 9
HEALTH STATUS VS. TIOTROPIUM
p<0.05
Wedzicha JA et al, Analysis of chronic obstructive pulmonary disease exacerbations with the dual
bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomized,
*St. George respiratory questionnaire
A multicenter parallel-group study, 2224 patients were randomly assigned to once-daily IND/GLYBreezhaler (fixed-dose
combination of indacaterol 110 μg and glycopyrronium 50 μg), glycopyrronium 50 μg, or tiotropium 18 μg for 64 weeks.
Assignment to IND/GLYBreezhaler and glycopyrronium was double-blind; tiotropium was open-label. The primary
objective was to show superiority of IND/GLYBreezhaler versus glycopyrronium for rate of moderate to severe COPD
exacerbations (defined by worsening symptoms and categorized by treatment requirements) during treatment.

HEALTH STATUS VS. TIOTROPIUM + FORMOTEROL
Percentage of patients achieving MCID* ≥4 in SGRQ-C** after 26 weeks
tiotropium 18 µg+
formoterol 12µg
(n=374)
IND/GLY
BREEZHALER
(n=373
SIGNIFICANT
18%
IN PATIENTS WHO
ACHIEVED A CLINICALLY
RELEVANT IMPROVEMENT
IN SGRQ
VS.
tiotropium + formoterol
0 42 50
Patients(%)
44 46
P<0.05
RR=1.18
48
*Minimum clinically important difference (≥4 unit).
**SGRQ-C: St George’s Respiratory Questionnaire-COPD
# In per protocol set analysis
52

0 2 4 6 8 10 12 14
Improvement in percentage of days patients able to performdaily
activities at week 26
3.03
11.48
p<0.001
% of days
open-label
tiotropium
18 µg vs
placebo
(n=480)
IND/GLY
BREEZHALER
vs placebo
(n=474)
SIGNIFICANT
279%
RELATIVE
INCREASE IN
PERCENTAGE OF
DAYS PATIENTS
ABLE TO PERFORM
DAILY ACTIVITIES
Vs.
tiotropium
IND/GLYBREEZHALER SIGNIFICANTLY IMPROVES DAILY
ACTIVITIES VS. TIOTROPIUM
monocomponents.

A NEW CHAPTER FOR
26
SIGNIFICANT REDUCTION IN
RESCUE MEDICATION

The use of rescue salbutamol over weeks
SIGNIFICANT
53%
Relative risk
reduction
vs.
tiotropium
Use of rescue
salbutamol puffs/day
-1.5
-2.3
0
p<0.0001
QVA149−tiotropium least squares mean treatment difference
−0.76, p<0.0001
IND/GLYBREEZHALER SIGNIFICANTLY REDUCES RESCUE
MEDICATION vs. TIOTROPIUM
open-label
tiotropium 18
µg
(n=737)
IND/GLY
BREEZHALER
(n=729)
- 0.5- 1-1.5 -2 -2.5

A NEW CHAPTER FOR
28
SIGNIFICANT REDUCTION IN
EXACERBATIONS

SIGNIFICANT
Zhong N et al: LANTERN: a randomized study of QVA149 versus salmeterol/fluticasone combination
in patients with COPD. Int J Chron Obstruct Pulmon Dis. 2015;10(1):1015-1026
RISK REDUCTION OF
IND/GLYBREEZHALER SIGNIFICANTLY REDUCED THE
RATE OF MODERATE OR SEVERE EXACERBATIONS
Annualized rate of moderate or severe exacerbations
IND/GLY BREEZHALER (n=372)vs.
fluticasone/salmeterol (n=369)
31%
MODERATE OR SEVERE
EXACERBATIONS
vs.fluticasone/salmeterol
P=0.048
A double-blind, double-dummy, parallel-group study, 744 patients with moderate-to-severe COPD with a history of ≤1
exacerbations in the previous year were randomized (1:1) to IND/GLYBREEZHALER 110/50 μg once daily or salmeterol-
fluticasone 50/500 μg twice daily for 26 weeks. The primary endpoint was non-inferiority of IND/GLYBREEZHALER versus
salmeterol-fluticasone for trough forced expiratory volume in 1 second (FEV1) at week 26.6

SIGNIFICANT
REDUCTION OF
Zhong N et al: LANTERN: a randomized study of QVA149 versus salmeterol/fluticasone combination
in patients with COPD. Int J Chron Obstruct Pulmon Dis. 2015;10(1):1015-1026
69%IND/GLY BREEZHALER (n=372)vs
fluticasone/salmeterol(n=369)
* In a post-hocanalysis
SEVERE
EXACERBATIONS
vs.fluticasone/salmeterol
P=0.023
Annualized rate of severe exacerbations
A double-blind, double-dummy, parallel-group study, 744 patients with moderate-to-severe COPD with a history of ≤1
exacerbations in the previous year were randomized (1:1) to IND/GLYBREEZHALER 110/50 μg once daily or salmeterol-
fluticasone 50/500 μg twice daily for 26 weeks. The primary endpoint was non-inferiority of IND/GLYBREEZHALER versus
salmeterol-fluticasone for trough forced expiratory volume in 1 second (FEV1) at week 26.6

SIGNIFICANT
REDUCTION OF
14%
IND/GLYBREEZHALER SIGNIFICANTLY REDUCED RATE OF ALL
EXACERBATIONS VS. TIOTROPIUM
Annualized rate of all exacerbations
in all
EXACERBATIONS
vs.
tiotropium
P=0.0017

FLAME STUDY
EFFECT OF INDACATEROL GLYCOPYRRONIUM VS.
FLUTICASONE SALMETEROL ON COPD
EXACERBATIONS

EVALUATING EFFICACY OF IND/GLYBREEZHALER IN TERMS OF
EXACERBATIONS IN MODERATE-TO-VERY SEVERE PATIENTS*
Double-blind treatment period
(52 weeks)
Day –35 to
Day–29
Day 1 to Day 365
30-day
safety follow-up
Screening
period
IND/GLY 110/50 μg q.d.
Day –28 to
Day –1
Visit1
Day 366 to
Day 395
Visit101
• Patients had history of ≥1 exacerbation in the previous 12 months that required treatment with systemic
corticosteroids and/or antibiotics
52-week, multicenter, randomized, double-blind, parallel-group, double-dummy study
Prerandomization
Visit 20112 clinic visits
*FEV1 ≥25 and <60% predicted. IND = indacaterol; GLY = glycopyrronium
FEV1 = forced expiratory volume in 1 second; OL = open label
Randomization
Run-in period
OL tiotropium
18 μg q.d.
Wedzicha JA, et al. N Engl J Med 2016

KEY INCLUSION CRITERIA INCLUDED A HISTORY OF
≥1 EXACERBATION IN THE PREVIOUS YEAR
Inclusion
• Male or female adults aged ≥40 years
• Stable COPD according to the current GOLD strategy (GOLD 2011)
• Current or ex-smokers who have a smoking history of ≥10 pack years
• Post-bronchodilator FEV1 ≥25 and <60% of the predicted normal value, and
post-bronchodilator FEV1/FVC <0.70
• Documented history of ≥1 COPD exacerbation in the previous 12 months that
required treatment with systemic glucocorticosteroids and/or antibiotics
• Patients taking stable COPD medication for at least 60 days prior to study entry
• Patients with an mMRC grade of ≥2
FVC = forced vital capacity; mMRC = modified Medical Research Council

Patients targeted by inclusion criteria
CD
A B
PATIENT POPULATION APPROXIMATED TO GOLD D
Inclusion criteria
• Post-bronchodilator FEV1 ≥25
and <60%
of predicted normal
• Symptomatic as
defined by mMRC ≥2
• ≥1 documented COPD
exacerbation requiring
treatment with antibiotics
and/or systemic
corticosteroids
within 1 yearof
randomization
Primary outcome
Rate of all COPD exacerbations
(mild/moderate/severe) during
52 weeks of treatment
• Primary objective
Todemonstrate that
IND/GLY was at least non-inferior to
SFC
• Secondary objective
If non-inferiority could be
established, the secondary objective
was to demonstrate that IND/GLY is
superior to SFC

PRIMARY OBJECTIVE OF FLAME WAS TO DEMONSTRATE
THAT IND/GLY IS NON-INFERIOR TO SFC IN TERMS OF
RATE OF COPD EXACERBATIONS
Primary
• Rate of all COPD exacerbations (mild/moderate/severe) during 52 weeks of
treatment
Secondary
• Time to first COPD exacerbation (mild/moderate/severe)
 Rate and time to first moderate/severe COPD exacerbation

FURTHER STUDY OBJECTIVES INCLUDED THE
ASSESSMENT OF LUNG FUNCTION AND HEALTH STATUS
Secondary (continued)
• Lung function:
– Trough FEV1
– Standardized FEV1 AUC0–12h in a subset ofpatients
• St George’s Respiratory Questionnaire (SGRQ-C)
• Use of rescue therapy
• 24-hour urinary cortisol in a subset of patients
• Safety and tolerability of IND/GLY versus SFC
Subgroup analyses
• Subgroup analyses (e.g. by baseline blood eosinophil count) were pre-specified in the
Statistical Analysis Plan prior to unblinding but not in the protocol

PATIENT DEMOGRAPHICS WERE WELL
BALANCED BETWEEN TREATMENT GROUPS (1/2)
IND/GLY
110/50 μg q.d.
(n=1,680)
SFC
50/500 μgb.i.d.
(n=1,682)
Total
(N=3,362)
Age,years 64.6(7.9) 64.5(7.7) 64.6(7.8)
Male, n(%) 1,299 (77.3) 1,258 (74.8) 2,557 (76.1)
Duration of COPD,years 7.2(5.3) 7.3(5.5) 7.3(5.4)
ICS use at baseline, n(%) 954(56.8) 939(55.8) 1,893 (56.3)
LAMA use at baseline, n(%) 1,008 (60.0) 1,029 (61.2) 2,037 (60.6)
LABA use at baseline, n(%) 1,129 (67.2) 1,128 (67.1) 2,257 (67.1)
Current smoker, n(%) 664(39.5) 669(39.8) 1,333 (39.6)
Severity of COPD (GOLD 2015), n(%)
Low risk and less symptoms (GroupA) 2 (0.1) 0 2 (0.1)
Low risk and more symptoms (GroupB) 400(23.8) 422(25.1) 822(24.4)
High risk and less symptoms (GroupC) 1 (0.1) 2 (0.1) 3 (0.1)
High risk and more symptoms (GroupD) 1,265 (75.3) 1,249 (74.3) 2,514 (74.8)
Severity of airflow limitation (GOLD 2011–2014), n(%)
Mild (GOLD1) 0 0 0
Moderate (GOLD2) 560(33.3) 563(33.5) 1,123 (33.4)
Severe (GOLD3) 973(57.9) 981(58.3) 1,954 (58.1)
Very severe (GOLD4) 133(7.9) 124(7.4) 257(7.6)
Data are mean (SD) unless otherwise stated

PATIENT DEMOGRAPHICS WERE WELL
BALANCED BETWEEN TREATMENT GROUPS (2/2)
IND/GLY
110/50 μg q.d.
(n=1,680)
SFC
50/500 μg b.i.d.
(n=1,682)
Total
(N=3,362)
Pre-bronchodilator FEV1, L 1.0(0.3) 1.0(0.3) 1.0(0.3)
Post-bronchodilator FEV1,L 1.2(0.3) 1.2(0.4) 1.2(0.3)
Post-bronchodilator FEV1, %predicted 44.0(9.5) 44.1(9.4) 44.1(9.5)
Post-bronchodilator FEV1 reversibility, % of baseline value 22.2(16.0) 22.5(16.0) 22.4(16.0)
Post-bronchodilator FEV1/FVC,% 41.7(9.8) 41.5(9.9) 41.6(9.9)
Number of COPD exacerbations in previous year, n(%)
1 1,355 (80.7) 1,355 (80.6) 2,710 (80.6)
≥2 324(19.3) 325(19.3) 649(19.3)
SGRQ-C totalscore 47.3(15.8) 47.2(15.9) 47.3(15.8)
CATscore 16.9(7.1) 16.6(7.0) 16.7(7.0)
mMRC dyspnea scale, n(%)
Grade2 1,202 (71.5) 1,210 (71.9) 2,412 (71.7)
Grade3 439(26.1) 432(25.7) 871(25.9)
Grade4 36 (2.1) 38 (2.3) 74 (2.2)
Rescue medication use,puffs/day 3.95(3.8) 4.12(4.0) 4.0(3.9)
Urine cortisol*,ng/mL 16.3(20.7) 15.8(24.0) 16.0(22.4)
*24-hour urine cortisol measured in a total of 535 patients (266 on IND/GLYand 269 on SFC). Data are mean(SD)
unless otherwise stated

IND/GLYBREEZHALER WAS NON-INFERIOR (PRIMARY ENDPOINT) AND SUPERIOR TO SFC
FOR THE RATE OF ALL (MILD/MODERATE/SEVERE) EXACERBATIONS OVER 52 WEEKS
0.8 1.0 1.15
Rate ratio (95% Cl)
Per-protocol set
(Primary analysis)
Modified intention-to-treat set
(Supportive analysis)
Superiority
margin
Non-inferiority
margin
0.9
FavorsIND/GLY FavorsSFC
p=0.003
0.89 0.960.83
p<0.001
0.88 0.940.82
FLAME is the first study to demonstrate superiority of
IND/GLYBreezhaler in exacerbation prevention versus SFC in
COPD patients with ≥1 exacerbation in the preceding year

RATE OF ALL (MILD/MODERATE/SEVERE)
EXACERBATIONS VERSUS SFC OVER 52 WEEKS
4.03 3.59
Allexacerbations(annualizedrate)
3.0
4.0
2.0
RR (95% CI)
0.89 (0.83, 0.96), p=0.003
1.0
0
11% reduction
SFC 50/500 μg b.i.d. (n=1,544)
IND/GLY 110/50 μg q.d. (n=1,518)
5.0

CONSISTENT RESULTS OBSERVED FOR THE RATE OF ALL
(MILD/MODERATE/SEVERE) EXACERBATIONS ACROSS ALL DEMOGRAPHIC
SUBPOPULATIONS
1.0 2.0
IND/GLY SFC R ate ratio of IND/GLY vsSFC *Rate ratio (95%CI)
Agegroup <55years 148 155 0.80 (0.63, 1.01)
55<65years 655 666 0.80 (0.71, 0.90)
65<75years 661 678 0.94 (0.84, 1.05)
≥75years 187 157 0.98 (0.78, 1.23)
Gender Male 1,271 1,238 0.88 (0.81, 0.96)
Female 380 418 0.88 (0.76, 1.02)
Race Caucasian 1,286 1,283 0.89 (0.82, 0.96)
Asian 301 308 0.88 (0.74, 1.05)
Other 64 65 0.90 (0.62, 1.29)
Region Africa 49 47 0.86 (0.57, 1.30)
Asia 297 307 0.89 (0.75, 1.06)
EasternEurope 537 565 0.80 (0.71, 0.91)
Latin and SouthAmerica 146 153 0.83 (0.66, 1.05)
NorthAmerica 24 25 0.93 (0.50, 1.75)
WesternEurope 598 559 0.97 (0.86, 1.10)
0.5
Favors IND/GLY
1.5
Favors SFC

CONSISTENT RESULTS OBSERVED FOR THE RATE OF ALL
(MILD/MODERATE/SEVERE) EXACERBATIONS ACROSS ALL BASELINE DISEASE
CHARACTERISTICS SUBPOPULATIONS
1.0 1.5 2.0
IND/GLY SFC Rate ratio of IND/GLY vs SFC *Rate ratio (95% CI)
Severity of airflow limitation Moderate (GOLD2) 557 557 0.93 (0.82,1.06)
Severe (GOLD3) 962 975 0.84 (0.76,0.92)
Very Severe (GOLD4) 132 124 0.94 (0.72,1.22)
Severity of COPD 2015 (GOLD 2015) GroupB 398 417 0.98 (0.85,1.14)
GroupD 1,252 1,243 0.86 (0.78,0.92)
COPD exacerbation history 1exacerbation 1,329 1,335 0.87 (0.81,0.95)
≥2 exacerbations 321 320 0.89 (0.76,1.05)
Reversibility Notreversible 900 904 0.88 (0.80,0.97)
Reversible 735 741 0.88 (0.79,0.98)
ICS use atscreening No ICSuse 710 729 0.88 (0.79,0.98)
ICSuse 941 927 0.88 (0.80,0.97)
LABA use atscreening No LABAuse 540 542 0.91 (0.81,1.04)
LABAuse 1,111 1,114 0.86 (0.79,0.94)
ICS/LABA use at screening No ICS/LABAuse 879 889 0.88 (0.80,0.97)
ICS/LABAuse 772 767 0.88 (0.79,0.97)
LAMA use atscreening No LAMAuse 662 643 0.91 (0.81,1.02)
LAMAuse 989 1,013 0.86 (0.78,0.94)
Smoking status at screening Ex-smoker 1,004 998 0.92 (0.83,1.01)
Currentsmoker 647 658 0.83 (0.74.0.92)
Overall 1,651 1,656 0.88 (0.82,0.94)
0.5
Favors IND/GLY Favors SFC

IND/GLYBREEZHALER SIGNIFICANTLY PROLONGED THE
TIME TO FIRST MILD, MODERATE OR SEVERE
EXACERBATION VERSUS SFC OVER 52 WEEKS
0 6 12 38 5245
100
90
80
70
60
50
40
30
20
10
0
Percentageofpatientswithevent(%)
192632
Time to events (weeks)
Patients atrisk
IND/GLY 1,675 763 535 409 281
SFC 1,679 642 415 313 217
HR (95%CI):
0.84 (0.78, 0.91), p<0.001
16% risk
reduction
SFC 50/500 μg b.i.d.

VERSUS SFC OVER 52 WEEKS
1.19 0.98
RR (95% CI)
0.83 (0.75, 0.91), p<0.001
1.5
Moderateorsevereexacerbations(annualized
rate)
0.75
1.0
1.25
0.5
0.25
0
SFC 50/500 μg b.i.d. (n=1,656)
IND/GLY 110/50 μg q.d. (n=1,651)
17% reduction

CONSISTENT RESULTS OBSERVED FOR THE RATE OF
MODERATE OR SEVERE EXACERBATIONS ACROSS ALL
DEMOGRAPHIC SUBPOPULATIONS
1.0 2.0
IND/GLY SFC Rate ratio of IND/GLY vsSFC Rate ratio (95%CI)
Agegroup <55years 148 155 1.00 (0.73, 1.37)
55<65years 655 666 0.85 (0.72, 0.99)
65<75years 661 678 0.83 (0.72, 0.97)
≥75years 187 157 0.62 (0.46, 0.84)
Gender Male 1,271 1,238 0.81 (0.73, 0.91)
Female 380 418 0.89 (0.74, 1.07)
Race Caucasian 1,286 1,283 0.87 (0.78, 0.98)
Asian 301 308 0.71 (0.56, 0.89)
Other 64 65 0.81 (0.51, 1.30)
Region Africa 49 47 0.89 (0.54, 1.48)
Asia 297 307 0.71 (0.56, 0.88)
EasternEurope 537 565 0.84 (0.70, 1.01)
Latin and SouthAmerica 146 153 0.88 (0.65, 1.19)
NorthAmerica 24 25 0.97 (0.47, 2.01)
WesternEurope 598 559 0.86 (0.73, 1.01)
0.00.5
Favors IND/GLY
1.5
Favors SFC

CONSISTENT RESULTS OBSERVED FOR THE RATE OF
MODERATE OR SEVERE EXACERBATIONS ACROSS ALL
BASELINE DISEASE CHARACTERISTICS SUBPOPULATIONS
1.0 2.00.00.5
Favors IND/GLY
1.5
Favors SFC
IND/GLY SFC Rate Ratio of IND/GLY vs SFC Rate ratio (95% CI)
Severity of airflow limitation Moderate (GOLD2) 557 557 0.81 (0.68,0.97)
Severe (GOLD3) 962 975 0.81 (0.72,0.92)
Very Severe (GOLD4) 132 124 1.04 (0.75,1.44)
Severity of COPD 2015 (GOLD 2015) GroupB 398 417 0.86 (0.69,1.06)
GroupD 1,252 1,243 0.83 (0.74,0.92)
COPD exacerbation history 1exacerbation 1,329 1,335 0.83 (0.75,0.93)
≥2 exacerbations 321 320 0.85 (0.70,1.03)
Reversibility Notreversible 900 904 0.81 (0.71,0.93)
Reversible 735 741 0.85 (0.73,0.98)
ICS use atscreening No ICSuse 710 729 0.78 (0.67,0.91)
ICSuse 941 927 0.86 (0.76,0.97)
LABA use atscreening No LABAuse 540 542 0.81 (0.68,0.96)
LABAuse 1,111 1,114 0.84 (0.75,0.94)
ICS/LABA use at screening No ICS/LABAuse 879 889 0.86 (0.75,0.98)
ICS/LABAuse 772 767 0.80 (0.70,0.92)
LAMA use atscreening No LAMAuse 662 643 0.83 (0.71,0.97)
LAMAuse 989 1,013 0.83 (0.74,0.94)
Smoking status at screening Ex-smoker 1,004 998 0.84 (0.74,0.95)
Currentsmoker 647 658 0.82 (0.70,0.95)
Overall 1651 1656 0.83 (0.75, 0.91)

IND/GLYBREEZHALER SIGNIFICANTLY PROLONGED THE TIME TO
FIRST MODERATE OR SEVERE EXACERBATION VERSUS SFC OVER
52 WEEKS
0 6 38 5245
100
90
80
70
60
50
40
30
20
10
0
12 192632
Time to events (weeks)
HR (95%CI):
0.78 (0.70, 0.86), p<0.001
22% risk
reduction
Patients atrisk
IND/GLY 1,675 1,299 1,091 948 711
SFC 1,679 1,210 975 820 608

THE RATE OF SEVERE EXACERBATIONS WAS 13% LOWER
WITH IND/GLYBREEZHALER COMPARED WITH SFC
(NOT SIGNIFICANT)
0.17 0.15
RR (95% CI)
0.87 (0.69, 1.09), p=0.231
Severeexacerbations(annualizedrate)
0.25
0
SFC 50/500 μg b.i.d. (n=1,656)
IND/GLY 110/50 μg q.d. (n=1,651)
0.20
13% numerical
reduction
0.15
0.10
0.05

IND/GLYBREEZHALER SIGNIFICANTLY PROLONGED THE
TIME TO FIRST SEVERE EXACERBATION VERSUS SFC OVER 52 WEEKS
40
30
20
10
0
0 6 12 19 26 32 38
Patients atrisk
Time to event (weeks)
IND/GLY 1,675 1,530 1,434 1,368 1,138
SFC 1,679 1,507 1,389 1,303 1,071
HR (95%CI):
0.81 (0.66, 1.00), p=0.046
4552
19% risk
reduction

4.22 4.023.56 3.63
IND/GLYBREEZHALER REDUCED THE RATE OF ALL
(MILD/MODERATE/SEVERE) EXACERBATIONS VERSUS SFC OVER 52 WEEKS
IN PATIENTS WITH <2 AND ≥2% BLOOD EOSINOPHILS AT RANDOMIZATION
RR (95% CI)
0.84 (0.75, 0.95) p=0.004 RR (95% CI)
0.90 (0.82, 0.99) p=0.030
<2
Percentage blood eosinophils(%)
≥2
SFC 50/500 µg b.i.d
IND/GLY 110/50 µg q.d
4
3.5
3
2.5
2
1.5
1
0.5
4.5
Allexacerbations(annualizedrate)
5
0

1.24 1.150.99 0.98
IND/GLYBREEZHALER REDUCED THE RATEOF
MODERATE OR SEVERE EXACERBATIONS VERSUS SFC OVER 52 WEEKS IN
RR (95% CI)
0.80 (0.68, 0.93), p=0.004
RR (95% CI)
0.85 (0.75, 0.96), p=0.010
1.5
1.25
1
0.75
0.5
0.25
0
Moderatetosevereexacerbations
(annualizedrate)
PATIENTS WITH <2 AND ≥2% BLOOD EOSINOPHILS AT RANDOMIZATION
SFC 50/500 µg b.i.d
IND/GLY 110/50 µg q.d
<2
Percentage blood eosinophils(%)
≥2

TROUGH FEV1 VERSUS SFC ATWEEK 52
–48
15
SFC 50/500 μg b.i.d. (n=1,595)
IND/GLY 110/50 μg q.d.(n=1,597)
∆=62 mL, p<0.001
Adjustedmeanchangefrombaselinein
pre-dosetroughFEV1(mL)
50
–50
0
–25
25

LS = least square Time(days)
AdjustedmeanSGRQ-Ctotalscore
48
41
47
46
45
Day 0 (baseline)
44
43
42
0
Day29 Day85 Day 183 Day 267 Day 365
SFC 50/500 µg b.i.d (n=1,593)
IND/GLY 110/50 µg q.d. (n=1,602)
LS mean
difference–1.3
P<0.001
LS mean
difference–1.2
P=0.001
LS mean
difference–1.3
P=0.003
LS mean
difference–1.8
P<0.001
LS mean
difference0
P=NS
Improvement
SGRQ-C responder rates: IND/GLY 49.2%; SFC 43.7% (OR 1.30; p<0.001)
HEALTH STATUS VERSUS SFC AT EACH MEASURED
TIMEPOINT BETWEEN WEEKS 12 AND 52

IND/GLYBREEZHALER SIGNIFICANTLY DECREASED RESCUE
MEDICATION USE COMPARED WITH SFC ATWEEK 52
‒0.76 ‒1.01
SFC 50/500 μg b.i.d. (n=1,624)
IND/GLY 110/50 μg q.d. (n=1,609)
∆=–0.25, p<0.001
Adjustedmeanchangeinrescuemedicationusefrom
baseline(puffs/day)
0
–0.25
–0.50
–0.75
–1.0
–1.25
–1.5

THE INCIDENCE OF PNEUMONIA WAS SIGNIFICANTLY LOWER
WITH IND/GLYBREEZHALER THAN WITH SFC
Radiographic imaging was required to confirm pneumonia
AE = adverse event; SAE = serious adverse event
Preferred term, n(%)
IND/GLY
110/50 μg q.d.
(n=1,678)
SFC
50/500 μg b.i.d.
(n=1,680)
Patients with at least one AE 1,459 (86.9) 1,498 (89.2)
Adverse events ≥3% in any treatment group
Chronic obstructive pulmonarydisease 1,299 (77.4) 1,374 (81.8)
Nasopharyngitis 197 (11.7) 195 (11.6)
Viral upper respiratory tract infection 132 (7.9) 138 (8.2)
Upper respiratory tract infection bacterial 125 (7.4) 168 (10.0)
Lower respiratory tract infection 82(4.9) 98(5.8)
Upper respiratory tract infection 81(4.8) 83(4.9)
Pneumonia 53(3.2) 80(4.8)
Cough 50(3.0) 51 (3.0)
P=0.01
7
Dyspnea 49(2.9) 51(3.0)
Influenza 35(2.1) 56(3.3)
Oralcandidiasis 20 (1.2) 71 (4.2)
SAE(s) 308 (18.4) 334 (19.9)
Death 24(1.4) 24 (1.4)
Discontinuation due to AE(s) 126 (7.5) 143 (8.5)
Discontinuation due toSAE(s) 85(5.1) 87 (5.2)
Discontinuation due to non-SAE(s) 49(2.9) 70 (4.2)

• IND/GLYBreezhaler significantly:
– reduced the rate of all (mild, moderate and severe) and moderate or severe
exacerbations compared with SFC
– delayed the time to first exacerbation (all, moderate or severe, and severe) compared
with SFC
• Results for demographic and baseline disease characteristics subpopulations were
consistent with those for the overall population
• IND/GLYBreezhaler was superior to SFC in terms of all exacerbations and moderate
or severe exacerbations in patients with <2 and ≥2% blood eosinophils at
randomization
• IND/GLYBreezhaler was also superior to SFC with regards to improving lung function
and health status and reducing rescue medication use
• IND/GLYBreezhaler had a comparable safety profile to SFC, while being associated
with a lower incidence of pneumonia
FLAME summary: the first study to demonstrate superiority of
IND/GLYBreezhaler in exacerbation prevention versus SFC in
COPD patients with ≥1 exacerbation in the preceding year

Dual bronchodilation in COPD

More Related Content

What's hot

Similar to Dual bronchodilation in COPD

More from Gamal Agmy

Recently uploaded

Dual bronchodilation in COPD