Conditions: Chronic Obstructive Pulmonary Disease
Keywords: COPD, QVA149, Tiotropium, FDC, GlycOpyrronium With IndacatERol, POWER
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 401
Healthy volunteers: no

Brief summary:
This is a single cohort, prospective post approval study conducted on patients with COPD in Canada. The study will enroll patients that have not responded to their current treatment of tiotropium alone, or who are on the fixed dose combinations fluticasone propionate/salmeterol. Only patients for whom the physician has decided to change treatment due to lack of efficacy will be eligible to be enrolled in the study.

Also will evaluate the real-life effectiveness of QVA149 (indacaterol 110 mcg/glycopyrronium 50 mcg) in the management of patients.

Detailed description:

Arms:
arm 1: Patients diagnosed with chronic obstructive pulmonary disorder (COPD) who are symptomatic (CAT score over 10) and who are treated with Tiotropium (SPIRIVA HANDALER) or Fluticasone propionate/Salmeterol- ADVAIR DISKUS (FDC).

Interventions: intervention 1: Glycopyrronium /Indacaterol maleate
Intervention descriptions: intervention 1: Glycopyrronium 50mcg/Indacaterol maleate 110mcg once daily by a breezhaler device

Protocol document:
Prot_000.pdf: 
_______________________________________________________________________________________ 
Clinical Development 
Indacaterol maleate 110 mcg/glycopyrronium bromide 50 mcg (QVA149) 
Clinical Trial Protocol CQVA149ACA01 / NCT02202616 
POWER: Prospective Cohort Study for the Real – Life Effectiveness 
Evaluation of GlycOpyrronium With IndacatERol combination in the 
management of COPD in Canada  
Authors: 
 
Document type: 
Amended Protocol  
EUDRACT number: 
NA 
Version number: 
Vs 2.0 (Amendment 1) 
Development phase: 
IV 
Release date: 
June 3, 2015 
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed  
without the consent of Novartis 
NCDS Template Version 03‐Feb‐2012 


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Table of contents 
Table of contents ......................................................................................................................... 1 
List of abbreviations .................................................................................................................... 4 
Glossary of terms ......................................................................................................................... 5 
Amendment rationale ................................................................................................................. 6 
Protocol synopsis ......................................................................................................................... 8 
1 
Introduction ............................................................................................................................... 14 
1.1 
Background ................................................................................................................... 14 
1.2 
Purpose ........................................................................................................................... 15 
2 
Study objectives .......................................................................................................................... 15 
2.1 
Primary objectives .......................................................................................................... 15 
2.2 
Secondary objectives ...................................................................................................... 15 
2.3 
Exploratory objectives ................................................................................................... 15 
3 
Investigational plan ................................................................................................................... 16 
3.1 
Study design .................................................................................................................. 16 
3.2 
Rationale of study design .............................................................................................. 17 
3.3 
Rationale of dose/regimen, route of administration and duration of treatment ...... 17 
3.4 
Rationale for choice of comparator .............................................................................. 17 
3.5 
Purpose and timing of interim analyses/design adaptations ..................................... 17 
3.6 
Risks and benefits ......................................................................................................... 18 
4 
Population .................................................................................................................................. 18 
4.1 
Inclusion criteria ........................................................................................................... 18 
4.2 
Exclusion criteria .......................................................................................................... 19 
5 
Treatment .................................................................................................................................... 21 
5.1 
Protocol requested treatment ....................................................................................... 21 
5.1.1 
Investigational treatment ............................................................................ 21 
5.1.2 
Additional study treatment ......................................................................... 21 
5.2 
Treatment arms .............................................................................................................. 21 
5.3 
Treatment assignment, randomization ........................................................................ 21 
5.4 
Treatment blinding ........................................................................................................ 21 
5.5 
Treating the patient ....................................................................................................... 21 
5.5.1 
Patient numbering ....................................................................................... 21 
5.5.2 
Dispensing the investigational treatment ................................................. 22 
5.5.3 
Handling of study treatment ...................................................................... 22 
5.5.4 
Instructions for prescribing and taking study treatment ......................... 22 
5.5.5 
Permitted dose adjustments and interruptions of study treatment .......  22 
5.5.6 
Rescue medication ...................................................................................... 22 
5.5.7 
Concomitant treatment .............................................................................. 23 


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5.5.8 
Prohibited Treatment ................................................................................. 23 
5.5.9 
Discontinuation of study treatment and premature patient withdrawal 23 
5.5.10 
Emergency breaking of treatment assignment ......................................... 23 
5.5.11 
Study completion and post‐study treatment ............................................ 23 
5.5.12 
Early study termination .............................................................................. 24 
6 
Visit schedule and assessments ................................................................................................ 24 
6.1 
Information to be collected on screening failures ...................................................... 25 
6.2 
Patient demographics/other baseline characteristics ................................................ 25 
6.3 
Treatment exposure and compliance .......................................................................... 26 
6.4 
Efficacy ........................................................................................................................... 26 
6.4.1 
FEV1: ............................................................................................................. 26 
6.4.2 
COPD Assessment Test: .............................................................................. 27 
6.4.3 
Baseline Dyspnea Index –Transitional Dyspnea Index (BDI‐TDI): ........  27 
6.4.4 
Medical Outcomes Study Short Form – 36 (SF‐36) and the dimension 
Health Status Questionnaire (EQ‐5D: ....................................................... 27 
6.4.5 
Appropriateness of efficacy assessments ................................................... 27 
6.5 
Safety .............................................................................................................................. 28 
6.5.1 
Physical examination .................................................................................. 28 
6.5.2 
Vital signs ..................................................................................................... 28 
6.5.3 
Height and weight ....................................................................................... 28 
6.5.4 
Laboratory evaluations ............................................................................... 28 
6.5.5 
Electrocardiogram (ECG) ............................................................................ 29 
6.5.6 
Pregnancy and assessments of fertility ...................................................... 29 
6.5.7 
Appropriateness of safety measurements .................................................. 29 
6.5.8 
Pharmacokinetics ........................................................................................ 29 
6.5.9 
Pharmacogenetics /pharmacogenomics .................................................... 29 
6.5.10 
Other biomarkers ........................................................................................ 29 
7 
Safety monitoring ...................................................................................................................... 29 
7.1 
Adverse events............................................................................................................... 29 
7.2 
Serious adverse event reporting ................................................................................... 32 
7.3 
Pregnancy reporting ..................................................................................................... 33 
7.4 
Lack Of Efficacy, (LOE), and LOE reporting .............................................................. 33 
7.5 
Periodic Reconciliation……………………………………………………………………………….34 
8 
Data review and database management .................................................................................. 34 
8.1 
Site monitoring ............................................................................................................. 34 
8.2 
Data collection .............................................................................................................. 35 
8.3 
Database management and quality control ................................................................ 35 
8.4 
Data Monitoring Committee........................................................................................ 35 


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8.5 
Adjudication Committee .............................................................................................. 35 
9 
Data analysis .............................................................................................................................. 36 
9.1 
Analysis sets .................................................................................................................. 36 
9.2 
Patient demographics and other baseline characteristics ......................................... 36 
9.3 
Treatments .................................................................................................................... 36 
9.4 
Analysis of the primary and key secondary variable(s) .............................................. 36 
9.4.1 
Variable(s) .................................................................................................... 36 
9.4.2 
Statistical model, hypothesis, and method of analysis ............................. 37 
9.4.3 
Handling of missing values/censoring/discontinuations ......................... 37 
9.4.4 
Supportive analyses ..................................................................................... 37 
9.5 
Analysis of secondary variables .................................................................................... 37 
9.5.1 
Efficacy variables ......................................................................................... 37 
9.5.2 
Safety variables ............................................................................................ 37 
9.5.3 
Health‐related Quality of Life .................................................................... 38 
9.5.4 
Pharmacokinetics ........................................................................................ 38 
9.5.5 
Pharmacogenetics/pharmacogenomics ..................................................... 38 
9.5.6 
Biomarkers ................................................................................................... 38 
9.5.7 
PK/PD ........................................................................................................... 38 
9.6 
Interim analyses ............................................................................................................ 38 
9.7 
Sample size calculation ................................................................................................ 38 
10 
Ethical considerations ............................................................................................................... 39 
10.1 
Regulatory and ethical compliance ............................................................................. 39 
10.2 
Informed consent procedures ...................................................................................... 39 
10.3 
Responsibilities of the investigator and IRB/IEC ....................................................... 40 
10.4 
Publication of study protocol and results ................................................................... 40 
11 
Protocol adherence .................................................................................................................... 40 
11.1 
Protocol Amendments .................................................................................................. 41 
12 
References .................................................................................................................................. 41 
13   Appendix 1  CAT  ......................................................................................................................... 45 
 
Appendix 2  BTI‐TDI ................................................................................................................. 46 
 
Appendix 3 SF‐36 ....................................................................................................................... 50 
 
Appendix 4 EQ‐5D .................................................................................................................... 56 
 
 
 


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List of abbreviations 
AE 
Adverse event 
b.i.d. 
Twice a day 
CRF 
Case Report/Record Form (paper or electronic) 
CPO 
Country Pharma Organization 
CRO 
Contract Research Organization 
DS&E 
Drug Safety & Epidemiology 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ICS 
Inhaled Corticosteroids 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRT 
Interactive Randomization Technology 
o.d. 
Once a day 
p.o. 
Oral 
SAE 
Serious adverse event 


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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Enrollment 
Point/time of patient entry into the study; the point at which 
informed consent must be obtained (i.e. prior to starting any 
of the procedures described in the protocol) 
Investigational drug 
The drug whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is 
synonymous with “investigational new drug” or 
“investigational medicinal product.” 
Investigational treatment 
All investigational drug(s) whose properties are being tested 
in the study as well as their associated treatment controls.  
This includes any placebos, any active controls, as well as 
approved drugs used outside of their indication/approved 
dosage or tested in a fixed combination.  
Investigational treatment generally does not include other 
treatments administered as concomitant background therapy 
required or allowed by the protocol when used within 
approved indication/dosage 
Subject Number  
A number assigned to each patient who enrolls into the study  
Part  
A subdivision of a single protocol into major design 
components. These parts often are independent of each other 
and have different populations or objectives. For example, a 
single dose design, a multiple dose design that are combined 
into one protocol, or the same design with different patient 
populations in each part. 
Premature patient 
withdrawal 
Point/time when the patient exits from the study prior to the 
planned completion of all investigational/study treatment 
administration and all assessments (including follow‐up) 
Stop study participation 
Point/time at which the patient came in for a final evaluation 
visit or when study/investigational treatment was 
discontinued whichever is later 
Study drug/ treatment 
Any single drug or combination of drugs administered to the 
patient as part of the required study procedures; includes 
investigational drug (s), active drug run‐ins or background 
therapy  
Study/investigational 
treatment discontinuation 
Point/time when patient permanently stops taking 
study/investigational treatment  for any reason; may or may 
not also be the point/time of premature patient withdrawal 
Variable 
Information used in the data analysis; derived directly or 
indirectly from data collected using specified assessments at 
specified time points 
Pack‐Years 
Number of Packs per day multiplied by the number of years 
smoking. 


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Amendment 1 
Amendment rationale 
According to the study protocol, the primary study objective is to evaluate the real‐life effectiveness 
of QVA149 in the management of patients with COPD as assessed with the mean change in trough 
FEV1 from baseline to 16 weeks. As a secondary objective, the impact of QVA149 on the mean change 
in  trough  FEV1  from  baseline  to  4  weeks  is  to  be  assessed.  The  sponsor  would  like  to  clarify  that 
trough FEV1 is defined as the measurement made pre‐dose. The purpose of this change is to ensure 
that there is no confusion with regards to the definition of the primary endpoint.  
In addition, the minimum duration of on‐going treatment with tiotropium or fixed dose combination 
of  LABA/ICS,  specifically  combinations  fluticasone  propionate/salmeterol,  while  demonstrating 
persistence  of  symptoms  indicating  change  of  treatment  to  combination  therapy,  required  for 
inclusion in the study has been reduced from 3 months to 6 weeks. The reason for this change is the 
fact that the benefits of tiotropium monotherapy or fixed dose combination of LABA/ICS are apparent 
within 6 weeks of treatment. 
For drugs marketed in Canada, domestic reports of unusual failure in efficacy must be reported to the 
Marketed Health Product Directorate within 15 calendar days of the receipt of information by the 
Market Authorization Holder, (Novartis Canada). The protocol is therefore revised to add the 
obligation of reporting unusual Lack Of Efficacy, within 24 hours of becoming aware of such event to 
the local Novartis Drug Safety and Epidemiology department, for further processing. 
Changes to the protocol 
The described changes in the aforementioned amendment rationale are implemented throughout the 
protocol: 
 Change “trough FEV1” to “trough FEV1 (pre‐dose)” to clarify the definition of trough 
FEV1 throughout the protocol. 
 Change inclusion criterion #5 in the Inclusion Criteria sections of the Synopsis and 
section  4.1  of  the  protocol  from  “On‐going  treatment  with  tiotropium  or  fixed  dose 
combination of LABA/ICS, specifically combinations fluticasone propionate/salmeterol 
for a minimum of three months but demonstrating persistence of symptoms indicating 
change of treatment to combination therapy **using a CAT score > 10” to “On‐going 
treatment  with  tiotropium  or  fixed  dose  combination  of  LABA/ICS,  specifically 
combinations  fluticasone  propionate/salmeterol  for  a  minimum  of  6  weeks  but 
demonstrating persistence of symptoms indicating change of treatment to combination 
therapy **using a CAT score > 10”. 
 The safety reporting section 7 was modified to include the definition of Unusual Lack of 
Efficacy for the study medication, and describe the reporting requirement associated with this 
reportable Adverse Event, (section 7.4). 
 
 
 
 


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The opportunity was also taken to make the following changes: 
 
The  3rd  paragraph  of  Section  5.5.9,  stating  that  ‘’Patients  who  discontinue  QVA149  treatment 
should NOT be considered withdrawn from the study. See Section 6 for the required assessments of 
these patients after discontinuation of QVA149 treatment.’’ was removed, as there are no further 
follow‐up visits being done on patients who discontinue treatment with QVA149, except for a last 
evaluation, to be done, if possible, as per routine clinical care.  
 
The  3rd  paragraph  of  Section  5.5.9,  referenced  above,  was  replaced  by:  ‘’If  premature 
discontinuation of study occurs, after Visit 2, the patient should return to the clinic as soon 
as possible for a last follow‐up visit, as per routine clinical care.’’  Section 6.1 was modified to 
specify the CRFs to be completed, for patients who discontinue the study after Visit 2 and 
after having received a first dose of study medication,  
 
Specifications were added to Section 6.4.3 to clarify the requirements for the assessor performing 
the Baseline Dyspnea Index –Transitional Dyspnea Index (BDI‐TDI) interview. 
 
The patient population was further defined in the protocol synopsis and in protocol Section 4, to 
specify the FEV1 range defining the moderate to severe airflow limitations according to the Global 
Initiative for Chronic Obstructive Lung Disease. 
 
The Assessment Schedule (Table 6‐1) has been updated to add footnote 5, to clarify that no study 
medication should be taken at the last study visit, (Visit 5) and to specify that the last dose of 
study medication will be taken 24 hours before the last study visit, (Visit 5). 
 
The  opportunity  was  also  taken  to  correct  any  typographical  errors  and  provide  further 
clarification where required. 
 
Changes to specific sections of the protocol are shown in the track changes version of the protocol 
using strike through red font for deletions and red underlined for insertions.  
A copy of this amended protocol will be sent to the Institutional Review Board (IRBs)/Independent 
Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to implementation. 
In  addition,  if  the  changes  herein  affect  the  Informed  Consent,  sites  are  required  to  update  and 
submit for approval a revised Informed Consent that takes into account the changes described in this 
amended protocol. 
 


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Protocol synopsis 
 
Protocol number 
CQVA149ACA01 
Title 
Prospective Cohort Study for the Real – Life Effectiveness 
Evaluation of GlycOpyrronium With IndacatERol in 
combination in the management of COPD in Canada 
(POWER) 
Brief title 
 
POWER ‐ Effectiveness of Glycopyrronium with Indacaterol 
combination in COPD.  
Sponsor and 
Clinical Phase 
Novartis, Phase IV 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and 
rationale 
Chronic  Obstructive  Pulmonary  Disease  (COPD)  affects  over 
770,000 Canadians or 4% of those over the age of 35 years. The 
symptoms  include  shortness  of  breath,  cough  and  sputum 
production with progressive deterioration that eventually leads 
to early mortality.  
Long 
acting 
bronchodilators 
such 
as 
long 
acting 
anticholinergics and long acting β2‐agonists are recommended 
first line treatments for the treatment of COPD patients with 
persistent  symptoms.  Guidelines  position  the  use  of  Inhaled 
Corticosteroids (ICS) in patients with frequent exacerbations – 
defined  as  more  than one  in  the previous  year.  Although  the 
majority of patients have few (or no) exacerbations, the current 
practice  shows  that  more  than  65%  of  patients  are  on  triple 
therapy and that there is a gap in applying the guidelines.  
 
Indacaterol  is  the  first  long‐acting  β2‐agonist  (LABA) 
bronchodilator  providing  24‐hour  bronchodilation  with  once‐
daily  dosing  in  patients  with  moderate  to  severe  COPD.  The 
efficacy  and  tolerability  of  indacaterol  in  COPD  have  been 
previously  evaluated  in  placebo‐controlled  studies.  In  these 
studies  the  daily  dose  of  indacaterol  tested  was  75  mcg,  150 
mcg, 300 mcg and 600 mcg once daily.  
Glycopyrronium  bromide  is  a  long  acting  muscarinic 
antagonist  (LAMA)  that  has  been  approved  as  a  once‐daily 
inhaled  maintenance  therapy  for  COPD.  The  data  from 


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randomized clinical trials (GLOW 1, 2 and 3) have shown that 
glycopyrronium  is  superior  to  placebo  and  non  –  inferior  to 
tiotropium with respect to improved lung function, shortness 
of  breath,  exacerbations,  use  of  rescue  medication,  improved 
quality  of  life  and  improved  exercise  tolerance  (20,21,22)..    The 
safety profile and tolerability of glycopyrronium was similar to 
that of placebo in these trials. These results would support the 
use of glycopyrronium as first line monotherapy as well as part 
of  combination  therapy  for  the  management  of  patients  with 
COPD.  
QVA149  is  the  combination  of  both  indacaterol  110  mcg  and 
glycopyrronium  50  mcg  that  have  showed  significant 
improvement of lung function and clinical outcomes compared 
to  standard  care  (23,  24).    Results  from  ILLUMINATE  and 
SHINE  showed  that  FEV1  was  superior  and  clinically 
meaningful with QV149 compared than with fixed combination 
or  with  tiotropium  respectively.    Results  from  the  trials  also 
have shown a safety and tolerability profile similar to placebo, 
monotherapy  or  fixed  dose  combination  versus  QVA149 
therapy (23, 24). 
To date, there are no real – life Canadian studies evaluating the 
effectiveness 
of 
indacaterol 
in 
combination 
with 
glycopyrronium  bromide  in  the  management  of  symptomatic 
patients   when treated with tiotropium or fixed dose LABA/ICS 
specifically 
the 
combination 
of 
fluticasone 
propionate/salmeterol.    In  addition,  data  on  the  effectiveness 
and tolerability of this regimen under routine clinical care as 
administered 
by 
general 
practitioners 
and 
community 
physicians in the Canadian setting are not available.  
The  purpose  of  this  prospective  interventional  study  is  to 
evaluate  the  effectiveness  of  QVA149  on  FEV1,  COPD 
symptoms, quality of life in COPD patients managed under a 
routine clinical care setting in Canada.  
Primary Objective(s) 
and Key Secondary 
Objective 
1. To 
evaluate 
the 
real‐life 
effectiveness 
of 
QVA149 
(indacaterol  110  mcg/glycopyrronium  50  mcg)  in  the 
management  of  patients  with  COPD  who  have  symptoms 
defined  as  CAT  score  >10  with  tiotropium  monotherapy; 
effectiveness will be assessed as the mean change in trough 
FEV1 (pre‐dose) from baseline to 16 weeks. 
2. To 
evaluate 
the 
real‐life 
effectiveness 
of 
QVA149 
(indacaterol  110  mcg/glycopyrronium  50  mcg)  in  the 


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management  of  patients  with  COPD  who  have  symptoms 
defined as CAT score > 10 while on treatment with FDC of 
fluticasone  propionate/salmeterol;  effectiveness  will  be 
assessed  as  the  mean  change  in  trough  FEV1  (pre‐dose) 
from baseline to 16 weeks. 
Secondary 
Objectives 
 
In  COPD  patients  that  are  managed  in  the  routine  clinical 
setting  and  are  symptomatic  while  on  treatment  with 
tiotropium 
monotherapy 
or 
FDC 
of 
fluticasone 
propionate/salmeterol: 
1. To evaluate the impact of QVA149 on the mean change in 
trough FEV1 (pre‐dose) from baseline to 4 weeks. 
2. To evaluate the impact of QVA149 on dyspnea as measured 
by the Baseline and Transition Dyspnea Index (BDI/TDI) at 
4 and 16 weeks. 
3. To evaluate the impact of QVA149 on patient quality of life 
as measured by the COPD Assessment Questionnaire (CAT) 
at baseline, week 4 and 16 weeks. 
Exploratory objectives:  
In  COPD  patients  that  are  managed  in  the  routine  clinical 
setting  and  are  symptomatic  while  on  treatment  with 
tiotropium 
monotherapy 
or 
FDC 
of 
fluticasone 
propionate/salmeterol;  
 To evaluate the impact of QVA149 on patient quality of life 
as measured by the Medical Outcomes Study Short Form – 
36  (MOS  ‐  SF‐36)  and  the  Dimension  Health  Status 
Questionnaire (EQ‐5D) at 4 (EQ‐5D only) and 16 weeks of 
treatment. 
 To  describe  the  patient  and  physician  satisfaction  with 
QVA149 treatment compared to previous therapies. 
Study design 
This  is  a  single  cohort,  prospective  post  approval  study 
conducted  on  approximately  710  patients  with  COPD  treated 
by  approximately  100  community  and  hospital  based  general 
practitioners  and  specialists  across  Canada.  The  study  will 
enroll  patients  that  have  not  responded  to  their  current 
treatment of tiotropium alone or with fixed a dose combination 
of  fluticasone  propionate/salmeterol.  All  patients  will  be 
treated with QVA149 and will be followed for 16 weeks. With 
evaluations at ‐1 week, baseline 4, 12 and 16 weeks.  
Population 
The study will enroll adult patients with confirmed COPD, with 


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moderate to severe airflow limitations, according to the Global 
Initiative for Chronic Obstructive Lung Disease (GOLD 2010), 
(specifically  with  baseline  trough  FEV1  (pre‐dose)  values  of 
30%≤FEV1˂ 80%),  that  have  not  responded  to  their  current 
treatment on tiotropium alone or on a fixed dose combinations 
of  fluticasone  propionate/salmeterol.  Only  patients  for  whom 
the physician has decided to change treatment due to lack of 
efficacy will be eligible to be enrolled in the study. The decision 
and  choice  of  changing  treatment  must  be  reached  prior  to 
enrolling the patient in the study.  
Inclusion criteria 
1. Patient  diagnosed  and  treated  for  moderate  to  severe 
COPD  according  to  the  Global  Initiative  for  Chronic 
Obstructive  Lung  Disease  according  to  physician’s 
assessment.*  Patient  must  have  moderate  to  severe 
airflow limitation indicated by a trough FEV1, (pre‐dose) 
≥ 30% and <80%, obtained at the baseline, Visit 2. 
2. Male or Female patients. 
3. Age > 40 years. 
4. Smoking history of > 10 pack – years. 
5. On‐going  treatment  with  tiotropium    or  fixed  dose 
combination of LABA/ICS, specifically combinations of 
fluticasone  propionate/salmeterol  for  a  minimum  of  6 
weeks,  but  demonstrating  persistence  of  symptoms 
indicating change of treatment to combination therapy 
**using a CAT score > 10. 
6. Treatment with QVA149 is indicated as per the product 
monograph  and  appropriate  for  the  patient  as  per  the 
judgment of the treating physician. 
7. Patient  has  signed  informed  consent  agreeing  to 
participate  in  the  study  and  undergo  the  study 
treatments  and  allowing  the  use  of  their  data  for  the 
purposes of the study. 
8. Patient  is  expected  to  be  available  for  16  weeks  after 
study enrolment 
* 
Assessed as per routine care or as documented in 
the patient’s chart. 
**  
As  determined  and  decided  by  the  treating 
physician prior to enrolment of the patient in the 
study.  
 
Exclusion criteria 
 
Patients not willing to sign an informed consent. 


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 
Patients  on  maintenance  treatment  including  triple 
therapy (LABA/LAMA/CS) for COPD 
 
Patients with a diagnosis of asthma or history of asthma.
 
Patients who have had two or more moderate to severe 
exacerbations  during  the  last  12  months  prior  to  study 
enrolment.  A  moderate  COPD  exacerbation  is  defined 
by 
requirement 
for 
treatment 
with 
systemic 
corticosteroids  or  antibiotics  or  both.    A  severe  COPD 
exacerbation is defined by hospitalization, including an 
emergency room visit of longer than 24 h. 
 
Patients who had an exacerbation within 6 weeks prior 
to enrolment.  
 
Patients  who  as  per  physician  clinical  judgment  will 
require  ICS  treatment  co‐administered  with  QVA149 
during the study period. 
 
Patients with other chronic respiratory conditions that 
may affect the outcome of treatment including but not 
limited to lung cancer. 
 
Patients  with  cancer  or  other  condition  that,  in  the 
opinion  of  the  investigator  will  prevent  them  from 
participating in the study. 
 
Patients participating in an investigational drug trial. 
 
Patients  with  hypersensitivity  to  indacaterol  maleate, 
glycopyrronium bromide or to any of their components. 
Investigational and 
reference therapy 
All 
patients 
will 
be 
treated 
with 
indacaterol 
110 
mcg/glycopyrronium 50 mcg combinations as per the Canadian 
Product  Monograph.  Study  drug  will  be  provided  by  the 
sponsor during the course of the study. 
Efficacy 
assessments 
The primary efficacy endpoint will be the change from baseline 
in trough FEV1 (pre‐dose) at 16 weeks of treatment measured at 
the physician’s office using a portable spirometer.  
Safety assessments 
Information about all AEs, whether volunteered by the patient, 
discovered  by  investigator  questioning,  or  detected  through 
physical  examination,  laboratory  test  or  other  means,  will  be 
collected and recorded on an Adverse Event Case Report Form 
and will be followed up as appropriate. 
All  serious  adverse  events  will  also  be  reported  to  Novartis 
Drug  Safety  &  Epidemiology  (DS&E)  within  24  hours  of  the 
investigator  (or  designee)  being  aware  of  the  serious  adverse 
event.  Specific  definitions  of  adverse  events,  and  serious 
adverse  events,  are  outlined  below,  along  with  reporting 


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criteria required by Novartis.    
Other assessments 
Secondary Effectiveness Endpoints: 
 
Change  from  baseline  in  trough  FEV1  (pre‐dose)  at  4 
weeks of treatment. 
 
Change from baseline in the CAT score at baseline and 
16 weeks of treatment. 
 
Change in the Transition Dyspnea Index (TDI) after 16 
weeks of treatment. 
Exploratory Endpoints: 
 
Change  from  baseline  to  16  weeks  in  Quality  of  Life  and 
Functional  Status  as  measured  by  the  Medical  Outcomes 
Study Short Form – 36 (MOS ‐ SF‐36) and the Dimension 
Health Status Questionnaire (EQ‐5D). 
 
Patient  and  Physician  Global  Satisfaction  with  COPD 
treatment measured at 4, 12 & 16 weeks. 
Data analysis 
The primary effectiveness outcome measure of the study will be 
the change from baseline to 16 weeks in trough FEV1 (pre‐dose) 
measurements 
in 
patients 
treated 
with 
indacaterol 
/ 
glycopyrronium  combination.  This  will  assessed  by  the  mean 
change  in  FEV1  between  week  16  and  the  baseline  visits.  The 
precision  of  the  estimate  will  be  assessed  with  the  95% 
confidence  interval.  Multivariate  methods  and  sub  group 
analyses will be used to identify possible determinants of the 
change  in  FEV1  at  16  weeks  of  treatment.  Similar  descriptive 
methods will be used to address the secondary and exploratory 
objectives of the study. 
Key words 
COPD,  indacaterol,  glycopyrronium,  FEV1,  Quality  of  Life, 
Effectiveness, Safety. 
 


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1 
Introduction 
1.1 
Background  
Chronic  Obstructive  Pulmonary  Disease  (COPD)  affects  over  770,000  Canadians  or  4%  of 
those over the age of 35 years. The symptoms include shortness of breath, cough and sputum 
production  with  progressive  deterioration  that  eventually  leads  to  early  mortality.  The 
disease  is the  leading cause  of  all  hospitalizations  in  Canada  with  direct  health  care  costs 
being  over  1.5  billion  dollars  per  year  (1‐7).  To  date  there  is  no  cure  for  COPD  and  patient 
management  is  focused  on  managing  symptoms,  reducing  the  severity  and  frequency  of 
exacerbations and improving the patient’s quality of life (8‐11).  
Long acting bronchodilators such as long acting anticholinergics and long acting β2‐agonists 
are recommended first line treatments for the treatment of COPD patients with persistent 
symptoms.  Guidelines  position  the  use  of  ICS  in  patients  with  frequent  exacerbations  – 
defined as more than one in the previous year. Although the majority of patients have few (or 
no)  exacerbations,  current  practice  shows  that  more  than  65%  of  patients  are  on  triple 
therapy indicating that there is a gap in applying the guidelines (12‐ 17).  
 
Indacaterol  is  the  first  long‐acting  β2‐agonist  (LABA)  bronchodilator  providing  24‐hour 
bronchodilation  with  once‐daily  dosing  in  patients  with  moderate  to  severe  COPD.  The 
efficacy and tolerability of indacaterol in COPD have been previously evaluated in placebo‐
controlled studies. In these studies the daily dose of indacaterol tested was 75 mcg, 150 mcg, 
300  mcg  and  600  mcg  once  daily(18‐19,2528).  Glycopyrronium  bromide  (GB)  is  a  long  acting 
muscarinic antagonist (LAMA) that has been approved as a once‐daily inhaled maintenance 
therapy for COPD. The data from randomized clinical trials (GLOW 1, 2 and 3) have shown 
that GB is superior to placebo and non – inferior to tiotropium with respect to improved lung 
function, shortness of breath, exacerbations, use of rescue medication, improved quality of 
life and improved exercise tolerance  (20,21,22)..  The safety profile and tolerability of GB was 
similar  to  that  of  placebo  in  these  trials.  These  results  support  the  use  of  GB  as  first  line 
monotherapy as well as part of combination therapy for the management of patients with 
COPD.  
QVA149 is a combination of both indacaterol 110 mcg and glycopyrronium 50 mcg and has 
demonstrated significant improvement of lung function and clinical outcomes compared to 
standard of care (23, 24).  Results from ILLUMINATE and SHINE showed that treatment with 
QVA149  was  associated  with  clinically  important  and  statistically  significantly  higher 
improvement  in  FEV1  when  compared  to  fixed  dose  combination  salmeterol  –  fluticasone 
and tiotropium monotherapy.(23, 24). 
 
 


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1.2 
Purpose  
To date, there are no real – life Canadian studies evaluating the effectiveness of indacaterol in 
combination  with  glycopyrronium  bromide  in  the  management  of  symptomatic  patients   
when  treated  with  tiotropium  or  fixed  dose  LABA/ICS  (specifically  the  combination  of 
fluticasone propionate/salmeterol).  In addition, data on the effectiveness and tolerability of 
this  regimen  under  routine  clinical  care  as  administered  by  general  practitioners  and 
community physicians in the Canadian setting are not available.  
The  purpose  of  this  prospective  interventional  study  is  to  evaluate  the  effectiveness  of 
QVA149 on FEV1; COPD symptoms, and quality of life in COPD patients managed under a 
routine clinical care setting in Canada.  
2 
Study objectives 
2.1 
Primary objectives 
1. To evaluate the real‐life effectiveness of QVA149 (indacaterol 110 mcg/glycopyrronium 
50 mcg) in the management of patients with COPD who have symptoms defined as 
CAT  score  >10  with  tiotropium  monotherapy;  effectiveness  will  be  assessed  as  the 
mean change in trough FEV1 (pre‐dose) from baseline to 16 weeks. 
2. To evaluate the real‐life effectiveness of QVA149 (indacaterol 110 mcg/glycopyrronium 
50 mcg) in the management of patients with COPD who have symptoms defined as 
CAT  score  >10  while  on  treatment  with  FDC  of  fluticasone  propionate/salmeterol; 
effectiveness  will  be  assessed  as  the  mean  change  in  trough  FEV1  (pre‐dose)  from 
baseline to 16 weeks. 
2.2 
Secondary objectives 
In COPD patients that are managed in a routine clinical setting and are symptomatic while 
on treatment with tiotropium monotherapy or FDC of fluticasone propionate/salmeterol: 
1. To  evaluate  the  impact  of  QVA149  on  the  mean  change  in  trough  FEV1  (pre‐dose) 
from baseline to 4 weeks. 
2. To  evaluate  the  impact  of  QVA149  on  dyspnea  as  measured  by  the  Baseline  and 
Transition Dyspnea Index (BDI/TDI) at 4 and 16 weeks. 
3. To evaluate the impact of QVA149 on patient quality of life as measured by the COPD 
Assessment Questionnaire (CAT) at 4 and 16 weeks. 
2.3 
Exploratory objectives  
In COPD patients that are managed in a routine clinical setting and are symptomatic while 
on treatment with tiotropium monotherapy or FDC of fluticasone propionate/salmeterol;  


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 To evaluate the impact of QVA149 on patient quality of life as measured by the Medical 
Outcomes  Study  Short  Form  –  36  (MOS  ‐  SF‐36)  and  the  Dimension  Health  Status 
Questionnaire (EQ‐5D), 4 (EQ‐5D only) and at 16 weeks of treatment. 
 To describe the patient and physician satisfaction with QVA149 treatment at 4, 12, and 16 
weeks. 
3 
Investigational plan 
3.1 
Study design 
This is a real – life, prospective post approval study conducted on approximately 710 patients 
diagnosed  with  COPD  and  treated  by  approximately  100  general  practitioners  and 
community  specialists  across  Canada.  The  study  will  enroll  patients  who  are  symptomatic 
while 
on 
current 
monotherapy 
with 
tiotropium 
alone 
or 
FDC 
(fluticasone 
propionate/salmeterol) with a 3:2 ratio. Only patients for whom the physician has decided to 
change  treatment  due  to  the  persistence  of  symptoms  (based  on  CAT  score)  despite 
treatment will be eligible to be enrolled in the study. On‐going treatment will be interrupted 
for  24  hours  for  patients  treated  with  Tiotropium  and  12  hours  for  patients  on  FDC 
treatment. Subsequently  all patients will be treated with QVA149 for 16 weeks as part of the 
active  treatment  in  the  study  in  order  to  describe  the  course  of  treatment,  change  in 
treatments and disease outcomes including incidence of exacerbations.  
The following diagram describes the study design: 
 
Figure 1.  
Study Design 
 
 
 


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3.2 
Rationale of study design 
This  is  a  single  cohort  prospective  study  that  is  aimed  at  assessing  the  effectiveness  of 
Indacaterol/glycopyrronium  combination  in  COPD  patients  that have  failed  to  respond  to 
previous  treatment  with  tiotropium  monotherapy  or  with  an  ICS/LABA  fixed  dose 
combination. Given that the objective of the study is to describe the incremental benefit of 
indacaterol/glycopyrronium combination on respiratory function in this patient population 
that has failed previous treatment, the single cohort design is appropriate. In this study the 
pre‐treatment respiratory function of the patient will serve as the control against which the 
incremental effect of the interventional treatment will be assessed. Furthermore, this design 
best  emulates  the  routine  care  setting  in  which  physicians  will  decide  the  switch  patients 
from one treatment to another when adequate therapeutic response cannot be achieved.   
The open label design of the study may make it susceptible to ascertainment bias given that 
the patients and physicians will be aware of the fact that a new treatment regimen will be 
used. However, standardization of the efficacy endpoint assessments including FEV1 and the 
use of validated tools to measure patient centric outcomes will reduce this bias. Confounding 
by indication will be reduced by the fact that the decision to change treatment will have been 
reached prior to enrolment of the patient in the study and it will be on the basis of a‐priori 
established criteria indicating treatment failure. Random confounding will be prevented by 
the fact that patients will act as their own controls. 
3.3 
Rationale of dose/regimen, route of administration and duration of 
treatment 
All  patients  will  be  treated  with  the  indacaterol  110  mcg  /glycopyrronium  50  mcg 
combination in accordance with the approved Canadian product labeling and monograph.  
3.4 
Rationale for choice of comparator 
Not Applicable 
3.5 
Purpose and timing of interim analyses/design adaptations 
An interim analysis will be performed when 300 patients will have completed their Visit 3. 


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3.6 
Risks and benefits  
The  risk  to  subjects  in  this  trial  will  be  minimized  by  compliance  with  the 
inclusion/exclusion  criteria,  close  clinical  monitoring  and  use  of  the  study  medications 
according  to  the  product  monograph  and  label  under  the  supervision  of  the  treating 
physician.  Potential  benefits  to  the  patients  may  be  related  to  steroid  sparing.  More 
specifically,  the  benefits  of  ICS  over  and  above  LAMA  /  LABA  combinations  in  the 
management of COPD are debatable while the increased risk for adverse outcomes related to 
long term use of corticosteroids is well documented. Therefore, the benefit – risk ratio for 
LAMA  –  ICS/  LABA  combination  may  be  suboptimal  for  patients  with  COPD.  Treatment 
with  Indacaterol/glycopyrronium  combination  does  not  involve  the  use  of  ICS  and  hence 
may  provide  a  corticosteroid  free  treatment  to  COPD  patients  without  compromising 
therapeutic efficacy. 
4 
Population 
The  target  population  of  the  current  study  is  patients  with  moderate  to  severe  COPD, 
according  to  the  Global  Initiative  for  Chronic  Obstructive  Lung  Disease  (GOLD  2010), 
(specifically with baseline trough FEV1 (pre‐dose) values of FEV1 30%≤FEV1˂ 80%), that have 
not  achieved  therapeutic  response  with  respect  to  control  of  their  symptoms  while  on 
treatment with tiotropium as monotherapy or a FDC of fluticasone propionate/salmeterol. 
COPD  patients  that  are  intolerant  to  tiotropium  or  the  FDC  of  fluticasone 
propionate/salmeterol are included in the target population. For these patients a change in 
treatment  is  indicated.  The  study  will  exclude  patients  with  more  than  one  previous 
exacerbation in the previous year to ensure that homogeneous cohorts of low exacerbation 
risk patients are included in the study. Approximately 710 patients will be recruited from the 
practices of about 100 general practitioners and community physicians or specialists will be 
enrolled in the study. 
4.1 
Inclusion criteria 
Patients eligible for inclusion in this study have to fulfill all of the following criteria: 
 
1. Patient diagnosed and treated for moderate to severe COPD according to the Global 
Initiative for Chronic Obstructive Lung Disease according to physician’s assessment*. 
Patient must have moderate to severe airflow limitation indicated by a trough FEV1 
(pre‐dose) ≥ 30% and <80%, obtained at the baseline, Visit 2. 
2. Male or Female patients. 
3. Age > 40 years. 
4. Smoking history of > 10 pack – years. 
5. On‐going  treatment  with  tiotropium    or  fixed  dose  combination  of  LABA/ICS, 
specifically combinations fluticasone propionate/salmeterol for a minimum of 6 weeks 
but  demonstrating  persistence  of  symptoms  indicating  change  of  treatment  to 
combination therapy **using a CAT score > 10. 


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6. Treatment with QVA149 is indicated as per the product monograph and appropriate 
for the patient as per the judgment of the treating physician. 
7. Patient has signed informed consent agreeing to participate in the study and undergo 
the study treatments and allowing the use of their data for the purposes of the study. 
8. Patient is expected to be available for 16 weeks after study enrolment 
 
* 
Assessed as per routine care or as documented in the patient’s chart. 
**  
As determined and decided by the treating  physician prior to enrolment of the 
patient in the study.  
 
 
4.2 
Exclusion criteria 
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients. 
 
1. Patients not willing to sign an informed consent. 
2. Patient  on  maintenance  treatment  including  triple  therapy  (LABA  +LAMA+ICS) 
for COPD 
3. Patients with a diagnosis of asthma or history of asthma. 
4. Patients who have had two or more moderate to severe exacerbations during the 
last 12 months prior to study enrolment.  A moderate COPD exacerbation is 
defined by requirement for treatment with systemic corticosteroids or antibiotics 
or both.  A severe COPD exacerbation is defined by hospitalization, including an 
emergency room visit of longer than 24 h. 
5. Patients who had an exacerbation within the previous 6 weeks to enrolment. 
6. Patients  who  as  per  physician  clinical  judgment  will  require  ICS  treatment  co‐
administered with QVA149 during the study period. 
7. Patients with other chronic respiratory conditions that may affect the outcome of 
treatment including but not limited to lung cancer. 
8. Patients with cancer or other condition that, in the opinion of the investigator will 
prevent them from participating in the study. 
9. Patients participating in an investigational drug trial. 
10. Patients with hypersensitivity to indacaterol maleate, glycopyrronium bromide or 
to any of their components and any excipients of their formulations. 
11. Use of other investigational drugs within 30 days of enrollment in the study. 
12. Patients who are unable or unwilling to comply with study procedures, attend 
scheduled study visits, complete questionnaires and daily diaries, or who may 
otherwise be unable to comply with the study requirements. 


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13. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of 
a female after conception and until the termination of gestation, confirmed by a 
positive hCG laboratory test. 
14. Women of child‐bearing potential, defined as all women physiologically capable of 
becoming  pregnant,  unless  they  are  using  effective  methods  of  contraception 
during dosing of study treatment. Effective contraception methods include: 
 Total abstinence (when this is in line with the preferred and usual lifestyle of 
the  subject.  Periodic  abstinence  (e.g.,  calendar,  ovulation,  symptothermal, 
post‐ovulation  methods)  and  withdrawal  are  not  acceptable  methods  of 
contraception 
 Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy)  or  tubal  ligation  at  least  six  weeks  before  taking  study 
treatment.  In case of oophorectomy alone, only when the reproductive status 
of the woman has been confirmed by follow up hormone level assessment 
 Male sterilization (at least 6 m prior to screening). For female subjects on the 
study,  the  vasectomized  male  partner  should  be  the  sole  partner  for  that 
subject 
 Barrier  methods  of  contraception:  Condom  or  Occlusive  cap  (diaphragm  or 
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository  
 Use of oral, injected or implanted hormonal methods of contraception or other 
forms  of  hormonal  contraception  that  have  comparable  efficacy  (failure  rate 
<1%),  for  example  hormone  vaginal  ring  or  transdermal  hormone 
contraception. In case of use of oral contraception women should have been 
stabile  on  the  same  pill  for  a  minimum  of  3  months  before  taking  study 
treatment. 
 
Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
Women  are  considered  post‐menopausal  and  not  of  child  bearing 
potential if they have had 12 months of natural (spontaneous) amenorrhea 
with  an  appropriate  clinical  profile  (e.g.  age  appropriate,  history  of 
vasomotor symptoms) or have had surgical bilateral oophorectomy (with 
or without hysterectomy) or tubal ligation at least six weeks ago. In the 
case  of  oophorectomy  alone,  only  when  the  reproductive  status  of  the 
woman has been confirmed by follow up hormone level assessment is she 
considered not of child bearing potential.  
 


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5 
Treatment 
5.1 
Protocol requested treatment 
5.1.1 
Investigational treatment 
 
All  patients  will  be  treated  with  receive  Indacaterol  (as  maleate)/  glycopyrronium  (as 
bromide)  inhalation  powder  hard  capsules  110  mcg/50mcg  per  capsule  with  ULTIBRO® 
BREEZHALER®.  The  product  will  be  obtained  from  commercial  stocks  and  sent  to 
individual  investigational  site  once  all  regulatory  documents  and  those  individual  site 
preparation activities are completed.   
ULTIBRO® is a registered trademark. BREEZHALER® is a registered trademark. 
5.1.2 
Additional study treatment 
No additional treatment beyond investigational treatment is allowed for this trial. 
5.2 
Treatment arms 
All patients will be treated with indacaterol 110 mcg/glycopyrronium bromide 50 mcg. This is 
a single cohort open label study in which no randomization for treatment allocation applies. 
5.3 
Treatment assignment, randomization  
This is a single cohort open label study in which no randomization for treatment allocation 
applies. Selection bias will be prevented by enrolling sequential eligible patients at each site. 
5.4 
Treatment blinding  
Not applicable. 
5.5 
Treating the patient 
5.5.1 
Patient numbering  
Each patient is uniquely identified by a Subject Number which is composed of the 4‐digit site 
number assigned by Novartis and a sequential 5‐digit number assigned to each patient by the 
investigator. Once assigned to a patient, the Subject Number will not be reused. If a patient 
had  initially  failed  based  on  eligibility  and  is  further  re‐screened,  a  new  Subject  Number 
should be used for this patient.  
Upon signing the informed consent form during the first Visit, the patient is assigned the 
next sequential Subject Number by the investigator. If the patient fails to be treated for any 
reason,  the  investigator  will  complete  the  Study  Completion  /  Premature  Discontinuation 
CRF and the reason for not being treated will be entered.  


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5.5.2 
Dispensing the investigational treatment 
Each study site will be supplied by Novartis with investigational treatment in packaging from 
commercial stock with additional labels to comply with Novartis requirements for drugs used 
for clinical research purpose. 
5.5.3 
Handling of study treatment 
5.5.3.1 
Handling of investigational treatment 
Investigational treatment must be received by a designated person at the study site, handled 
and stored safely and properly, and kept in a secured location to which only the investigator 
and  designees  have  access.  Upon  receipt,  all  investigational  treatment  should  be  stored 
according to the instructions specified on the labels. Clinical supplies are to be dispensed 
only in accordance with the protocol. 
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the investigational treatment but no 
information about the patient except for the unique study identification number. 
The  investigator  must  maintain  an  accurate  record  of  the  shipment  and  dispensing  of 
investigational treatment in a drug accountability log. Monitoring of drug accountability will 
be  performed  by  the  field  monitor  during  site  visits  and  at  the  completion  of  the  trial. 
Patients will be asked to return all unused investigational treatment and packaging at the 
end of the study or at the time of discontinuation of investigational treatment.  
At  the  conclusion  of  the  study,  and  as  appropriate  during  the  course  of  the  study,  the 
investigator will return all unused investigational treatment, packaging, drug labels, and a 
copy  of  the  completed  drug  accountability  log  to  the Novartis  monitor  or  to  the  Novartis 
address provided in the investigator folder at each site. 
5.5.4 
Instructions for prescribing and taking study treatment 
Indacaterol  110  mcg/50  mcg  glycopyrronium,  i.e.  ULTIBRO®  BREEZHALER®.  will  be  taken 
once daily as indicated in the Canadian product monograph.  
The  investigator  should  promote  compliance  by  instructing  the  patient  to  take  the  study 
treatment exactly as prescribed and by stating that compliance is necessary for the patient’s 
safety  and  the  validity  of  the  study.  The  patient  should  be  instructed  to  contact  the 
investigator if he/she is unable for any reason to take the study treatment as prescribed. 
5.5.5 
Permitted dose adjustments and interruptions of study treatment 
For  patients  who  are  unable  to  tolerate  the  protocol‐specified  dosing  scheme  should 
discontinue QVA149 treatment and be discontinued from the trial. 
5.5.6 
Rescue medication 
In  the  current  study  use  of  inhaled  SABA,  theophylline  will  be  allowed.  Use  of  rescue 
medication must be recorded on the COPD Concomitant medications section in the CRF. 


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5.5.7 
Concomitant treatment 
The  investigator  should  instruct  the  patient  to  notify  the  study  site  about  any  new 
medications  he/she  takes  after  the  patient  was  enrolled  into  the  study.  All  medications, 
procedures  and  significant  non‐drug  therapies  (including  physical  therapy  and  blood 
transfusions) administered after the patient was enrolled into the study must be recorded. 
5.5.8 
Prohibited Treatment 
Corticosteroids  should  not  be  prescribed  to  the  study  patient  during  the  trial.    If  it  is 
determined as per clinical judgment that a patient needs to be treated with corticosteroids 
the patient should be discontinued from the trial.  
5.5.9 
Discontinuation of study treatment and premature patient withdrawal 
Patients may voluntarily withdraw from the study for any reason at any time. They may be 
considered  withdrawn  if  they  state  an  intention  to  withdraw,  fail  to  return  for  visits,  or 
become lost to follow‐up for any other reason. 
If premature withdrawal occurs for any reason, the investigator must make every effort to 
determine  the  primary  reason  for  a  patient’s  premature  withdrawal  from  the  study  and 
record this information. QVA149 treatment must be discontinued. 
The investigator should discontinue QVA149 treatment for a given patient and/or withdraw 
the patient from study if, on balance, he/she believes that continuation would be detrimental 
to the patient’s well‐being or if the patient no longer fulfills the study inclusion and exclusion 
criteria, namely the use of ICS during the trial. 
If premature discontinuation of study occurs, after Visit 2, the patient should return to the 
clinic as soon as possible for a last follow‐up visit, as per routine clinical care.   
For patients who are lost to follow‐up (i.e. those patients whose status is unclear because 
they fail to appear for study visits without stating an intention to withdraw), the investigator 
should show "due diligence" by documenting in the source documents steps taken to contact 
the patient, e.g. dates of telephone calls, registered letters, etc. 
Patients  who  are  prematurely  withdrawn  from  the  study  will  not  be  replaced  by  an  equal 
number of newly enrolled patients.   
5.5.10 
Emergency breaking of treatment assignment 
Not Applicable. 
5.5.11 
Study completion and post‐study treatment 
Patients completing 16 weeks of treatment will be considered as completing the study. The 
investigator  must  provide  follow‐up  medical  care  for  all  patients  who  are  prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care.  


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5.5.12 
Early study termination 
The  study  can  be  terminated  at  any  time  for  any  reason  by  Novartis.  Should  this  be 
necessary,  the  patient  should  be  seen  as  soon  as  possible  and  treated  for  a  prematurely 
withdrawn patient. The investigator may be informed of additional procedures to be followed 
in  order  to  ensure  that  adequate  consideration  is  given  to  the  protection  of  the  patient’s 
interests.  The  investigator  will  be  responsible  for  informing  IRBs  and/or  ECs  of  the  early 
termination of the trial. 
6 
Visit schedule and assessments 
Table 6‐1 lists all of the assessments and indicates with an “x” when the visits are performed. 
Patients should be seen for all visits on the designated day with an allowed “visit window” of 
“5” days, or as close to it as possible. 
Table 6‐1 
Assessment schedule 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit number 
11  
2 
3 
4 
5 
Time of Visit (weeks) 
Time window 
‐1 
0 
(‐6 
days)1 
4
(±5 
days) 
12
(±5 
days) 
16
(±2 
days) 
Informed consent 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Inclusion & Exclusion Criteria 
X 
 
 
 
 
Physical Examination 
X2 
X 3 
X 3 
X 3 
X 3 
Medical History 
X 
 
 
 
 
COPD History 
X 
 
 
 
 
Smoking History 
X 
 
 
 
 
Alcohol Use History 
X 
 
 
 
 
Concomitant Medication Use 
X 
X 
X 
X 
X 
Current Treatment for COPD 
X 
 
 
 
 
Previous Treatment for COPD 
X 
 
 
 
 
Instruction to interrupt COPD medication 
(tiotropium or LABA/ICS) before V2  
 
X 
 
 
 
 
Urine pregnancy test for women with childbearing 
potential 
X 
 
 
 
X 
Pre‐dose FEV1  
 
X 
X 
 
X 
BDI  
 
X 
 
 
 
TDI 
 
 
X 
 
X 
CAT  
X 
 
X 
 
X 
Sf‐36, EQ‐5D 
 
X 
X4 
 
X 
Treatment Compliance (Missed Doses) 
 
 
X 
X 
X 
Physician Global Satisfaction 
 
 
X 
X 
X 
Patient Global Satisfaction 
 
 
X 
X 
X 
Adverse Events  
 
X 
X 
X 
X 
Drug Accountability 
 
X 
X 
X 
X 5 


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1. The  visit  1  is  a  screening  visit.    Patients  may  come  back  for  their  visit  2  for  24  hours  after 
interrupting their COPD medication with Tiotropium or 12 hours if they are on a FDC. The visit 2 
should not occur later than 6 days after the visit 1. 
  
2. Physical examinations per routine care. 
3. Changes in physical examination only 
4. At visit 3 only the EQ‐5D questionnaire should be completed 
5. The last dose of study medication will be taken 24 hours before the last study visit, (Visit 5). 
 
6.1 
Information to be collected on screening failures 
All patients who have signed informed consent but not completing the trial beyond V1 will 
have  CRF  completed  for  the  demographics,  inclusion/exclusion,  and  SAE  data  collected. 
Adverse events that are not SAEs will be followed by the investigator and collected only in 
the source data.  Patients who discontinue the study after Visit 2 and after having received a 
first  dose  of  study  medication,  should  have  the  study  completion/discontinuation  page 
completed, in addition to the above listed CRF.  
For  all  patients  who  have  signed informed  consent  and  are  continuing  study  will  have  all 
adverse events occurring after informed consent is signed recorded on the Adverse Event 
CRF. 
6.2 
Patient demographics/other baseline characteristics 
For  each  potentially  eligible  patient,  during  the  baseline  assessment  the  eligibility  criteria 
will be determined. At the same visit the following data will be collected: 
 Date of Birth  
 Gender 
 Race 
 Smoking History and Status: 
 Number of Pack‐Years 
 Current Smoker (Y/N) 
- 
Number of packs /  day 
 Alcohol Consumption History and Status 
 Number of alcoholic beverages / day 
 Medical History 
 Presence  of  Targeted  Chronic  Conditions:  osteoporosis,  diabetes,  allergy, 
dysphonia  
 Physical Examination (as per routine care) 
 Vital Signs (Blood Pressure, Pulse) 
 Weight 
 Height  
 BMI (Calculated from Weight and Height) 


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 Concomitant Medication Use 
 Medication Name 
 Dose 
 Indication 
 Start Date 
 COPD History: 
 Duration of the Disease (Time since diagnosis) 
 Prior Treatment with duration and reason for discontinuation 
 Number of Exacerbations during the 12 months prior to entry in the study 
 Current COPD treatments: 
 Medication name  
 Dose 
6.3 
Treatment exposure and compliance 
Self‐reported compliance with treatment will be ascertained at every visit by determining the 
number of daily QVA149 doses missed   
6.4 
Efficacy 
The following efficacy assessments will be conducted:: 
 
Primary Effectiveness Assessment:  
 
 
Pre‐dose FEV1  
 
Secondary Effectiveness Endpoints: 
 
 
COPD Assessment Questionnaire (CAT) 
 
Baseline Dyspnea Index –Transitional Dyspnea Index (BDI‐TDI) 
 
Medical Outcomes Study Short Form 36 (SF‐36) and in the Dimension Health Status 
Questionnaire (EQ‐5D) 
 
Patient and Physician Global Satisfaction with COPD Treatment 
 
6.4.1 
FEV1: 
The  evaluation  of  the  primary  endpoint  is  based  on  change  from  baseline  in  trough  FEV1 
(pre‐dose)  at  16  weeks  of  treatment.  Investigator  should  instruct  patient  to  not  take  their 
study  drug  before  measuring  their  FEV1  at  the  clinic.    Investigators  may  opt  to  use  the 
services of spirometry center if readily accessible for FEV1 measurements.  For investigators 
who have no access to spirometry, portable spirometers will be provided to investigators and 
they will use this device for all of their patient measurements of FEV1 during the trial. The 
devices will be returned to Novartis at the end of the study. 


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6.4.2 
COPD Assessment Test: 
Change from baseline in the CAT will be assessed at baseline 4 and 16 weeks. The CAT is an 8 
item questionnaire that assesses the impact of COPD on the patient’s functional status. The 
item scores range from 0 to 5 (0 = no impairment). An overall score is calculated by adding 
the score from each item. 
6.4.3 
Baseline Dyspnea Index –Transitional Dyspnea Index (BDI‐TDI): 
The BDI and TDI measure dyspnea symptoms at a single point in time (BDI), and measuring 
changes in breathlessness from this baseline state over time (TDI). BDI and TDI are scores 
are obtained by interview conducted by the assessor, at 4 and 16 weeks. The questions assess 
the  patient’s  subjective  experience  of  breathlessness  and  its  impact  on  activities  of  daily 
living. The assessor is the designated site personnel qualified, with experience in obtaining 
history of respiratory disease or documented training on administration of BDI‐TDI. 
6.4.4 
Medical Outcomes Study Short Form – 36 (SF‐36) and the Dimension Health 
Status Questionnaire (EQ‐5D): 
Change in the SF – 36 from baseline will be assessed at 16 weeks. The  SF‐36  is  a  self‐
administered general quality of life assessment tool that consists of 36 items that converge 
into  eight  scales  measuring  Physical  Function  (PF),  Role  Limitations  caused  by  Physical 
Problems (RP), Pain (BP), General Health (GH), Vitality/Energy (VT), Social Function (SF), 
Mental  Health/Emotional  Well‐Being  (MH)  and  Role  Limitations  caused  by  emotional 
problems/mental  health  (RE).  The  eight  scales  are  summarized  even  more  into  two 
dimensions,  one  assessing  physical  and  the  other  mental  health.  The  SF‐36  has  been 
validated in a large number of disease states and Canadian age – specific normal values are 
available  for  comparison.  In  addition,  the  tool  has  been  used  in  several  studies  assessing 
quality of life in patients with COPD and can be used to calculate QALY values. 
Change in the EQ‐5D from baseline will be assessed at 4 and 16 weeks. The EQ‐5D is a simple 
but  effective  standardized  instrument  designed  for  use  as  a  measure  of  health  outcome.  
There are two parts to this questionnaire.  The first, ‘health state classification’ consists of 
five  questions.  The  second,  ‘Visual  Analogue  Scale  Thermometer’  consists  of  a  visual 
analogue scale.  This generates a self‐rating of current health‐related quality of life.  EQ‐5D 
enables  an  accurate  self‐description  of  current  health‐related  quality  of  life  to  be  easily 
recorded.  Self‐explanatory instructions to respondents are provided within the questionnaire 
and it takes about 2 min to complete. 
6.4.5 
Appropriateness of efficacy assessments  
 
 COPD Assessment Questionnaire (CAT): 
- This is a standardized questionnaire used to assess quality of life and functional 
capacity in patients with COPD. 
 Baseline Dyspnea Index –Transitional Dyspnea Index (BDI‐TDI): 


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- These are measurements assessing the severity of COPD symptoms at baseline 
and the change in symptoms over time.  
 Medical  Outcomes  Study  Short  Form  36  (SF‐36)  and  the  Dimension  Health  Status 
Questionnaire (EQ‐5D): 
- The SF‐36 and EQ‐5D as a general measure of Quality of Life  
 Patient and Physician Global Satisfaction with COPD Treatment 
6.5 
Safety 
The safety assessments include adverse events. 
6.5.1 
Physical examination 
A complete physical examination will be conducted if part of regular clinical practice at the 
baseline visit and may include the examination of general appearance, skin, neck (including 
thyroid),  eyes,  ears,  nose,  throat,  lungs,  heart,  abdomen,  back,  lymph  nodes,  extremities, 
vascular, and neurological. If indicated based on medical history and/or symptoms, rectal, 
external genitalia, breast, and pelvic exams will be performed. Blood pressure (SBP/DBP) and 
pulse will also be measured and recorded. 
A  short  physical  exam  will  be  conducted  at  all  follow  up  visits  and  will  include  the 
examination of general appearance and vital signs (blood pressure [SBP and DBP] and pulse).  
Information for all physical examinations should be included in the source documentation at 
the study site. Significant findings that are present prior to signing informed consent must be 
included in the Medical History part of the CRF. Significant findings made after signing the 
informed consent which meet the definition of an Adverse Event must be recorded on the 
Adverse Event section of the CRF. 
6.5.2 
Vital signs 
Blood pressure measurements and pulse will be recorded when assessed as per routine care. 
6.5.3 
Height and weight 
Height  in  centimeters  (cm)  and  body  weight  (to  the  nearest  0.1  kilogram  [kg]  in  indoor 
clothing, but without shoes) will be measured at the baseline visit. 
6.5.4 
Laboratory evaluations 
Not applicable. 
6.5.4.1 
Hematology 
Not applicable. 
6.5.4.2 
Clinical chemistry 
Not applicable. 


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6.5.4.3 
Urinalysis 
Not applicable 
6.5.5 
Electrocardiogram (ECG) 
Not applicable. 
6.5.6 
Pregnancy and assessments of fertility 
All pre‐menopausal women who are not surgically sterile (women of child‐bearing potential) 
will have a local urine pregnancy test performed at Screening (Visit1) and at the end of the 
trial.  If a local urine pregnancy test at screening shows a positive result, then a serum β‐hCG 
test must be done.  If positive, the patient should not enter in the study. 
6.5.7 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/patient population. 
6.5.8 
Pharmacokinetics 
Not Applicable. 
6.5.9 
Pharmacogenetics /pharmacogenomics 
Not Applicable. 
6.5.10 
Other biomarkers 
Not Applicable. 
7 
Safety monitoring 
7.1 
Adverse events 
An  adverse  event  (AE)  is  any  untoward  medical  occurrence  (i.e.,  any  unfavorable  and 
unintended sign [including abnormal laboratory findings], symptom or disease and unusual 
lack  of  therapeutic  efficacy*)  in  a  subject  or  clinical  investigation  subject  after  providing 
written informed consent for participation in the study. Therefore, an AE may or may not be 
temporally  or  causally  associated  with  the  use  of  a  medicinal  (investigational)  product. 
(*Refer  to  section  7.4  for  unusual  lack  of  therapeutic  efficacy  definition  and  reporting 
requirements). 
The  occurrence  of  adverse  events  should  be  sought  by  non‐directive  questioning  of  the 
patient at each visit during the study. Adverse events also may be detected when they are 
volunteered  by  the  patient  during  or  between  visits  or  through  physical  examination, 
laboratory test, or other assessments. 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 


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 they induce clinical signs or symptoms,  
 they are considered clinically significant,  
 they require therapy.  
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline  or  the  previous  visit,  or  values  which  are  considered  to  be  non‐typical  in  patient 
with  underlying  disease.  Investigators  have  the  responsibility  for  managing  the  safety  of 
individual patient and identifying adverse events.  
Adverse events should be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them accompanied by the following information. 
 the severity grade:  
 mild: usually transient in nature and generally not interfering with normal activities 
 moderate: sufficiently discomforting to interfere with normal activities 
 severe: prevents normal activities 
 its relationship to the study treatment (suspected and not suspected)  
 its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved should be reported. 
 whether it constitutes a serious adverse event (SAE)  
 action taken regarding study treatment  
 whether other medication or therapies have been taken (concomitant medication/non‐
drug therapy) 
 its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown) 
An SAE is any adverse event (appearance of (or worsening of any pre‐existing) undesirable 
sign(s), symptom(s) or medical conditions(s) which meets any one of the following criteria  
 is fatal or life‐threatening  
 results in persistent or significant disability/incapacity 
 constitutes a congenital anomaly/birth defect 
 requires  inpatient  hospitalization  or  prolongation  of  existing  hospitalization,  unless 
hospitalization is for:  
 routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
 elective or pre‐planned treatment for a pre‐existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent  
 treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission  
 social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 


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 is  medically  significant,  i.e.  defined  as  an  event  that  jeopardizes  the  patient  or  may 
require medical or surgical intervention to prevent one of the outcomes listed above. 
 All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
 
For QVA149, there are events which are the object of more targeted follow‐up activities as 
per regulatory commitments.  The local Novartis DS&E Department will perform the follow‐
up: on the following events regardless of seriousness: 
 Atrial fibrillation  
 Cardiac arrhythmias (Brady‐Tachy arrhythmias)  
 Cardiac Failure 
 Cerebrovascular events 
 Hyperglycemia 
 Intubation,  hospitalization  and  death  due  to  asthma  related  events  in  asthma  (off 
label use)  
 Ischemic Heart disease 
 Myocardial Infarction 
 Narrow‐angle glaucoma 
 QTc prolongation 
 
Unlike  routine  safety  assessments,  SAEs,  pregnancies  and  Unusual  Lack  of  Efficacy  are 
monitored continuously and have special reporting requirements; see Section 7.2 and 7.4. 
All adverse events should be treated appropriately. Treatment may include one or more of 
the  following:  no  action  taken  (i.e.  further  observation  only);  study  treatment  dosage 
adjusted/temporarily  interrupted;  study  drug(s)  permanently  discontinued;  concomitant 
medication given; non‐drug therapy given. The action taken to treat the adverse event should 
be recorded on the Adverse Event CRF.  
Once  an  adverse  event  is  detected,  it  should  be  followed  until  its  resolution  or  until  it  is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study treatment, the 
interventions required to treat it, and the outcome. 
The investigator should also instruct each patient to report any new adverse event (beyond 
the protocol observation period) that the patient, or the patient’s personal physician, believes 
might reasonably be related to study treatment. This information should be recorded in the 
investigator’s source documents; however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis. 


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7.2 
Serious adverse event reporting 
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days after the last study visit must be reported to 
Novartis within 24 hours of learning of its occurrence. Any SAEs experienced after the 30 
days  period  should  only  be  reported  to  Novartis  if  the  investigator  suspects  a  causal 
relationship to study treatment.  
Recurrent  episodes,  complications,  or  progression  of  the  initial  SAE  must  be  reported  as 
follow‐up to the original episode, regardless of when the event occurs. This report must be 
submitted within 24 hours of the investigator receiving the follow‐up information. An SAE 
that  is  considered  completely  unrelated  to  a  previously  reported  one  should  be  reported 
separately as a new event. 
Information about all SAEs (either initial or follow up information) is collected and recorded 
on  the  paper  Serious  Adverse  Event  Report  Form.  The  investigator  must  assess  the 
relationship  to  each  specific  component  of  study  treatment  (if  study  treatment  consists  of 
several  drugs)  complete  the  SAE  Report  Form  in  English,  and  send  the  completed,  signed 
form by fax within 24 hours after awareness of the SAE to the local Novartis Drug Safety and 
Epidemiology Department. The telephone and fax number of the contact persons in the local 
department  of  Drug  Safety  and  Epidemiology,  specific  to  the  site,  are  listed  in  the 
investigator folder provided to each site. The original copy of the SAE Report Form and the 
fax confirmation sheet must be kept with the case report form documentation at the study 
site. Follow‐up information should be provided using a new paper SAE Report Form stating 
that this is a follow‐up to a previously reported SAE 
Information about all SAEs (either initial or follow up information) is collected and recorded 
in English on the paper Serious Adverse Event Report Form. The Investigator must assess the 
relationship  to  each  specific  component  of  the  study  treatment  (if  the  study  treatment 
consists of several components).  
SAEs (initial and follow‐up) that are recorded on the paper SAE form should be faxed within 
24  hours  of  awareness  of  the  SAE  to  the  local  Novartis  Drug  Safety  and  Epidemiology 
Department.  The telephone and fax number of the contact persons in the local department 
of  Drug  Safety  and  Epidemiology,  specific  to  the  site,  are  listed  in  the  investigator  folder 
provided to each site.  The original copy of the SAE Report Form and the fax confirmation 
sheet must be kept with the case report form documentation at the study site. Follow‐up 
information should be provided using a new paper SAE Report Form stating that this is a 
follow‐up to a previously reported SAE.  
Follow‐  up  information  provided  should  describe  whether  the  event  has  resolved  or 
continues, if and how it was treated, and whether the patient continued or withdrew from 
study participation.  Each re‐occurrence, complication, or progression of the original event 
should be reported as a follow‐up to that event regardless of when it occurs. 


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If the SAE is not previously documented in the Product Monograph (new occurrence) and is 
thought  to  be  related  to  the  investigational  treatment  a  Drug  Safety  and  Epidemiology 
Department  associate  may  urgently  require  further  information  from  the  investigator  for 
Health Authority reporting. Novartis may need to issue an Investigator Notification (IN) to 
inform all investigators involved in any study with the same investigational treatment that 
this SAE has been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will 
be  collected  and  reported  to the  competent  authorities  and  relevant  ethics  committees in 
accordance  with  Directive  2001/20/EC  or  as  per  national  regulatory  requirements  in 
participating countries. 
7.3 
Pregnancy reporting 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should  be  followed  up  to  determine  outcome,  including  spontaneous  or  voluntary 
termination, details of the birth, and the presence or absence of any birth defects, congenital 
abnormalities, or maternal and/or newborn complications. 
Pregnancy  should  be  recorded  on  a  Clinical  Trial  Pregnancy  Form  and  reported  by  the 
investigator  to  the  local  Novartis  Drug  Safety  and  Epidemiology  Department.  Pregnancy 
follow‐up  should  be  recorded  on  the  same form  and  should  include  an  assessment  of  the 
possible relationship to the study treatment.  
Any SAE experienced during pregnancy must be reported on the SAE Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the female partner. 
7.4 
Lack of Efficacy, (LOE) and LOE reporting  
Lack of Efficacy is defined as a technical failure of a compound to meet its efficacy goals, to 
produce the expected intended effect, and is subject to quality assurance testing to confirm 
that the manufacturing of the compound is appropriate. Therefore, unusual lack of efficacy 
should  be  sent  within  24  hours  of  awareness  to  the  local  Novartis  Drug  Safety  and 
Epidemiology  Department  at 
.    The  original  copy  of  the  e‐mail 
correspondence should be kept at the study site. 
   
Clinical judgment should be exercised by a qualified health care professional to determine if 
the problem reported is related to the product itself, rather than one of treatment selection 
or disease progression since health products cannot be expected to be effective in 100% of the 
patients. One example of unusual failure in efficacy is a previously well‐stabilized condition 
that deteriorates when the patient changes to a different brand or receives a new prescription 
 
The following situations are examples when Unusual Lack of Efficacy is considered:  


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• The patient’s disease was stable and controlled. Suddenly, an unexplainable loss of efficacy 
is reported, with no change in the drug dosage or the severity of the medical condition.  
• The loss of efficacy happened despite proper dosage administration and adequate duration 
of therapy, as per labeling instructions.  
• The loss of efficacy happened after switching to a new batch of medication. 
• The loss of efficacy reported is in association with some specific units within the same 
package / box, only.  
7.5 
Periodic Reconciliation 
Periodic  reconciliation  between  the  clinical  and  safety  databases  shall  be  performed  at  a 
frequency of at least 6 months, at interim analysis (if applicable) and at the end of the study.  
8 
Data review and database management 
8.1 
Site monitoring 
Sites will be selected to participate in the study based on their clinical research experience 
and  their  responses  to  the  Novartis  feasibility  questionnaire.  Before  study  initiation,  each  
site will have initiation visit  where the CRO monitor will review the protocol and CRFs with 
the investigators and their staff. Investigator and their staff will also be invited to participate 
in an Investigator’s Meeting. During the study, the field monitor will visit the site regularly to 
check  the  completeness  of  patient  records,  the  accuracy  of  entries  on  the  CRFs,  the 
adherence to the protocol and to Good Clinical Practice, the progress of enrollment, and to 
ensure  that  study  treatment  is  being  stored,  dispensed  and  accounted  for  according  to 
specifications. Key study personnel must be available to assist the field monitor during these 
visits. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information,  laboratory  data,  electrocardiograms,  and  the  results  of  any  other  tests  or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. Data not requiring a separate written record will be defined before study start 
and  will  be  recorded  directly  on  the  CRFs.  The  investigator  must  also  keep  the  original 
informed consent form signed by the patient (a signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Verification of the source documents with the CRFs 
and other data verification requirements will be performed according to the study‐specific 
monitoring plan.  Novartis monitoring standards require full verification for the presence of 
informed consent, adherence to the inclusion/exclusion criteria, documentation of SAEs, and 
of data that will be used for all primary variables. Additional checks of the consistency of the 
source data with the CRFs are performed according to the study‐specific monitoring plan. No 
information in source documents about the identity of the patients will be disclosed. 


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8.2 
Data collection 
Designated investigator staff must enter the information required by the protocol onto the 
Novartis paper CRFs.  CRO monitors will review the CRFs for completeness and accuracy and 
instruct  site  personnel  to  make  any  required  corrections  or  additions.  The  CRFs  are 
forwarded  to  the  Medical  Documents  Reception  Center  of  Novartis  by  the  investigational 
site,  with  one  copy  being  retained  at  the  investigational  site.  Once  the  CRFs  are  faxed  to 
Novartis their receipt is kept and date entered into a database. Original CRF will remain at 
the site.  
8.3 
Database management and quality control 
Data from the CRFs are entered into the study database by Novartis staff following internal 
standard operating procedures.  
Subsequently, the entered data are systematically checked by Data Management staff, using 
error  messages  printed  from  validation  programs  and  database  listings.  Other  errors  or 
omissions are entered on Data Query Forms, which are returned to the investigational site 
for resolution. The signed original and resolved Data Query Forms are kept with the CRFs at 
the investigator site, and a copy is sent to Novartis so the resolutions can be entered into the 
database. Quality control audits of all key safety and efficacy data in the database are made 
prior to locking the database. 
Concomitant  medications  entered  into  the  database  will  be  coded  using  the  WHO  Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Concomitant  procedures,  non‐drug  therapies  and  adverse  events  will  be  coded  using  the 
Medical dictionary for regulatory activities (MedDRA) terminology. 
8.4 
Data Monitoring Committee 
Not required. 
8.5 
Adjudication Committee 
Not required. 
9 
Data analysis 
9.1 
Analysis sets 
This is a single cohort interventional study. All patients receiving the study treatment and 
have returned for at least one follow up visit will be included in the Intent to Treat (ITT) 
analysis set. All patients receiving one dose of the study treatment will be included in the 
safety data set. All patients fulfilling all the study inclusion and exclusion criteria and have 
undergone all study visit assessments will be included in the Per‐Protocol data set. 


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9.2 
Patient demographics and other baseline characteristics 
The patient demographics will be analyzed descriptively. Means, medians, standard deviation 
and 95% confidence interval of the mean will be used to describe the patient demographics. 
9.3 
Treatments 
Exposure to the study treatment and other concomitant treatments will be ascertained by 
patient questionnaires and prescription refills.  
9.4 
Analysis of the primary and key secondary variable(s) 
9.4.1 
Variable(s) 
The  primary  effectiveness  variable  will  be  the  absolute  change  in  trough  FEV1  (pre‐dose) 
from baseline to the Week 16 visit.  
The following secondary effectiveness variables will also be analyzed: 
 
Change in trough FEV1 (pre‐dose) between baseline and 4 weeks of treatment. 
 
Change in COPD Assessment Questionnaire (CAT) between baseline, 4 and 16 weeks 
of treatment. 
 
Baseline Dyspnea Index –Transitional Dyspnea Index (BDI‐TDI) at baseline, 4 and 16 
weeks of treatment. 
 
Change in the Medical Outcomes Study Short Form 36 (SF‐36) and in the Dimension 
Health Status Questionnaire (EQ‐5D) between baseline, 4 (EQ‐5D only) and 16 weeks 
of treatment. 
 
Change in Patient and Physician Global Satisfaction with COPD Treatment between at 
4, 12 and 16 weeks of treatment. 
9.4.2 
Statistical model, hypothesis, and method of analysis 
The primary objective of the current study is to describe the effectiveness of treatment of 
QVA149 in the management of patients with COPD. Effectiveness will be assessed primarily 
with the change in FEV1 between baseline and 16 weeks of treatment. Given the descriptive 
nature of the study there is no a priori‐defined hypothesis. The mean change in trough FEV1 
(pre‐dose)  between  baseline  and  16  weeks  of  treatment  will  be  estimated.  The  95% 
confidence interval of the change in FEV1 will be used to assess the precision of the estimate 
and to make inferences to the target population. The analysis will be repeated for subgroup 
of  patients  classified  according  to  prior  COPD  treatment,  specifically,  tiotropium 
monotherapy or ICS/LABA fixed dose combination.  
Between  subgroup  differences  with  respect  to  the  effectiveness  variables  will  be  assessed 
descriptively with appropriate bivariate statistical methods, specifically the Student’s t‐test 
for  independent  samples  for  continuous  scale  variables  and  the  Chi‐Square  test  for 
categorical variables.  


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General linear models with repeated measures and random effects will be used to describe 
the change in the effectiveness variables over time, to assess the adjusted between subgroup 
differences and to identify determinants of variability in response to treatment. 
9.4.3 
Handling of missing values/censoring/discontinuations 
There will be no imputation for missing data. The analysis will be conducted on observed 
cases.  However,  the  mixed  effects  repeated  measures  models  will  compensate  for  missing 
data. 
9.4.4 
Supportive analyses 
Not Applicable. 
9.5 
Analysis of secondary variables 
9.5.1 
Efficacy variables 
Similar analyses as those used for the primary objective will be used to assess the secondary 
objectives pertaining to the secondary effectiveness variables.  
9.5.2 
Safety variables 
All treatment emergent adverse events will be coded and classified according to the MedDRA 
dictionary  of  terms.  The  incidence  of  adverse  events  will  be  reported  as  the  number  of 
patients  with  more  than  one  event  and  the  number  of  events  per  patient.  Incidence  of 
adverse events will be described according to severity and causality in relation to the study 
treatment.  
9.5.3 
Health‐related Quality of Life 
All  scales  of  the  SF‐36  and  EQ‐5D  will  be  analyzed  with  emphasis  on  the  physical  health 
dimension. The CAT will be analyzed as a whole. 
9.5.4 
Pharmacokinetics 
Not Applicable.  
9.5.5 
Pharmacogenetics/pharmacogenomics 
Not Applicable.  
9.5.6 
Biomarkers 
Not Applicable.  
9.5.7 
PK/PD 
Not Applicable.  


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9.6 
Interim analyses 
An interim analysis will be performed when 300 patients will have completed their V3 . 
9.7 
Sample size calculation 
The primary effectiveness outcome measure of the study will be the change from baseline to 
16  weeks  in  trough  FEV1  (pre‐dose)  measurements  in  patients  treated  with  QVA149. 
Therefore, the study must have sufficient sample size to produce a precise estimate of these 
changes in FEV1. Precision is assessed by the width of the 95% confidence interval. 
In  the  SPARK  study  the  mean  difference  between  QVA149  (indacaterol  110  mcg  + 
glycopyrronium) and tiotropium with respect to trough FEV1 was between 0.060 L – 0.080 L 
during 64 weeks of treatment. In the SHINE study the difference between tiotropium and 
QVA149 at 26 weeks was 0.08 L. 
In  the  ILLUMINATE  study  the  difference  between  QVA149  and  fixed  dose  combination 
LABA/ICS with respect to FEV1 at 12 weeks was 0.092 L.  
Using the 95% CI and SEM estimates from these studies the calculated SD for the change in 
FEV1 at 16 weeks is approximately 0.220 L.  
Sample size calculations for the current study are based on the primary objective which is to 
describe the change in FEV1 at 16 weeks after the initiation of treatment on indacaterol + 
glycopyrronium. The precision of the estimated mean change in FEV1 at 16 weeks, as assessed 
by the 95% confidence interval, is the parameter driving the sample size.  
For the current study we can assume a mean change in FEV1 at 16 weeks of 0.080 L for the 
patients previously treated with tiotropium monotherapy and approximately 0.092 L for the 
patients previously treated fixed dose combination with LABA / ICS.  
The sample size requirements of the study have been determined on the basis of the above 
parameters and in order to achieve a 95% confidence interval of the mean change in FEV1 at 
16 weeks with a width (ω/2) of ± 30% of the point estimate. This value is comparable with the 
results reported in the above clinical trials and provides reasonable precision of the estimated 
FEV1  change  at  16  weeks.  Assuming  a  0.080  L  mean  change  in  FEV1  for  the  patients 
previously  treated  with  tiotropium  the  95%  confidence  interval  for  this  cohort  will  be 
between 0.056 L – 0.104 L; for the patients previously treated with fixed dose combination 
LABA/ICS assuming a mean change in FEV1 of 0.092 L the 95% confidence interval will be 
between 0.064 L and 0.120 L. For purposes of sample size calculations, for both cohorts the 
SD of the mean change in FEV1 between baseline and 16 weeks will be assumed to be 0.220 L.   
Based on the above criteria and assumptions, for the cohort of patients previously treated 
with  tiotropium  the  sample  size  requirement  is  323  patients.  For  the  patients  previously 
treated with fixed dose combination LABA/ICS the sample size requirement is 245 patients. 
The  total  sample  size  of  the  study  will  be  568.  Assuming  a  20%  attrition  rate,  the  total 
number  of  patients  recruited  will  be  710  (404  previously  treated  with  tiotropium  and  306 
previously treated with fixed dose combination LABA/ICS). 


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Patient enrolment will be designed to enroll at a 3:2 ratio of patients previously treated with 
tiotropium to those previously treated with fixed dose combination LABA/ICS per individual 
site and at the study level. Once study‐wise recruitment has been completed for one of the 
strata, the each site will be instructed to pursue recruitment onto the other stratum only. 
10 
Ethical considerations 
10.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented and reported in accordance with 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 
21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid 
down in the Declaration of Helsinki. 
10.2 
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed, where 
required  by  law  or  regulation),  IRB/IEC‐approved  informed  consentIn  cases  where  the 
patient’s representative gives consent, the patient should be informed about the study to the 
extent  possible  given  his/her  understanding.  If  the  patient  is  capable  of  doing  so,  he/she 
should  indicate  assent  by  personally  signing  and  dating  the  written  informed  consent 
document or a separate assent form. Informed consent must be obtained before conducting 
any  study‐specific  procedures  (i.e.  all  of  the  procedures  described  in  the  protocol).  The 
process  of  obtaining  informed  consent  should  be  documented  in  the  patient  source 
documents.  
Novartis will provide to investigators in a separate document a proposed informed consent 
form  that  complies  with  the  ICH  GCP  guideline  and  regulatory  requirements  and  is 
considered appropriate for this study. Any changes to the proposed consent form suggested 
by the investigator must be agreed to by Novartis before submission to the IRB/IEC, and a 
copy  of  the  approved  version  must  be  provided  to  the  Novartis  monitor  after  IRB/IEC 
approval. 
Women of child bearing potential should be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree 
that in order to participate in the study they must adhere to the contraception requirement 
for the duration of the study. If there is any question that the patient will not reliably comply, 
they should not be entered in the study. 


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10.3 
Responsibilities of the investigator and IRB/IEC 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly  constituted  Institutional  Review  Board/Independent  Ethics  Committee/Research 
Ethics Board (IRB/IEC) before study start. A signed and dated statement that the protocol 
and informed consent have been approved by the IRB/IEC must be given to Novartis before 
study initiation. Prior to study start, the investigator is required to sign a protocol signature 
page  confirming  his/her  agreement  to  conduct  the  study  in  accordance  with  these 
documents  and  all  of  the  instructions  and  procedures  found  in  this  protocol  and  to  give 
access  to  all  relevant  data  and  records  to  Novartis  monitors,  auditors,  Novartis  Clinical 
Quality Assurance representatives, designated agents of Novartis, IRBs/IECs, and regulatory 
authorities  as  required.  If  an  inspection  of  the  clinical  site  is  requested  by  a  regulatory 
authority,  the  investigator  must  inform  Novartis  immediately  that  this  request  has  been 
made. 
10.4 
Publication of study protocol and results 
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible  database  such  as  clinicaltrials.gov.  In  addition,  upon  study  completion  and 
finalization of the study report the results of this trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results. 
11 
Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
trial to request approval of a protocol deviation, as requests to approve deviations will not be 
granted. 
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants.  Under no circumstances should an investigator collect additional data 
or  conduct  any  additional  procedures  for  any  research  related  purpose  involving  any 
investigational drugs.  
If  the  investigator  feels  a  protocol  deviation  would  improve  the conduct  of  the  study  this 
must be considered a protocol amendment, and unless such an amendment is agreed upon 
by Novartis and approved by the IRB/IEC it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR. 


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11.1 
Protocol Amendments 
Any change or addition to the protocol can only be made in a written protocol amendment 
that  must  be  approved  by  Novartis,  Health  Authorities  where  required,  and  the  IRB/IEC. 
Only amendments that are required for patient safety may be implemented prior to IRB/IEC 
approval.  Notwithstanding  the  need  for  approval  of  formal  protocol  amendments,  the 
investigator is expected to take any immediate action required for the safety of any patient 
included in this study, even if this action represents a deviation from the protocol. In such 
cases, Novartis should be notified of this action and the IRB/IEC at the study site should be 
informed within 10 working days or less, if required by local regulations.  
12 
References 
1. Chronic Obstructive Pulmonary Disease (COPD).2008. Public Health Agency of Canada.18 
Feb. 2011 <http://www.phac.aspc.gc.ca/cd‐mc/crd‐mrc/copd‐mpoc‐eng.php>. 
 
2. Mittmann, N., L. Kuramoto, S.J. Seung, J.M. Haddon, C. Bradely‐Kennedy and J.M. 
FitzGerald. “The cost of moderate and severe COPD exacerbations to the Canadian 
healthcare system.” Respiratory Medicine. 2008; 102, 413‐421.    
 
3. Centre for Chronic Disease Prevention and Control, Public Health Agency of Canada, 
using data from Canadian Community Health Survey, Statistics Canada, 2009‐10. 
 
4. Health Indicators 2008. Canadian Institute of Health Information. Page 21. HYPERLINK 
"http://secure.cihi.ca/cihiweb/products/ 
Healthindicators2008_Engweb.pdf"http://secure.cihi.ca/cihiweb/products/ 
Healthindicators2008_Engweb.pdf 
 
5. COPD Facts and Figures. From Life and Breath: Respiratory Disease in Canada. Report of 
the Public Health Agency of Canada, 2007. 
 
6. Dala, Anand A., Laura Christensen, Fang Liu and Aylin A Riedel. “Direct costs of chronic 
obstructive disease among managed care patients.” International Journal of Chronic 
Obstructive Pulmonary Disease. 2010:5, 341‐349. 
 
7. Sharafkhaneh, Amir, Nancy J. Petersen, Hong‐Jen Yu, Anand A. Dalal, Michael L Johnson 
and Nicola A. Hanania. “Burden of COPD in a government health care system: a 
retrospective observational study using data from the US Veterans Affair population.” 
International Journal of COPD. 2010:5 125‐132. 
 


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8. Gold Executive Committee & Gold Science Committee. Global Strategy for the Diagnosis, 
Management, and Prevention of Chronic Obstructive Pulmonary Disease. Global Initiative 
for Chronic Obstructive Lung Disease, 2010. 
 
9. Gold Executive Committee. Pocket Guide to COPD Diagnosis, Management, and 
Prevention:  A Guide for Healthcare Professionals. Global Initiative for Chronic 
Obstructive Lung Disease, 2010. 
 
10. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for 
Diagnosis, Management and Prevention of COPD. Updated on December 2010. Available 
from http://www.goldcopd.com/Guidelineitem.asp?l1=2&l2=1&intId=989. Accessed on 
February 16, 2011. 
 
11. Bateman ED, Hurd SS, Barnes PJ et al. Global strategy for COPD management and 
prevention: GINA executive summary. Eur Respir J. 2008;31:143‐78. 
 
12. Medications for COPD.2010. Canadian Lung Association.24 Jan. 2011 
<http://www.lung.ca/diseases‐maladies/copd‐mpoc/treatment‐traitement/medications‐
medicaments_e.php>. 
 
13. Chen, Andrea M., Suzanne G. Bollmeier and Patrick M Finnegan. “Long‐Acting 
Bronchodilator Therapy for the Treatment of Chronic Obstructive Pulmonary Disease.” 
The annals of Pharmacotherapy. 2008; volume 42, 1832‐1842. 
 
14. Douglas,  Mapel W., Judith S Hurley, Anand A Dalal and Christopher M Blanchette. “The 
role of combination inhaled corticosteroid/long‐acting B‐agonist therapy in COPD 
management.” Primary Care Respiratory Journal. 2010; 19(2): 93‐103. 
 
15. Maper DW, Hurley JS, Dalal AA, Blanchette CM. The role of combination inhaled 
corticosteroid/long‐acting beta‐agonist therapy in COPD management. Prim Care Respir J 
2010;19:93‐103. 
 
16. Restrepo, Ruben D. “A Stepwise Approach to Management of Stable COPD With Inhaled 
Pharmacotherapy: A Review.” Respiratory Care. 2009; Vol. 54 No. 8, 1058‐1080. 
 
17. Niewoehner DE, Rice K, Cote C, et al. Prevention of exacerbations of chronic obstructive 
pulmonary disease with tiotropium, a once‐daily inhaled anticholinergic bronchodilator: a 
randomized trial. Ann Intern Med 2005;143:317‐26. 
 
18. Dahl R. et. Al. Efficacy of a new once‐daily long acting inhaled β2 agonist indacaterol verus 
twice daily formoterol in COPD. Thorax 2102; 65: 473‐479 


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19. Cope S., Kraemer M, Zhang J., Capkun‐Niggli G. and Jansen J. Efficacy of indacaterol 75 µg 
versus fixed‐dose combinations of formoterol‐budenoside or salmeterol fluticasone for 
COPD: a network meta‐analysis. International Journal of COPD 2012:7 415‐420. 
 
20. D'Urzo A, Ferguson GT, van Noord JA, Hirata K, Martin C, Horton R, Lu Y, Banerji D, 
Overend T. Efficacy and safety of once‐daily NVA237 in patients with moderate‐to‐severe 
COPD: the GLOW1 trial. Respiratory Research 2011, 12:156. 
 
21. Kerwin E, Hebert J, Gallagher N Martin C, Overend T, Alagappan VK, Lu Y, Banerji D. 
Efficacy and safety of NVA237 versus placebo and tiotropium in patients with COPD: the 
GLOW2 study. Eur Respir J 2012; 40 (5): 1106‐14.  
 
22. Beeh KM, Singh D, Di Scala L, Drollmann A. Once‐daily NVA237 improves exercise 
tolerance from the first dose in patients with COPD: the GLOW3 trial.Int J Chron Obstruct 
Pulmon Dis. 2012;7:503‐13 
 
23. Bateman ED, Ferguson GT, Barnes N, Gallagher N, Green Y, Henly M, Banerji D.Dual 
bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study.Eur 
Respir. J. 2013 May 30.  
 
24. Vogelmeier, CF, Bateman ED, Pallante J, Alagappan VKT, D<andrea P, Chen H, Banerji D. 
Efficacy and safety of once daily QVA149 compared with twice daily salmeterol‐fluticasone 
in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomized, 
double‐blind, parallel study. 
 
25. Cope S., Zhang J., Williams JP and Jansen J. Efficacy of once daily indacaterol 75 mcg 
relative to alternative bronchodilators in COPD: A study level and a patient level network 
meta‐analysis. BMC Pulmonary Medicine 2012, 12:29. 
 
26. Cope S., Zhang J., Capkun‐Niggli, G.,Gale R., Lassen C., Owen R., Ouwens M.J.N.M., 
Bergman G. and Jansen J. Efficacy of once daily indacaterol 75 mcg relative to alternative 
bronchodilators in COPD: A patient level mixed treatment comparison. Value in Health 15 
(2012) 524‐533. 
 
27. Mahler DA, D'Urzo A, Bateman ED, Ozkan SA, White T, Peckitt C, Lassen C, Kramer B; 
INTRUST‐1 and INTRUST‐2 study investigators. Concurrent use of indacaterol plus 
tiotropium in patients with COPD provides superior bronchodilation compared with 
tiotropium alone: a randomised, double‐blind comparison. Thorax. 2012 Sep; 67(9):781‐8. 
Epub 2012 Apr 27. 


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28. Renard D, Looby M, Kramer B, Lawrence D, Morris D, Stanski DR. Characterization of the 
bronchodilatory dose response to indacaterol in patients with chronic obstructive 
pulmonary disease using model‐based approaches. Respir Res. 2011 Apr 26;12:54. doi: 
10.1186/1465‐9921‐12‐54. 
 
29. Aaron S. et. Al. Tiotropium in Combination with Placebo, Salmeterol, or Fluticasone‐
Salmeterol for Treatment of Chronic Obstructive Pulmonary Disease. A randomized Trial. 
Annals of Internal Medicine 2007; 146:545‐555. 
 
30. Hanania NA, Crater GD, Morris AN, Emmett AH, O'Dell DM, Niewoehner DE. Benefits of 
adding fluticasone propionate/salmeterol to tiotropium in moderate to severe COPD. 
Respir Med. 2012 Jan;106(1):91‐101. doi: 10.1016/j.rmed.2011.09.002. Epub 2011 Oct 29. 
 
31. Cazzola M, Andò F, Santus P, Ruggeri P, Di Marco F, Sanduzzi A, D'Amato M. A pilot 
study to assess the effects of combining fluticasone propionate/salmeterol and tiotropium 
on the airflow obstruction of patients with severe‐to‐very severe COPD. Pulm Pharmacol 
Ther. 2007;20(5):556‐61. Epub 2006 Jul 7. 
 
32. Hoshino M, Ohtawa J. Effects of adding salmeterol/fluticasone propionate to tiotropium 
on airway dimensions in patients with chronic obstructive pulmonary disease. Respirology. 
2011 Jan;16(1):95‐101. doi: 10.1111/j.1440‐1843.2010.01869. 
 
 
 


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Appendix 1: COPT Assessment Test    
(Samples of questionnaires provided here are for illustrative purposes only) 
There are eight questions in the CAT. COPD patients should read the two statements for 
each item, and mark where on the scale (0-5) they fit. Scores for each of the 8 items are 
summed to give an overall score (out of 40). 
The CAT questionnaire:
 
 
 


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Appendix 2:  Baseline Dyspnea Index and Transition Dyspnea 
Index (BTI-TDI) 
(Samples of questionnaires provided here are for illustrative purposes only) 
 
 


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Appendix 3:  SF-36 version 2 questionnaire 
(Samples of questionnaires provided here are for illustrative purposes only) 
 
 
Your Health and Well-Being 
 
This survey asks for your views about your health.  This information will help keep track 
of how you feel and how well you are able to do your usual activities. Thank you for 
completing this survey! 
 
For each of the following questions, please mark an 
 in the one box that best 
describes your answer. 
 
1. 
In general, would you say your health is: 
Excellent 
Very good 
Good 
Fair 
Poor 





  
 1 
  
 2 
  
 3 
  
 4 
  
 5 
 
 
 
2. Compared to one year ago, how would you rate your health in general 
now? 
Much better 
now than one 
year ago 
Somewhat 
better 
now than one 
year ago 
About the 
same as 
one year ago 
Somewhat 
worse 
now than one 
year ago 
Much worse 
now than one 
year ago 





  
 1 
  
 2 
  
 3 
  
 4 
  
 5 
 


 
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3. The following questions are about activities you might do during a 
typical day.  Does your health now limit you in these activities?  If so, 
how much? 
 
 
 
Yes, 
limited 
a lot 
Yes, 
limited 
a little 
No, not 
limited 
at all 
 



 
a Vigorous activities, such as running, lifting  
heavy objects, participating in strenuous sports ...................... 
 1 ............. 
 2 ............. 
 3 
 
b Moderate activities, such as moving a table, pushing  
a vacuum cleaner, bowling, or playing golf ............................ 
1 ............. 
 2 ............. 
3
 
c Lifting or carrying groceries .................................................... 
 1 ............. 
 2 ............. 
 3 
 
d Climbing several flights of stairs ............................................. 
 1 ............. 
 2 ............. 
 3 
 
e Climbing one flight of stairs .................................................... 
 1 ............. 
 2 ............. 
 3 
 
f Bending, kneeling, or stooping ................................................ 
 1 ............. 
 2 ............. 
 3 
 
g Walking more than a kilometre ............................................... 
 1 ............. 
 2 ............. 
 3 
 
h Walking several hundred metres ............................................. 
 1 ............. 
 2 ............. 
 3 
 
i Walking one hundred metres ................................................... 
 1 ............. 
 2 ............. 
 3 
 
j Bathing or dressing yourself .................................................... 
 1 ............. 
 2 ............. 
 3 


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4. During the past 4 weeks, how much of the time have you had any of the 
following problems with your work or other regular daily activities as a 
result of your physical health? 
 
All of 
the time 
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
 




 
a Cut down on the amount of  
 
 time you spent on work or  
 
 other activities .................................. 
 1 ............. 
 2 .............. 
 3 .............. 
 4 ............. 
 5
 
b Accomplished less than you  
 
 would like ........................................ 
 1 ............. 
 2 .............. 
 3 .............. 
 4 ............. 
 5 
 
c Were limited in the kind of  
 
 work or other activities .................... 
 1 ............. 
 2 .............. 
 3 .............. 
 4 ............. 
 5
 
d Had difficulty performing the 
 
 work or other activities (for  
 
 example, it took extra effort) ........... 
 1 ............. 
 2 .............. 
 3 .............. 
 4 ............. 
 5 
 
 
5. During the past 4 weeks, how much of the time have you had any of the 
following problems with your work or other regular daily activities as a 
result of any emotional problems (such as feeling depressed or anxious)? 
 
All of 
the time 
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
 




 
a Cut down on the amount of  
 
 time you spent on work or  
 
 other activities .................................. 
 1 ............. 
 2 .............. 
 3 .............. 
 4 ............. 
 5
 
b Accomplished less than you  
 
 would like ........................................ 
 1 ............. 
 2 .............. 
 3 .............. 
 4 ............. 
 5 
 
c Did work or other activities 
 
 less carefully than usual ................... 
 1 ............. 
 2 .............. 
 3 .............. 
 4 ............. 
 5
 
 


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6. During the past 4 weeks, to what extent has your physical health or 
emotional problems interfered with your normal social activities with 
family, friends, neighbours, or groups? 
Not at all 
Slightly 
Moderately 
Quite a bit 
Extremely 





  
 1 
  
2
 
3
 
4
  
 5 
 
 
 
 
 
7. How much bodily pain have you had during the past 4 weeks? 
None 
Very mild 
Mild 
Moderate 
Severe 
Very severe 





  
 1 
  
 2 
 
3
 
4
 
5
  
 6 
 
 
 
 
 
8. During the past 4 weeks, how much did pain interfere with your normal 
work (including both work outside the home and housework)? 
Not at all 
A little bit 
Moderately 
Quite a bit 
Extremely 





  
 1 
  
2
 
3
 
4
  
 5 
 
 
 


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9. These questions are about how you feel and how things have been with 
you during the past 4 weeks.  For each question, please give the one 
answer that comes closest to the way you have been feeling.  How much 
of the time during the past 4 weeks… 
 
 
10. During the past 4 weeks, how much of the time has your physical health 
or emotional problems interfered with your social activities (like visiting 
with friends, relatives, etc.)? 
All of 
the time 
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 





  
 1
  
2
 
3
 
4
  
 5 
 
 
All of 
the time 
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
 





 
a Did you feel full of life? ................. 
 1 ............. 
 2 ............. 
 3 ............. 
 4 ............. 
 5 
 
b Have you been very nervous? ......... 
 1 .............. 
 2 ............. 
 3 .............. 
 4 ............. 
 5 
 
c Have you felt so down in the  
dumps that nothing could  
cheer you up? .................................. 
 1 ............. 
 2 ............. 
 3 ............. 
 4 ............. 
 5
 
d Have you felt calm and   
peaceful? ......................................... 
 1 .............. 
 2 ............. 
 3 .............. 
 4 ............. 
 5
 
e Did you have a lot of energy? ......... 
 1 ............. 
 2 ............. 
 3 ............. 
 4 ............. 
 5 
 
f Have you felt downhearted   
and depressed? ................................ 
 1 .............. 
 2 ............. 
 3 .............. 
 4 ............. 
 5
 
g Did you feel worn out? ................... 
 1 .............. 
 2 ............. 
 3 .............. 
 4 ............. 
 5 
 
h Have you been happy? .................... 
 1 .............. 
 2 ............. 
 3 .............. 
 4 ............. 
 5 
 
i Did you feel tired? .......................... 
 1 ............. 
 2 ............. 
 3 ............. 
 4 ............. 
 5 


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11. How TRUE or FALSE is each of the following statements for you? 
 
Definitely 
true 
Mostly 
true 
Don’t 
know 
Mostly 
false 
Definitely
false 




 
a I seem to get sick a little 
easier than other people .................. 
 1 ............. 
 2 ............. 
 3 ............... 
 4 .............. 
 5
 
b I am as healthy as  
anybody I know .............................. 
 1 ............. 
 2 ............. 
 3 ............... 
 4 .............. 
 5
 
c I expect my health to  
get worse ......................................... 
 1 ............. 
 2 ............. 
 3 ............... 
 4 .............. 
 5 
 
d My health is excellent ..................... 
 1 ............. 
 2 ............. 
 3 ............... 
 4 .............. 
 5


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Appendix 4: EQ-5D Questionnaire 
 
By placing a check-mark in one box in each group below, please indicate which statements 
best describe your own state of health today. 
 
 
Mobility 
I have no problems in walking about 
 
 
I have some problems in walking about  
 
I am confined to bed 
 
 
 
Self-Care 
I have no problems with self-care 
 
 
I have some problems washing or dressing myself 
 
 
I am unable to wash or dress myself 
 
 
 
Usual Activities (e.g. work, study, housework, family or 
leisure activities) 
I have no problems with performing my usual activities 
 
 
I have some problems with performing my usual activities 
 
 
I am unable to perform my usual activities 
 
 
 
Pain/Discomfort 
I have no pain or discomfort 
 
 
I have moderate pain or discomfort 
 
 
I have extreme pain or discomfort 
 
 
 
Anxiety/Depression 
I am not anxious or depressed  
 
I am moderately anxious or depressed  
 
I am extremely anxious or depressed 
 
 


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 To help people say how good or bad their state of health is, we 
have drawn a scale (rather like a thermometer) on which the 
best state you can imagine is marked 100 and the worst state 
you can imagine is marked 0. 
 
We would like you to indicate on this scale how good or bad 
your own health is today, in your opinion. Please do this by 
drawing a line from the box below to whichever point on the 
scale indicates how good or bad your state of health is today. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
9 0
8 0
7 0
6 0
5 0
4 0
3 0
2 0
1 0
100
Worst 
imaginable 
state of health
0
Best  
imaginable 
state of health
Your own 
state of health 
today 

SAP_001.pdf: 
Clinical Development 
CQVA149A 
CQVA149ACA01 / NCT02202616
POWER: Prospective Cohort Study for the Real – Life Effectiveness 
Evaluation of GlycOpyrronium With IndacatERol combination in the 
management of COPD in Canada 
RAP Module 3 – Detailed Statistical Methodology 
Author: 
 
Document type: 
RAP Documentation 
Document status: 
Amendment 1  
Release date: 
14-Sep-17
Number of pages: 
21 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Document History – Changes compared to previous version of RAP module 3 
Not applicable. 


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Table of contents 
Document History – Changes compared to previous version of RAP module 3 ....................... 2 
1 
Introduction ......................................................................................................................... 5 
1.1 
Analysis sets ............................................................................................................ 5 
1.2 
Patient disposition, background and demographic characteristics .......................... 5 
1.2.1 
Patient disposition ................................................................................... 5 
1.2.2 
Protocol deviations .................................................................................. 6 
1.2.3 
Background and demographic characteristics ......................................... 6 
1.2.4 
Medical history and current medical condition ....................................... 7 
1.3 
Study medication ..................................................................................................... 7 
1.3.1 
Study drug administration ....................................................................... 7 
1.3.2 
Compliance ............................................................................................. 7 
1.4 
Prior and concomitant medication ........................................................................... 8 
1.5 
Efficacy evaluation .................................................................................................. 8 
1.5.1 
Primary variable ...................................................................................... 8 
1.5.1.1 
Statistical model, hypothesis and method of analysis ............................. 8 
1.5.1.2 
Handling of missing values/censoring/discontinuations ......................... 9 
1.5.2 
Analysis of secondary variable ............................................................... 9 
1.5.2.1 
Change from baseline in pre-dose trough FEV1 (L) to Week 4 .............. 9 
1.5.2.2 
Change from baseline in COPD Assessment Test (CAT) score to Week 
4 and Week 16 .............................................................................................................. 10 
1.5.2.3 
Baseline Dyspnea Index –Transitional Dyspnea Index (BDI‐TDI) at 
baseline, 4 and 16 ......................................................................................................... 10 
1.5.3 
Analysis of exploratory variables .......................................................... 10 
1.5.3.1 
Change from baseline in the Medical Outcomes Study Short Form 36 
(SF‐36) to Week 16 ...................................................................................................... 11 
1.5.3.2 
Change from baseline in the Dimension Health Status Questionnaire 
(EQ‐5D) to Week 4 and Week 16 ................................................................................ 11 
1.5.3.3 
Patient and Physician Global Satisfaction with COPD Treatment 
between at 4, 12 and 16 weeks of treatment ................................................................. 11 
1.6 
Pharmacokinetic evaluations (change / add PD, PK/PD, Biomarkers, as 
needed) ................................................................................................................... 11 
1.7 
Safety evaluation ................................................................................................... 11 
1.7.1 
Adverse events (AE) ............................................................................. 12 
1.7.1.1 
Common Adverse events ...................................................................... 12 
1.7.1.2 
Serious adverse events (SAE) ............................................................... 13 
1.7.1.3 
Adverse events of special interest ......................................................... 13 
1.7.2 
Deaths .................................................................................................... 13 
1.8 
Interim analyses ..................................................................................................... 14 


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1.9 
Other topics ............................................................................................................ 14 
1.10 
Determination of sample size ................................................................................ 14 
1.11 
Changes in the conduct of the study ...................................................................... 15 
  Appendix 16.1.9  Documentation of statistical methods ................................................. 16 
16.1.9.1 
Major protocol deviations and other exclusion criteria ......................... 16 
16.1.9.2 
Patient classification .............................................................................. 18 
16.1.9.3 
Assessment windows, baseline and post-baseline definitions, missing 
data handling 18 
16.1.9.4 
Statistical methodology and assumptions ............................................. 20 


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Statistical methods planned in the protocol and determination of sample size 
1 Introduction 
This document contains details of the statistical methods which will be used in the phase IV 
clinical trial CQVA149ACA01. This is a single cohort interventional study which is designed 
to evaluate the effectiveness of QVA149 (indacaterol 110 mcg / glycopyrronium 50 mcg) on 
pre-dose trough FEV1, COPD symptoms and quality of life in COPD patients with moderate to 
severe airflow limitation, managed under a routine clinical care setting (i.e., treatment with 
either tiotropium or, fixed dose combination of fluticasone propionate/salmeterol) in Canada.  
Data will be analyzed by statistical software SAS version 9.4 according to the data analysis 
section 9 of the study protocol which is available in Appendix 16.1.1 of the CSR.  Important 
information is given in the following sections and details are provided, as applicable, in 
Appendix 16.1.9 of the CSR. 
Statistical and analytical plans 
Patients and treatments 
1.1 
Analysis sets 
Intent to Treat (ITT) set will include all patients who received the study treatment and 
returned for at least one post-treatment follow-up visit. The ITT set will be used for summaries 
of patient disposition, analysis sets, listings of major protocol deviations, premature study 
discontinuations, demographic and baseline characteristics and all efficacy analyses including 
the primary analysis.  
Modified intent to treat (mITT) set will include all patients from the ITT set except those 
who had the percent predicted FEV1 value greater than 80% (severity of mild COPD, GOLD 
guidelines 2017) at screening.  
Safety set (SAF) will include all patients who received at least one dose of the study treatment. 
The SAF will be used for all safety analyses and demographic characteristics.   
Per protocol set (PPS) will include all patients without any major deviations from the protocol, 
i.e., who have fulfilled all the study inclusion and exclusion criteria and undergone all study 
visits and assessments as per the schedule mentioned in the protocol. The major protocol 
deviations will be defined prior to database lock. The list of major protocol deviations is 
available in Appendix 16.1.9. The PPS will be used to assess the robustness of the results drawn 
for the primary and key secondary analysis using the ITT set.  
1.2 
Patient disposition, background and demographic characteristics 
1.2.1 
Patient disposition 
The SAF set will be used for the summary and listing of patient disposition. 


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The number and percentage of patients screened, included in the SAF set, included in the ITT 
set, attended each visit, completed and discontinued the study will be summarized. Number and 
percentage of patients in the ITT set will be summarized by center. 
The reasons for premature discontinuation will also be summarized for patients who were 
discontinued from the study. Patient identification number and whether they completed or 
discontinued from the study (and/or treatment) will be listed, with date of last dose and primary 
reason for premature discontinuation.  
1.2.2 
Protocol deviations 
The number and percentage of patients with protocol deviations will be tabulated by category 
and deviation for the ITT set. Protocol deviations will be listed with date and study day of 
occurrence, deviation code and severity for the ITT set. 
The number of patients included in each analysis set will be tabulated for all screened patients. 
Reasons for exclusion from analysis sets will be tabulated for all screened subjects. Subject 
exclusion from analysis sets will be listed for all patients with reasons of exclusion (i.e., both 
protocol and non-protocol deviation). 
1.2.3 
Background and demographic characteristics 
Demographics and baseline characteristics will be summarized using the SAF and ITT sets. 
The following demographic variables collected in the CRF at screening (Visit 1) will be 
summarized: 
 age (in years) 
 gender (Male or Female) 
 predominant race (Caucasian, Black, Asian, Native American, Pacific Islander, Other) 
 height (cm) 
 weight (kg) 
 body mass index (BMI) (kg/m2) 
 
The following baseline disease characteristics collected at screening (Visit 1) will be 
summarized: 
 treatment regimen (tiotropium or FDC – fluticasone propionate/salmeterol) 
 smoking history (never smoked, current smoker, ex-smoker) 
 number of pack-years 
 alcohol consumption history  
– number of alcoholic beverages per day 
 duration of COPD (years), experience of moderate and/or severe COPD exacerbations 
in the 12 months/6 months prior to study initiation 
 use of rescue medication at baseline, type and frequency of rescue medication 
 CAT score  
 vital signs (sitting systolic/diastolic blood pressure (mmHg), sitting pulse rate (bpm))  


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In addition, the following categorizations will be done: 
 Age into 40 - 64 years, 65 - 74 years, and ≥ 75 years; 
 BMI into ≤ 30.0 kg/m2 and > 30.0 kg/m2; 
 Duration of COPD into < 1 year, 1 - 5 years, > 5 - 10 years, > 10 - 15 years, > 15 – 20       
years, and > 20 years; 
 CAT scores into 0 - 10, 11 - 20, 21 - 30 and 31 - 40 representing mild, moderate, severe 
or, very severe clinical impact of COPD on patients. 
 
Baseline and demographic variables: continuous variables will be summarized using descriptive 
statistics (mean, median, standard deviation, 95% confidence intervals (95% CI), minimum and 
maximum) and categorical variables will be summarized in terms of the number and percentage 
of patients in each category. 
Details regarding the definition of baseline measurements are given in Appendix 16.1.9. 
1.2.4 
Medical history and current medical condition 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
terminology (MedDRA version 17.1 or later). History/conditions will be summarized for the 
SAF and ITT sets by primary system organ class and preferred term, and overall. Verbatim 
recorded history/conditions will be listed together with the coded terms, date of 
diagnosis/surgery and whether the problem was ongoing at start of the study. 
1.3 
Study medication 
1.3.1 
Study drug administration 
Duration of exposure to the treatment will be calculated as the number of days between the first 
dose date and the last dose date exposed to that treatment over the specified period (expressed 
as: Duration of exposure = Date of last known dose of study drug – Date of first dose of study 
drug + 1). 
The duration of exposure (in days) will be summarized for the SAF and ITT sets as  
 a continuous variable with the standard descriptive statistics, and  
 a categorical variable classified into ≤ 4 weeks, > 4 – 8 weeks, > 8 - 12 weeks, > 12 
- 16 weeks and > 16 weeks, with number and percentage of patients in each category. 
1.3.2 
Compliance 
As per the protocol, QVA149 inhalation powder hard capsules 110 mcg/50mcg per capsule with 
ULTIBRO® BREEZHALER® are to be prescribed to each patient once daily.  
Compliance with treatment will be defined as the percentage of doses taken by the patient and 
will be calculated as follows:  


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Step 1: to calculate the duration (in days) for each patient in the study (treatment end date – 
treatment start date +1). The prescribed dose is to be taken once daily. So the number of dose 
prescribed is equal to the duration of exposure in days.  
Step 2: Number of capsule consumed = Capsules dispensed – Capsule returned. (based on the 
data entered in the CRF) 
Step 3: Compliance (%) = (Number of doses consumed/Number of doses prescribed) X 100%. 
Compliance will be summarized by visit for the ITT set as 
 a continuous variable with the standard descriptive statistics, and  
 a categorical variable classified into < 80%, ≥ 80% to < 100%, ≥ 100 to < 120%, ≥ 
120%, with number and percentage of patients in each category. 
1.4 
Prior and concomitant medication 
COPD-related (COPD or COPD exacerbation) medications, including rescue medications, 
will be coded using the WHO Dictionary and summarized by the respective ATC level I and 
IV terms. 
Non COPD related medications will be summarized in the same way as COPD-related 
medications.  
Both COPD-related and non COPD-related medications will be summarized separately for prior 
and concomitant medications. 
All summaries will be on the SAF and ITT sets. 
1.5 
Efficacy evaluation 
All effectiveness analysis will be performed on the ITT set and selected analyses will be 
repeated on the PPS. 
1.5.1 
Primary variable  
The primary variable is pre-dose trough FEV1 (L). 
The primary effectiveness variable is the absolute change in trough FEV1 from baseline (Visit 
1) to the Week 16 visit. 
1.5.1.1 
Statistical model, hypothesis and method of analysis  
The primary objective of the study is to evaluate the effectiveness of treatment with QVA149 
(110/50) in the management of patients with moderate to severe COPD. The effectiveness will 
be assessed by change from baseline in pre-dose trough FEV1 (L) to Week 16. Baseline pre-
dose trough FEV1 (L) is the assessment taken prior to the start of QVA 149, which is typically 
the value at Visit 2. If the trough FEV1 (L) value at Visit 2 is missing, then the baseline value 
will be set to missing. The primary analysis will include patients with a valid observation at 
baseline and Week 16.    


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The mean change from baseline in pre-dose trough FEV1 (L) will be summarized using standard 
descriptive statistics and estimated along with the 95% confidence interval, which will be used 
to assess the precision of the estimate and to make inferences to the target population.  
The above analysis will be repeated separately for the two subgroups of patients based on the 
prior COPD treatment (i.e., Tiotropium or FDC – fluticasone/salmeterol). 
In addition, between subgroup comparison (Tio – Flu/Sal) for change from baseline in pre-dose 
trough FEV1 (L) to Week 16, will be performed using a Student’s t-test for independent 
samples. 
All the analyses mentioned in this section will be repeated for the PPS, to support the results 
obtained using the ITT set. 
As a sensitivity analysis, the primary analysis will also be repeated on the mITT set. 
1.5.1.2 
Handling of missing values/censoring/discontinuations 
There will be no imputation for missing data at Week 16, and the primary analysis will be based 
on only observed data.  
1.5.1.3 
Subgroup analysis 
The primary variable, change from baseline in pre-dose trough FEV1 (L) to Week 16 will also 
be summarized for the subgroups of interest defined below. The mean change from baseline in 
pre-dose trough FEV1 (L) will be summarized by subgroups using standard descriptive statistics 
and estimated along with the 95% confidence interval. 
 gender (male/female) 
 age (≤ 65 years, > 65 years) 
 smoking status (never smoked, current smoker, ex-smoker) 
 severity of airflow limitation (GOLD guidelines 2017) as  
 GOLD 1: Mild (FEV1 ≥ 80% predicted),  
 GOLD 2: Moderate (50% ≤ FEV1 < 80% predicted),  
 GOLD 3 and GOLD 4 : Severe and Very severe (FEV1< 50% predicted) 
 exacerbation history in the previous year ( 0 exacerbation/1 exacerbation) 
 treatment regimen (tiotropium or FDC – fluticasone propionate/salmeterol) 
1.5.2 
Analysis of secondary variable 
All endpoints mentioned below will be listed. These analysis will be performed on the ITT set. 
1.5.2.1 
Change from baseline in pre-dose trough FEV1 (L) to Week 4 
The change from baseline in pre-dose trough FEV1 (L) to Week 4 will be analyzed in a similar 
manner as the primary variable, i.e.  
 The mean change from baseline in pre-dose trough FEV1 to Week 4 will be summarized 
using standard descriptive statistics and estimated along with the 95% confidence interval.  


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 The above analysis will be repeated separately for the two subgroups of patients based on 
the prior COPD treatment (i.e., Tio or, Flu/Sal). 
 In addition, between subgroup comparison (Tio – Flu/Sal) for change from baseline in 
pre-dose trough FEV1 (L) to Week 4, will be performed using a Student’s t-test for 
independent samples. 
1.5.2.2 
Change from baseline in COPD Assessment Test (CAT) score to Week 
4 and Week 16 
The change from baseline in CAT score to Week 4 and Week 16 will be analyzed similar to the 
primary variable. Baseline is the CAT score obtained prior to the start of QVA 149, which is 
typically the score at Visit 2. If the score at Visit 2 is missing, then the baseline value will be 
set to missing. This analysis will include patients with a valid CAT score at baseline and Week 
4 and/or Week 16.    
 The mean change from baseline to Week 4 and Week16 will be summarized using 
standard descriptive statistics and estimated along with the 95% confidence interval.  
 This analysis will be repeated separately for the two subgroups of patients based on the 
prior COPD treatment (i.e., Tio or, Flu/Sal). 
 In addition, between subgroup comparison (Tio – Flu/Sal) for change from baseline in 
CAT score to Week 4 and Week 16 will be performed separately using a Student’s t-
test for independent samples.  
1.5.2.3 
Baseline Dyspnea Index –Transitional Dyspnea Index (BDI‐TDI) at 
baseline, 4 and 16 
Dyspnea is measured at baseline Visit 2 using the baseline dyspnea index (BDI) and at Week 4 
and Week 16 using the transition dyspnea index (TDI), which captures changes from baseline. 
The BDI grades and TDI scores at Week 4 and Week 16 will be summarized using number and 
percentages and standard descriptive statistics, respectively. The TDI scores at Week 4 and 
Week 16 will be analyzed similar to the primary variable. 
 The estimated mean change from baseline and corresponding 95% confidence intervals 
will be displayed for each visit.  
 This analysis will be repeated separately for the two subgroups of patients based on the 
prior COPD treatment (i.e., Tio or, Flu/Sal). 
 In addition, between subgroup comparison (Tio – Flu/Sal) of TDI scores to Week 4 and 
Week 16 will be performed separately using a Student’s t-test for independent samples. 
1.5.3 
Analysis of exploratory variables 
All endpoints mentioned below will be listed. These analysis will be performed on the ITT set. 


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1.5.3.1 
Change from baseline in the Medical Outcomes Study Short Form 36 
(SF‐36) to Week 16 
Change from baseline in the SF-36 (overall and physical heath only) to Week 16 will be 
summarized using standard descriptive statistics and analyzed using the same analysis used for 
the primary variable. 
 The mean change from baseline to Week16 will be estimated along with the 95% 
confidence interval.  
 This analysis will be repeated separately for the two subgroups of patients based on the 
prior COPD treatment. 
 In addition, between subgroup comparison of this change to Week 4 and Week 16 will 
be performed separately using a Student’s t-test for independent samples.  
1.5.3.2 
Change from baseline in the Dimension Health Status Questionnaire 
(EQ‐5D) to Week 4 and Week 16 
Change from baseline in the EQ-5D summary score using the UK weights to Week 4 and Week 
16 will be summarized using standard descriptive statistics and analyzed using the same 
analysis used for the primary variable. 
 The mean change from baseline to Week 16 will be estimated along with the 95% 
confidence interval.  
 This analysis will be repeated separately for the two subgroups of patients based on the 
prior COPD treatment. 
 In addition, between subgroup comparison of this change to Week 4 and Week 16 will 
be performed separately using a Student’s t-test for independent samples.  
1.5.3.3 
Patient and Physician Global Satisfaction with COPD Treatment 
between at 4, 12 and 16 weeks of treatment 
 The patient’s and physician’s global satisfaction responses with QVA149 at Weeks 4, 
12 and 16 will be summarized with absolute and percentage of patients in each of the 
response categories specified in the study CRF (i.e., Very dissatisfied, Dissatisfied, 
Neither satisfied or dissatisfied, Satisfied and Very satisfied).  
 Further to assess the dependency of the global satisfaction level on prior COPD 
treatment, the McNemar’s test will be performed. 
1.6 
Pharmacokinetic evaluations (change / add PD, PK/PD, 
Biomarkers, as needed) 
Not applicable. 
1.7 
Safety evaluation 
All safety evaluations will be based on the safety set. 


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1.7.1 
Adverse events (AE) 
All adverse events (including COPD exacerbations) will be coded with MedDRA version 17.1 
(or later) and listed. Adverse events starting on or after the time of the first inhalation of study 
drug but not later than 7 days (30 days in the case of a SAE) after the date of last dose of study 
drug taken will be classified as a treatment emergent adverse event and will be included in all 
summaries.  
1.7.1.1 
Common Adverse events 
AEs by primary system organ class and preferred term 
The number and percentage of patients who reported treatment emergent adverse events will be 
summarized by primary system organ class and preferred term. Primary system organ classes 
will be sorted alphabetically and, within each primary system organ class, the preferred terms 
will be sorted in descending order of frequency.  
If a patient reported more than one adverse event with the same preferred term, the adverse 
event will be counted only once. If a patient reported more than one adverse event within the 
same primary system organ class, the patient will be counted only once at the system organ 
class level.  
AEs by severity 
All treatment emergent adverse events will also be summarized by maximum severity, primary 
system organ class and preferred term. If a patient reports more than one adverse event within 
the same primary system organ class, only one adverse event will be counted for that patient at 
the highest severity level in the total row for each primary system organ class. If a patient 
reported more than one adverse event with the same preferred term, the highest (maximum) 
severity will be presented. Missing severity will be assumed to be severe in the summary table. 
AEs suspected to be related to study drug 
The treatment emergent adverse events suspected to be related to study drug (according to the 
investigators) will be summarized by primary system organ class and preferred term. 
Relationship to study drug is considered as suspected for those events where "Relationship to 
study drug" is answered by the investigator as "Suspected". 
AEs leading to permanent study drug discontinuation 
Treatment emergent adverse events leading to permanent study drug discontinuation, regardless 
of study drug relationship, will be summarized by primary system organ class and preferred 
term. 
AEs requiring dose adjustment or interruption 
Treatment emergent adverse events requiring dose adjustment or temporary interruption, 
regardless of study drug relationship, will be summarized by primary system organ class and 
preferred term. 


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AEs requiring significant additional medication or therapy 
Treatment emergent adverse events requiring significant additional therapy (concomitant 
medication, non- drug therapy), regardless of study drug relationship, will be summarized by 
primary system organ class and preferred term. 
 
AEs requiring hospitalization or prolonged hospitalization 
Treatment emergent adverse events requiring hospitalization or prolonged hospitalization will 
be summarized by primary system organ class and preferred term. The number and percentages 
of the most frequent treatment emergent AEs will be summarized separately by primary system 
organ class and preferred term. 
 
1.7.1.2 
Serious adverse events (SAE) 
Number and percentage of patients with treatment emergent serious adverse events, regardless 
of study drug relationship, will be presented by primary system organ class and preferred term. 
Additionally separate tables will be provided for SAEs occurring more than 30 days after the 
last dose administration for patients who discontinued the study treatment but remained in the 
study for more than 30 days and for SAEs which happened between Visit 1 (screening) and the 
time of first dose for all patients in the safety set. 
1.7.1.3 
Adverse events of special interest 
Number and percentage of patients with the following adverse events of special interest will be 
identified from the aforementioned summary tables:  
 Atrial fibrillation  
 Cardiac arrhythmias (Brady-Tachy arrhythmias) 
 Cardiac Failure 
 Cerebrovascular events 
 Hyperglycemia 
 Intubation, hospitalization and death due to asthma related events in asthma (off label use) 
 Ischemic Heart disease 
 Myocardial Infarction 
 Narrow-angle glaucoma 
 QTc prolongation 
These events will be determined by pre-defined MedDRA version 17.1 search terms.  
1.7.2 
Deaths 
All the deaths in the clinical database will be listed with the investigator-reported principal 
cause. Deaths occurring after the first dose of study treatment until 30 days after the date of last 
treatment will be summarized with numbers and percentages by visits.  


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1.8 
Interim analyses 
An interim analysis will be performed when 300 patients will have completed their Visit 3. 
1.9 
Other topics  
No other topics were studied. 
1.10 
Determination of sample size 
The primary effectiveness outcome measure of the study will be the change from baseline to 16 
weeks in trough FEV1 measurements in patients treated with QVA149. Therefore, the study 
must have sufficient sample size to produce a precise estimate of these changes in FEV1. 
Precision is assessed by the width of the 95% confidence interval. 
In the SPARK study the mean difference between QVA149 (indacaterol 110 mcg + 
glycopyrronium) and tiotropium with respect to trough FEV1 was between 0.060 L – 0.080 L 
during 64 weeks of treatment. In the SHINE study the difference between tiotropium and 
QVA149 at 26 weeks was 0.08 L. In the ILLUMINATE study the difference between QVA149 
and fixed dose combination LABA/ICS with respect to FEV1 at 12 weeks was 0.092 L. Using 
the 95% CI and SEM estimates from these studies the calculated SD for the change in FEV1 at 
16 weeks is approximately 0.220 L. 
Sample size calculations for the current study are based on the primary objective which is to 
describe the change in FEV1 at 16 weeks after the initiation of treatment on indacaterol + 
glycopyrronium. The precision of the estimated mean change in FEV1 at 16 weeks, as assessed 
by the 95% confidence interval, is the parameter driving the sample size. 
For the current study we can assume a mean change in FEV1 at 16 weeks of 0.080 L for the 
patients previously treated with tiotropium monotherapy and approximately 0.092 L for the 
patients previously treated fixed dose combination with LABA / ICS.  
The sample size requirements of the study have been determined on the basis of the above 
parameters and in order to achieve a 95% confidence interval of the mean change in FEV1 at 
16 weeks with a width (ω/2) of ± 30% of the point estimate. This value is comparable with the 
results reported in the above clinical trials and provides reasonable precision of the estimated 
FEV1 change at 16 weeks. Assuming a 0.080 L mean change in FEV1 for the patients 
previously treated with tiotropium the 95% confidence interval for this cohort will be between 
0.056 L – 0.104 L; for the patients previously treated with fixed dose combination LABA/ICS 
assuming a mean change in FEV1 of 0.092 L the 95% confidence interval will be between 0.064 
L and 0.120 L. For purposes of sample size calculations, for both cohorts the SD of the mean 
change in FEV1 between baseline and 16 weeks will be assumed to be 0.220 L. 
Based on the above criteria and assumptions, for the cohort of patients previously treated with 
tiotropium the sample size requirement is 323 patients. For the patients previously treated with 
fixed dose combination LABA/ICS the sample size requirement is 245 patients. The total 
sample size of the study will be 568. Assuming a 20% attrition rate, the total number of patients 
recruited will be 710 (404 previously treated with tiotropium and 306 previously treated with 
fixed dose combination LABA/ICS). 


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Patient enrolment will be designed to enroll at a 3:2 ratio of patients previously treated with 
tiotropium to those previously treated with fixed dose combination LABA/ICS per individual 
site and at the study level. Once study‐wise recruitment has been completed for one of the 
strata, the each site will be instructed to pursue recruitment onto the other stratum only. 
1.11 
Changes in the conduct of the study or planned analysis 
 The mITT set is introduced in the analysis plan in addition to protocol defined analysis 
set based on the discussion with Clinical Trial Team. This set is identical to ITT set 
except it excludes patients who had a percent predicted FEV1 value of greater than or 
equal to 80% at screening.  
The primary analysis involving the ITT set will be include all patients. As a sensitivity 
analysis the primary analysis will also be repeated on the mITT set. 
 Based on the strong positive results for primary and secondary objectives observed in 
the planned interim analysis, the study team in consultation with respective medical and 
statistical experts confirmed that there were no anticipated additional statistical benefits 
in reaching the initially planned sample size of 710 enrolled subjects (assuming 20% 
attrition rate, whereas the actual attrition rate observed in the study was much less than 
20%).  
After conducting proper scientific and methodological due diligences, the recruitment 
was closed on the 31st of January 2017. As a result of this decision, the sample size in 
the final CSR analysis is reduced to 401. 
      


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Appendix 16.1.9 Documentation of statistical methods 
This appendix gives details about statistical methods in addition to the report text. All analyses 
will be performed by using SAS version 9.4 (or higher). 
16.1.9.1 Protocol deviations and other exclusion criteria 
Deviation 
code 
Text description 
Severity codes 
Exclude from 
analysis set 
Additional notes 
I01A 
No diagnosis of COPD 
according to GOLD 
guidelines 
1 
Exclude from PPS 
  
I01B 
No diagnosis of COPD 
according to GOLD 
guidelines 
1 
 Exclude from PPS 
Exclude from mITT 
I04 
Smoking History of < or = 
10 pack years 
1 
 Exclude from PPS 
  
C03 
Compliance with 
treatment < 80% or > 
120%  during any 
treatment/dispensing 
period 
49 
Include in all 
analysis 
  
I06 
Treatment with QVA149 
is indicated not as per 
product monograph or 
inappropriate for the 
patient  
1 
 Exclude from PPS 
  
I07 
Signed informed consent 
not obtained 
8 
Exclude from all 
analysis 
  
C09 
Prohibited Medication 
taken 
1 Exclude from PPS 
  
E04 
Patient had > or = 2 
moderate to severe 
exacerbations in past 
year 
1 Exclude from PPS 
  
I03 
Age < or = 40 years 
1 
 Exclude from PPS 
  
E06 
Patient requires ICS 
treatment with QVA149 
1 Exclude from PPS 
  
E07 
Patient with chronic 
respiratory conditions 
excluding lung cancer 
1 Exclude from PPS 
  
I05 
No persistent symptom as 
CAT score < or = 10 
1 
Exclude from PPS 
Exclude from mITT 
E08 
Patient has cancer or 
other conditions 
1 Exclude from PPS 
  
E09 
Patients participating in 
an investigational drug 
trial. 
1 Exclude from PPS 
  


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E10 
Hypersentivity to 
indacaterol maleate, 
glycopyrronium 
bromide or similar 
component or excipient 
1 Exclude from PPS 
  
E11 
Use of other 
investigational drugs 
within 30 days of 
enrollment 
1 Exclude from PPS 
  
E02 
Patient on triple therapy 
for COPD 
1 Exclude from PPS 
  
E13 
Patient pregnant or 
nursing anytime during 
the study 
1 Exclude from PPS 
  
E14 
Effective contraceptive 
methods not followed by 
WCBP 
1 Exclude from PPS 
  
E03 
Patient has asthma or a 
history of asthma 
1 Exclude from PPS 
  
E05 
Patient had > or = 1 
exacerbations in past 6 
weeks 
1 Exclude from PPS 
  
S13 
Patient took study drug 
not as per protocol 
49 
Include in all 
analysis 
  
E072 
Medical History- Lung 
Cancer 
1 Exclude from PPS 
  
C07 
Other GCP deviation  
49 
Include in all 
analysis 
  
C08 
Major GCP deviation  
1 Exclude from PPS 
  
C01 
Treatment interruption 
instructions not followed 
49 
Include in all 
analysis 
  
S06 
Time of study drug is 
before pre-dose FEV1 at 
BL  
0 
Exclude from all 
efficacy analysis 
(ITT, mITT and PPS) 
Exclude from mITT 
S07 
Spirometry date is same 
as the Last study 
treatment date, and 
Dosing time is prior to the 
Spirometry time.  
0 
Exclude from all 
efficacy analysis 
(ITT, mITT and PPS) 
Exclude from mITT 
C05 
Patient was administerd 
screening TDI 
questionnaire by 
unqualified study 
personnel.  
 
1 Exclude from PPS 
 
 


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16.1.9.2  Patient classification 
Protocol deviations severity codes defined in VAP Module 3 leading to patient classification 
into the analysis sets are as follows: 
 
Severity codes 
Actions 
0 
Exclude from all efficacy analyses (ITT set, PPS) 
1 
Exclude from Per-Protocol analysis only (PPS) 
5* 
Exclude from all safety analyses (SAF) 
8 
Exclude from all analyses (ITT set, PPS, SAF) 
9 
Included in all efficacy analyses 
49 
Report relevant PD, include in all analyses 
Patient classification based on severity codes 
Analysis set 
PD severity codes that cause a 
subject to be excluded 
Criteria that cause a subject to be excluded 
ITT 
0, (5*), 8 
Enrolled but no study drug received. Not having 
a follow-up assessment. 
Safety 
5, 8 
Enrolled but no study drug received 
Per Protocol 
0, 1, (5*), 8 
 
 
* Note: given that the PPS is nested within the ITT set, which is itself nested within the SAF, 
severity code 5 implies exclusion from all three of these analysis sets (i.e. SAF, ITT and PPS). 
Unless otherwise stated, summary tables, figures and listings will be on all subjects included in 
the analysis set under consideration. 
16.1.9.3 Assessment windows, baseline and post-baseline definitions, missing 
data handling 
Data pooling and assessment windows 
Data from unplanned or unscheduled visits or the early treatment/study discontinuation visits 
will be listed. For subjects who do not complete the study, the treatment discontinuation visit 
will be an unscheduled visit.  
All efficacy data from unscheduled or premature discontinuation visits will not be used for 
missing data imputation. 
For values with missing date/time, scheduled visit date and time will be used. This rule will be 
applied to data from scheduled visits only. 
Study day 
Study day is defined as the number of days since the date of first dose of study medication 
(QVA149 110/50). The date of first dose of study medication is defined as Day 1 and the day 
before the first dose of study medication is defined as Day -1. 


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Therefore, for a particular date, study day will be calculated as follows: 
 
for dates on or after the first date of study medication, 
Study day = Assessment date – Date of first dose of study medication + 1; 
 
for dates prior to the first date of study medication, 
Study day = Assessment date – Date of first dose of study medication. 
Baseline measurements 
In general, baseline is defined as the last measurement before the first dose of study drug at 
Visit 2 or Day 1. 
Baseline pre-dose trough FEV1 (L) is defined as the value taken prior to the first dose of study 
drug (QVA 110/50) typically on Day 1 i.e., Visit 2. If FEV1 value on Visit 2 is missing, then 
baseline will be set to missing.  
Baseline dyspnea scale (BDI), baseline CAT, SF-36 and EQ-5D scores are the values obtained 
prior to the first dose of study treatment on Day 1 i.e. Visit 2. 
Post-baseline assessments 
Post-baseline values are defined as assessment taken after first dose of study treatment.  
For efficacy, pre-dose trough FEV1 (L), TDI, CAT, SF-36 and EQ-5D assessments taken at any 
of the post-baseline visits will be considered for the analysis. Missing values will not be 
imputed. Post-baseline study visits are Visit 3, 4 and 5 (End of study).  
For safety data, all AEs starting on or after the first dose of study treatment until 7 days (30 
days for SAEs and death) after the date of last treatment will be considered as post-baseline 
observations. 
Deaths (if any) that happened to occur after the clinical database lock will be manually 
described in the CSR main text, but not in the post-text table that will be done by programming. 
When change from baseline is of interest the following formula will be used for each scheduled 
visit and time-point where baseline and post-baseline values are both available: Change from 
baseline = post-baseline value – baseline value. 
Derivation of demographics and baseline characteristics 
Baseline values are as described in “Baseline measurements” section above. 
1. Airflow limitation is classified based on % of predicted FEV1 and FEV1/FVC post 
bronchodilation as per GOLD guidelines:  
Mild (GOLD 1): FEV1/FVC < 70 % and % of predicted FEV1  ≥ 80 %  
Moderate (GOLD 2): FEV1/FVC < 70 % and 50% ≤ % of predicted FEV1 < 80 % 
Severe (GOLD 3): FEV1/FVC < 70 % and 30% ≤ % of predicted FEV1 < 50 %  
Very Severe (GOLD 4): FEV1/FVC < 70 % and % of predicted FEV1 < 30 % 
      According to the study inclusion criteria 1, patients diagnosed and treated for moderate to 
severe COPD according to GOLD guideline are enrolled in the study. Thus, it can be 


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assumed that all enrolled patients with an exception of some who have protocol 
deviations (not meeting the inclusion criteria 1) will have FEV1/FVC < 70 % (as FVC is 
not databased, this ratio cannot be verified). Further, the statistical programming will 
categorize patients to moderate or severe based on the following criteria (50% ≤ % of 
predicted FEV1 < 80 %) or, (30% ≤ % of predicted FEV1 < 50 %), respectively. 
2. Duration of COPD is calculated from the date of COPD first diagnosed as recorded on the 
CRF until the date of Visit 1. If the date is missing in day and/or month, it will be imputed 
as follows. If the year is before Visit 1, the missing days will be imputed as the first of the 
month and the missing months will be imputed as July. If the year is the current year of 
Visit 1, the missing days will be imputed as the first of the month and the missing months 
will be imputed as January. 
3. The estimated number of pack years is defined as the total years of smoking multiplied by 
cigarette packs smoked per day (e.g.10 pack years = 1 pack /day x 10 yrs., or ½ pack/day 
x 20 yrs.). The number of pack years will be analyzed as recorded on the CRF. 
4. Years since subject stopped smoking is calculated using the formula: Years since subject 
stopped smoking = (Date of visit 1 – date stopped smoking)/365.25. If the date stopped 
smoking is missing in day and/or month, it will be imputed in the same way as described 
above for the date of COPD diagnosis. 
5. Percent of predicted FEV1 is obtained as a percentage of FEV1 relative to the predicted 
normal value of FEV1.  
6. For subjects greater than 18 years of age, this study will utilize the spirometric prediction 
equation standards for the European Community for Coal and Steel (Quanjer et al. 1993) 
or Nhanes (Hankinson et al. 1999). The equation of Quanjer et al. (1993) will be used by 
third party vendors to calculate predicted FEV1 (L): 
Male: (4.30 x Height in meters) – (0.029 x Age in years) – 2.49 
Female: (3.95 x Height in meters) – (0.025 x Age in years) – 2.60 
If Race = Black or Ethnicity = Indian then the predicted normal given by the formulae above 
was multiplied by 0.9. 
16.1.9.4 Statistical methodology and assumptions 
Students t-test for change from baseline in pre-dose trough FEV1 (L) to Week 
16 
proc ttest data=<……..>; 
class trt; 
var chg; 
run; 
where trt = prior COPD treatment, 
 
chg = change from baseline in pre-dose trough FEV1 (L) to Week 16. 


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Chi-square test to assess the relationship between prior COPD treatment and 
patient’s/physician’s global satisfaction:     
proc freq data = <........>; 
tables trt*satis / chisq; 
run; 
where trt = prior COPD treatment, 
satis = global satisfaction response.