Conditions: COPD
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 500
Healthy volunteers: no

Brief summary:
This study will investigate whether switching symptomatic COPD patients from a fixed-dose combination of salmeterol/fluticasone 50/500 µg b.i.d. to a fixed dose combination of QVA149 110/50 µg o.d. leads to improved lung function and airflow. It will also assess the effect on symptom burden, breathlessness, and use of rescue medication after this switch.

Detailed description:

Arms:
arm 1: QVA149 110/50 micrograms o.d. Capsules for inhalation arm 2: salmeterol/fluticasone 50/500 micrograms b.i.d. Dry inhalation powder

Interventions: intervention 1: QVA149 110/50 micrograms intervention 2: Salmeterol/fluticasone 50/500 microgrammes
Intervention descriptions: intervention 1: QVA149 110/50 micrograms o.d. capsules for inhalation, supplied in blisters via a single dose dry powder inhalater (SDDPI) intervention 2: Salmeterol/fluticasone 50/500 microgrammes b.i.d.dry inhalation powder delivered via Accuhaler / Diskus device

Protocol document:
Prot_001.pdf: 
Region AMAC CD&MA 
QVA149A (indacaterol maleate/glycopyrronium bromide) 
CQVA149A3405 / NCT02516592
A 12-week treatment, multi-center, randomized, double-
blind, double-dummy, parallel group study to assess the 
efficacy and safety of switching from 
salmeterol/fluticasone to QVA149 (indacaterol 
maleate/glycopyrronium bromide) in symptomatic COPD 
patients 
Authors: 
 
Document type: 
Amended protocol  
EUDRACT number: 
Not applicable 
Version number: 
v02  
Development phase: 
IIIb/IV 
Release date: 
17-Jun-2015
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed  
without the consent of Novartis 
Clinical Trial Protocol Template Version 2.0, November, 2013 


Novartis 
Confidential 
Page 2 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 5 
List of abbreviations ............................................................................................................ 6 
Glossary of terms ................................................................................................................. 8 
Amendment 2 ............................................................................................................................. 9 
Amendment 1 ........................................................................................................................... 10 
Protocol summary .............................................................................................................. 12 
1 
Introduction ....................................................................................................................... 15 
1.1 
Background ............................................................................................................ 15 
1.2 
Purpose .................................................................................................................. 16 
2 
Study objectives ................................................................................................................. 16 
2.1 
Primary objective ................................................................................................... 16 
2.2 
Secondary objectives ............................................................................................. 16 
3 
Investigational plan ........................................................................................................... 16 
3.1 
Study design........................................................................................................... 16 
3.2 
Rationale of study design ....................................................................................... 18 
3.3 
Rationale of dose/regimen, route of administration and duration of treatment ..... 19 
3.4 
Rationale for choice of comparator ....................................................................... 19 
3.5 
Purpose and timing of interim analyses/design adaptations .................................. 19 
3.6 
Risks and benefits .................................................................................................. 19 
4 
Population .......................................................................................................................... 20 
4.1 
Inclusion criteria .................................................................................................... 20 
4.2 
Exclusion criteria ................................................................................................... 21 
5 
Treatment ........................................................................................................................... 23 
5.1 
Protocol requested treatment ................................................................................. 23 
5.1.1 
Investigational treatment ....................................................................... 23 
5.1.2 
Additional study treatment .................................................................... 23 
5.2 
Treatment arms ...................................................................................................... 24 
5.3 
Treatment assignment, randomization ................................................................... 24 
5.4 
Treatment blinding ................................................................................................. 24 
5.5 
Treating the patient ................................................................................................ 25 
5.5.1 
Patient numbering ................................................................................. 25 
5.5.2 
Dispensing the investigational treatment .............................................. 25 


Novartis 
Confidential 
Page 3 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
5.5.3 
Handling of study treatment .................................................................. 26 
5.5.4 
Instructions for prescribing and taking study treatment ........................ 27 
5.5.5 
Permitted dose adjustments and interruptions of study treatment ........ 28 
5.5.6 
Rescue medication ................................................................................ 28 
5.5.7 
Concomitant treatment .......................................................................... 28 
5.5.8 
Prohibited Treatment ............................................................................. 28 
5.5.9 
Discontinuation of study treatment ....................................................... 30 
5.5.10 
Withdrawal of consent .......................................................................... 30 
5.5.11 
Loss to follow-up .................................................................................. 31 
5.5.12 
Emergency breaking of assigned treatment code .................................. 31 
5.5.13 
Study completion and post-study treatment .......................................... 31 
5.5.14 
Early study termination ......................................................................... 32 
6 
Visit schedule and assessments ......................................................................................... 32 
6.1.1 
Timing of assessments .......................................................................... 33 
6.2 
Information to be collected on screening failures .................................................. 34 
6.3 
Patient demographics/other baseline characteristics ............................................. 34 
6.4 
Treatment exposure and compliance ..................................................................... 34 
6.5 
Efficacy .................................................................................................................. 35 
6.5.1 
Spirometry ............................................................................................. 35 
6.5.2 
Baseline Dyspnea Index and Transitional Dyspnea Index 
(BDI/TDI) ............................................................................................. 36 
6.5.3 
COPD Assessment Test (CAT) ............................................................. 36 
6.5.4 
Rescue medication ................................................................................ 36 
6.5.5 
Appropriateness of efficacy assessments .............................................. 36 
6.6 
Safety ..................................................................................................................... 37 
6.6.1 
Physical examination ............................................................................ 37 
6.6.2 
Vital signs.............................................................................................. 37 
6.6.3 
Height and weight ................................................................................. 37 
6.6.4 
Laboratory evaluations .......................................................................... 37 
6.6.5 
Electrocardiogram (ECG) ..................................................................... 37 
6.6.6 
Pregnancy and assessments of fertility ................................................. 38 
6.6.7 
Pneumonia ............................................................................................. 38 
6.6.8 
COPD exacerbations ............................................................................. 38 
6.6.9 
Appropriateness of safety measurements .............................................. 39 
6.7 
Other assessments .................................................................................................. 39 
7 
Safety monitoring .............................................................................................................. 40 


Novartis 
Confidential 
Page 4 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
7.1 
Adverse events ....................................................................................................... 40 
7.2 
Serious adverse events ........................................................................................... 41 
7.2.1 
Definition of SAE ................................................................................. 41 
7.2.2 
SAE reporting........................................................................................ 42 
7.3 
Liver safety monitoring ......................................................................................... 43 
7.4 
Renal safety monitoring ......................................................................................... 43 
7.5 
Pregnancy reporting ............................................................................................... 43 
7.6 
Prospective suicidality assessment ........................................................................ 43 
8 
Data review and database management ............................................................................. 44 
8.1 
Site monitoring ...................................................................................................... 44 
8.2 
Data collection ....................................................................................................... 44 
8.3 
Database management and quality control ............................................................ 45 
8.4 
Data Monitoring Committee .................................................................................. 45 
8.5 
Adjudication Committee ........................................................................................ 45 
9 
Data analysis ...................................................................................................................... 46 
9.1 
Analysis sets .......................................................................................................... 46 
9.2 
Patient demographics and other baseline characteristics ....................................... 46 
9.3 
Treatments ............................................................................................................. 46 
9.4 
Analysis of the primary variable(s) ....................................................................... 47 
9.4.1 
Variable(s) ............................................................................................. 47 
9.4.2 
Statistical model, hypothesis, and method of analysis .......................... 47 
9.4.3 
Handling of missing values/censoring/discontinuations ....................... 48 
9.4.4 
Supportive analyses ............................................................................... 48 
9.5 
Analysis of secondary variables ............................................................................ 48 
9.5.1 
Efficacy variables .................................................................................. 48 
9.5.2 
Safety variables ..................................................................................... 49 
9.5.3 
Resource utilization ............................................................................... 51 
9.5.4 
Pharmacokinetics .................................................................................. 51 
9.5.5 
Pharmacogenetics/pharmacogenomics ................................................. 51 
9.5.6 
Biomarkers ............................................................................................ 51 
9.5.7 
PK/PD ................................................................................................... 51 
9.6 
Interim analyses ..................................................................................................... 52 
9.7 
Sample size calculation .......................................................................................... 52 
10 Ethical considerations ........................................................................................................ 52 
10.1 
Regulatory and ethical compliance ........................................................................ 52 
10.2 
Informed consent procedures ................................................................................. 52 


Novartis 
Confidential 
Page 5 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
10.3 
Responsibilities of the investigator and IRB/IEC .................................................. 53 
10.4 
Publication of study protocol and results............................................................... 53 
11 Protocol adherence ............................................................................................................ 53 
11.1 
Protocol Amendments ........................................................................................... 54 
12 References ......................................................................................................................... 54 
Appendix 1: Spirometry guidelines .......................................................................................... 55 
Appendix 2: Instructions for use of the SDDPI ........................................................................ 58 
Appendix 3: Instructions for use of the Accuhaler®/Diskus® ................................................ 63 
Appendix 4: Baseline dyspnea index/transitional dyspnea index (BDI/TDI) .......................... 64 
Appendix 5: COPD Assessment Test (CAT) ........................................................................... 69 
Appendix 6: Clinically notable vital signs ............................................................................... 70 
Appendix 7: Patient diary (example) ........................................................................................ 71 
 
List of tables 
Table 5-1 
Prohibited treatment .............................................................................. 28 
Table 5-2 
Prohibited COPD-related medications during the trial ......................... 29 
Table 5-3 
Medication allowed under specific conditions ...................................... 29 
Table 6-1 
Assessment schedule ............................................................................. 33 
Table 6-2 
Spirometry schedule .............................................................................. 35 
 
List of figures 
Figure 3-1 
Study design .......................................................................................... 18 
Figure 6-1 
Order of assessments ............................................................................. 34 
 


Novartis 
Confidential 
Page 6 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
List of abbreviations  
AE 
Adverse Event 
ATS 
American Thoracic Society 
BDI 
Baseline Dyspnea Index 
b.i.d. 
twice a day 
BMI 
Body Mass Index 
BPH 
Benign Prostatic Hyperplasia 
CAT 
COPD Assessment Test 
CFR 
US Code of Federal Regulations  
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 
EOS 
End Of Study 
ER 
Emergeny Room 
ERS 
European Respiratory Society 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FEV1 
Forced Expiratory Volume in one second 
FDC 
Fixed Dose Combination 
FVC 
Forced Vital Capacity 
GCP 
Good Clinical Practice 
GOLD 
Global Initiative for Chronic Obstructive Lung Disease  
H0 
null hypotesis 
Ha 
alternative hypothesis  
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ICS 
Inhaled Corticosteroids 


Novartis 
Confidential 
Page 7 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IUD 
Intrauterine Device 
IUS 
Intrauterine System 
LABA 
Long-Acting Beta-2 Agonist 
LAMA 
Long-Acting Muscarinic Antagonist 
LOCF 
Last Observation Carried Forward 
MDDPI 
Multi-Dose Dry Powder Inhaler 
MDI 
Metered Dose Inhaler 
MedDRA 
Medical dictionary for regulatory activities  
o.d. 
once a day 
p.o. 
oral(ly) 
PPS 
Per-Protocol Set 
QTcF 
QT correction formula  
RAN 
randomized set 
SABA 
Short-Acting Beta-2 Agonist  
SAE 
Serious Adverse Event 
SAMA 
Short-Acting Muscarinic Antagonist 
SDDPI 
Single Dose Dry Powder Inhaler 
SmPC 
Summary of Products Characteristics 
SNRI 
Serotonin Noradrenaline Reuptake Inhibitors 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TDI 
Transition Dyspnea Index 
WHO 
World Health Organization  


Novartis 
Confidential 
Page 8 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
Glossary of terms  
 
Assessment 
A procedure used to generate data required by the study 
Control drug 
Any drug (an active drug or an inactive drug, such as a placebo) 
which is used as a comparator to the drug being tested in the trial 
Dose level 
The dose of drug given to the patient (total daily or weekly etc.) 
Enrollment 
Point/time of patient entry into the study 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 protocol-
specified concomitant background therapies  when these are 
standard treatments in that indication 
Medication number 
A unique identifier on the label of each investigational/study drug 
package in studies that dispense medication using an IRT system 
Period 
A portion of the study which serves a specific purpose. Typical 
Periods are: screening/recruitment, wash-out, treatment, and 
follow-up 
Premature subject/patient 
withdrawal 
Point/time when the patient exits from the study prior to the 
planned completion of all study treatment administration and/or 
assessments; at this time all study treatment administration is 
discontinued and no further assessments are planned, unless the 
patient will be followed for progression and/or survival 
Protocol 
A written account of all the procedures to be followed in a trial, 
which describes all the administrative, documentation, analytical 
and clinical processes used in the trial. 
Randomization number 
A unique identifier assigned to each randomized patient, 
corresponding to a specific treatment arm assignment 
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 
Subject Number  
A number assigned to each patient who enrolls into the study  
Variable 
A measured value or assessed response that is determined in 
specific assessments and used in data analysis to evaluate the 
drug being tested in the study 


Novartis 
Confidential 
Page 9 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
Amendment 2  
Amendment rationale  
The purpose of this amendment is to update the eligibility criteria related to COPD 
exacerbations before the patients are screened, to clarify washout periods for parenteral or oral 
corticosteroids and intra-muscular depot corticosteroids before visit 1 and to revise the 
spirometry guidelines for the reversibility test at screening visit. 
This amendment should be implemented prior to the start of enrollment.  
Changes to the protocol 
The following sections of the protocol were changed: 
1. Protocol Summary, section Exclusion criteria, is revised to add exclusion criteria related 
to COPD exacerbation within 6 weeks before Visit 1 and to align with revised Protocol 
section 4.2.  
2. Protocol section 4.2, Exclusion criteria number 14 is revised to ensure patients enrolled 
did not have COPD exacerbation within the 6 weeks before Visit 1.  
3. Protocol section 5.5.8, Table 5-2, is revised to provide clarity on the wash-out period prior 
to visit 1 for parenteral or oral corticosteroids and intra-muscular depot corticosteroids. 
4. Protocol section 6.5.1, Table 6-2-Spirometry schedule at Visit 1 (screening), pre-dose time 
point is revised from -15 minutes to -5 minutes and post-dose time point is revised from 
+15 minutes to +60 minutes. In addition, further guidance on the reversibility test is 
provided within the section. 
5. Appendix 1: Spirometry guidelines, Reversibility section at Visit 1 (screening) is revised 
to align the time point of pre-dose and post-dose spirometry test as in Protocol section 6.5, 
Table 6-2. In addition, the wording is revised to provide more clarity. 
 
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.  


Novartis 
Confidential 
Page 10 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
Summary of previous amendments  
Amendment 1  
Amendment rationale  
The purpose of this amendment is to update eligibility criteria and to correct an inconsistency 
regarding the use of intramuscular corticosteroids for treating COPD exacerbations. 
This amendment is provided prior to the start of enrollment. 
Changes to the protocol 
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. 
Protocol summary and Section 4.1 Inclusion criteria 
Inclusion criterion number 3 in the original protocol includes current or ex-smokers who have 
a smoking history of at least 10 pack years (e.g. 10 pack years = 1 pack/day x 10 years, or ½ 
pack/day x 20 years). An ex-smoker is defined as a patient who has not smoked for ≥ 6 
months at visit 1.   
The definition of pack years is revised to reflect the number of cigarettes in order to account 
for variations in pack size. The revision states that ten pack years are defined as 20 cigarettes 
a day for 10 years, or 10 cigarettes a day for 20 years.  
Section 4.2 Exclusion criteria 
Criterion number 4 in the original protocol, which excludes patients diagnosed with Type I or 
uncontrolled Type II diabetes, is removed. Where QVA149 currently has marketing 
authorization in more than 60 countries (including countries in the European Union, Asia, and 
the Middle East as well as Canada, Japan and Australia) diabetes is not a contraindication. 
Though this criterion was used in the development phase QVA149 studies, it has been 
excluded from post-approval protocols. In compliance with the exclusion criterion for 
“clinically significant co-morbidity that could interfere with the assessment of the safety and 
efficacy of the study medication”, investigators should decide to exclude such patients. 
Minor edits and corrections 
• In Section 5.5.8 in Table 5-2 Prohibited COPD-related medications during the trial: intra-
muscular depot corticosteroids were incorrectly footnoted to state that they are allowed for 
treating COPD exacerbations.  The footnote reference is deleted. 
• In Sections 5.1.2 and 5.5.6, and Appendix 1 an edit is made to clarify that salbutamol or 
albuterol is administered for reversibility testing. This was presented in the original 
protocol as salbutamol/albuterol which could be interpreted to mean salbutamol and 
albuterol. 
• In the synopsis and Section 6.3, CAT score is corrected to “≥ 10”. 


Novartis 
Confidential 
Page 11 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
• In Section 8.3, an edit is made to remove description that ECG data will be processed 
centrally since this could lead to an incorrect interpretation that ECG will have central 
readings.  ECG results will not have a central reading, the reading and interpretation is 
only performed locally. 
• In Table 6-2, “albuterol” is added to the footnote. 
Implementation 
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. 


Novartis 
Confidential 
Page 12 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
Protocol summary 
 
Protocol number 
CQVA149A3405 
Title 
A 12-week treatment, multi-center, randomized, double-blind, double-
dummy, parallel group study to assess the efficacy and safety of 
switching from salmeterol/fluticasone to QVA149 (indacaterol 
maleate/glycopyrronium bromide) in symptomatic COPD patients 
Brief title 
 
Efficacy and safety of switching from salmeterol/fluticasone to QVA149 in 
symptomatic COPD patients 
Sponsor and Clinical 
Phase 
Novartis  
Phase 3b/4 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale 
To investigate whether switching symptomatic COPD patients from a 
fixed-dose combination of salmeterol/fluticasone 50/500 µg b.i.d. to a 
fixed dose combination of QVA149 110/50 µg o.d. leads to improved lung 
function and airflow and to assess the effect on symptom burden, 
breathlessness, and use of rescue medication. 
Primary Objective(s)  
To demonstrate superiority of QVA149 110/50 µg o.d. compared to 
salmeterol/fluticasone 50/500 µg b.i.d. in trough pre-dose FEV1 at week 
12  
Secondary Objectives 
 
To evaluate the effect of QVA149 110/50 µg o.d. compared to 
salmeterol/fluticasone 50/500 µg b.i.d. on:  
• 
Total score of TDI at week 12 
• 
FVC at week 12 
• 
COPD symptoms at week 12 as measured by the COPD 
Assessment Test (CAT) 
• 
The mean number of puffs of rescue medication use, and 
percentage of days without rescue medication use over the 12 
week treatment period  
• 
Safety and tolerability during the 12 week treatment period 
Study design 
This is a randomized, double-dummy, double-blind, parallel group study. 
Eligibility is assessed during a 2 week screening period, during which 
open-label salmeterol/fluticasone 50/500 µg b.i.d., is provided. At the 
baseline (randomization) visit, eligible patients are randomized to one of 
the two treatment arms: 1) QVA149 110/50 µg o.d. or 2) 
salmeterol/fluticasone 50/500 µg b.i.d., at a ratio of 1:1. Randomized 
patients enter a 12 week, double-blind, double dummy treatment period. 
Visits are scheduled at weeks 6 and 12 (i.e. end of study) to conduct 
safety and efficacy assessments (see Table 6-1). No interim analysis is 
planned.  
Population 
The study population consists of approximately 492 randomized male 
and female adults age ≥ 40 years, with a clinical diagnosis of COPD, a 


Novartis 
Confidential 
Page 13 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
smoking history of at least 10 pack years, treated with 
salmeterol/fluticasone 50/500 µg b.i.d. for at least 3 months prior to study 
entry, who are symptomatic as defined by a CAT score ≥ 10, and with not 
more than one COPD exacerbation in the previous year. 
Inclusion criteria 
• 
Written informed consent must be obtained before any assessment is 
performed. 
• 
Male and female ≥ 40 years 
• 
Current or ex-smokers who have a smoking history of at least 10 
pack years (ten pack years are defined as 20 cigarettes per day for 
10 years or 10 cigarettes per day for 20 years). An ex-smoker is 
defined as a patient who has not smoked for ≥ 6 months at visit 1 
• 
Confirmed diagnosis of COPD and post-bronchodilator FEV1 ≥ 30% 
and < 80% of the predicted normal value and post-bronchodilator 
FEV1/FVC < 0.70 at visit 1 
• 
Treated with salmeterol/fluticasone 50/500 µg b.i.d. for at least 3 
months prior to visit 1 
• 
Documented CAT score of ≥ 10 at Visit 1 and 2 
Exclusion criteria 
• 
Treatment with any LAMA in the 2 weeks prior to visit 1 
• 
Presence 
of 
any 
contraindication, 
warning, 
precaution, 
hypersensitivity 
in 
the 
approved 
prescribing 
information 
for 
salmeterol/fluticasone 
• 
Prior or current diagnosis of asthma 
• 
More than one COPD exacerbation requiring treatment with 
antibiotics and/or systemic corticosteroids and/or hospitalization in 
the year prior to Visit 1 
• 
Patients who developed a COPD exacerbation of any severity 
within the 6 weeks before the screening (Visit 1) or between 
screening (Visit 1) and start of treatment (Visit 2) will not be 
eligible but will be permitted to be re-screened after a minimum 
of 6 weeks after the resolution of the COPD exacerbation  
• 
Respiratory tract infection within 4 weeks prior to Visit 1 
• 
Respiratory tract infection between Visit 1 and 2. Patients can be re-
screened 4 weeks after resolution of the infection 
• 
Requiring oxygen therapy prescribed for >12 hours per day 
• 
Onset of respiratory symptoms, including a COPD diagnosis prior to 
age 40 years 
Investigational and 
reference therapy 
1. QVA149 110/50 µg o.d. capsules for inhalation, supplied in blisters 
via a single dose dry powder inhaler (SDDPI) 
2. Salmeterol/fluticasone 50/500 µg b.i.d. dry inhalation powder 
delivered via Accuhaler®/ Diskus® device 
Efficacy assessments 
• 
Spirometry 
• 
Baseline dyspnea index/transitional dyspnea index (BDI/TDI) 
• 
COPD assessment test (CAT) 
• 
Use of rescue medication 


Novartis 
Confidential 
Page 14 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
Safety assessments 
• 
Adverse events and serious adverse events 
• 
Vital signs 
• 
ECG 
• 
COPD exacerbations 
Other assessments 
Not applicable 
Data analysis 
The analysis of the primary objective will be performed on the FAS. The 
PPS may be used for the supportive analysis of the primary variable. The 
FAS will be used for the analysis of all other efficacy variables. The safety 
set will be used in the analysis of all safety variables. 
The following null hypothesis (Ho) versus the alternative hypothesis (Ha) 
will be tested at a significance level of 0.05 in the FAS: 
Ho: There is no difference in mean trough pre-dose FEV1 after 12 weeks 
of treatment between QVA149 110/50 µg o.d. and salmeterol/fluticasone 
50/500 µg b.i.d. 
Ha: There is a significant difference in mean trough pre-dose FEV1 after 
12 weeks of treatment between QVA149 110/50 µg o.d. and 
salmeterol/fluticasone 50/500 µg b.i.d. 
Key words 
Chronic Obstructive Pulmonary Disease, COPD, Glycopyrronium 
bromide, Indacaterol maleate, salmeterol/fluticasone, COPD assessment 
test, baseline dyspnea index/transitional dyspnea index, spirometry 


Novartis 
Confidential 
Page 15 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
1 
Introduction 
1.1 
Background  
Chronic Obstructive Pulmonary Disease (COPD) is a disease of the lungs characterized by 
airflow limitation which is not fully reversible, and associated with an enhanced chronic 
inflammatory response in the airways and the lung to noxious particles or gases.  Worldwide, 
COPD is projected to rank fifth in burden of disease and third with respect to mortality by 
2020 (Buist AS et al 2007). 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 (GOLD 2014). 
Current treatment guidelines for COPD recommend the use of bronchodilators for all 
severities, either on an as-required (pro re nata: prn) basis, or on a regular basis (GOLD 2014). 
Inhaled long-acting bronchodilators such as β2-adrenergic agonists (LABAs) and muscarinic 
antagonists (LAMAs) are recommended as a monotherapy or in combination 
(LABA+LAMA) (in GOLD B, C and D patients) for treatment of COPD patients.  
QVA149 is a fixed combination of a long-acting β2-agonist (Indacaterol maleate – QAB149) 
and a long-acting muscarinic antagonist (Glycopyrronium bromide – NVA237) that has been 
recently approved in Europe, Japan and several other countries worldwide for the maintenance 
treatment of COPD. QVA149 has been evaluated in a comprehensive Phase III development 
program comprising more than 11,000 COPD patients across 47 countries. Available data has 
demonstrated improvement in lung function, health-related quality of life, decrease in COPD 
symptoms and decrease in use of short-acting β2-adrenergic agonist (SABA) with a safety 
profile similar to the individual monotherapy components (Dahl et al 2013; Bateman et al 
2013; Mahler et al 2014). 
GOLD 2014 COPD strategy document states that long term treatment with inhaled 
corticosteroids is recommended for patients with severe and very severe COPD and frequent 
exacerbations that are not adequately controlled by long-acting bronchodilators (Evidence A). 
It also suggests that long-term treatment containing inhaled corticosteroids should not be 
prescribed outside their indications, due to the risk of pneumonia and the possibility of an 
increased risk of fractures following long-term exposure (GOLD 2014). 
QVA149 once daily provided significantly and clinically relevant improvements in lung 
function compared with salmeterol/fluticasone twice daily with significant symptomatic 
benefits in patients with moderate-to-severe COPD with no history of exacerbation in the last 
year (Vogelmeier et al 2013). This study confirmed the superiority of dual bronchodilator 
treatment to a Fixed Dose Combination (FDC) of ICS/LABA in this population.  
Many COPD patients remain symptomatic despite their current standard of care treatment, 
which often includes LABA/ICS (Hersh 2010). While ILLUMINATE, a 26-week study, 
(Vogelmeier et al 2013) showed superiority of QVA149 versus ICS/LABA in a head to head 
randomized study, it is unclear if switching symptomatic, infrequently exacerbating patients 
from ICS/LABA treatment to QVA149, without a washout period (i.e. real-life scenario), will 
benefit the patient with regard to efficacy and safety.  


Novartis 
Confidential 
Page 16 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
1.2 
Purpose  
To investigate whether switching symptomatic COPD patients from a fixed-dose combination 
of salmeterol/fluticasone 50/500 µg b.i.d. to a fixed dose combination of QVA149 110/50 µg 
o.d. leads to improved lung function and airflow, and to assess the effect on symptom burden, 
breathlessness, and use of rescue medication. 
2 
Study objectives 
2.1 
Primary objective 
To demonstrate superiority of QVA149 110/50 µg o.d. compared to salmeterol/fluticasone 
50/500 µg b.i.d. in trough pre-dose FEV1 at week 12.  
2.2 
Secondary objectives 
To evaluate the effect of QVA149 110/50 µg o.d. compared to salmeterol/fluticasone 50/500 
µg b.i.d. on:  
• Total score of TDI at week 12 
• FVC at week 12 
• COPD symptoms at week 12 as measured by the COPD Assessment Test (CAT) 
• The mean number of puffs per day of rescue medication use, and percentage of days 
without rescue medication use over the 12 week treatment period  
• Safety and tolerability during the 12 week treatment period 
3 
Investigational plan 
3.1 
Study design 
This is a randomized, double-dummy, double-blind, parallel group study. Eligibility is 
assessed during a 2 week screening period during which open-label salmeterol/fluticasone 
50/500 µg b.i.d. is provided. At the baseline (randomization) visit, eligible patients are 
randomized to one of the two treatment arms: 1) QVA149 110/50 µg o.d. or 2) 
salmeterol/fluticasone 50/500 µg b.i.d., at a ratio of 1:1. Randomized patients enter a 12 week, 
double-blind, double dummy treatment period. Visits are scheduled at weeks 6 and 12 (i.e. 
end of study) to conduct safety and efficacy assessments (see Table 6-1). No interim analysis 
is planned.  
Screening period – Visit 1 
Visit 1 is the screening visit during which the investigator checks the patient’s eligibility, 
detailed in Sections 4.1 and 4.2, and performs all assessments outlined in Table 6-1. The 
investigator must obtain written informed consent from the patient before conducting Visit 1. 
Informed consent may occur at a date prior to Visit 1.   


Novartis 
Confidential 
Page 17 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
The required assessments at Visit 1 include spirometry reversibility testing.  Spirometry 
testing should only be performed if the last dose of salmeterol/fluticasone was taken ≥ 24 
hours, last dose of any SABA was taken ≥ 6 hours and last dose of any SAMA was taken ≥ 8 
hours prior to spirometry.  Visit 1 should only be conducted if the spirometry testing can 
be performed. If not, this visit must be scheduled for a later date. An example follows: a 
patient presents for a routine visit, the investigator presents the study and the patient provides 
written informed consent to participate. The investigator determines that the patient had taken 
salmeterol/fluticasone within the last 3 hours. In this case, the investigator must schedule 
study Visit 1 to take place at a later time. After the patient has provided informed consent, the 
investigator should instruct the patient on the medication “wash-out” timing required for the 
spirometry testing.  Refer to Appendix 1: Spirometry Guidance for detailed instructions.  At 
Visit 1, after initial eligibility is determined, patients then begin the 2 week screening period. 
During the screening period, all patients are provided open-label salmeterol/fluticasone 
50/500 µg b.i.d. multi-dose dry-powder inhaler (MDDPI) treatment. Patients are also provided 
with a SABA (salbutamol or albuterol) for use as a rescue inhaler on an “as needed” basis 
throughout the study; for more details on rescue medication please refer to Section 5.5.6. 
Patients are also supplied with a paper diary (see Appendix 7) to collect information on study 
and rescue medication usage throughout the duration of the study. The diary is reviewed by 
the investigator at each study visit and is intended to help with assessing study medication 
compliance and use (i.e. quantity) of rescue medication. Patients should be resupplied with 
diary pages as needed. 
Treatment period – Visits 2, 3 and 4 
Visit 2 (Day 1) is the visit during which final eligibility is confirmed and patients who meet 
all criteria are randomized. This visit is to be conducted in the morning. It is recommended 
that the investigator phones the patient on the day prior to the visit to remind the patient that 
s/he should take the usual morning and evening doses on the day prior to the visit but must not 
take the morning dose on the day of the visit. This visit should occur 14 days after Visit 1. 
At this visit patients complete the CAT questionnaire and eligibility is reviewed. After the 
CAT questionnaire is completed, the diary data is reviewed and all assessments per Table 6-1, 
including spirometry, are performed.  
Patients who meet the eligibility criteria are randomized in a 1:1 ratio to one of the 2 treatment 
arms for the duration of the 12-week treatment period. Study treatment is dispensed (see 
Section 5.5.2) and instructions are given on the correct use of the inhalation device and study 
treatment.  
Visit 3 (Day 42) is conducted 6 weeks after randomization (Day 1) and should take place in 
the morning. It is recommended that the investigator phones the patient on the day prior to the 
visit to remind the patient that s/he should take the usual morning and evening doses of the 
day prior to the visit but not the morning dose on the day of the visit. Study medication is 
dispensed during the visit after all pre-dose procedures and assessments are performed. 
Visit 4 (Day 84) is conducted 12 weeks after randomization (Day 1) and should take place in 
the morning. This is the final end of study (EOS) visit. All EOS assessments are conducted as 


Novartis 
Confidential 
Page 18 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
outlined in Table 6-1. It is recommended that the investigator phones the patient on the day 
prior to the visit to remind the patient that s/he should take the usual morning and evening 
doses of the day prior to the visit but not the morning dose on the day of the visit. 
Patients should be seen for all visits on the designated day or as close as possible with an 
allowable visit window of +/- 3 days for Visits 2, 3 and 4. 
The investigator should instruct the patient to notify the study site about any new medications 
s/he takes after the start of the study. All medications and significant non-drug therapies 
(including physical therapy and blood transfusions) administered after the patient starts the 
study must be listed on the concomitant medications of the electronic Case Report Form 
(eCRF). 
Patients who discontinue study treatment early should complete the end of study assessments 
per Table 6-1.  
If a patient refuses to return for any assessments or is unable or unwilling to do so, every 
effort should be made to contact the patient or a knowledgeable informant to ensure the safety 
of the patient. Attempts to contact the patient should be documented in the source records. 
Figure 3-1 
Study design 
 
3.2 
Rationale of study design 
The randomized double-blind, double-dummy, parallel-group design provides the most robust 
methodology, with the least amount of bias, to evaluate the effect of switching from 
salmeterol/fluticasone to QVA149 in symptomatic COPD patients.  
 
Double blind, double-dummy 12-wk treatment 
Screening period 
Current 
maintenance:  
Sal/flu  
50/500 µg b.i.d. 
Visit 1 
Day -14 
 
Sal/flu 50/500 µg b.i.d. 
Visit 3 
Day 42
QVA149 110/50 µg o.d. 
Visit 2 
Day 1 
 Randomization 
Visit 4 
Day 84 
End of study
treatment 


Novartis 
Confidential 
Page 19 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
3.3 
Rationale of dose/regimen, route of administration and duration 
of treatment 
QVA149 110/50 µg o.d. is the registered dose for the COPD indication and for some 
participating countries this study is conducted in the post-approval phase. The 12-week 
duration is considered appropriate in order to show the impact of the treatment switch in terms 
of safety and efficacy. 
3.4 
Rationale for choice of comparator 
Salmeterol/fluticasone is widely used as maintenance therapy for COPD, and for many 
countries 50/500 µg b.i.d. is the only registered regimen indicated for COPD. 
3.5 
Purpose and timing of interim analyses/design adaptations 
Not applicable 
3.6 
Risks and benefits  
The risk to subjects in this trial will be minimized by compliance with all of the eligibility 
criteria and by close clinical monitoring. Although altering the current COPD medication 
regimen carries a potential risk, this population is defined as not optimally controlled by their 
current medication and therefore needs treatment adaptation/adjustment and according to 
guidelines, switching to a LABA/LAMA combination is recommended as one of the 2nd 
treatment choices, therefore switching patients to QVA149 is an expected benefit. The 
treatment duration of 12 weeks is a reasonable duration to detect any measurable change in 
lung function by any inhaled medication. Furthermore, patients will be allowed to use rescue 
medication (SABA) as needed during the screening and blinded treatment periods, thus 
mitigating these risks. The short duration of the trial (14 weeks including screening) and the 
provision of rescue medication (SABA) for both treatment arms provides sufficient risk 
mitigation for changing the treatment (QVA149 treatment arm) as well as keeping sub 
optimally-treated patients on their current treatment (salmeterol/ fluticasone treatment arm). 
Similarly, repetitive lung function measurement maneuvers during the study can lead to 
cough, shortness of breath, dizziness, or exhaustion. Since the patient only carries out forced 
maneuvers during clinic visits (not at home), these are performed under medical supervision 
to ensure availability of immediate aid if required. The assessments are infrequent and part of 
the regular medical assessments of this patient population. 
The risks of side effects from the study medication are those known for the compounds 
QVA149, QAB149 and NVA237. The most frequently reported side effects in the 
development of QVA149 to date are nasopharyngitis, upper respiratory tract infection, cough, 
and headache. Further information can be obtained from the QVA149 Investigator’s 
Brochure. For QAB149 and NVA237, please refer to the QAB149 and NVA237 sections of 
the QVA149 Investigator’s Brochure.  
The risk of side effects for the active comparator (salmeterol/fluticasone 50/500 µg b.i.d.) are 
those known for salmeterol and fluticasone, such as tremor, headache, palpitations, 
pneumonia, bronchitis, hypokalemia, nasopharyngitis, throat irritation, sinusitis, muscle 


Novartis 
Confidential 
Page 20 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
cramps, traumatic fractures, hoarseness and candidiasis in the mouth and throat. Further 
information can be obtained from the SmPC of Seretide®. 
The United States Food and Drug Administration (FDA) issued a warning concerning long-
acting beta-2 agonists (LABA).  The warning states that LABAs may increase the chance of 
severe asthma episodes and asthma related death in patients with asthma.  The warning was 
based on a study that evaluated the safety of salmeterol, which showed an increase in asthma 
related deaths in patients with asthma receiving salmeterol and their usual asthma medication. 
Indacaterol, which is one part of the study medication QVA149, is a LABA. However, 
indacaterol is not indicated to treat asthma and there have not been studies done that show 
whether or not indacaterol has the same risks as salmeterol when given to patients with 
asthma.  There is also currently no data that show whether or not there is the same risk when 
given to patients with COPD. Per the eligibility criteria in Section 4.2, patients with a prior or 
current asthma diagnosis are excluded. 
The potential benefit for the patient lies in a thorough medical evaluation of the patients’ 
disease and close clinical monitoring for the duration of the study. 
4 
Population 
The study population consists of approximately 492 male and female adults age ≥ 40 years, 
with a clinical diagnosis of COPD, a smoking history of at least 10 pack years, treated with 
salmeterol/fluticasone 50/500 µg b.i.d. for at least 3 months prior to study entry, who are 
symptomatic as defined by a CAT score ≥ 10, and with not more than one COPD exacerbation 
in the previous year.  
It is anticipated that approximately 492 patients will be randomized in order to end the study 
with 418 completed patients (considering a 15% drop-out rate).  Drop-outs will not be 
replaced. The study will be multinational. 
4.1 
Inclusion criteria 
Patients eligible for inclusion in this study must fulfill all of the following criteria: 
1. Written informed consent must be obtained before any assessment is performed. 
2. Male and female ≥ 40 years 
3. Current or ex-smokers who have a smoking history of at least 10 pack years (Ten pack 
years is defined as 20 cigarettes per day for 10 years or 10 cigarettes per day for 20 years). 
An ex-smoker is defined as a patient who has not smoked for ≥ 6 months at visit 1 
4. Confirmed diagnosis of COPD and post-bronchodilator FEV1 ≥ 30% and < 80% of the 
predicted normal value and post-bronchodilator FEV1/FVC < 0.70 at visit 1 
5. Treated with salmeterol/fluticasone 50/500 µg b.i.d. for at least 3 months prior to visit 1* 
6. Documented CAT score of ≥ 10 at Visit 1 and 2 
*Salmeterol/fluticasone 50/500 µg b.i.d. treatment has been decided by the patient’s primary 
physician who has full discretion of the appropriateness of this treatment. This treatment 


Novartis 
Confidential 
Page 21 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
decision has been taken outside the context of study and prior to the patient’s consideration 
for participating 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. Treatment with any LAMA in the 2 weeks prior to visit 1 
2. Presence of any contraindication, warning, precaution, hypersensitivity in the approved 
prescribing information for salmeterol/fluticasone 
3. Prior or current diagnosis of asthma 
4. History or current diagnosis of clinically significant ECG abnormalities including: 
a. Concomitant clinically significant cardiac arrhythmias, e.g. sustained 
ventricular tachycardia, and clinically significant second or third degree AV 
block without a pacemaker 
b. History of familial long QT syndrome or known family history of Torsades de 
Pointes 
5. Resting QTcF (Fridericia preferred) ≥ 450 msec (male) or ≥ 460 msec (female) during 
screening (Visit 1 or 2) 
6. Concomitant use of medication known to significantly prolong the QT interval unless it 
can be permanently discontinued for the duration of the study 
7. Clinically significant co-morbidity that could interfere with the assessment of the safety 
and efficacy of the study medication 
8. Paroxysmal (e.g. intermittent) atrial fibrillation; patients with persistent atrial fibrillation 
as defined by continuous atrial fibrillation for at least 6 months and controlled with a rate 
control strategy (i.e., beta blocker, calcium channel blocker, pacemaker placement, 
digoxin or ablation therapy), for at least 6 months, may be considered for inclusion. In 
such patients, atrial fibrillation must be present at Visit 1 and 2, with a resting ventricular 
rate < 100/min.  
9. Contraindications or hypersensitivity to  
a. Anticholinergic agents 
b. Long and short-acting β2-agonists  
c. Sympathomimetic amines 
d. Lactose or any other excipient of the study medication or to drugs of similar 
chemical classes 
10. Any malignancy within the past 5 years except localized basal cell carcinoma of the skin 


Novartis 
Confidential 
Page 22 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
11. Narrow-angle glaucoma, symptomatic benign prostatic hyperplasia (BPH) or bladder-neck 
obstruction or moderate to severe renal impairment or urinary retention. Asymptomatic 
BPH patients are not excluded. 
12. Not achieved acceptable spirometry results at visit 1 or 2 in accordance with the American 
Thoracic Society (ATS) or European Respiratory Society (ERS) criteria for acceptability. 
One retest may be performed for patients not meeting the acceptability criteria.  
13. More than one COPD exacerbation requiring treatment with antibiotics and/or systemic  
corticosteroids and/or hospitalization in the year prior to Visit 1 
14. Patients who developed a COPD exacerbation of any severity within the 6 weeks before 
the screening (Visit 1) or between screening (Visit 1) and start of treatment (Visit 2) will 
not be eligible but will be permitted to be re-screened after a minimum of 6 weeks after 
the resolution of the COPD exacerbation   
15. Respiratory tract infection within 4 weeks prior to Visit 1 
16. Respiratory tract infection between Visit 1 and 2. Patients can be re-screened 4 weeks 
after resolution of the infection 
17. Requiring oxygen therapy prescribed for >12 hours per day 
18. Onset of respiratory symptoms, including a COPD diagnosis prior to age 40 years 
19. Intermittent treatment with a H1-antagonist or intra-nasal corticosteroids for allergic 
rhinitis (treatment with a stable dose/regimen is permitted). 
20. Concomitant pulmonary disease (e.g. lung fibrosis, sarcoidosis, interstitial lung disease, 
pulmonary hypertension, clinically significant bronchiectasis)  
21. Diagnosed with α-1 anti-trypsin deficiency 
22. Active pulmonary tuberculosis, unless confirmed by imaging, within the past year, to be 
no longer active unless there is a documented record of appropriate treatment and a chest 
radiograph suggesting that the disease is no longer active 
23. Pulmonary lobectomy or lung volume reduction surgery or lung transplantation 
24. Participating in or planning to participate in the active phase of a supervised pulmonary 
rehabilitation program during the study (maintenance program is permitted) 
25. Receiving any medication in the classes listed in Table 5-1 
26. Receiving medications in the classes listed in Table 5-3 should be excluded unless the 
medication has been stable for the specified period and the stated conditions are met 
27. Use of investigational drugs/devices (approved or unapproved) at the time of enrollment, 
or within 30 days or 5 half-lives of Visit 1, whichever is longer. 
28. Unable to use a dry powder inhaler device, Metered Dose Inhaler (MDI) or a pressurized 
MDI (rescue medication) or comply with the study regimen. 
29. 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 urine test. 


Novartis 
Confidential 
Page 23 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
30. 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 defined as surgical hysterectomy, bilateral oophorectomy, or 
tubal ligation at least six weeks before taking the study treatment (Single 
oophorectomy does not meet the definition of female sterilization). 
• Male sterilization (at least 6 months 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 stable 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. 
5 
Treatment 
5.1 
Protocol requested treatment 
5.1.1 
Investigational treatment 
• QVA149 110/50 µg o.d. capsules for inhalation, supplied in blisters via a single dose dry 
powder inhaler (SDDPI) 
• Salmeterol/fluticasone 50/500 µg b.i.d. dry inhalation powder delivered via 
Accuhaler®/Diskus® device 
5.1.2 
Additional study treatment 
At Visit 1 all patients are administered ipratropium bromide for the purpose of reversibility 
testing. Ipratropium bromide is supplied to the investigator site by Novartis or provided by the 
study center and reimbursed by Novartis.  


Novartis 
Confidential 
Page 24 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
At Visit 1 all patients are administered inhaled SABA (salbutamol or albuterol) for 
reversibility testing. All patients entering the screening period are asked to retain the SABA 
inhalers to use as rescue medication on an “as needed” basis throughout the study, and are 
resupplied as needed. Salbutamol or albuterol must not to be administered within 6 hours prior 
to Visit 2 and 3. If use is unavoidable, the visit must be rescheduled. 
Salbutamol (100µg) or albuterol (90µg) is supplied to the investigator sites by Novartis or 
provided by the study center and reimbursed by Novartis.  
At Visit 1 all patients are provided open-label salmeterol/fluticasone 50/500 µg b.i.d. MDDPI 
medication to take during the 2 week screening period. 
Please refer to Section 5.5.6 for more details regarding rescue medication. 
5.2 
Treatment arms 
Patients are assigned to one of the following 2 double-blind treatment arms in a ratio of 1:1: 
1. QVA149 110/50 µg o.d. and placebo for salmeterol/fluticasone 
2. Salmeterol/fluticasone 50 /500µg b.i.d. and placebo for QVA149 
5.3 
Treatment assignment, randomization  
At Visit 2 all eligible patients are randomized via Interactive Response Technology (IRT) to 
one of the treatment arms. The investigator or his/her delegate contacts the IRT after 
confirming that the patient fulfills all the inclusion/exclusion criteria. The IRT assigns a 
randomization number to the patient, which is used to link the patient to a treatment arm and 
specifies a unique medication number for the first package of study treatment to be dispensed 
to the patient. The randomization number is not to be communicated to the caller. 
The randomization number is generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list is produced by the IRT provider using a validated system that automates 
the random assignment of patient numbers to randomization numbers. These randomization 
numbers are linked to the different treatment arms, which in turn are linked to medication 
numbers. A separate medication list is produced by or under the responsibility of Novartis 
Drug Supply Management using a validated system that automates the random assignment of 
medication numbers to packs containing the investigational drug(s).  
Randomization is not stratified. 
5.4 
Treatment blinding 
Patients, investigator staff, persons performing the assessments, and data analysts are blind to 
the identity of the treatment from the time of randomization until database lock, using the 
following methods:  
(1) Randomization data are kept strictly confidential until the time of unblinding, and are not 
accessible by anyone else involved in the study.  


Novartis 
Confidential 
Page 25 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
(2) The identity of the treatments is concealed by the use of study treatment that are all 
identical in packaging, labeling, schedule of administration, appearance, taste and odor. 
A double-dummy design is used because the identity of the study treatment cannot be 
disguised, as the drug products are visibly different. In other words the two treatments (i.e. 
salmeterol/fluticasone and QVA149) cannot be made to look identical. To employ the double 
dummy blinding method each patient receives active drug and an indistinguishable placebo.   
5.5 
Treating the patient  
5.5.1 
Patient numbering  
Each patient is uniquely identified in the study by a combination of his/her center number and 
patient number. The center number is assigned by Novartis to the investigative site. Upon 
signing the informed consent form, the patient is assigned a patient number by the 
investigator. At each site, the first patient is assigned patient number 1, and subsequent 
patients are assigned consecutive numbers (e.g. the second patient is assigned patient number 
2, the third patient is assigned patient number 3). The investigator or his/her staff will contact 
the IRT and provide the requested identifying information for the patient to register them into 
the IRT. For studies using eCRFs, only the assigned patient number should be entered in the 
field labeled “Patient ID” on the EDC data entry screen (e.g. enter ‘1’, ‘2’, etc.). Once 
assigned to a patient, the patient number will not be reused.  If the patient fails to be 
randomized for any reason, the IRT must be notified within 2 days that the patient was not 
randomized.  The reason for not being randomized will be entered on the Screening Log, and 
the Demography eCRF should also be completed. 
5.5.2 
Dispensing the investigational treatment  
Screening Period:  Open label salmeterol/fluticasone 50/500 µg b.i.d. MDDPI is supplied by 
Novartis. The medication is dispensed at Visit 1 for treatment during the screening period. 
Treatment period: Each study site is supplied by Novartis with study treatment in packaging 
of identical appearance. Each patient receives medication kits at each dispensing visit, 
containing QVA149 active or placebo and salmeterol/fluticasone active or placebo. 
Medication kits are dispensed at Visits 2 and 3 to cover the treatment period between patient 
visits and to allow for late visits and other unforeseen events.  
The study treatment packaging has a 2-part label. A unique randomization number is printed 
on each part of this label which corresponds to one of the 2 treatment arms. Investigator staff 
will identify the study treatment kit(s) to dispense to the patient by contacting the IRT and 
obtaining the medication number(s). Immediately before dispensing the kit to the patient, 
investigator staff will detach the outer part of the label from the packaging and affix it to the 
source document (Drug Label Form) for that patient’s unique patient number. 
Initial training kits will be provided to study sites following registration of the center by study 
site personnel after site initiation and prior to the first patient at that center attending for Visit 
1. Training kits will contain blister strips with placebo capsules to QVA149, SDDPI devices 
and Accuhaler®/Diskus® placebo devices for training use only. 


Novartis 
Confidential 
Page 26 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
Capsules should only be removed from the blister immediately before dosing. 
At randomization - Visit 2 
Investigator staff contacts the IRT to randomize the patient and obtain the assigned study 
treatment kit number. QVA149/placebo and fluticasone/salmeterol/placebo kits are dispensed 
at this visit.  
Visits 3 and 4 
The patient’s study treatment supplies should be checked at each visit and the drug 
accountability log completed appropriately. 
Additional investigation treatment is dispensed according to the Assessment Schedule (Table 
6-1) and at other times, if required, due to unexpected events. Study center personnel should 
ensure that patients always have more than sufficient investigational treatment to last until the 
next scheduled visit and must always call the IRT to obtain the specific medication kit 
numbers to be issued before dispensing supplies. 
All devices and associated blister kits must be returned to the site at Visits 3 and 4 (or for 
patients who withdraw from the study prematurely). 
5.5.3 
Handling of study treatment  
5.5.3.1 
Handling of investigational treatment  
Study 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 study treatment should be stored according to the 
instructions specified on the labels. Clinical supplies are to be dispensed only in accordance 
with the protocol. Technical complaints are to be reported to the respective Novartis Country 
Pharma Organization (CPO) Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the study treatment but no information 
about the patient except for the medication number. 
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Patients will be asked 
to return all unused study treatment and packaging at the end of the study or at the time of 
discontinuation of study 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. 


Novartis 
Confidential 
Page 27 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
5.5.3.2 
Handling of other study treatment  
Rescue medication (salbutamol or albuterol) and ipratropium bromide for reversibility testing  
must be provided 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. All study treatment must be stored according to the instructions specified on the 
labels. Clinical supplies are to be dispensed only in accordance with the protocol. Technical 
complaints are to be reported to the respective Novartis CPO Quality Assurance. 
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Patients will be asked 
to return all unused study treatment and packaging at the end of the study or at the time of 
discontinuation of study treatment.  
5.5.4 
Instructions for prescribing and taking study treatment  
Patients are instructed on how to use the study treatment SDDPIs and Accuhaler®/Diskus® 
devices. Additional kits are provided with SDDPI and blisters with placebo capsules, and 
Accuhaler®/Diskus® placebo devices for training and demonstration purposes (see Appendix 
2 and Appendix 3 for the patient instructions on how to use the study inhalers).  
Patients are instructed to come to the clinic in time to complete pre-dosing assessments and to 
allow investigation treatment to be taken in the morning between 08:00 and 11:00 am. 
Patients are instructed to withhold the use of SABA (rescue medication) for at least 6 hours 
prior to all clinic visits, unless the use is absolutely necessary. If use of rescue medication is 
unavoidable then the visit must be rescheduled. It is recommended that the investigator 
phones the patient on the day prior to the visit to provide these reminders to the patient. 
Patients are instructed to take one capsule, each day, in the morning between 08:00 and 11:00 
from each of their medication kits in the following order;  
Morning (08:00-11:00): one inhalation from the QVA149 SDDPI followed by one inhalation 
from fluticasone/salmeterol Accuhaler®/Diskus® device. 
Afternoon (approximately 12 hours after their AM dose +/- 30 minutes): one inhalation 
from fluticasone/salmeterol Accuhaler®/Diskus® device.  
All used and unused study medication must be returned by the patient at each study visit. The 
date and time of dose administration at each visit is recorded on the Dosage Administration 
Record eCRF. 
All kits of study treatment assigned by the IRT are recorded in the IRT. 
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 s/he is unable for any reason to take the study treatment as prescribed. 


Novartis 
Confidential 
Page 28 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
5.5.5 
Permitted dose adjustments and interruptions of study treatment 
Study treatment dose adjustments and/or interruptions are not permitted. 
5.5.6 
Rescue medication 
All patients are provided with a SABA (salbutamol or albuterol) which they are instructed to 
use throughout the trial as rescue medication. Nebulized salbutamol or albuterol is not 
allowed as rescue medication. Salbutamol (100µg) or albuterol (90µg) will either be supplied 
to the investigator sites locally by a Novartis designee or provided by the study center and 
reimbursed by Novartis. During the treatment period salbutamol or albuterol should be taken 
for rescue (when required) purposes only. No other rescue treatment is permitted. 
In order to standardize measurements, patients are instructed to abstain from taking rescue 
medication (salbutamol or albuterol) within 6 hours prior to each visit when spirometry is 
scheduled. If rescue medication is taken within 6 hours prior to a visit, the visit should be 
rescheduled to the next day, if possible. The investigator must use their judgment when 
deciding how many times a visit for an individual patient should be rescheduled. 
Use of rescue medication (number of puffs taken in the previous 12 hours) is recorded (once 
in the morning and once in the evening) by the patient, in the patient diary. At each study 
visit, the investigator should review the patient diary to assess the use of rescue medication. 
Use of rescue medication must be recorded on the Rescue Medication CRF. 
5.5.7 
Concomitant treatment  
The investigator should instruct the patient to notify the study site about any new medications 
s/he 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  
Use of treatments displayed listed in Table 5-1 and Table 5-2 are NOT allowed after the 
patient enters screening. 
Patients requiring the treatments in Table 5-1 are considering ineligible for study participation 
(see Section 4).  Patients who have discontinued these medications according to the minimum 
cessation period are eligible. Washout of the prohibited medications, for the purpose of 
study participation, should not be done. 
Table 5-1 
Prohibited treatment 
Class of Medication1 
Minimum cessation period prior to 
Visit 1 
Non-potassium sparing diuretics (unless administered 
as a fixed-dose combination with a potassium 
conserving drug) 
7 days 
Non-selective systemic beta-blocking agents2 
7 days 
Other drugs with potential to significantly prolong the 
14 days or 5 half-lives, whichever is 


Novartis 
Confidential 
Page 29 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
Class of Medication1 
Minimum cessation period prior to 
Visit 1 
QT interval 
longer 
Antibiotics3 
30 days 
Systemic Mast cell stabilizers (e.g., cromoglycate, 
nedocromil, ketotifen) 
7 days 
Systemic anticholinergics 
7 days 
IgE inhibitors (e.g, Xolair) 
6 months  
Leukotriene antagonists and leukotriene synthesis 
inhibitors 
7 days 
1This table is not considered all-inclusive.  Medications should be assessed for adherence to the indication and 
other inclusion/exclusion criteria. 
2 Selective β1 blocking agents are permitted. 
3If antibiotics were taken to treat a COPD exacerbation in the 6 weeks prior to Visit 1 the patient should be 
excluded; please refer to exclusion criteria (Section 4.2) for more details. Antibiotics are permitted to treat a COPD 
exacerbation from V2 until the end of the study. 
Table 5-2 
Prohibited COPD-related medications during the trial 
Class of Medication1 
Minimum cessation period prior to Visit 1 
Long-acting muscarinic antagonist (LAMA) 
(except 
combination 
of 
LABA/LAMA 
as 
study 
medication) 
Two weeks 
Short-acting β2 agonists (SABA) 
(except rescue medication see section 5.5.6) 
6 hours 
Short-acting muscarinic antagonist (SAMA)  
8 hours 
Fixed combinations of short-acting β2 agonists and 
short-acting muscarinic antagonist (SABA/SAMA)  
8 hours 
Long-acting β2 agonists (LABA)  
(except combination of LABA/ICS or LABA/LAMA as 
study medication) 
24 hours 
Oral Phosphodiesterase-IV inhibitor 
Not applicable 
Xanthines (any formulation) 
Not applicable 
Parenteral or oral corticosteroids2 
30 days 
Intra-muscular depot corticosteroids 
90 days 
1This table is not considered all-inclusive.  Medications should be assessed for adherence to the indication and 
other inclusion/exclusion criteria. These medications are also prohibited if administered for other indications. 
2Allowed for treating COPD exacerbations. 
Table 5-3 
Medication allowed under specific conditions  
Class of Medication1 
Condition under which medication is permitted 
Selective Serotonin Re-uptake Inhibitors 
Stable dose for at least 30 days prior to Visit 1 and 
during the trial 
H1-antagonists  
Stable dose for at least 5 days prior to Visit 1. 
(Except mizolastin or terfenadine) 
Inactivated influenza, pneumococcal or any 
other inactivated vaccine 
Not administered within 48 hours prior to a trial visit 


Novartis 
Confidential 
Page 30 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
1This table is not considered all-inclusive. Medications should be assessed for adherence to the indication and 
other inclusion/exclusion criteria. 
5.5.9 
Discontinuation of study treatment 
Patients may voluntarily discontinue study treatment for any reason at any time.  
The investigator should discontinue study treatment for a given patient if, on balance, s/he 
believes that continuation would be detrimental to the patient’s well-being. 
Study treatment must be discontinued under the following circumstances: 
• Withdrawal of informed consent (See Section 5.5.10) 
• Adverse events for which continued use of study treatment would be detrimental to the 
patient 
• Abnormal test procedure results indicating risk for the patient to continue study treatment  
• Pregnancy  
• Need to treat a COPD exacerbation with intra-muscular depot corticosteroids (e.g. Depo-
Medrone®). 
• Any protocol deviation that results in a significant risk to the patient’s safety  
If premature discontinuation of study treatment occurs, the patient should return for the EOS 
visit, as soon as possible, and complete the assessments per Table 6-1. The investigator must 
determine the primary reason for the patient’s premature discontinuation of study treatment 
and record this information on the Dosage Administration eCRF. At a minimum, the 
investigator should make every effort to obtain information regarding serious adverse events. 
The appropriate personnel from the site and Novartis will assess whether investigational 
treatment should be discontinued for any patient whose treatment code has been broken 
inadvertently for any reason. 
The investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment. 
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 
Withdrawal of consent  
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time. In case of study withdrawal, data collected up to that point is processed and analyzed. 
Withdrawal of consent occurs only when a patient does not want to participate in the study 
anymore, does not want any further visits or assessments, does not want any further study 
related contacts and does not allow analysis of already obtained biologic material. 


Novartis 
Confidential 
Page 31 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
If a patient withdraws consent, the investigator must make every effort (e.g. telephone, e-mail, 
letter) to determine the primary reason for this decision and record this information. Study 
treatment must be discontinued and no further assessments conducted. All biological material 
that has not been analyzed at the time of withdrawal must not be used. Further attempts to 
contact the patient are not allowed unless safety findings require communicating or follow-up. 
5.5.11 
Loss to follow-up 
For 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 contacting the 
patient, family or family physician as agreed in the informed consent and by documenting in 
the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be formally considered lost to follow-up until 
his/her scheduled end of study visit would have occurred. 
5.5.12 
Emergency breaking of assigned treatment code  
Emergency treatment code breaks should only be undertaken when it is essential to treat the 
patient safely and efficaciously. Most often, study treatment discontinuation and knowledge of 
the possible treatment assignments are sufficient to treat a study patient who presents with an 
emergency condition. Emergency treatment code breaks are performed using the IRT. When 
the investigator contacts the system to break a treatment code for a patient, s/he must provide 
the requested patient identifying information and confirm the necessity to break the treatment 
code for the patient. The investigator will then receive details of the investigational drug 
treatment for the specified patient and a fax or email confirming this information. The system 
will automatically inform the Novartis monitor for the site and the Global Trial Lead (GTL) 
that the code has been broken. 
It is the investigator’s responsibility to ensure that there is a procedure in place to allow access 
to the IRT in case of emergency. The investigator will inform the patient how to contact 
his/her backup in cases of emergency when s/he is unavailable. The investigator will provide 
protocol number, study treatment name if available, patient number, and instructions for 
contacting the local Novartis Country Pharma Organization (CPO) (or any entity to which it 
has delegated responsibility for emergency code breaks) to the patient in case an emergency 
treatment code break is required at a time when the investigator and backup are unavailable. 
In case of a treatment code break, the patient must be discontinued from the study. 
5.5.13 
Study completion and post-study treatment  
Completion of the study for an individual patient is when s/he has completed the 12 week 
treatment period. When the patient has completed all scheduled assessments the investigator 
must call IRT to record patient completion. 
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.  


Novartis 
Confidential 
Page 32 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
5.5.14 
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 the Institutional Review Board/Independent 
Ethics Committee (IRBs/IECs) 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” the visits during which the 
assessments are performed. All data obtained from these assessments must be supported in the 
patient’s source documentation. 
The following assessments are scheduled to be performed in order as follows: COPD 
Assessment Test (CAT), BDI/TDI, followed by spirometry. Whenever other assessments are 
scheduled at the same time-point, spirometry must take precedence such that it occurs as near 
as possible to the scheduled time point. 
Patients who discontinue from the study or are withdrawn from study treatment should return 
for the EOS visit assessments per Table 6-1 as soon as possible. 
 


Novartis 
Confidential 
Page 33 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
Table 6-1 
Assessment schedule 
Period 
Screening 
Treatment 
Visit number 
1 
2 
3 
4 
Day 
-14 
 
1 
 
42 
84 
End of study 
(EOS) 
Information & Informed consent 
x1 
 
 
 
Inclusion/Exclusion criteria  
x 
x 
 
 
Medical history, smoking history, 
demographics 
x 
 
 
 
COPD exacerbation history/events 
x 
x 
x 
x 
Vital signs 
x 
x 
x 
x 
Height and weight 
x 
 
 
x 
Physical exam 
S 
 
S 
S 
ECG 
x 
x 
 
x 
Prior and current medications 
x 
x 
x 
x 
Pregnancy test (urine)2 
x 
 
 
x 
Spirometry 
x 
x 
x 
x 
BDI 
 
x 
 
 
TDI 
 
 
x 
x 
CAT 
x 
x 
x 
x 
Issue & instruct on paper diary 
x 
 
 
 
Review diary; provide as needed 
 
x 
x 
x 
Record study treatment compliance 
 
x 
x 
x 
Record rescue medication use 
 
x 
x 
x 
Contact IRT 
x 
x 
x 
x 
Randomization via IRT 
 
x 
 
 
Dispense sal/flu for screening period 
x 
 
 
 
Inhalation device training  
x 
x 
 
 
Dispense double-blind, double dummy 
study medication 
 
x 
x 
 
Dispense rescue medication 
x 
x 
x 
 
Adverse events (AE/SAE) 
x 
x 
x 
x 
1On or before Visit 1 
2Only women of child-bearing potential 
S = source documentation only 
6.1.1 
Timing of assessments 
Assessments must be conducted in the following order (see Figure 6-1): 
Visit 1: CAT → ECG → Vital signs → Spirometry 
Visit 2: CAT → BDI → ECG → Vital signs → Spirometry 
Visit 3: CAT → TDI → Vital signs → Spirometry 
Visit 4: CAT → TDI → ECG → Vital signs → Spirometry 


Novartis 
Confidential 
Page 34 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
Figure 6-1 
Order of assessments 
 
  
6.2 
Information to be collected on screening failures  
All patients who have signed informed consent but not entered into the next period will have 
the study completion page for the screening period, demographics, inclusion/exclusion, and 
adverse events/serious adverse event data collected. Adverse events that are not SAEs will be 
followed by the investigator and collected only in the source data. 
6.3 
Patient demographics/other baseline characteristics  
Patient demographic and baseline characteristic data to be collected on all patients include: 
• Date of birth 
• Sex 
• Race and ethnicity 
• Height and weight 
• Date of COPD diagnosis  
• COPD exacerbation history 
• Relevant medical history / current medical condition present before signing informed 
consent 
• Smoking history and status 
• Prior (taken within the 1 year prior to study entry) and concomitant medications  
• Pre- and post-bronchodilator spirometry (screening spirometry) 
• COPD related symptoms as defined by a CAT score ≥ 10 
• Baseline physical examination (only relevant co-morbidities recorded as medical history) 
• Vital signs 
6.4 
Treatment exposure and compliance  
Study treatment compliance is assessed by the investigator at all visits. The Investigator or 
designee collects, from the patient, the used / unused investigational medication and 
packaging (morning and evening capsules / blister strips and SDDPIs) at all dispensing visits. 
Study drug compliance is assessed from the capsule count and from information provided by 
the patient and/or caregiver. The investigator should also review the patient diary to help 
assess study drug compliance. This information should be captured in the source 
documentation.  
CAT
(visits 1, 2, 3 & 
4)
BDI (visit 2)
TDI (visit 3 & 4)
ECG
(visit 1, 2 & 4)
Vital Signs
(visits 1, 2, 3 & 
4)
Spirometry
(visits 1, 2, 3 & 
4)


Novartis 
Confidential 
Page 35 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
The time of study treatment administration at each visit is collected on the eCRF. For 
assessments where spirometry is performed, the time of dosing is to be taken from the 
spirometer. 
The date of any dosing interruptions/missed doses is entered in the eCRF. 
6.5 
Efficacy 
6.5.1 
Spirometry 
Table 6-2 provides the scheduled timing for spirometry measurements. All study visits take 
place in the morning. It is recommended that the investigator phones the patient on the day 
prior to the visit to remind the patient that s/he should take the usual morning and evening 
doses on the day prior to the visit but must not take the morning dose on the day of the visit.  
Study medication is administered on the day of the visit after all required assessments are 
performed. If patients have taken salmeterol/fluticasone on the day of Visit 1 then spirometry 
should be rescheduled for the following day or as soon as possible. Visit 1 should only take 
place if spirometry testing can be performed (see Section 3.1). A central reading is performed 
for spirometry and the results are usually available within 48 hours. 
Table 6-2 
Spirometry schedule 
 
Time point 
FEV1 and FVC 
Visit 1 (Screening)1 
-5 min 
x 
+60 min 
x 
Visit 2 (Day 1)2 
-45 min 
x 
-15 min 
x 
Visit 3 (Day 42)2 
-45 min 
x 
-15 min 
x 
Visit 4 (Day 84)2 
-45 min 
x 
-15 min 
x 
1Time point is relative to administration of ipratropium and salbutamol 
or albuterol. 
 2Time point is relative to the morning dose of the visit day 
 
At Visit 1, reversibility testing is conducted in order to evaluate a patient’s eligibility (see 
inclusion criteria). 
The reversibility test should be performed in the morning as follows: 
• Perform pre-bronchodilator spirometry and record FEV1 and FVC. 


Novartis 
Confidential 
Page 36 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
• Administer 84 μg (or equivalent dose) of ipratropium bromide. The administration of 
ipratropium bromide should be within 5 minutes of pre-bronchodilator spirometry. 
• Administer 400 μg of salbutamol (or 360 μg albuterol) a few minutes after the 
administration of ipratropium bromide. 
• Perform post-bronchodilator spirometry and record FEV1 and FVC 1 hour after the 
administration of salbutamol/albuterol. 
At Visits 2, 3 and 4, FEV1 and FVC measurements are performed. 
Please refer to the detailed instructions provided in Appendix 1: Spirometry guidance. 
6.5.2 
Baseline Dyspnea Index and Transitional Dyspnea Index (BDI/TDI) 
Patients must be interviewed by an assessor experienced in the use of such questionnaires. 
The assessor will grade the degree of impairment due to dyspnea at Visit 2 (BDI only), at 
Visit 3 and at Visit 4, or at the time of discontinuation for patients who discontinue 
prematurely (TDI only). Every attempt should be made to ensure it is the same assessor that 
completes all the BDI/TDI assessments for an individual patient. 
An example of the BDI and TDI (Mahler & Wells 1988) is provided in Appendix 4. 
6.5.3 
COPD Assessment Test (CAT)  
The COPD assessment test (CAT) is a short instrument used to quantify the symptom burden 
of COPD and is used to assess the health status of patients in this study (Jones et al 2009, 
Jones et al 2012). It is completed by the patient at the beginning of the study visit before any 
other assessment to avoid influencing the responses. The CAT is completed by the patient at 
the investigator's site at Visits 1, 2, 3 and 4 or at the time of discontinuation for patients who 
prematurely withdraw from the study. It consists of eight items, each presented as a semantic 
6-point differential scale, providing a total score out of 40. A higher score indicates a worse 
health status. The result is immediately available without the need for any calculation, apart 
from summing the scores on individual items. Scores of 0 - 10, 11 - 20, 21 - 30 and 31 - 40 
represent a mild, moderate, severe or very severe clinical impact of COPD upon the patient. 
An example of the COPD Assessment Test (CAT) is provided in Appendix 5.  
6.5.4 
Rescue medication  
Use of rescue medication (number of puffs taken in the previous 12 hours) is recorded 
morning and evening, by the patient, in the paper diary. The use of rescue medication is 
entered in the eCRF.  
6.5.5 
Appropriateness of efficacy assessments 
The efficacy assessments planned for this study: trough pre-dose FEV1, FVC, rescue 
medication usage and patient symptoms (BDI/TDI and CAT) are standard for COPD clinical 
trials. 


Novartis 
Confidential 
Page 37 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
6.6 
Safety  
6.6.1 
Physical examination  
A physical examination will be performed at Visits 1, 3 and 4; please refer to Table 6-1. It 
will 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 are performed. 
Information for all physical examinations must be included in the source documentation at the 
study site. Significant findings that are present prior to the start of study must be included in 
the Relevant Medical History/Current Medical Conditions screen on the patient’s eCRF. 
Significant findings made after the start of study which meet the definition of an Adverse 
Event must be recorded on the Adverse Event screen of the patient’s eCRF. 
6.6.2 
Vital signs  
Vital signs include radial pulse rate (measured for 60 seconds) and systolic and diastolic blood 
pressure. Pulse rate and blood pressure is assessed after the patient has rested in the 
sitting/supine position for at least 5 minutes. If an automated blood pressure device is used, it 
should be calibrated according to the manufacturer’s guidelines. Clinically notable vital signs 
are defined in Appendix 6. Vital signs will be obtained at each visit described in Table 6-1. 
6.6.3 
Height and weight  
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor 
clothing, but without shoes) is measured at Visit 1. Weight is recorded again at Visit 4. 
6.6.4 
Laboratory evaluations  
Not applicable 
6.6.5 
Electrocardiogram (ECG)  
A standard single 12 lead ECG is collected at Visit 1, 2 and 4. ECGs must be recorded after 
10 minutes rest in the supine position to ensure a stable baseline. The preferred sequence of 
cardiovascular data collection during study visits is ECG collection first, followed by vital 
signs, and spirometry. The Fridericia QT correction formula (QTcF) should be used for 
clinical decisions. 
The original ECGs appropriately signed, should be collected and archived at the study site. 
Each ECG tracing should be labeled with study number, subject initials, subject number, date 
and time, and filed in the study site source documents. For any ECGs with subject safety 
concerns, two additional ECGs should be performed to confirm the safety finding. Clinically 
significant ECG findings at baseline must be discussed with the sponsor before administration 
with investigational treatment. 
Clinically significant abnormalities are recorded on the relevant section of the medical 
history/Current medical conditions/AE eCRF page as appropriate. 


Novartis 
Confidential 
Page 38 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
Only local reading/interpretation of ECGs is performed.  The ECG equipment provides an 
immediate computer-generated interpretation but no central reading performed. 
6.6.6 
Pregnancy and assessments of fertility  
A urine pregnancy test is performed in pre-menopausal women who are not surgically sterile 
per Assessment Schedule Table 6-1. A positive pregnancy test at Visit 1 or at any time during 
the study requires the patient to be discontinued from the study treatment. Refer to Section 
5.5.9 for more details. 
Women of child-bearing potential should be instructed to notify the investigator staff 
immediately if the woman becomes pregnant at any time during the study. The patient must 
be discontinued from the study treatment.  
6.6.7 
Pneumonia 
Pneumonia is defined as an event characterized by increased respiratory symptoms (e.g. 
increased cough, dyspnea, wheezing, purulent sputum and fever) (i.e. body temperature 
greater than 38°C) or pleuritic chest pain or leukocytosis or other clinical signs consistent with 
pneumonia considered relevant in the opinion of the investigator.   Radiographic imaging, 
preferably a chest x-ray, is required to facilitate the diagnosis. The diagnosis of COPD 
exacerbation does not preclude a diagnosis of pneumonia. The investigator will use clinical 
judgment to determine if the events are occurring simultaneously. All pneumonia events are 
recorded on the AE CRF and follow SAE reporting if applicable. 
6.6.8 
COPD exacerbations   
COPD exacerbation is defined as: 
A worsening of the following two or more major symptoms for at least 2 consecutive days: 
• dyspnea 
• sputum volume 
• sputum purulence 
OR 
A worsening of any 1 major symptom together with an increase in any one of the following 
minor symptoms for at least 2 consecutive days: 
• sore throat 
• colds (nasal discharge and/or nasal congestion) 
• fever without other cause 
• cough 
• wheeze 
A COPD exacerbation is considered of moderate severity if treatment with systemic 
corticosteroids or antibiotics or both was required and severe, if hospitalization was required. 
An emergency room (ER) visit of longer than 24 hours will be considered a hospitalization.  


Novartis 
Confidential 
Page 39 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
In the event of a COPD exacerbation matching the above definition occurring at any time after 
signing of informed consent, patients should be treated for the exacerbation as deemed 
necessary by the investigator.  
All moderate or severe COPD exacerbations (as per definition above) should be recorded on 
the COPD exacerbation eCRF. 
A worsening of symptoms that either do not meet the above symptom definition but is 
treated by the investigator with systemic corticosteroids or antibiotics, or that meets the 
symptom definition but does not receive antibiotics and/or systemic corticosteroids,  is 
not considered a moderate or severe COPD exacerbation for the study.  However, these 
events should still be captured on the COPD exacerbation CRF as mild exacerbations. 
The start date for a COPD exacerbation recorded in the eCRF should be the first day of 
symptom worsening of two or more major symptoms or of one major and one minor 
symptom, as defined above. The end of a COPD exacerbation episode is marked by the return 
to pre-exacerbation symptom status. At the end of an exacerbation the patient must attend the 
clinic, where possible, for assessment of the episode. 
Patients who develop a COPD exacerbation between Visits 1 and 2 are discontinued but are 
permitted to be re-screened after a minimum of 6 weeks after the resolution of the COPD 
exacerbation (see exclusion criteria). 
If systemic corticosteroids are taken for a COPD exacerbation within 7 days prior to any study 
visit, the visit must be rescheduled to allow a washout of 7 days (Patient should be 
discontinued if treated with Depo-Medrone® as discussed in (Section 5.5.9).  Scheduled 
spirometry should not be performed during an exacerbation until it has completely resolved. 
Any spirometry data collected during an exacerbation will not be used in the data analysis if 
the systemic corticosteroids to treat the exacerbation were administered within 7 days of the 
spirometry assessment. 
Following treatment for the exacerbation, the patient will be expected to continue in the study 
provided the investigator considers that the patient can safely return to their pre-exacerbation 
medications. No spirometry assessments should be taken until after the exacerbation has 
resolved. 
6.6.9 
Appropriateness of safety measurements  
The safety assessments selected are standard for this indication/patient population. 
6.7 
Other assessments  
No additional tests are performed on patients entered into this study. 


Novartis 
Confidential 
Page 40 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
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) 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. 
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: 
• 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 (no/yes), or indistinguishable 
• 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 - See section 7.2 for definition of 
SAE) 
• action taken regarding study treatment  
• its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown) 
All adverse events should be treated appropriately. Treatment may include one or more of the 
following:  
• no action taken (i.e. further observation only)  


Novartis 
Confidential 
Page 41 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
• study treatment dosage adjusted/temporarily interrupted  
• study treatment permanently discontinued due to this adverse event  
• concomitant medication given  
• non-drug therapy given  
• patient hospitalized/patient’s hospitalization prolonged  
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 drug, the 
interventions required to treat it, and the outcome. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB) or will be communicated between IB updates in the 
form of Investigator Notifications. This information will be included in the patient informed 
consent and should be discussed with the patient during the study as needed. 
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. 
7.2 
Serious adverse events  
7.2.1 
Definition of SAE  
An SAE is defined as 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 (specify what this includes) 
• 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 


Novartis 
Confidential 
Page 42 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
• is medically significant, i.e. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention. 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if more severe (see Annex IV, ICH-E2D Guideline). 
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse (see Annex IV, ICH-E2D Guideline). 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All AEs (serious and non-serious) are captured on the CRF, SAEs also require individual 
reporting to DS&E as per section 7.2.2. 
7.2.2 
SAE 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 (for which the 
investigator learns via routine medical care and interactions with the patient) 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. 


Novartis 
Confidential 
Page 43 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
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, whether the treatment code was broken or not 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. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study 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 study 
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 EU Guidance 2011/C 172/01 or as per national regulatory 
requirements in participating countries. 
7.3 
Liver safety monitoring  
Not Applicable 
7.4 
Renal safety monitoring  
Not Applicable 
7.5 
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 the Pharmacovigilance 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. 
In addition to the pregnancy form, all pregnancies must be reported on the AE CRF. Any SAE 
experienced during the pregnancy and unrelated to the pregnancy must be reported on a SAE 
report form and AE CRF. 
7.6 
Prospective suicidality assessment  
Not Applicable 


Novartis 
Confidential 
Page 44 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
8 
Data review and database management  
8.1 
Site monitoring  
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative (or designated CRO representative) will review the protocol and CRFs with the 
investigators and their staff. During the study, Novartis employs several methods of ensuring 
protocol and GCP compliance and the quality/integrity of the sites’ data. The field monitor 
will visit the site to check the completeness of patient records, the accuracy of entries on the 
(e)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.  Continuous remote monitoring of each site’s data may be performed by 
centralized Novartis (or CRO) study personnel.   Additionally, a central analytics organization 
may analyze data & identify risks & trends for site operational parameters, and provide 
reports to Novartis Clinical Teams to assist with trial oversight. 
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. 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. 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. 
8.2 
Data collection  
Designated investigator staff will enter the data required by the protocol into the eCRF using 
fully validated software that conforms to US CFR 21Part 11 requirements. Designated 
investigator site staff will not be given access to the electronic data collection (EDC) system 
until they have been trained.  
Automatic validation programs check for data discrepancies and, by generating appropriate 
error messages, allow the data to be confirmed or corrected before transfer of the data to the 
CRO working on behalf of Novartis. The Investigator must certify that the data entered into 
the eCRFs are complete and accurate. After database lock, the investigator will receive copies 
of the patient data for archiving at the investigational site.  


Novartis 
Confidential 
Page 45 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
8.3 
Database management and quality control  
Novartis staff or CRO working on behalf of Novartis review the data entered into the CRFs by 
investigational staff for completeness and accuracy and instruct the site personnel to make any 
required corrections or additions. Queries are sent to the investigational site using an 
electronic data query. Designated investigator site staff are required to respond to the query 
and confirm or correct the data. If the electronic query system is not used, a paper Data Query 
Form will be faxed to the site. Site personnel will complete and sign the faxed copy and fax it 
back to Novartis staff that will make the correction to the database. The signed copy of the 
Data Query Form is kept at the investigator site. 
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. 
ECG results will be sent electronically to Novartis (or a designated CRO). 
Spirometry readings will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO). 
Randomization codes and data about all study drug(s) dispensed to the patient and all dosage 
changes will be tracked using an Interactive Response Technology (IRT). The system will be 
supplied by a vendor, who will also manage the database. The database will be sent 
electronically to Novartis (or a designated CRO). 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor.  
The code break functionality will remain available until study shut down or upon request of 
Novartis.  
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unblinded and made available for data analysis. Any 
changes to the database after that time can only be made after written agreement by Novartis 
Development management. 
8.4 
Data Monitoring Committee 
Not required 
8.5 
Adjudication Committee 
Not required 


Novartis 
Confidential 
Page 46 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
9 
Data analysis  
9.1 
Analysis sets 
The randomized set (RAN) will include all randomized patients, regardless of whether or not 
they actually received randomized study medication. Patients in the RAN will be analyzed 
according to the treatment they were randomized to. 
The full analysis set (FAS) will include all randomized patients who received at least one dose 
of randomized study medication. Following the intent-to-treat principle, patients will be 
analyzed according to the treatment they were assigned to at randomization. 
The per-protocol set (PPS) will include all patients in the FAS without any major protocol 
deviations. Major protocol deviations will be defined prior to database lock and the un-
blinding of the study. Patients will be analyzed according to the randomized treatment. 
The safety set will include all patients who received at least one dose of randomized study 
treatment. Patients will be analyzed according to the treatment they received during the 
randomized treatment period. If a patient took both treatments the patient will be analyzed 
according to the randomized treatment. 
The analysis of the primary objective will be performed on the FAS. The PPS may be used for 
supportive analysis of the primary variable. The FAS will be used for the analysis of all other 
efficacy variables. The safety set will be used in the analysis of all safety variables. 
Note that the FAS and safety sets will contain the same patients except that the safety set 
allows the inclusion of non-randomized patients who receive randomized study treatment in 
error. 
9.2 
Patient demographics and other baseline characteristics  
Demographic and baseline characteristics including age, sex, race, ethnicity, height, weight, 
body mass index (BMI), severity and duration of COPD, smoking history and estimated 
number of pack years, COPD exacerbation history, other relevant medical history, 
concomitant medications (COPD related and non-COPD related) discontinued prior to start of 
randomized study drug, results from CAT score, and results of screening and baseline 
spirometry will be summarized by treatment in the FAS. Baseline ECG and vital signs results 
will be summarized for the safety set. 
Demographic data and SAEs of screening failures will be listed only. 
9.3 
Treatments  
The number of patients and the length of time (in days) exposed to the randomized study drug 
will be summarized by treatment in the safety set. 
Concomitant medications will be summarized by treatment in the safety set. Concomitant 
COPD related medications will be summarized by pre-specified categories, route of 
administration and preferred term. Concomitant medications not related to COPD will be 
summarized by preferred term. 


Novartis 
Confidential 
Page 47 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
Treatment compliance will be summarized by treatment for the safety set according to 
percentage of days compliant. 
9.4 
Analysis of the primary variable(s) 
The primary objective of this study is to demonstrate the superiority of QVA149 110/50 µg 
o.d. compared to salmeterol/fluticasone 50/500 µg b.i.d. in mean trough pre-dose FEV1 at 
Week 12. 
9.4.1 
Variable(s) 
Mean trough pre-dose FEV1 at Week 12 is defined as the average of the measurements taken -
45min and -15min pre study medication dose in the clinic after 12 weeks of treatment (Day 
84). The baseline measurement is defined as the average of the scheduled FEV1 values prior 
to first intake of randomized study drug at Day 1 (Visit 2). 
Trough pre-dose for QVA corresponds to 24 hours after the last QVA dose (i.e. last dose prior 
to the FEV1 measurement) and 12 hours after the last dose of salmeterol/fluticasone. 
Spirometry is performed in the morning prior to the administration of the morning dose of 
study medication. 
9.4.2 
Statistical model, hypothesis, and method of analysis 
The following null hypothesis (Ho) versus the alternative hypothesis (Ha) will be tested at a 
significance level of 0.05 in the FAS: 
Ho: There is no difference in mean trough pre-dose FEV1 after 12 weeks of treatment 
between QVA149 100/50 µg o.d. and salmeterol/fluticasone 50/500 µg b.i.d. 
Ha: There is a significant difference in mean trough pre-dose FEV1 after 12 weeks of 
treatment between QVA149 100/50 µg o.d. and salmeterol/fluticasone 50/500 µg b.i.d. 
The treatment difference between QVA149 110/50 µg o.d. and salmeterol/fluticasone 50/500 
µg b.i.d. in terms of mean trough pre-dose FEV1 after 12 weeks of treatment will be estimated 
using ANCOVA for repeated measures. The model will include terms of treatment, baseline 
FEV1, 
smoking 
status 
at 
baseline, 
region, 
visit, 
treatment*visit 
interaction, 
baseline FEV1*visit interaction and an unstructured variance-covariance structure assuming 
normal distribution of the FEV1 data, where visit will be treated as a categorical variable. 
Center nested within region may be added as random effect depending on model convergence. 
Missing values of mean pre-dose FEV1 at Day 42 and Day 84 will not be imputed. 
The estimated treatment difference of QVA149 110/50 µg o.d. – salmeterol/fluticasone 
50/500 µg b.i.d. will be displayed along with the associated 95% confidence interval and p-
value. Superiority of QVA149 110/50 µg o.d. to salmeterol/ fluticasone 50/500 µg b.i.d. will 
be demonstrated if the p-value is less than 0.05 and the 95% confidence interval lies entirely 
to the right of 0 L. 


Novartis 
Confidential 
Page 48 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
9.4.3 
Handling of missing values/censoring/discontinuations 
If any of the values contributing to trough pre-dose FEV1 or baseline FEV1 are collected 
within 6 hours of rescue medication or less than 7 days after systemic corticosteroid use then 
the individual FEV1 value will be set to missing. Also if a value is taken post-dose instead of 
pre-dose it will not be used for calculation of trough pre-dose or baseline values. Since dosing 
times are only recorded in the diary for the days prior to scheduled visits no further time 
window will be applied for deriving pre-dose values. For the primary analysis, values will not 
be carried forward since ANCOVA for repeated measures will be applied. If all values 
contributing to the baseline FEV1 are missing (or are not confirmed to be pre-dose), then the 
pre-bronchodilator measurements taken at Screening will be used as the baseline. 
9.4.4 
Supportive analyses 
The following supportive analyses may be conducted for mean pre-dose FEV1 at Week 12: 
(1) Imputation of missing Week 12 data by Last Observation Carried Forward (LOCF), i.e., 
using the value from Day 42. A linear mixed model including the terms of treatment, baseline 
FEV1, smoking status at baseline, and region as fixed effects and center nested within region 
as random effect will be applied. 
(2) Analysis based on pattern mixture model: 
An additional method for handling missing data will be implemented to explore the sensitivity 
to the Missing At Random (MAR) assumption. A pattern-mixture model based on non-
ignorable missing, i.e., Missing Not At Random (MNAR) will be used, where all drop-outs 
are assumed to switch back to salmeterol/fluticasone 50/500 µg b.i.d. treatment. This 
approach will be implemented by multiple imputations, where missing values are repeatedly 
replaced by sampling from the Bayesian posterior predictive distribution based on the 
switching model. Each of the completed datasets is then analyzed using the primary analysis, 
and then the estimates are combined to get the final inference.  
(3) Applying the ANCOVA for repeated measurements using the PPS. 
9.5 
Analysis of secondary variables 
9.5.1 
Efficacy variables 
TDI  
The TDI focal score at Week 6 and Week 12 will be analyzed using ANCOVA for repeated 
measures. The model will be similar to the model of the primary analysis with the baseline 
BDI instead of baseline FEV1 included in the model.  
Additionally the percentage of patients with a clinically significant improvement after 
12 weeks of treatment in TDI (of >=1 change from baseline) will be analyzed using a logistic 
regression model which includes the same terms as used for the analysis of the TDI focal 
score. 
Mean pre-dose FVC 


Novartis 
Confidential 
Page 49 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
The same analyses as for mean trough pre-dose FEV1 will be done for mean pre-dose FVC 
with the baseline FVC instead of baseline FEV1 included in the model. 
FEV1 at individual post-baseline time points 
A similar method as for the primary endpoint will be applied for the analysis of FEV1 at Week 
6 (Visit 3) and Week 12 (EOS/Visit 4), i.e., separate ANCOVA for repeated measures will be 
performed for each time point using visit as repeated variable. 
FVC at individual post-baseline time points 
The same analyses as for FEV1 at Week 6 (Visit 3) and Week 12 (EOS/Visit 4) will be done 
for FVC. 
CAT 
A similar method as for the primary endpoint will be applied for the analysis of CAT with the 
baseline CAT result instead of baseline FEV1 included in the model. Additionally the 
proportions of patients with different levels of clinical impact, i.e., total CAT scores of 0-10 
(mild), 11-20 (moderate), 21-30 (severe) and 31-40 (very severe), will be summarized 
descriptively by treatment for each visit. 
Daily use of rescue medication (number of puffs) 
The mean daily number of puffs will be calculated for each patient over 12 weeks. Mean daily 
number of puffs during the screening period will be used to calculate the baseline. The mean 
daily number of puffs will be analyzed using a linear mixed model. The model will contain 
treatment, baseline mean daily number of puffs, smoking status at baseline, and region as 
fixed effects with center nested within region as a random effect. 
Percentage of days without rescue medication usage over 12 weeks 
The percentage of days without rescue medication usage will be calculated for each patient 
over the 12 week treatment period. This endpoint will be analyzed using a similar model as 
for rescue medication use, but with baseline percentage of days without rescue medication 
usage instead of baseline mean number of puffs included in the model. 
9.5.2 
Safety variables 
Adverse events 
All adverse events including COPD exacerbations, coded using MedDRA, will be listed. 
Treatment emergent adverse events are defined as those events starting on or after the time of 
the first administration of randomized study drug but not later than 7 days (30 days in the case 
of serious adverse events) after the last administration of study medication.  
Summaries of treatment emergent adverse events will be produced, overall by system organ 
class and preferred term for the following types of adverse events: 
• all adverse events, 
• all adverse events by maximum severity,  
• adverse events suspected to be study drug related, 


Novartis 
Confidential 
Page 50 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
• adverse events leading to permanent discontinuation of study treatment, 
• adverse events leading to interruption of study treatment, 
• adverse events leading to adjustment (dose increase or decrease) of study treatment, 
• adverse events requiring significant additional therapy, 
• serious adverse events (SAEs), 
• fatal adverse events. 
COPD exacerbations during the 12 week treatment period 
COPD exacerbations will be included in all adverse event analyses described above. In 
addition, COPD exacerbations reported during the 12 week treatment period will be 
summarized descriptively by severity. 
In patients with multiple exacerbations, if the start date of an exacerbation is less than 7 days 
after the end date of a previous episode then this will be assumed to be one continuous 
exacerbation with the start date taken from the first episode and the end date from the second 
or last episode. The worst severity of these episodes will be taken as the severity of the 
combined exacerbation. 
Vital signs and ECG 
Vital signs (blood pressure, pulse rate, and body weight) and ECG data will be summarized by 
treatment and scheduled visit including changes from baseline. The baseline value will be the 
pre-dose measurement at Visit 2. Data measured more than 7 days after last inhalation of 
study drug are regarded as post-treatment data and will not be summarized, only listed.  
The analyses will include maximum and minimum vital signs data and maximum QTc and 
ventricular rate during randomized treatment (up to 7 days after end of treatment). 
In addition, frequencies of notable vital signs and Fridericia's QTc (QTcF) will be 
summarized by treatment. Notable values are defined as follows: 


Novartis 
Confidential 
Page 51 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
Clinical notable criteria for vital signs 
Vital sign parameter (unit) 
Lower bound of clinically 
notable range 
Upper bound of clinically 
notable range 
Notable value considering newly occurring or worsening cases 
Systolic blood pressure (mmHg) 
< 75 
> 200 
Diastolic blood pressure (mmHg) 
< 40 
 
> 115 
Pulse rate (bpm) 
< 40 
> 130 
Notable change from baseline 
Systolic blood pressure (mmHg) 
≤ 90 and decrease from 
baseline by ≥ 20  
≥ 180 and increase from 
baseline by ≥ 20 
Diastolic blood pressure (mmHg) 
≤ 50 and decrease from 
baseline by ≥ 15 
≥ 105 and increase from 
baseline by ≥ 15 
Pulse rate (bpm) 
≤ 50 and decrease from 
baseline by ≥ 15 
≥ 120 and increase from 
baseline by ≥ 15 
Weight (kg) 
Decrease ≥ 7% from 
baseline 
Increase ≥ 7% from 
baseline 
The following table shows the clinical notable criteria for QTcF. 
Clinical notable criteria for QTcF (Fridericia's formula) 
ECG parameter (unit) 
Clinically notable range 
Notable value considering newly occurring or worsening cases 
QTc (ms) 
> 450 (both male and female) 
QTc (ms) 
> 480  
QTc (ms) 
> 500  
Notable change from baseline 
QTc 
30 – 60 
QTc 
> 60 
9.5.3 
Resource utilization  
Not Applicable 
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 


Novartis 
Confidential 
Page 52 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
9.6 
Interim analyses  
No interim analysis is planned. 
9.7 
Sample size calculation 
For the endpoint trough pre-dose FEV1 change from baseline, a SD of 220mL was used based 
on a review of the results of Novartis phase III COPD studies. Discontinuation rate = 15% 
was assumed. 
Sample size calculation for trough pre-dose FEV1 change 
alpha=0.05, 2-sided 
 
 
 
Power(%) 
90 
90 
90 
Difference to detect 
65 
70 
75 
SD 
220 
220 
220 
n per arm 
242 
209 
182 
with 15% drop-out rate  
285 
246 
215 
Total 
570 
492 
430 
 
Based on these calculations, a sample size of 418 completed patients is selected in order to 
detect a trough pre-dose FEV1 change of 70mL with 90% power. Assuming a 15% drop out 
rate, 492 patients will be randomized.  
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 CFR 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 consent, or, if incapable of doing 
so, after such consent has been provided by a legally acceptable representative(s) of the 
patient. In 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, s/he 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 
Confidential 
Page 53 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
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. 
10.3 
Responsibilities of the investigator and IRB/IEC  
Before initiating a trial, the investigator/institution should obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment 
procedures (e.g., advertisements) and any other written information to be provided to patients. 
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 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 
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safety of patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances should an 
investigator collect additional data or conduct any additional procedures for any research 
related purpose involving any investigational drugs. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
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 and health authorities, where required, it cannot be 
implemented. All significant protocol deviations will be recorded and reported in the CSR. 


Novartis 
Confidential 
Page 54 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
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 prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate 
hazard to patients may be implemented immediately provided the Health Authorities are 
subsequently notified by protocol amendment and the reviewing IRB/IEC is notified. 
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, the reporting 
requirements identified in Section 7 Safety Monitoring should be followed. 
12 
References 
Bateman ED, Ferguson GT, Barnes N, Gallagher N, Green Y, Henley M, Banerji D (2013) 
Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study. 
Eur Respir J 42(6):1484-94. 
Buist AS, McBurnie MA, Vollmer WM, et al. (2007) International variation in the prevalence 
of COPD (the BOLD Study): a population-based prevalence study. Lancet 370(9589):741-50. 
Dahl R, Chapman KR, Rudolf M, et al (2013) Safety and efficacy of dual bronchodilation 
with QVA149 in COPD patients: The ENLIGHTEN study. Respir Med 107(10):1558-67. 
Global Initiative for Chronic Obstructive Lung Disease [GOLD] (2014) Global strategy for 
the diagnosis, management and prevention of chronic obstructive pulmonary disease. 
Available from www.goldcopd.com 
Hersh CP (2010) Pharmacogenetics of chronic obstructive pulmonary disease: challenges and 
opportunities. Pharmacogenomics 11(2): 237-247. 
Jones PW, et al (2012) (on behalf of the CAT Development Steering Group) The COPD 
Assessment Test healthcare professional user guide: expert guidance on frequently asked 
questions. Issue 3: February 2012. 
Jones PW, et al (2009). Development and first validation of the COPD Assessment Test. Eur 
Respir J 34(3):648-54. 
Mahler D and Wells CK (1988) Evaluation of clinical methods for rating dyspnea. Chest 
93:580-586. 
Mahler DA, Decramer M, D’Urzo, A et al. (2014) Dual bronchodilation with QVA149 
reduces patient-reported dyspnoea in COPD: the BLAZE study. Eur Respir J 43(6): 1599-609. 
Vogelmeier CF, Bateman ED, Pallante J, et al. (2013) Efficacy and safety of once-daily 
QVA149 compared with twice-daily salmeterol-fluticasone in patients with chronic 
obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group 
study. Lancet Respir Med 1(1):51-60. 


Novartis 
Confidential 
Page 55 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
Appendix 1: Spirometry guidelines 
Equipment 
Spirometers must meet the specifications and performance criteria recommended in the 
American Thoracic Society (ATS)/European Respiratory Society (ERS) Standardization of 
Spirometry1. Spirometers must have the capacity to print FVC tracings.  All spirometry values 
should be reported at BTPS by the method established by the manufacturer. 
Calibration 
The spirometer should be calibrated every morning before any spirometric measurements for 
the study are performed. Calibration reports should be printed and stored as source data at the 
site.  
Preparing the test subject 
On study days when spirometry will be performed, patients should refrain from the following: 
• Coffee, tea, chocolate, cola and other caffeine-containing beverages and foods and ice-
cold beverages  for 4 hours prior to spirometry 
• Alcohol for 4 hours prior to spirometry 
• Strenuous activity for 12 hours prior to spirometry  
• Smoking within at least 1 hour of testing 
• Exposure to environmental smoke, dust or areas with strong odors  
Every effort should be made to assure consistent testing conditions throughout the study.  A 
seated position with nose clips is recommended to reduce risks related to dizziness or 
syncope.  When possible, spirometry should be conducted by the same technician using the 
same spirometer.  To minimize the effects of diurnal variation on lung function, spirometry 
visits should start at approximately the same time of day at each visit.   
Performing Spirometry 
The subject’s age, height and gender will be entered into the spirometer.  It is important that 
the height is measured accurately at the study site. Spirometry, an effort-dependent test, 
requires careful instruction and cooperation of the subject.  The technician should ensure a 
good seal around the mouthpiece, and confirm that the subject’s posture is correct. The 
subject should be instructed to perform a maximal inspiration, followed by maximum forced 
expiration until no more air can be exhaled or for at least 6 seconds. Expiration must be rapid 
with exertion of maximal effort. The results of spirometry should meet the ATS/ERS criteria 
for acceptability and repeatability. Acceptability criteria should be applied before repeatability 
is determined.   
Number of trials 
A minimum of 3 acceptable forced vital capacity (FVC) maneuvers should be performed.  If a 
subject is unable to perform a single acceptable maneuver after 8 attempts, testing may be 
discontinued.  


Novartis 
Confidential 
Page 56 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
Acceptability 
An acceptable maneuver has the following characteristics:  
• No hesitation or false start; 
• A rapid start; 
• No cough, especially during the first second of the maneuver; 
• No glottic closure or obstruction by tongue or dentures 
• No early termination of exhalation (minimum exhalation time of 6 seconds is 
recommended, or no volume change for at least 1 second) or the subject cannot continue 
to exhale further 
Repeatability 
The 2 largest FVC and FEV1 values from 3 acceptable maneuvers should not vary by more 
than 0.150 L.   
Recording of data 
The greatest FEV1 and FVC from any of the acceptable curves are recorded. (The greatest 
FEV1 and FVC may not necessarily result from the same acceptable curve).     
Predicted normal 
For subjects greater than 18 years of age, this study will utilize the spirometric predication 
equation standards for the European Community for Coal and Steel 2 or Nhanes3.  
Reversibility (Visit 1 only) 
All reversibility evaluations should follow the recommendations of the ATS/ERS Task force: 
Standardization of Lung Function Testing1. A pre-bronchodilator spirometry assessment 
should be performed after a washout period of at least: 
• 6 h for short-acting β2-agonists  
• 8 h short-acting anticholinergics  
• 24 h for long-acting β2-agonist 
• 7 days long-acting anticholinergics  
• 3 days indacaterol 
Administer 84 μg (or equivalent dose) of ipratropium bromide within 5 minutes of pre-
bronchodilator spirometry, followed by the administration of 400 μg of salbutamol (or 360 μg 
albuterol) a few minutes later. 
Post-bronchodilator spirometry is performed 1h after the administration of 
salbutamol/albuterol 
 
Reversibility is calculated as:  
100 x        FEV1 (post-bronchodilator) – FEV1 (pre-bronchodilator) 
                                     FEV1 (pre-bronchodilator) 


Novartis 
Confidential 
Page 57 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
 
Following the reversibility testing assessment for post-bronchodilator FEV1, if lung function 
has deteriorated (i.e. there is a decrease in post bronchodilator FEV1 compared to pre-
bronchodilator FEV1 as opposed to an increase) after administration of ipratropium and 
salbutamol or albuterol, then the patient should be screen failed. Patients with COPD 
demonstrating significant reversibility (i.e. 20%) may require further clinical evaluation by the 
investigator to rule out a diagnosis of asthma.    
 
 
References 
1 Miller MR et al, Standardization of Spirometry. Eur Resp J 2005;26:319-338. 
2 Quanjer PH at al. Lung volumes and forced ventilatory flows, Report Working Party 
Standardization of Lung Function Tests, European Community for Steel and Coal.  Official 
Statement of the European Respiratory society.  Eur Resp J 1993;6: Suppl. 16, 5-40. 
3 Hankinson JL,  Odencrantz JR, Fedan KB (1999) Spirometric reference values from a 
sample of the general US population. Am J Respir Crit Care Med 159:179–187. 
 


Novartis 
Confidential 
Page 58 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
Appendix 2: Instructions for use of the SDDPI 
How to use the SDDPI 
 
 


Novartis 
Confidential 
Page 59 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
 


Novartis 
Confidential 
Page 60 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
 


Novartis 
Confidential 
Page 61 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
 


Novartis 
Confidential 
Page 62 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
 
 


Novartis 
Confidential 
Page 63 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
Appendix 3: Instructions for use of the Accuhaler®/Diskus® 
 
 
How to use the Accuhaler®/Diskus® 
 
 
How to clean your inhaler 
Wipe the mouthpiece of the Accuhaler®/Diskus® with a dry tissue to clean it. 
 
 


Novartis 
Confidential 
Page 64 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
Appendix 4: Baseline dyspnea index/transitional dyspnea index 
(BDI/TDI) 
(Samples for illustrative purposes only) 
 
BASELINE DYSPNEA INDEX (BDI) 
 
Baseline Functional Impairment 
 
        Grade 4 
No Impairment 
Able to carry out usual activities and occupation 
without shortness of breath. 
        Grade 3 
Slight Impairment 
Distinct impairment in at least one activity but no 
activities completely abandoned. Reduction, in 
activity at work or in usual activities, that seems 
slight or not clearly caused by shortness of breath. 
        Grade 2 
Moderate Impairment 
Subject has changed jobs and/or has abandoned at 
least one usual activity due to shortness of breath. 
        Grade 1 
Severe Impairment 
Subject unable to work or has given up most or all 
usual activities due to shortness of breath. 
        Grade 0 
Very Severe Impairment 
Unable to work and has given up most or all usual 
activities due to shortness of breath. 
        W 
Amount Uncertain 
Subject is impaired due to shortness of breath, but 
amount cannot be specified. Details are not sufficient 
to allow impairment to be categorized. 
        X 
Unknown 
Information unavailable regarding 
impairment. 
 
        Y 
Impaired for Reasons 
Other than Shortness 
of Breath 
For example, musculoskeletal problem or chest 
pain. 
 
Usual activities refer to requirements of daily living, maintenance or upkeep of residence, yard 
work, gardening, shopping, etc. 
 
 
 
 


Novartis 
Confidential 
Page 65 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
Baseline Magnitude of Task 
 
        Grade 4 
Extraordinary 
Becomes short of breath only with extraordinary 
activity such as carrying very heavy loads on the level, 
lighter loads uphill, or running. No shortness of breath 
with ordinary tasks. 
        Grade 3 
Major 
Becomes short of breath only with such major 
activities as walking up a steep hill, climbing more 
than three flights of stairs, or carrying a moderate load 
on the level. 
        Grade 2 
Moderate 
Becomes short of breath with moderate or average 
tasks such as walking up a gradual hill, climbing fewer 
than three flights of stairs, or carrying a light load on the 
level. 
        Grade 1 
Light 
Becomes short of breath with light activities such as 
walking on the level, washing, or standing. 
        Grade 0 
No Task 
Becomes short of breath at rest, while sitting, or lying 
down. 
        W 
Amount Uncertain 
Subject's ability to perform tasks is impaired due to 
shortness of breath, but amount cannot be specified. 
Details are not sufficient to allow impairment to be 
categorized. 
        X 
Unknown 
Information unavailable regarding limitation of 
magnitude of task. 
        Y 
Impaired for Reasons 
Other than Shortness 
of Breath 
For example, musculoskeletal problem or chest 
pain. 
 
 
 
Baseline Magnitude of Effort 
 
        Grade 4 
Extraordinary 
Becomes short of breath only with the greatest 
imaginable effort. No shortness of breath with 
ordinary effort. 
        Grade 3 
Major 
Becomes short of breath with effort distinctly 
submaximal, but of major proportion. Tasks performed 
without pause unless the task requires extraordinary 
effort that may be performed with pauses. 


Novartis 
Confidential 
Page 66 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
        Grade 2 
Moderate 
Becomes short of breath with moderate effort. 
Tasks performed with occasional pauses and 
requiring longer to complete than the average 
person. 
        Grade 1 
Light 
Becomes short of breath with little effort. Tasks 
performed with little effort or more difficult tasks 
performed with frequent pauses and requiring 50-
100% longer to complete than the average person 
might require. 
        Grade 0 
No Effort 
Becomes short of breath at rest, while sitting, or lying 
down. 
        W 
Amount Uncertain 
Subject's exertional ability is impaired due to shortness 
of breath, but amount cannot be specified. Details are 
not sufficient to allow impairment to be categorized. 
        X 
Unknown 
Information unavailable regarding limitation of effort. 
        Y 
Impaired for Reasons 
Other than Shortness 
of Breath 
For example, musculoskeletal problems, or chest 
pain. 
 
 
 
TRANSITION DYSPNEA INDEX (TDI) 
 
Change in Functional Impairment 
 
        -3 
Major Deterioration 
Formerly working and has had to stop 
working and has completely abandoned 
some of usual activities due to shortness 
of breath. 
        -2 
Moderate Deterioration 
Formerly working and has had to stop 
working or has completely abandoned some 
of usual activities due to shortness of breath. 
        -1 
Minor Deterioration 
Has changed to a lighter job and/or has 
reduced activities in number or duration due 
to shortness of breath. Any deterioration less 
than preceding categories. 
        0 
No Change 
No change in functional status due to 
shortness of breath. 


Novartis 
Confidential 
Page 67 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
        +1 
Minor Improvement 
Able to return to work at reduced pace or has 
resumed some customary activities with 
more vigor than previously due to 
improvement in shortness of breath. 
        +2 
Moderate Improvement 
Able to return to work at nearly usual pace 
and/or able to return to most activities with 
moderate restriction only. 
        +3 
Major Improvement 
Able to return to work at former pace and 
able to return to full activities with only mild 
restriction due to improvement of shortness 
of breath. 
        Z 
Further Impairment for 
Reasons Other than 
Shortness of Breath 
Subject has stopped working, reduced work, 
or has given up or reduced other activities for 
other reasons. For example, other medical 
problems, being “laid off” from work, etc. 
 
 
Change in Magnitude of Task 
 
        -3 
Major Deterioration 
Has deteriorated two grades or greater from 
baseline status. 
        -2 
Moderate Deterioration 
Has deteriorated at least one grade but fewer 
than two grades from baseline status. 
        -1 
Minor Deterioration 
Has deteriorated less than one grade from 
baseline. Subject with distinct deterioration 
within grade, but has not changed grades. 
        0 
No Change 
No change from baseline. 
        +1 
Minor Improvement 
Has improved less than one grade from 
baseline. Subject with distinct improvement 
within grade, but has not changed grades. 
        +2 
Moderate Improvement 
Has improved at least one grade but fewer 
than two grades from baseline. 
        +3 
Major Improvement 
Has improved two grades or greater from 
baseline. 
        Z 
Further Impairment for 
Reasons Other than 
Shortness of Breath 
Subject has reduced exertion capacity, 
but not related to shortness of breath. 
For example, musculoskeletal problem or 
chest pain. 
 


Novartis 
Confidential 
Page 68 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
 
 
Change in Magnitude of Effort 
 
        -3 
Major Deterioration 
Severe decrease in effort from baseline to avoid 
shortness of breath. Activities now take 
50-100% longer to complete than required at 
baseline. 
        -2 
Moderate Deterioration 
Some decrease in effort to avoid shortness 
of breath, although not as great as preceding
category. There is greater pausing with some
activities. 
        -1 
Minor Deterioration 
Does not require more pauses to avoid 
shortness of breath, but does things with 
distinctly less effort than previously to avoid 
breathlessness. 
        0 
No Change 
No change in effort to avoid shortness of 
breath. 
        +1 
Minor Improvement 
Able to do things with distinctly greater effort 
without shortness of breath. For example, may be 
able to carry out tasks somewhat more rapidly 
than previously. 
        +2 
Moderate Improvement 
Able to do things with fewer pauses and 
distinctly greater effort without shortness of 
breath. Improvement is greater than 
preceding category, but not of major 
proportion. 
        +3 
Major Improvement 
Able to do things with much greater effort than 
previously with few, if any, pauses. For 
example, activities may be performed 
50-100% more rapidly than at baseline. 
        Z 
Further Impairment for 
Reasons Other than 
Shortness of Breath 
Subject has reduced exertional capacity, but 
not related to shortness of breath. 
For example, musculoskeletal problem or 
chest pain. 
 


Novartis 
Confidential 
Page 69 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
Appendix 5: COPD Assessment Test (CAT) 
 


Novartis 
Confidential 
Page 70 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
Appendix 6: Clinically notable vital signs 
 
Notable values for vital signs and change from baseline will be summarized. A notable value 
is defined as follows: 
Systolic blood pressure 
• “Low” criterion: <75 mmHg, or ≤90 mmHg and decrease from baseline ≥20 mmHg 
• “High” criterion: >200 mmHg, or ≥180 mmHg and increase from baseline ≥20 mmHg 
Diastolic blood pressure 
• “Low” criterion: <40 mmHg, or ≤50 mmHg and decrease from baseline ≥15 mmHg 
• “High” criterion: >115 mmHg, or ≥105 mmHg and increase from baseline ≥15 mmHg 
Pulse rate 
• ”Low” criterion: <40 bpm, or ≤50 bpm and decrease from baseline ≥15 bpm 
• “High” criterion: >130 bpm, or ≥120 bpm and increase from baseline ≥15 bpm 
 
 


Novartis 
Confidential 
Page 71 
Amended Protocol v02-Tracked Changes 
 
Protocol No. CQVA149A3405 
 
 
 
Appendix 7: Patient diary (example) 
 
PATIENT COPD TREATMENT DIARY 
Instructions: 
 
1. Please use this diary to record the time when you take your COPD medication each morning and 
evening. Please (√) check if you missed the dose.  
2. Each morning and evening record the number of puffs of reliever medication taken during the past 
12 hours. 
Date 
IN THE MORNING 
IN THE EVENING 
 
Morning time 
of study 
medication 
Number of puffs 
of reliever 
medication taken 
in the past 12 
hours 
Evening time 
of study 
medication 
Number of puffs 
of reliever 
medication taken 
in the past 12 
hours  
___ /___ /20_ _ 
   (day) / (month) 
_____:_____ 
 missed 
_______   
puffs 
_____:_____ 
 missed 
_______   
puffs 
___ /___ /20_ _ 
   (day) / (month) 
_____:_____ 
 missed 
_______ 
puffs 
_____:_____ 
 missed 
_______   
puffs 
___ /___ /20_ _ 
   (day) / (month) 
_____:_____ 
 missed 
_______ 
puffs 
_____:_____ 
 missed 
_______ 
puffs 
___ /___ /20_ _ 
   (day) / (month) 
_____:_____ 
 missed 
_______ 
puffs 
_____:_____ 
 missed 
_______ 
puffs 
___ /___ /20_ _ 
   (day) / (month) 
_____:_____ 
 missed 
_______ 
puffs 
_____:_____ 
 missed 
_______ 
puffs 
___ /___ /20_ _ 
   (day) / (month) 
_____:_____ 
 missed 
_______ 
puffs 
_____:_____ 
 missed 
_______ 
puffs 
___ /___ /20_ _ 
   (day) / (month) 
_____:_____ 
 missed 
_______ 
puffs 
_____:_____ 
 missed 
_______ 
puffs 
 

SAP_000.pdf: 
Clinical Development 
QVA149 (indacaterol maleate/glycopyrronium bromide) 
CQVA149A3405 / NCT02516592
A 12-week treatment, multi-center, randomized, 
doubleblind, double-dummy, parallel group study to assess 
the efficacy and safety of switching from 
salmeterol/fluticasone to QVA149 (indacaterol 
maleate/glycopyrronium bromide) in symptomatic COPD 
patients 
RAP Module 3 – Detailed Statistical Methodology 
Author: 
 
Document type: 
RAP Documentation 
Document status: 
Amendment 2 
Release date: 
13-Jun-2017
Number of pages: 
26 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


Novartis 
Confidential 
Page 2 
RAP Module 3 
23-Jan-2018 (11:37) 
QVA149A3405 
 
Document History – Changes compared to previous version of RAP module 3. 
Version 
Date 
Changes 
Amendment 1 
3-Feb- 2017 
Combined assessment of COPD (according to GOLD 2014 and 
2017) included in baseline characteristics and as subgroup.  
Added FEV1 reversibility as categorized variable. 
Additional subgroup analysis added for the primary endpoint. 
Included ECG analysis as described in protocol. Clinical notable 
criteria for QTcF were included 
Compliance calculation was adapted since number of 
capsules/doses taken is not available on eCRF. Compliance >100% 
can not be detected. 
Further categories for COPD related medications were included. 
Baseline definition for CAT score was changed. 
Added more detail for derivation of rescue medication use in 
Appendix 16.1.9.4. 
Amendment 2 
13-Jun-2017 
Correction: Removed minor protocol deviations (those not excluding 
the patient from any analysis) from Section 16.1.9.2. 
Updated Section 16.1.9.3: Added the exclusion for FAS, PP and 
SAF for patients which are not treated, as per definition of the 
analysis sets.  
 
 
 
 
 
 
 


Novartis 
Confidential 
Page 3 
RAP Module 3 
23-Jan-2018 (11:37) 
QVA149A3405 
 
Table of contents 
Table of contents ................................................................................................................. 3 
1 
Introduction ......................................................................................................................... 4 
1.1 
Changes to RAP from protocol specified analysis: ................................................. 4 
2 
Detailed statistical methodology ......................................................................................... 4 
2.1 
Study objectives ....................................................................................................... 4 
2.1.1 
Primary objective .................................................................................... 4 
2.1.2 
Secondary objectives ............................................................................... 4 
2.2 
Analysis sets ............................................................................................................ 5 
2.3 
Patient disposition, background and demographic characteristics .......................... 5 
2.3.1 
Patient disposition ................................................................................... 5 
2.3.2 
Demographics and baseline characteristics ............................................. 6 
2.3.3 
Medical history ........................................................................................ 7 
2.4 
Study medication ..................................................................................................... 7 
2.4.1 
Study drug administration ....................................................................... 7 
2.4.2 
Compliance ............................................................................................. 7 
2.5 
Concomitant medication .......................................................................................... 7 
2.6 
Efficacy evaluation .................................................................................................. 8 
2.6.1 
Analysis of the primary efficacy variable ............................................... 8 
2.6.2 
Analysis of secondary variables ............................................................ 10 
2.7 
Safety evaluation ................................................................................................... 12 
2.7.1 
Adverse Events ...................................................................................... 12 
2.7.2 
COPD exacerbations during the 12 week treatment period .................. 13 
2.7.3 
Vital signs and ECG .............................................................................. 14 
2.8 
Interim analyses ..................................................................................................... 15 
2.9 
Determination of sample size ................................................................................ 15 
Clinical Study Report -  Appendix 16.1.9  Documentation of statistical methods ........... 16 
16.1.9.1 Introduction ........................................................................................... 16 
16.1.9.2 Major protocol deviations ..................................................................... 16 
16.1.9.3 Subject classification ............................................................................. 17 
16.1.9.4 Baseline and post-baseline definitions, missing data handling ............. 18 
16.1.9.5 Derivation of demographics and baseline characteristics ..................... 19 
16.1.9.6 Vital signs – definition of clinically notable values .............................. 21 
16.1.9.8 Statistical methodology and assumptions ............................................. 22 


Novartis 
Confidential 
Page 4 
RAP Module 3 
23-Jan-2018 (11:37) 
QVA149A3405 
 
1 
Introduction 
This document contains details of the statistical methods which will be used in the phase 
IIIb/IV clinical trial CQVA149A3405. The purpose of this study is to investigate whether 
switching 
symptomatic 
COPD 
patients 
from 
a 
fixed-dose 
combination 
of 
salmeterol/fluticasone 50/500 μg b.i.d. to a fixed dose combination of QVA149 110/50 μg o.d. 
leads to improved lung function and airflow, and to assess the effect on symptom burden, 
breathlessness, and use of rescue medication. 
Data will be analyzed according to the data analysis section 9 of the study protocol. Important 
information is given in the following sections and details are provided, as applicable, in 
Appendix 16.1.9 of the CSR. 
1.1 
Changes to RAP from protocol specified analysis: 
The following changes from the planned analyses according to the Clinical Trial Protocol 
(release date 17-Jun-2015) will be performed. 
1) Compliance 
Compliance is not calculated as percentage of days but as percentage of doses taken, since 
only the number of doses are recorded on the eCRF. 
2) Logistic regression model 
According to the protocol clinically significant improvement in TDI after 12 weeks of 
treatment should be analyzed using a logistic regression. A logistic regression model for 
repeated measures will be performed in accordance with the analysis of the other efficacy 
variables. 
2 
Detailed statistical methodology 
2.1 
Study objectives 
The study protocol section 2 lists the following primary and secondary objectives. 
2.1.1 
Primary objective 
To demonstrate superiority of QVA149 110/50 μg o.d. compared to salmeterol/fluticasone 
50/500 μg b.i.d. in trough pre-dose FEV1 at week 12. 
2.1.2 
Secondary objectives 
To evaluate the effect of QVA149 110/50 μg o.d. compared to salmeterol/fluticasone 50/500 
μg b.i.d. on: 
• Total score of TDI at week 12 
• FVC at week 12 
• COPD symptoms at week 12 as measured by the COPD Assessment Test (CAT) 
• The mean number of puffs per day of rescue medication use, and percentage of days 


Novartis 
Confidential 
Page 5 
RAP Module 3 
23-Jan-2018 (11:37) 
QVA149A3405 
 
 
without rescue medication use over the 12 week treatment period 
• Safety and tolerability during the 12 week treatment period 
2.2 
Analysis sets 
• The randomized set (RAN) will include all randomized patients, regardless of whether 
or not they actually received randomized study medication. Patients in the RAN will 
be analyzed according to the treatment they were randomized to. 
• The full analysis set (FAS) will include all randomized patients who received at least 
one dose of randomized study medication. Following the intent-to-treat principle, 
patients will be analyzed according to the treatment they were assigned to at 
randomization. 
• The per-protocol set (PPS) will include all patients in the FAS without any major 
protocol deviations. Major protocol deviations will be defined prior to database lock 
and the unblinding of the study. The list of major protocol deviations is available in 
Appendix 16.1.9. The PPS will be used for supportive analysis to assess robustness of 
the primary analysis. Patients will be analyzed according to the randomized treatment. 
Patients who receive another than their randomized treatment because of a dispensing 
error will be excluded from the PPS. 
• The safety set will include all patients who received at least one dose of randomized 
study treatment, whether or not being randomized. Patients will be analyzed according 
to the treatment they received during the randomized treatment period. If a patient 
took both treatments the patient will be analyzed according to the randomized 
treatment. The safety set will be used for all safety endpoints.  
2.3 
Patient disposition, background and demographic 
characteristics 
2.3.1 
Patient disposition 
The RAN will be used for all patient disposition outputs, unless stated otherwise below. 
The number of patients randomized will be summarized, by region ("Asia" including 
Malaysia, Taiwan and Philippines, "Australia/South Africa", "India" and "Middle East" 
including Egypt, Lebanon, Saudi Arabia, Turkey and Israel), country and center. The overall 
number of patients who were screened, randomized, completed the study and discontinued 
from the study will be summarized with reasons for discontinuation. 
Number of patients with protocol deviations will be tabulated by deviation. Patients with 
protocol deviations will be listed with date and study day of occurrence, deviation and 
severity codes. 
The number of patients included in each analysis set will be tabulated. Reasons for exclusions 
from analysis sets will be tabulated for all patients. Patient exclusion from analysis sets will 
be listed for all patients with reasons for exclusion, including both protocol deviations and 
other exclusion criteria. 


Novartis 
Confidential 
Page 6 
RAP Module 3 
23-Jan-2018 (11:37) 
QVA149A3405 
 
2.3.2 
Demographics and baseline characteristics 
Demographics and baseline characteristics will be summarized using the FAS. Note that some 
of the parameters covered in this section (e.g. baseline FEV1 and FVC, BDI and rescue 
medication use, baseline ECG) will not appear in summaries of demographics and baseline 
characteristics, but will be included in the applicable efficacy or safety summaries.  
Age, sex, race, ethnicity, height, weight, body mass index (BMI), severity of air flow 
limitation (GOLD stages), severity of combined assessment of COPD (GOLD 2014 and 
2017), duration of COPD, smoking status (ex-/current smoker) at screening, estimated number 
of pack years, COPD exacerbation history (number of COPD exacerbations that occurred 
during the previous year prior to screening), other relevant medical history, concomitant 
medications (COPD related and non-COPD related) discontinued prior to start of randomized 
study drug, spirometry at screening (predicted FEV1, FEV1 pre and post use of bronchodilator, 
and % of predicted FEV1 prior to and after inhalation of ipratropium bromide and salbutamol 
or albuterol, FEV1 reversibility, FVC pre and post use of bronchodilator, % of FEV1/FVC 
prior to and after inhalation of ipratropium bromide and salbutamol or albuterol), baseline 
FEV1, baseline FVC, CAT score at screening, BDI score and baseline rescue medication will 
be summarized.  
In addition, the following categorizations will be done: 
- 
Age into <65 years, 65 - < 75 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;  
- 
Post-bronchodilator FEV1 into < 30 % of predicted FEV1, 30 - < 50 % of predicted FEV1, 
50 - < 80 % of predictive FEV1, and ≥ 80 % of predicted FEV1; 
- 
Post-bronchodilator FEV1/FVC ratio into < 0.70, and ≥ 0.70; 
- 
FEV1 reversibility (reversible [≥12% and ≥200ml increase]/not reversible) 
- 
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 ECG interpretation and vital signs results (radial pulse rate, systolic and diastolic 
blood pressure) will be summarized for the safety set. Clinical notable vital signs are defined 
in Appendix 16.1.9. 
Demographic data, inclusion/exclusion criteria, AEs and SAEs of screening failures will be 
listed only. 
Summarizations of continuous variables like age will include the number of observations (n), 
mean, standard deviation (SD), first and third quartile, median, minimum and maximum. 
Summarizations of categorical variables will include absolute (n) and relative (%) frequencies 
including a category for missing data if applicable.  
Details regarding the definition of baseline measurements are given in Appendix 16.1.9. 


Novartis 
Confidential 
Page 7 
RAP Module 3 
23-Jan-2018 (11:37) 
QVA149A3405 
 
2.3.3 
Medical history 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
terminology (MedDRA). History/conditions will be summarized for the FAS 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. 
2.4 
Study medication 
2.4.1 
Study drug administration 
The extent of exposure will be examined to determine the degree to which safety can be 
assessed for QVA149. The extent of exposure to study drug will be characterized according to 
the duration of exposure and the number of subjects exposed. 
Duration of exposure to a treatment will be calculated as the number of days between the 1st 
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 double-blind study drug – Date of first 
dose of double-blind study drug + 1). 
The duration of exposure (in days) will be summarized, by standard descriptive statistics, by 
treatment for the safety set. 
2.4.2 
Compliance 
Study drug compliance will be assessed by the investigator and/or center personnel at 
designated visits according to the procedures defined in the study protocol. The overall 
compliance will be calculated as the percentage of number of doses expected-number of doses 
missed/number of doses expected between Day 1 and the date of last dose..  
Compliance will be calculated separately for the SDDPI and the Accuhaler/Diskus and will be 
summarized by treatment for the safety set. In addition the following categories will be 
summarized: <80%, 80% - 100%. Compliance >100% can not be detected. 
2.5 
Concomitant medication 
Each medication will have the start and end dates recorded. Concomitant medications are 
defined as those medications that were taken on or after the first dose of study drug but not 
prior to the first dose of study drug. 
Concomitant medications will be summarized by treatment for the safety set. Concomitant 
COPD related medications will be summarized by pre-specified categories, route of 
administration and preferred term. Concomitant medications not related to COPD will be 
summarized by preferred term. 
The following pre-specified categories will be presented: 
• Leukotriene modifier 
• Short acting B2 agonist 


Novartis 
Confidential 
Page 8 
RAP Module 3 
23-Jan-2018 (11:37) 
QVA149A3405 
 
• Long acting anti-cholinergic 
• Short acting anti-cholinergic 
• Antibiotics 
• Long-acting B2 agonist 
• Xanthine 
• Anti-Histamines 
• Vaccine 
• Corticosteroid 
• Mast cell stabilizers 
• PDE-4 inhibitor 
• Anti-IGE 
• Other 
• LAMA/LABA 
• ICS/LAMA 
• ICS/LABA 
• SABA/SAMA 
2.6 
Efficacy evaluation 
The primary objective of this study is to investigate whether switching symptomatic COPD 
patients from a fixed-dose combination of salmeterol/fluticasone 50/500 μg b.i.d. to a fixed 
dose combination of QVA149 110/50 μg o.d. leads to improved lung function and airflow, 
and to assess the effect on symptom burden, breathlessness, and use of rescue medication. 
 
2.6.1 
Analysis of the primary efficacy variable 
2.6.1.1 
Variable 
Trough pre-dose FEV1 at Week 12 is defined as the average of the measurements taken - 
45min and -15min pre study medication dose in the clinic after 12 weeks of treatment (Day 
84). The baseline measurement is defined in Appendix 16.1.9. 
Trough pre-dose corresponds to 24 hours after the last randomized study drug dose (i.e. last 
dose prior to the FEV1 measurement) and 12 hours after the last dose of 
salmeterol/fluticasone. Spirometry is performed in the morning prior to the administration of 
the morning dose of study medication. 


Novartis 
Confidential 
Page 9 
RAP Module 3 
23-Jan-2018 (11:37) 
QVA149A3405 
 
2.6.1.2 
Statistical model, hypothesis, and method of analysis 
The following null hypothesis (Ho) versus the alternative hypothesis (Ha) will be tested at a 
significance level of 0.05 in the FAS: 
• Ho: There is no difference in trough pre-dose FEV1 after 12 weeks of treatment 
between QVA149 100/50 μg o.d. and salmeterol/fluticasone 50/500 μg b.i.d. 
• Ha: There is a significant difference in trough pre-dose FEV1 after 12 weeks of 
treatment between QVA149 100/50 μg o.d. and salmeterol/fluticasone 50/500 μg b.i.d. 
The treatment difference between QVA149 110/50 μg o.d. and salmeterol/fluticasone 50/500 
μg b.i.d. in terms of trough pre-dose FEV1 after 12 weeks of treatment will be estimated using 
ANCOVA for repeated measures. The model will include terms of treatment, baseline FEV1, 
smoking status at baseline, region, visit, treatment*visit interaction, baseline FEV1*visit 
interaction and an unstructured variance-covariance structure assuming normal distribution of 
the FEV1 data, where visit will be treated as a categorical variable. Center nested within 
region may be added as random effect depending on model convergence. Missing values of 
trough pre-dose FEV1 at Day 42 and Day 84 will not be imputed. The SAS code for the 
ANCOVA model is displayed in Appendix 16.1.9. 
The estimated treatment difference of QVA149 110/50 μg o.d. – salmeterol/fluticasone 
50/500 μg b.i.d. will be displayed along with the associated 95% confidence interval and p-
value. Superiority of QVA149 110/50 μg o.d. to salmeterol/ fluticasone 50/500 μg b.i.d. will 
be demonstrated if the p-value is less than 0.05 and the 95% confidence interval lies entirely 
to the right of 0 L. 
Trough pre-dose FEV1 will be summarized descriptively. 
Subgroup analyses will be done by gender, age (<65, 65-<75, >=75 years), race (Caucasian, 
Asian and Other), region (Asia, Australia/South Africa, India, Middle East), BMI 
(<=30, >30), severity of airflow limitation, combined assessment of COPD (2014 and 2017), 
FEV1 reversibility at screening (not reversible, reversible), smoking status at screening (ex-
smoker, current smoker) and exacerbation history (0 exacerbations/1 exacerbation).  
The same analysis models as those without subgroup analysis will be used. If the subgroup 
variable is not already included in the covariates of the model, then the terms for subgroup 
and treatment by subgroup interaction will be added to the model; otherwise only the 
treatment by subgroup interaction will be added. There are exceptions: In the subgroup 
analysis for race, the fixed effect of region will be removed from the model and as random 
effect center will be included only. 
2.6.1.3 
Handling of missing values/censoring/discontinuations 
Only spirometry measurements that are deemed acceptable (see Clinical Trial Protocol 
Appendix 1: Spirometry Guidance for more details) will be included in the analyses. If any of 
the values contributing to trough pre-dose FEV1 or baseline FEV1 are collected within 6 hours 
of rescue medication or less than 7 days after systemic corticosteroid use then the individual 
FEV1 value will be set to missing. Also if a value is taken post-dose instead of pre-dose it will 
not be used for calculation of trough pre-dose or baseline values. Since dosing times are only 


Novartis 
Confidential 
Page 10 
RAP Module 3 
23-Jan-2018 (11:37) 
QVA149A3405 
 
recorded in the diary for the days prior to scheduled visits no further time window will be 
applied for deriving pre-dose values. For the primary analysis, values will not be carried 
forward since ANCOVA for repeated measures will be applied. If all values contributing to 
the baseline FEV1 are missing (or are not confirmed to be pre-dose), then the pre-
bronchodilator measurements taken at Screening will be used as the baseline. 
2.6.1.4 
Supportive analyses 
The following supportive analyses may be conducted for trough pre-dose FEV1 at Week 12: 
(1) Imputation of missing Week 12 data by Last Observation Carried Forward (LOCF), i.e., 
using the value from Day 42. A linear mixed model including the terms of treatment, baseline 
FEV1, smoking status at baseline, and region as fixed effects and center nested within region 
as random effect will be applied. 
(2) Analysis based on pattern mixture model: An additional method for handling missing data 
will be implemented to explore the sensitivity to the Missing At Random (MAR) assumption. 
A pattern-mixture model based on nonignorable missing, i.e., Missing Not At Random 
(MNAR) will be used, where all drop-outs are assumed to switch back to 
salmeterol/fluticasone 50/500 μg b.i.d. treatment. This approach will be implemented by 
multiple imputations, where missing values are repeatedly replaced by sampling from the 
Bayesian posterior predictive distribution based on the switching model. Each of the 
completed datasets is then analyzed using the primary analysis, and then the estimates are 
combined using Rubin’s rules (Biometrika, 1976) to get the final inference. 
(3) Applying the ANCOVA for repeated measurements using the PPS. 
2.6.2 
Analysis of secondary variables 
The FAS will be used for the analysis of all secondary efficacy variables. 
2.6.2.1 
Dyspnea 
TDI 
Dyspnea is measured at baseline using the baseline dyspnea index (BDI), at week 6 and at the 
end of the treatment period (Week 12) using the transition dyspnea index (TDI), which 
captures changes from baseline.  
The BDI and TDI each have three domains: functional impairment, magnitude of task and 
magnitude of effort. The BDI domains are rated from 0 (severe) to 4 (unimpaired) and the 
rates are summed for the baseline focal score ranging from 0 to 12; the lower the score the 
worse the severity of dyspnea. The TDI domains are rated from -3 (major deterioration) to 3 
(major improvement) and the rates are summed for the transition  focal score ranging from -
9 to 9; minus scores indicate deterioration. A TDI focal score of 1 is considered to be a 
clinically significant improvement from baseline. 
The TDI focal score at Week 6 and Week 12 will be analyzed using ANCOVA for repeated 
measures. The model will be similar to the model of the primary analysis  with the baseline 
BDI instead of baseline FEV1 included in the model. 


Novartis 
Confidential 
Page 11 
RAP Module 3 
23-Jan-2018 (11:37) 
QVA149A3405 
 
Additionally the percentage of patients with a clinically significant improvement after 12 
weeks of treatment in TDI (of >=1 change from baseline) will be analyzed using a logistic 
regression model for repeated measures which includes the same terms as used for the 
analysis of the TDI focal score. 
BDI and TDI will be summarized descriptively. 
2.6.2.2 
Spirometry 
Trough pre-dose FVC 
The same analyses as for trough pre-dose FEV1 will be done for trough pre-dose FVC with 
the baseline FVC instead of baseline FEV1 included in the model. 
FEV1 at individual post-baseline time points 
A similar method as for the primary endpoint will be applied for the analysis of FEV1 at 
Week 6 (Visit 3) and Week 12 (EOS/Visit 4), i.e., separate ANCOVA for repeated measures 
will be performed for each time point using visit as repeated variable. FEV1 will be 
summarized descriptively by visit and time point. 
FVC at individual post-baseline time points 
The same analyses as for FEV1 at Week 6 (Visit 3) and Week 12 (EOS/Visit 4) will be done 
for FVC. 
2.6.2.3 
Rescue medication 
Use of rescue medication (number of puffs taken in the previous 12 hours) is recorded (once 
in the morning and once in the evening) by the patient, in the patient diary. The total number 
of puffs of rescue medication since last study visit and the total number of days without rescue 
use since last visit will be reported on the eCRF.  
Daily use of rescue medication (number of puffs) 
The mean daily number of puffs will be summarized descriptively and analyzed using a linear 
mixed model. The model will contain treatment, baseline mean daily number of puffs, 
smoking status at baseline, and region as fixed effects with center nested within region as a 
random effect. 
Percentage of days without rescue medication usage over 12 weeks 
The percentage of days without rescue medication usage will be calculated for each patient 
over the 12 week treatment period. This endpoint will be summarized descriptively and 
analyzed using a similar model as for rescue medication use, but with baseline percentage of 
days without rescue medication usage instead of baseline mean number of puffs included in 
the model.  
Rescue medication data prior to the first intake of study drug will be used to calculate the 
baseline. Details on how to calculate baseline and post-baseline measurements are given in 
Appendix 16.1.9. 


Novartis 
Confidential 
Page 12 
RAP Module 3 
23-Jan-2018 (11:37) 
QVA149A3405 
 
2.6.2.4 
COPD assessment test (CAT) 
The CAT is a short instrument used to quantify the symptom burden of COPD and is used to 
assess the health status of patients in this study. It is completed by the patient at the beginning 
of the study visit before any other assessment to avoid influencing the responses. The CAT is 
completed by the patient at the investigator's site at Visits 1, 2, 3 and 4 or at the time of 
discontinuation for patients who prematurely withdraw from the study. It consists of eight 
items, each presented as a semantic 6-point differential scale, providing a total score out of 40. 
A higher score indicates a worse health status. The result is immediately available without the 
need for any calculation, apart from summing the scores on individual items. Scores of 0 - 10, 
11 - 20, 21 - 30 and 31 – 40 represent a mild, moderate, severe or very severe clinical impact 
of COPD upon the patient. If one or two items are missing, they will be replaced with the 
mean of the completed items. If three or more items are missing, the CAT total score will be 
missing. 
A similar method as for the primary endpoint will be applied for the analysis of CAT with the 
baseline CAT result instead of baseline FEV1 included in the model. The CAT score will be 
summarized descriptively, in addition the proportions of patients with different levels of 
clinical impact, i.e., total CAT scores of 0-10 (mild), 11-20 (moderate), 21-30 (severe) and 
31-40 (very severe), will be summarized descriptively by treatment for each visit. 
2.7 
Safety evaluation 
The safety set will be used in the analysis of all safety variables. 
2.7.1 
Adverse Events 
All adverse events including COPD exacerbations, coded using MedDRA, will be listed. 
Treatment emergent adverse events are defined as those events starting on or after the time of 
the first administration of randomized study drug but not later than 7 days (30 days in the case 
of serious adverse events) after the last administration of study medication. 
Summaries of treatment emergent adverse events will be produced, overall by system organ 
class and preferred term for the following types of adverse events: 
(1) All adverse events 
The number and percentage of patients who reported adverse events will be summarized by 
primary system organ class, preferred term, and treatment. Unless otherwise specified, 
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 in the 
investigational study drug arm. 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. 
(2) Adverse events by maximum severity 
All adverse events will be summarized by maximum severity, primary system organ class, 
preferred term, and treatment. If a patient reported more than one adverse event within the 
same primary system organ class, only one adverse event will be counted for that patient at 


Novartis 
Confidential 
Page 13 
RAP Module 3 
23-Jan-2018 (11:37) 
QVA149A3405 
 
the highest severity level in the total row for each primary system organ class. Missing 
severity will be assumed to be severe in the summary table. 
(3) Adverse events suspected to be study drug related 
The adverse events suspected to be related to study drug (according to the investigators) will 
be summarized by primary system organ class, preferred term, and treatment. 
(4) Adverse events leading to permanent discontinuation of study treatment 
Adverse events leading to permanent study drug discontinuation, regardless of study drug 
relationship, will be summarized by primary system organ class, preferred term, and 
treatment. 
(5) Adverse events leading to dose adjustment / temporary interruption of study treatment 
Adverse events requiring dose adjustment / temporary interruption, regardless of study drug 
relationship, will be summarized by primary system organ class, preferred term, and 
treatment. 
(6) Adverse events requiring additional therapy 
Adverse events requiring additional therapy (i.e., concomitant medication or non-drug 
therapy), regardless of study drug relationship, will be summarized by primary system organ 
class, preferred term and treatment. 
(7) Serious adverse events (SAEs) 
Number and percentage of patients with treatment-emergent serious adverse events, 
regardless of study drug relationship, will be presented by primary system organ class, 
preferred term and treatment.  
Number and percentage of patients with onset of serious adverse events between visit 1 and 
first dose of randomized drug will be presented by primary system organ class, preferred term 
and treatment. 
(8) Fatal adverse events 
Fatal adverse events, regardless of study drug relationship, will be presented by primary 
system organ class, preferred term and treatment. 
(9) Investigator-reported cause of death 
Number and percentages of deaths will be presented by primary system organ class, preferred 
term, and treatment group, based on investigator-reported principal cause of death, regardless 
of study drug relationship.  
2.7.2 
COPD exacerbations during the 12 week treatment period 
COPD exacerbations are defined in the study protocol section 6.6.8 as worsening of two or 
more major symptoms (i.e., dyspnea, sputum volume, sputum purulence), or worsening of any 
1 major symptom together with any 1 of minor symptoms (i.e., sore throat, colds, fever 
without other cause, cough, wheeze) for at least 2 for consecutive days. The start date for a 
COPD exacerbation recorded in the eCRF should be the first day of symptom worsening of 
two or more major symptoms or of one major and one minor symptom, as defined above. The 


Novartis 
Confidential 
Page 14 
RAP Module 3 
23-Jan-2018 (11:37) 
QVA149A3405 
 
end of a COPD exacerbation episode is marked by the return to pre-exacerbation symptom 
status. 
A COPD exacerbation is considered of moderate severity if treatment with systemic 
corticosteroids or antibiotics or both was required and severe, if hospitalization was required. 
An emergency room (ER) visit of longer than 24 hours will be considered a hospitalization. 
A worsening of symptoms that either do not meet the above symptom definitions but is 
treated by the investigator with systemic corticosteroids or antibiotics, or that meets the 
symptom definition but does not receive antibiotics and/or systemic corticosteroids,  is 
captured as mild exacerbation on the eCRF. 
In patients with multiple exacerbations, if the start date of an exacerbation is less than 7 days 
after the end date of a previous episode then this will be assumed to be one continuous 
exacerbation with the start date taken from the first episode and the end date from the second 
or last episode. The worst severity of these episodes will be taken as the severity of the 
combined exacerbation. 
COPD exacerbations, as recorded on the eCRF,  will be included in all adverse event analyses 
described above.  
In addition, the number of collapsed COPD exacerbations reported during the 12 week 
treatment period will be summarized descriptively by severity (total (also including mild), 
moderate and/or severe, mild, moderate, severe). COPD exacerbations will be considered on 
treatment, if they started on or after the time of the first administration of randomized study 
drug but not later than 1 day after the last administration of study medication. 
A subgroup analysis based on the exacerbations history at baseline (0 exacerbations/1 
exacerbation) will be performed on the number of COPD exacerbations during treatment, by 
severity. 
2.7.3 
Vital signs and ECG 
Vital signs (blood pressure, pulse rate, and body weight) and ECG data will be summarized 
by treatment, scheduled visit and for the minimum and maximum post-baseline value for vital 
signs and the maximum QTc and ventricular rate for ECG data, including changes from 
baseline.  
In addition, frequencies of notable vital signs and Fridericia's QTc (QTcF) will be 
summarized by treatment, scheduled visit and for the minimum and maximum post-baseline 
value for vital sign and the maximum post-baseline value for Fridericia's QTc.  
Data measured more than 7 days after last inhalation of study drug are regarded as post-
treatment data and will not be summarized, only listed. For the derivation of the minimum and 
maximum post-baseline value all post-baseline data from scheduled, unscheduled and 
premature discontinuation visits will be considered. 
Listings of all patients with notable vital signs and notable Fridericia's QTc will be provided.  
Notable absolute values and notable changes from baseline for each vital sign parameter and 
for Fridericia's QTc are defined in Appendix 16.1.9.  


Novartis 
Confidential 
Page 15 
RAP Module 3 
23-Jan-2018 (11:37) 
QVA149A3405 
 
The overall ECG interpretation (normal, clinically significant abnormal) will be shown by 
visit and for the worst post-baseline measurement during treatment (considering all post-
baseline data from scheduled, unscheduled and premature discontinuation visits). In addition a 
shift table from baseline to the worst interpretation during treatment will be presented. 
2.8 
Interim analyses 
No interim analysis will be performed. 
2.9 
Determination of sample size 
For the endpoint trough pre-dose FEV1 change from baseline, a SD of 220mL was used based 
on a review of the results of Novartis phase III COPD studies. Discontinuation rate = 15% 
was assumed. 
Sample size calculation for trough pre-dose FEV1 change 
alpha=0.05, 2-sided 
 
 
 
Power(%) 
90 
90 
90 
Difference to detect 
65 
70 
75 
SD 
220 
220 
220 
n per arm 
242 
209 
182 
with 15% drop-out rate 
285 
246 
215 
Total 
570 
492 
430 
Based on these calculations, a sample size of 418 completed patients is selected in order to 
detect a trough pre-dose FEV1 change of 70mL with 90% power. Assuming a 15% drop out 
rate, 492 patients will be randomized. 


Novartis 
Confidential 
Page 16 
RAP Module 3 
23-Jan-2018 (11:37) 
QVA149A3405 
 
Clinical Study Report -  
Appendix 16.1.9  Documentation of statistical methods 
16.1.9.1 Introduction 
This appendix gives details about statistical methods in addition to the report text. All 
analyses will be performed by using SAS Version 9.3. 
16.1.9.2 Major protocol deviations  
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. 
• Informed consent not signed prior to assessments being performed  
• Age < 40 years 
• Smoking history < 10 pack years 
• Post-bronchodilator FEV1 <30% & >=80% of normal value or post-bronchodilator 
FEV1/FVC >= 0.70 
• Treated with salmeterol/fluticasone 50/500 μg b.i.d. for less than 3 months prior to 
visit 1 
• CAT score < 10 
• Treatment with any LAMA in the 2 weeks prior to visit 1 
• Prior or current diagnosis of asthma 
• Clinically significant co-morbidity that could interfere with the assessment of the 
safety and efficacy of the study medication. 
• Malignancy within the past 5 years (except localized basal cell carcinoma of the skin) 
• Not achieved acceptable spirometry results at visit 1 or 2 in accordance with the 
American Thoracic Society (ATS) or European Respiratory Society (ERS) criteria for 
acceptability. 
• More than one COPD exacerbation requiring treatment with antibiotics and/or 
systemic corticosteroids and/or hospitalization in the year prior to Visit 1 
• COPD exacerbation of any severity within the 6 weeks before the screening (Visit 1) 
or between screening (Visit 1) and start of treatment (Visit 2) 
• Respiratory tract infection within 4 weeks prior to Visit 1 
• Respiratory tract infection between Visit 1 and 2 
• Requiring oxygen therapy prescribed for >12 hours per day 
• Onset of respiratory symptoms, including a COPD diagnosis prior to age 40 years 
• Concomitant pulmonary disease 
• Diagnosed with α-1 anti-trypsin deficiency 
• Active pulmonary tuberculosis 
• Pulmonary lobectomy or lung volume reduction surgery or lung transplantation 


Novartis 
Confidential 
Page 17 
RAP Module 3 
23-Jan-2018 (11:37) 
QVA149A3405 
 
• Participating in or planning to participate in the active phase of a supervised 
pulmonary rehabilitation program during the study 
• Receiving prohibited medication 
• Use of investigational drugs/devices (approved or unapproved) at the time of 
enrollment, or within 30 days or 5 half-lives of Visit 1, whichever is longer 
• Unable to use a dry powder inhaler device, Metered Dose Inhaler (MDI) or a 
pressurized MDI (rescue medication) or comply with the study regimen. 
• Patient received study drug but not randomized into study 
• Use of prohibited indication medication during the study 
• Patient randomized in error 
• Major GCP deviation 
16.1.9.3 Subject classification 
Protocol deviations will lead to patient classification into the analysis sets as follows: 
Analysis set exclusion based on population codes 
Analysis set 
PD severity codes that cause 
a subject to be excluded 
Other criteria that cause a subject to be 
excluded 
RAN 
NA 
 
Safety 
5, 8 
Patient randomized but did not receive 
any double-blind study treatment 
FAS 
0, (5*), 8 
Patient randomized but did not receive 
any double-blind study treatment 
Per Protocol 
0, 1, (5*), 8 
Patients who receive another than their 
randomized treatment because of a 
dispensing error. 
Patient randomized but did not receive 
any double-blind study treatment 
* Note: given that the Per Protocol population is nested within the FAS, which is itself nested 
within the Safety population, severity code 5 implies exclusion from all three of these analysis 
populations (i.e. SAF, FAS and PP). 
 
Population code text 


Novartis 
Confidential 
Page 18 
RAP Module 3 
23-Jan-2018 (11:37) 
QVA149A3405 
 
Population Code  
Population code - text  
0 
Exclude from all efficacy analysis (FAS, PPS) 
1 
Exclude from Per-Protocol analysis  
5 
Exclude from all safety analyses (SAF) 
8 
Exclude from all analysis (FAS, PPS, and SAF) 
49 
Report relevant protocol deviation - include in all 
analyses 
Unless otherwise stated, summary tables, figures and listings will be on all subjects included 
in the analysis set under consideration. 
16.1.9.4 Baseline and post-baseline definitions, missing data handling 
16.1.9.4.1 
Baseline definitions 
In general, baseline is defined as the last measurement before the first dose of study drug at 
Day 1.  
1) For all FEV1 and FVC endpoints, the baseline value is defined as the average of the values 
taken at -45 and -15 min prior to first dose of study drug at Day 1. Checks will be performed 
to ensure values were indeed taken prior to the first dose of study drug. If one of the values is 
missing (or is not confirmed to be pre-dose) then the remaining non-missing value will be 
taken as baseline. If both values are missing (or are not confirmed to be pre-dose), then the 
pre-bronchodilator measurements taken at the screening visit 1 can be used as the baseline. If 
the FEV1 or FVC measurements are missing both on Day 1 and at screening visit, the 
respective baseline values will be set to missing. 
2) Baseline Dyspnea Index (BDI) and baseline CAT are defined as the assessments taken 
right before the first dose of the study drug on Day 1 (Visit 2). If the CAT assessment on Day 
1 is missing, then the last CAT assessment taken prior to first dose will be used as baseline. 
Missing baseline values will not be imputed. 
3) For rescue medication use, the baseline percentage of days without rescue use is defined 
as the difference between number of days between visit 1 and visit 2 (date of first dose of 
study drug) and the number of days with rescue medication use as entered on the eCRF at 
visit 2 divided by the total number of days between visit 1 and visit 2 multiplied by 100. 
The baseline mean number of puffs is defined as the number of puffs between visit 1 and visit 
2 divided by the number of days between visit 1 and visit 2. Missing diary data will not be 
imputed. 
4) Vital signs include pulse rate (measured as radial pulse for 60 seconds) and systolic and 
diastolic blood pressures. Baseline vital signs are defined as the assessments taken pre-dose 
on Day 1. Checks will be performed to ensure the assessments were indeed taken prior to the 
first dose of study drug on Day 1. If this assessment is missing or not confirmed to be pre-
dose, the last value taken prior to first dose will be used for baseline. 
5) Baseline height and weight are defined as the measurements taken at visit 1. Missing 
baseline will not be imputed. 


Novartis 
Confidential 
Page 19 
RAP Module 3 
23-Jan-2018 (11:37) 
QVA149A3405 
 
6) Baseline ECG is defined as ECG measured prior to the first dose of study drug on Day 1. 
Checks will be performed to ensure the ECG was indeed assessed prior to the first dose of 
study drug. If it is missing (or not confirmed to be pre-dose), then the last assessment taken 
prior to first dose will be used. Otherwise, the ECG baseline will be set to missing without 
imputation. 
16.1.9.4.2 
Post-baseline measurements 
Post-baseline measurements are defined as those assessments after the first dose of study 
drug. 
Trough pre-dose FEV1 and trough pre-dose FVC are defined as the mean of the respective 
measurements made at -45 min and -15 min before the morning dose. If one of the -45 and -
15 min values is missing (or is not confirmed to be pre-dose) then the remaining non-missing 
value will be taken as trough pre-dose FEV1 value. If both values are missing (or are not 
confirmed to be pre-dose), the trough pre-dose value will be set to missing. 
For rescue medication use, the post-baseline percentage of days without rescue medication 
use is defined as the difference between the sum of days between visit 2 (date of first dose of 
study drug) and visit 3 (date of dosing, and if missing visit date) and between visit 3 and 4 
(date of dosing, and if missing visit date)  and the sum of days with rescue medication use as 
entered on the eCRF at visit 3 and visit 4, divided by the total number of days between visit 2 
and visit 4 multiplied by 100. The treatment period ends at visit 4 /EOS. 
For safety data, post-baseline measurements comprise recordings up to the last dose of study 
drug (+ 7 days for patients who discontinued early) for ECG, vital signs, non-serious AE and 
up to the last dose of study drug + 30 days for SAEs and death.  
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. 
16.1.9.5 Derivation of demographics and baseline characteristics 
Baseline values are as described in “Baseline measurements” section above. 
• Years 
since 
patient 
stopped 
smoking 
is 
calculated 
using 
the 
formula:  
Years since patient 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 for the date of COPD diagnosis. 
• Duration of COPD is calculated from the date of COPD first diagnosed as recorded on 
the eCRF 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 


Novartis 
Confidential 
Page 20 
RAP Module 3 
23-Jan-2018 (11:37) 
QVA149A3405 
 
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. 
• 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. 
• Spirometry at screening: Only acceptable values will be analyzed. Moreover values 
with  
o SABA use less than 6 hours 
o LABA use less than 24 hours 
o SAMA use less than 8 hours 
o LAMA use less than 14 days 
o Indacaterol use less than 3 days 
 
prior to spirometry will be set to missing. 
• Airflow limitation is classified based on % of predicted FEV1 and FEV1/FVC post 
bronchodilation:  
− 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 % 
• Combined assessment of COPD (2014) is classified by using the stages of airflow 
limitation (see above), the number of COPD exacerbations, COPD exacerbations 
leading to hospital admission in the last year and CAT at baseline. When assessing 
risk (low or high), the highest risk according to GOLD grade or exacerbation history 
will be chosen in GOLD 2014. When assessing symptoms (less or more), the category 
according to the CAT score will be chosen. 
 
The following algorithm will be applied based on the standard in GOLD 2014: 
−  Group A (Low Risk and Less Symptoms): 
 
 
(GOLD 1-2 and history of exacerbation ≤ 1 not leading to hospital admission) and 
 
CAT < 10 
− Group B (Low Risk and More Symptoms): 
(GOLD 1-2 and history of exacerbation ≤ 1 not leading to hospital admission) and 
CAT ≥ 10 
− Group C (High Risk and Less Symptoms): 
(GOLD 3-4 or history of exacerbation ≥ 2 or ≥ 1 leading to hospital admission) and 
CAT < 10  
− Group D (High Risk and more Symptoms): 
(GOLD 3-4 or history of exacerbation ≥ 2 or ≥ 1 leading to hospital admission) and 
CAT ≥ 10  


Novartis 
Confidential 
Page 21 
RAP Module 3 
23-Jan-2018 (11:37) 
QVA149A3405 
 
• Combined assessment of COPD (2017) is classified by using the number of COPD 
exacerbations, COPD exacerbations leading to hospital admission in the last year and 
CAT at baseline. When assessing risk (low or high), the highest risk according to 
exacerbation history will be chosen in GOLD 2017. When assessing symptoms (less 
or more), the category according to the CAT score will be chosen. 
 
The following algorithm will be applied based on the standard in GOLD 2017: 
− Group A (Low Risk and Less Symptoms): 
 
 
(history of exacerbation ≤ 1 not leading to hospital admission) and  CAT < 10 
− Group B (Low Risk and More Symptoms): 
(history of exacerbation ≤ 1 not leading to hospital admission) and CAT ≥ 10 
− Group C (High Risk and Less Symptoms): 
(history of exacerbation ≥ 2 or ≥ 1 leading to hospital admission) and CAT < 10  
− Group D (High Risk and more Symptoms): 
(history of exacerbation ≥ 2 or ≥ 1 leading to hospital admission) and CAT ≥ 10  
• % of predicted FEV1 is the percentage of FEV1 relative to the predicted normal value.  
Quanjer equations to calculate predicted FEV1 (L)  
The following equations will be used by third party vendors to give 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. 
• FEV1 reversibility is calculated as percentage increase of FEV1 values after sequential 
inhalation of 84 µg of ipratropium bromide and 400 µg of salbutamol (or 360 µg 
albuterol) relative to FEV1 values prior to the inhalation. 
16.1.9.6 Vital signs – definition of clinically notable values 
The following table shows the clinical notable criteria for vital signs. 
Clinical notable criteria for vital signs 
Vital sign parameter (unit) 
Lower bound of clinically 
notable range 
Upper bound of clinically 
notable range 
Notable value considering newly occurring or worsening cases 
Systolic 
blood 
pressure 
(mmHg) 
< 75 
> 200 
Diastolic 
blood 
pressure 
(mmHg) 
< 40 
> 115 
Pulse rate (bpm) 
< 40 
> 130 
Notable range from baseline 
Systolic 
blood 
pressure 
(mmHg) 
≤ 90 and decrease from 
baseline by ≥ 20 
≥ 180 and increase from 
baseline by ≥ 20 
Diastolic 
blood 
pressure 
(mmHg) 
≤ 50 and decrease from 
baseline by ≥ 15 
≥ 105 and increase from 
baseline by ≥ 15 


Novartis 
Confidential 
Page 22 
RAP Module 3 
23-Jan-2018 (11:37) 
QVA149A3405 
 
Pulse rate (bpm) 
≤ 50 and decrease from 
baseline by ≥ 15 
≥ 120 and increase from 
baseline by ≥ 15 
Weight (kg) 
Decrease ≥ 7% from baseline 
Increase ≥ 7% from baseline 
 
Clinical notable criteria for QTcF (Friderica's formula) 
ECG parameter (unit) 
Clinically notable range 
Notable value considering newly occurring or worsening cases 
QTc (ms) 
> 450 (both male and female) 
QTc (ms) 
> 480 
QTc (ms) 
< 500 
Notable change from baseline 
QTc 
30 - 60 
QTc 
> 60 
16.1.9.8 Statistical methodology and assumptions 
• Mixed Model Repeated Measures (MMRM)  
The following MMRM ANCOVA model will be used for analysis of trough pre-dose FEV1: 
Trough pre-dose FEV1 = intercept + treatment + baseline FEV1 + baseline smoking status + 
region + visit + treatment*visit + baseline FEV1*visit + center(region) as random effect + 
error. 
The random effect in the mixed model will be represented by the use of an unstructured 
covariance matrix for the within-patient error.  
The SAS procedure MIXED will be used with the following code: 
 
proc mixed  data=....  order=internal; 
  where vis_1n in (3,4); 
  class trtn1 smh1c region vis_1n sid1a ctr1n; 
  model val_1n = trtn1 bsval_1n smh1c region vis_1n trtn1*vis_1n bsval_1n*vis_1n/ ddfm=kr; 
  random ctr1n(region); 
  repeated vis_1n / subject=sid1a type=un; 
  lsmeans trtn1*vis_1n / cl diff; 
run; 
where val_1n 
=  trough pre-dose FEV1  
 
trtn1 
= Treatment 
 
bsval_1n = baseline FEV1 value 
 
smh1c 
= Smoking status at baseline (ex-, current smoker) 
 
region 
= region (Australia/South Africa, Asia, India, Middle East) 
 
vis_1n 
= visit (include the scheduled visits only, no unscheduled or premature  
 
 
   discontinuation visits) 
 
ctr1n 
= center  
 
sid1a 
= subject identifier 


Novartis 
Confidential 
Page 23 
RAP Module 3 
23-Jan-2018 (11:37) 
QVA149A3405 
 
The estimated treatment difference of QVA149 110/50 μg o.d. – salmeterol/fluticasone 
50/500 μg b.i.d. will be displayed along with the associated 95% confidence interval and p-
value. 
Other variables (i.e., TDI, trough pre-dose FVC, FEV1and FVC at individual post-baseline 
time points, CAT) will be analyzed with the same MMRM model as used for the difference in 
treatments in trough pre-dose FEV1, however, by including appropriate baseline values. 
If the analysis fails to converge with an unstructured covariance matrix first choice is to 
remove the random effect of center nested within region and the second choice is to use a 
different covariance structure; either a compound symmetry (first choice) or first order 
autoregressive (AR1) (second choice). 
• Linear Mixed Model 
A linear mixed ANCOVA model will be used for trough pre-dose FEV1 with imputation of 
missing week 12 data by LOCF: 
Trough pre-dose FEV1 = intercept + treatment + baseline FEV1 + smoking status + region + 
center(region) as a random effect + error. 
The SAS procedure MIXED will be used with the following code: 
 
proc mixed  data=....  order=internal; 
  class trtn1 smh1c region ctr1n; 
  model val_1n = trtn1 bsval_1n smh1c region / ddfm=kr; 
  random ctr1n(region) / type=vc; 
  lsmeans trtn1 / cl diff; 
run; 
where val_1n 
= trough pre-dose FEV1 at Week 12 
 
trtn1 
= Treatment 
 
bsval_1n = baseline FEV1 
 
smh1c 
= Smoking status at baseline (ex-, current smoker) 
 
region 
= region (Australia/South Africa, Asia, India, Middle East) 
 
ctr1n 
= center 
Results will be presented with least squares mean and standard error for treatment effects and 
least squares mean, standard error, associated two-sided 95% confidence interval, and 
two-sided p-value for the treatment contrast. 
Other variables will be analyzed with the same mixed model (i.e. daily use of rescue 
medication, percentage of days without rescue medication over 12 weeks), however, by 
including appropriate baseline values. 
• Pattern mixture model 
An additional method for handling missing data will be implemented to explore the sensitivity 
to the Missing At Random (MAR) assumption. A pattern-mixture model based on 
nonignorable missing, i.e., Missing Not At Random (MNAR) will be used, where all drop-
outs are assumed to switch back to salmeterol/fluticasone 50/500 μg b.i.d. treatment. This 
approach will be implemented by multiple imputations, where missing values are repeatedly 
replaced by sampling from the Bayesian posterior predictive distribution based on the 


Novartis 
Confidential 
Page 24 
RAP Module 3 
23-Jan-2018 (11:37) 
QVA149A3405 
 
switching model. Each of the completed datasets is then analyzed using the primary analysis, 
and then the estimates are combined to get the final inference. 
In general, 4 programming steps will be done using the SAS procedures MI, MIXED, and 
MIANALYZE: 
1. Impute missing intermediate visit (i.e., Day 42 is missing but Week 12 is non-missing) 
to obtain a monotone missing data pattern.  
 
proc mi data=... out=_imp1 nimpute=100 seed=.....; 
  by trtn1; 
  mcmc chain=multiple impute=monotone; 
  var VIS3 VIS4; 
run;  
with VIS3 = Day 42 value and VIS4 = Week 12 value. 
 
The resulting output dataset _imp1 will have 100 copies of the original dataset where 
each copy will have a monotone missing pattern. 
2. Impute missing Week 12 data by using the dataset obtained from Step 1 and including 
all salmeterol/fluticasone subjects and only the subjects of QVA149 that have missing 
values at Week 12. Thus missing Week 12 values will be imputed based on the 
observed outcomes of completers on salmeterol/fluticasone. A regression model 
including preceding values will be used for imputation. 
 
proc sort data=_imp1 out=_imp2; 
  where trtn1=Salm/Flut or (trtn1=QVA149 and vis4=.); 
  by _imputation_; 
run; 
proc mi data=_imp2 out=_imp3 nimpute=1 seed=...; 
  by _imputation_; 
  var VIS3 VIS4; 
  monotone reg(VIS4); 
run;  
 
Pool the above imputed dataset with the dataset obtained from Step 1 but including 
only the subjects of the QVA149 group that have values at Week 12. 
 
data _imp4; 
  set _imp1(where=(trtn1=QVA149 and vis4 gt .)) 
      _imp3; 
run; 
proc sort data=_imp4; 
  by _imputation_; 
run; 
3. Analyze Week 12 data by using the pooled dataset derived from Step 2. 
 
proc mixed data=_imp4 order=internal; 
  by _imputation_; 
  class trtn1 smh1c region; 
  model vis4 = trtn1 bsval_1n smh1c region / solution covb ddfm=kr; 
  lsmeans  trtn1 / cl diff; 
  random ctr1n(region); 
  ods output lsmeans=ls diffs=con; 


Novartis 
Confidential 
Page 25 
RAP Module 3 
23-Jan-2018 (11:37) 
QVA149A3405 
 
run; 
 
4. Combine the results from Step 3analysis on 100 imputed datasets to derive an overall 
result. 
 
proc mianalyze parms=ls [parms=con in a second step] 
  clas trtn1; 
  modeleffects trtn1; 
run; 
 
Parms=ls gives the least squares means of treatments and parms=con of treatment 
contrasts. 
• Logistic regression analysis for repeated measures 
The percentage of patients with a clinically significant improvement after 12 weeks of 
treatment in TDI (of >=1 change from baseline) will be analyzed using a logistic regression 
model for repeated measures which includes the same terms as used for the analysis of the 
TDI focal score. 
Response = intercept + treatment + baseline BDI + smoking status at baseline + region + visit 
+ treatment*visit + baseline BDI*visit + error.  
The SAS procedure GENMOD will be used with the following code: 
 
proc genmod data=.... order=internal rorder=internal descending; 
where vis_1n in (3,4); 
class trtn1 bsval_1n smh1c region sid1a; 
model response = trtn1 bsval_1n smh1c region vis_1n trtn1*vis_1n  
                 bsval_1n*vis_1n / dist=bin link=logit; 
repeated subject=sid1a / type=un; 
lsmeans trtn1*vis_1n / cl diff oddsratio; 
run; 
where response = improvement TDI focal score (= 1, or 0 if no response) 
 
trtn1 
= Treatment (QVA, Salm/Flut) 
 
bsval_1n = baseline BDI 
 
smhgr1 = Smoking status (ex-, current smoker), as measured at baseline 
 
region 
= region (Australia/South Africa, Asia, India, Middle East) 
 
vis_1n 
= visit (include the scheduled visits only, no unscheduled or premature  
 
 
   discontinuation visits) 
 
sid1a 
= unique subject identifier 
The DESCENDING option of the PROC GENMOD statement causes the last ordered 
category (here = improvement) as the event. 
Odds ratios will be presented along with 95% confidence intervals and p-values for the 
treatment contrast of QVA vs. Salm/Flut. 
If the analysis fails to converge with an unstructured covariance matrix first choice is to use a 
different covariance structure; either a compound symmetry (first choice) or first order 
autoregressive (AR1) (second choice). 


Novartis 
Confidential 
Page 26 
RAP Module 3 
23-Jan-2018 (11:37) 
QVA149A3405