Conditions: Chronic Obstructive Pulmonary Disease, COPD
Keywords: QVA149, cardiac function, ventricular enddiastolic volume, hyperinflated COPD patients
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 62
Healthy volunteers: no

Brief summary:
This mechanistic study is a single-center, randomized, double-blind, placebo-controlled, cross-over study to evaluate the effect of dual bronchodilation with QVA149 on cardiac and lung function parameters in hyperinflated COPD patients.

Detailed description:

Arms:
arm 1: QVA149 from day 1 to day 15 followed by Placebo from day 29 to day 43 arm 2: Placebo from day 1 to day 15 followed by QVA149 from day 29 to day 43

Interventions: intervention 1: QVA149 intervention 2: Placebo
Intervention descriptions: intervention 1: QVA149 capsules 100/50 µg for inhalation via Concept-1-inhaler, taken once daily intervention 2: Placebo to QVA140 capsules 100/50 µg for inhalation via Concept-1-inhaler, taken once daily

Protocol document:
Prot_001.pdf: 
Clinical Development 
QVA149 (Indacaterol maleate / Glycopyrronium bromide)  
Clinical Trial Protocol CQVA149ADE05 / NCT02442206
 A randomized, double-blinded, single-center, placebo 
controlled, cross-over study to assess the effect of QVA149 
(indacaterol maleate / glycopyrronium bromide) on cardiac 
function in patients with chronic obstructive pulmonary disease 
(COPD) 
Authors: 
 
Document type: 
Amended Protocol Version 
EUDRACT number: 
2014-004680-21 
Version number: 
FINAL v03 (Clean)  
Development phase: 
IV 
Release date: 
20-April-2016
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
NOVDD Template Version 03-Feb-2012 


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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 
Protocol synopsis ............................................................................................................... 12 
1 
Introduction ....................................................................................................................... 15 
1.1 
Background ............................................................................................................ 15 
1.2 
Purpose .................................................................................................................. 16 
2 
Study objectives ................................................................................................................. 16 
2.1 
Primary and key secondary objective .................................................................... 16 
2.2 
Secondary objectives ............................................................................................. 16 
2.3 
Exploratory objectives ........................................................................................... 17 
3 
Investigational plan ........................................................................................................... 18 
3.1 
Study design .......................................................................................................... 18 
3.2 
Rationale of study design ...................................................................................... 20 
3.3 
Rationale of dose/regimen, route of administration and duration of treatment ..... 21 
3.4 
Rationale for choice of comparator ....................................................................... 21 
3.5 
Purpose and timing of interim analyses/design adaptations .................................. 21 
3.6 
Risks and benefits .................................................................................................. 21 
4 
Population .......................................................................................................................... 22 
4.1 
Inclusion criteria .................................................................................................... 22 
4.2 
Exclusion criteria ................................................................................................... 22 
5 
Treatment ........................................................................................................................... 25 
5.1 
Protocol requested treatment ................................................................................. 25 
5.1.1 
Investigational treatment ....................................................................... 25 
5.1.2 
Additional study treatment .................................................................... 26 
5.2 
Treatment arms ...................................................................................................... 26 
5.3 
Treatment assignment, randomization ................................................................... 26 
5.4 
Treatment blinding ................................................................................................ 26 
5.5 
Treating the patient ................................................................................................ 26 
5.5.1 
Patient numbering ................................................................................. 26 
5.5.2 
Dispensing the investigational treatment .............................................. 27 
5.5.3 
Handling of study treatment .................................................................. 27 


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5.5.4 
Instructions for prescribing and taking study treatment ........................ 28 
5.5.5 
Permitted dose adjustments and interruptions of study treatment ........ 29 
5.5.6 
Rescue medication ................................................................................ 29 
5.5.7 
Concomitant treatment .......................................................................... 29 
5.5.8 
Prohibited Treatment ............................................................................. 30 
5.5.9 
Discontinuation of study treatment and premature patient 
withdrawal ............................................................................................. 32 
5.5.10 
Emergency breaking of treatment assignment ...................................... 33 
5.5.11 
Study completion and post-study treatment .......................................... 33 
5.5.12 
Early study termination ......................................................................... 34 
6 
Visit schedule and assessments ......................................................................................... 34 
6.1 
Information to be collected on screening failures.................................................. 37 
6.2 
Patient demographics/other baseline characteristics ............................................. 37 
6.3 
Treatment exposure and compliance ..................................................................... 38 
6.4 
Efficacy .................................................................................................................. 38 
6.4.1 
Magnetic resonance imaging (MRI) ..................................................... 38 
6.4.2 
Bodyplethysmography .......................................................................... 40 
6.4.3 
Spirometry assessments ........................................................................ 42 
6.4.4 
Impulse oscillometry ............................................................................. 43 
6.4.5 
Echocardiography ................................................................................. 43 
6.4.6 
Activity with Actibelt ............................................................................ 44 
6.4.7 
COPD Assessment Test (CAT) ............................................................. 44 
6.4.8 
Modified Medical Research Council (mMRC) Dyspnea Scale ............ 44 
6.4.9 
Baseline/Transition Dyspnea Indexes (BDI/TDI) ................................. 44 
6.4.10 
Appropriateness of efficacy assessments .............................................. 45 
6.5 
Safety ..................................................................................................................... 45 
6.5.1 
Physical examination ............................................................................ 45 
6.5.2 
Vital signs.............................................................................................. 45 
6.5.3 
Height and weight ................................................................................. 46 
6.5.4 
Laboratory evaluations .......................................................................... 46 
6.5.5 
Electrocardiogram (ECG) ..................................................................... 46 
6.5.6 
Pregnancy and assessments of fertility ................................................. 47 
6.5.7 
Appropriateness of safety measurements .............................................. 47 
6.6 
Other assessments .................................................................................................. 47 
6.6.1 
Resource utilization ............................................................................... 47 
6.6.2 
Health-related Quality of Life ............................................................... 47 
6.6.3 
Pharmacokinetics .................................................................................. 47 


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6.6.4 
Pharmacogenetics/pharmacogenomics ................................................. 47 
6.6.5 
Other biomarkers ................................................................................... 47 
7 
Safety monitoring .............................................................................................................. 47 
7.1 
Adverse events ....................................................................................................... 47 
7.2 
Serious adverse event reporting ............................................................................. 49 
7.3 
COPD Exacerbation............................................................................................... 50 
7.4 
Liver safety monitoring ......................................................................................... 51 
7.5 
Pregnancy reporting ............................................................................................... 51 
7.6 
Prospective suicidality assessment ........................................................................ 51 
8 
Data review and database management ............................................................................. 52 
8.1 
Site monitoring ...................................................................................................... 52 
8.2 
Data collection ....................................................................................................... 52 
8.3 
Database management and quality control ............................................................ 53 
8.4 
Data Monitoring Committee .................................................................................. 53 
8.5 
Adjudication Committee ........................................................................................ 53 
9 
Data analysis ...................................................................................................................... 53 
9.1 
Analysis sets .......................................................................................................... 53 
9.2 
Patient demographics and other baseline characteristics ....................................... 54 
9.3 
Treatments ............................................................................................................. 54 
9.4 
Analysis of the primary variable............................................................................ 54 
9.4.1 
Variable(s) ............................................................................................. 54 
9.4.2 
Statistical model, hypothesis, and method of analysis .......................... 54 
9.4.3 
Significance Level: The significance level is 5% two-
sided.Handling of missing values/censoring/discontinuations ............. 55 
9.4.4 
Supportive analyses ............................................................................... 55 
9.5 
Analysis of secondary variables ............................................................................ 55 
9.5.1 
Efficacy variables .................................................................................. 55 
9.5.2 
Safety variables ..................................................................................... 55 
9.5.3 
Resource utilization ............................................................................... 56 
9.5.4 
Health-related Quality of Life ............................................................... 56 
9.5.5 
Pharmacokinetics .................................................................................. 56 
9.5.6 
Pharmacogenetics/pharmacogenomics ................................................. 56 
9.5.7 
Biomarkers ............................................................................................ 56 
9.5.8 
PK/PD ................................................................................................... 56 
9.6 
Interim analyses ..................................................................................................... 56 
9.7 
Sample size calculation ......................................................................................... 56 
9.8 
Regulatory and ethical compliance ........................................................................ 56 


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9.9 
Informed consent procedures ................................................................................. 57 
9.10 
Responsibilities of the investigator and IRB/IEC .................................................. 57 
9.11 
Publication of study protocol and results............................................................... 57 
10  Protocol adherence ............................................................................................................ 58 
10.1 
Protocol Amendments ........................................................................................... 58 
11  References ......................................................................................................................... 58 
12  Appendix 1: Clinically notable laboratory values and vital signs ..................................... 61 
13  Appendix 2: GOLD guidelines (2014) .............................................................................. 62 
14  Appendix 3: Spirometry Guidance .................................................................................... 63 
15  Appendix 4: Baseline Dyspnea Index and Transition Dyspnea Index .............................. 66 
16  Appendix 5: COPD Assessment Test (CAT) .................................................................... 70 
17  Appendix 6: modified Medical Research Council (mMRC) Dyspnea Scale .................... 71 
18  Appendix 7: Instructions for use of the SDDPI ................................................................. 72 
19  Appendix 8: List of MRI paramters captured in the eCRF ............................................... 77 
20  Appendix 9: List of echocardiography parameters captured in the eCRF ........................ 80 
 
List of tables 
Table 5-1 
Prohibited Concomitant  Medications1 ................................................. 30 
Table 5-2 
Prohibited COPD related medications during the trial1 ........................ 31 
Table 5-3 
Medications allowed under certain conditions1 .................................... 31 
Table 6-1 
Assessment schedule ............................................................................. 35 
Table 6-2 
Timed Assessments ............................................................................... 36 
 
List of figures 
Figure 3-1 
Study outline ......................................................................................... 18 
 


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List of abbreviations 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATS/ERS 
American Thoracic Society/European Respiratory Society 
BDI 
Baseline Dyspnea Index 
BTPS 
normal body temperature (37°C), ambient pressure, saturated with water 
vapor 
CAT 
COPD assessment test 
eCRF 
electronic Case Report/Record Form  
CCV 
Cardio- and Cerebro-Vascular events 
CPO 
Country Pharma Organization 
CRO 
Contract Research Organization 
CT 
Computed tomography 
DS&E 
Drug Safety & Epidemiology 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
GCP 
Good Clinical Practice 
GOLD  
Global Initiative for Chronic Obstructive Lung Disease 
FDC 
Fixed-dose combination 
FEV1 
Forced Expiratory Volume in 1 second 
FRC 
Functional Residual Capacity 
FVC 
Forced Vital Capacity 
IC 
Inspiratory capacity 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IOS 
Impulse Oscillometry 
i.v. 
intravenous 
IRB 
Institutional Review Board 
LABA 
Long acting beta 2 agonist 
LAMA 
Long acting muscarinic antagonist 


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LV 
Left ventricular 
mMRC 
Modified Medical Research Council mMRC Dyspnea Scale 
MRI 
Magnetic Resonance Imaging 
o.d. 
once a day 
p.o. 
oral 
PP 
per protocol 
PSW 
Premature Study Withdrawal 
RVol 
Residual Volume 
RV 
Right ventricular 
SABA 
Short acting beta2 agonist 
SAE 
Serious adverse event 
SAMA 
Short acting muscarinic antagonist 
SDDPI 
Single Dose Dry Powder Inhaler 
SmPC 
Summary of Product Characteristics 
sRAW 
Specific Airway Resistance 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TD 
Study treatment discontinuation 
TDI 
Transitional Dyspnea Index 
TLC 
Total lung capacity 


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Glossary of terms 
 
Assessment 
A procedure used to generate data required by the study 
Control drug 
Drugs(s) used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or 
evaluate comparative effects of the investigational drug 
Enrollment 
Point/time of patient entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol) 
Epoch  
The planned stage of the subjects’ participation in the study. Each epoch 
serves a purpose in the study as a whole. Typical epochs are: 
determination of subject eligibility, wash-out of previous treatments, 
exposure of subject to treatment or to follow-up on subjects after treatment 
has ended. 
Investigational drug 
The drug whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug” or “investigational medicinal product.” 
Investigational treatment 
All investigational drug(s) whose properties are being tested in the study 
as well as their associated treatment controls.  
This includes any placebos, any active controls, as well as approved drugs 
used outside of their indication/approved dosage or tested in a fixed 
combination.  
Investigational treatment generally does not include other treatments 
administered as concomitant background therapy required or allowed by 
the protocol when used within approved indication/dosage 
Medication number 
A unique identifier on the label of each investigational/study drug package 
in studies that dispense medication using an IRT system 
Subject Number  
A number assigned to each patient who enrolls into the study  
Part  
A subdivision of a single protocol into major design components. These 
parts often are independent of each other and have different populations or 
objectives. For example, a single dose design, a multiple dose design that 
are combined into one protocol, or the same design with different patient 
populations in each part. 
Period 
A subdivision of a cross-over study 
Premature patient withdrawal 
Point/time when the patient exits from the study prior to the planned 
completion of all investigational/study treatment administration and all 
assessments (including follow-up) 
Randomization number 
A unique identifier assigned to each randomized patient, corresponding to 
a specific treatment arm assignment 
Stop study participation 
Point/time at which the patient came in for a final evaluation visit or when 
study/investigational treatment was discontinued whichever is later 
Study drug/ treatment 
Any single drug or combination of drugs administered to the patient as part 
of the required study procedures; includes investigational drug (s), active 
drug run-ins or background therapy  
Study/investigational treatment 
discontinuation 
Point/time when patient permanently stops taking study/investigational 
treatment  for any reason; may or may not also be the point/time of 
premature patient withdrawal 
Variable 
Information used in the data analysis; derived directly or indirectly from 
data collected using specified assessments at specified time points 
 


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Amendment 3 
Amendment rationale 
The protocol is being amended to implement the possibility of re-screening patients that failed 
the screening phase (before Visit 4) due to increased blood pressure (mean sitting systolic 
blood pressure >160 mmHg and/or mean sitting diastolic blood pressure > 90 mmHg as per 
exclusion criterion 7). For those patients where the antihypertensive therapy is being initiated 
or intensified and leads to a controlled disease status a re-screening can be considered. Re-
screening is permitted to occur at V2, 4 weeks after change of antihypertensive medication. 
This scenario is described in Section 4.2.  
Changes to specific sections of the protocol are shown by track changes in the track changes 
version of the protocol, using strike through red font for deletions and red underlined for 
insertions. 
The changes in this amended protocol are substantial. An approval of this amended protocol 
by the Institutional Review Board (IRBs/Independent Ethics Committee (IECs) and Health 
Authorities prior to implementation is required. 
 
 
 
Summary of previous amendments 
Amendment 2 (dated July 14th, 2015) 
Amendment rationale 
The protocol is being amended to additionally implement fluorine-enhanced (19F) MRI-
technique as an optional measurement to assess regional pulmonary ventilation during steady-
state breathing. This method is complementary to the currently implemented MRI and allows 
getting further insights into the functional pulmonary effects of a dual bronchodilator therapy. 
This might also help to better understand the cardio-pulmonary interaction. Hence, an 
additional explorative objective is included on page 14 and Section 2.3, the assessment 
schedule is described in Section 6 (Table 6-1) and the method and rational is explained in 
Section 6.4.1. 
 
Additional changes to the protocol 
A full list of parameters that will be captured and documented in the eCRF is attached to this 
amended protocol: 
Appendix 8: MRI parameters 
Appendix 9: Echocardiography parameters 
 
Section 5.5.1: clarification was added that Visit numbers in the eCRF are suffixed by “a” if it 
is passed for the second time due to re-screening of the patient.  


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Changes to specific sections of the protocol are shown by track changes in the track changes 
version of the protocol, using strike through red font for deletions and red underlined for 
insertions. 
The changes in this amended protocol are substantial. An approval of this amended protocol 
by the Institutional Review Board (IRBs/Independent Ethics Committee (IECs) and Health 
Authorities prior to implementation is required. 
 
Amendment 1 (dated May 11th, 2014) 
Amendment rationale 
The protocol is being amended to primarily include echocardiographic measures as additional 
explorative objectives. Echocardiography is widely used and accepted as a clinical method of 
choice to determine ventricular diastolic function and thus serves as a complementary method 
to MRI in this mechanistic study to comprehensively evaluate the effect of dual 
bronchodilation on cardiac function. Additional explorative objectives are included on page 
13 and Section 2.3, the assessment schedule is described in Section 3.1. and 6 (Table 6-1, 6-2) 
and the method and rational is explained in Section 6.4.5 and 6.4.10, respectively. 
In addition, to account for blood pressure changes as potential con-founder of ventricular 
function, blood pressure will be measured 4 times during MRI and mean will be considered 
during data analysis (see Section 6.4.1 and 9.4.4). 
Some changes to the exclusion criteria on page 12 and in Section 4.2 were made:  
 to allow patients with stents to be enrolled in the study as stent material does not 
interfere with MRI and the indication for stent implantation does not per se influence 
the outcome of the study unless significant ischemic cardiac changes are present. For 
these cases exclusion criterion #4 will be applied.  
 to exclude patients with uncontrolled hypertension from the study  
 to allow patients with a history of hypersensitivity to i.v. contrast medium to 
participate in the study. In case patients suffer from such a hypersensitivity, the last 
MRI protocol sequence that require i.v. contrast medium will not be performed (see 
also Section 6.4.1).  
 
Additional changes to the protocol 
Section 3.1, 6 (Table 6-1) and 6.5.3: height will be determined and documented at Visit 1 
instead of Visit 3 as this information is crucial to determine FEV 1 % predicted at Screening. 
Section 3.1, 6 (Table 6-1) and 6.5.3: weight will additionally be measured at Visit 1 to allow 
calculation of the BMI. 
Section 3.1, 6 (Table 6-1) and 6.2: bodyplethysmography will also be performed after 
inhalation of salbutamol at Visit 3 to better characterize patients. 
Section 3.1 and 6 (Table 6-1): inclusion of device and inhalation technique training at Visit 4. 


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Section 4.2: the start to re-enter the study after allowed re-screening is defined as Visit 2. 
Section 5.5.4: the time interval for taking study medication at Visits 4 and 6 is prolonged due 
to the inclusion of echocardiography as additional efficacy measure. 
Section 5.5.9: COPD Exacerbation definition and reporting is inserted. 
Section 6 (Table 6-1) and 6.5.4: the time-point at which hematology and blood chemistry will 
be performed during the study is described more precisely.   
Section 6.4.1: additional changes to the MRI protocol are made to optimize measurements. 
Section 6.5.2: a description of how to take mean sitting blood pressure at Visit 3 is included. 
In addition some minor inconsistencies within the text or typos are corrected. 
The changes in this amended protocol are substantial. An approval of this amended protocol 
by the Institutional Review Board (IRBs/Independent Ethics Committee (IECs) and Health 
Authorities prior to implementation is required. 
 
 
 


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Protocol synopsis 
  
Protocol number 
CQVA149ADE05 
Title 
A randomized, double-blinded, single-center, placebo controlled, 
cross-over study to assess the effect of QVA149 (indacaterol 
maleate/glycopyrronium bromide) on cardiac function in patients 
with chronic obstructive pulmonary disease (COPD)  
Brief title 
 
Effect of QVA149 (indacaterol maleate/glycopyrronium bromide) 
on cardiac function in COPD patients  
Sponsor and Clinical 
Phase 
Novartis 
4 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale 
The purpose of the study is to evaluate the effect of dual 
bronchodilation with QVA149 on cardiac and lung function 
parameters in hyperinflated COPD patients. 
Primary Objective(s) 
and Key Secondary 
Objective 
To determine the effect of once-daily QVA149 compared with 
placebo on left ventricular enddiastolic volume as measured by MRI 
after 2 weeks of treatment. 
Secondary Objectives 
 
Objective 1: To evaluate the effects of QVA149 compared to 
placebo on lung function parameters as measured by forced 
spirometry 
75 
min 
post-dose 
(FEV1 
and 
FVC) 
and 
bodyplethysmography 60 min post-dose (inspiratory capacity (IC), 
total lung capacity (TLC), residual volume (RVol) and specific 
airway resistance (sRaw), functional residual capacity (FRC)) 
measured after 14 days of treatment 
Objective 2: To evaluate right and left ventricular ejection fraction 
measured by MRI after 14 days of treatment 
Objective 3: To evaluate right and left ventricular endsystolic 
volumes measured by MRI after 14 days of treatment 
Objective 4: To evaluate right ventricular enddiastolic volume 
measured by MRI after 14 days of treatment 
Objective 5: To evaluate cardiac output measured by MRI after 14 
days of treatment 
Study design 
This is a randomized, double-blinded, single-center, placebo 
controlled, cross-over study to assess the effect of a two weeks 
therapy each with QVA149 versus placebo on cardiac function. 


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Population 
The study population will consist of 62 hyperinflated adults age 40 
years and older, with a residual volume (RVol) >135% predicted, a 
smoking history of at least 10 pack years and a clinical diagnosis of 
COPD. 
Inclusion criteria 
1. Male or female subjects, aged ≥ 40 years 
2. Patients with airflow limitation indicated by a post-
bronchodilator FEV1 <80% of the predicted normal value 
and a post-bronchodilator FEV1/FVC<0.7 at Visit 3. Post-
bronchodilator refers to within 10-15 min of inhalation of 
400µg (4x100 µg) of salbutamol. 
3. Current or ex-smokers who have a smoking history of at 
least 10 pack years. (Ten pack-years are defined as 20 
cigarettes a day for 10 years, or 10 cigarettes a day for 20 
years etc.) 
4. Able and willing to give written informed consent 
5. Hyperinflated patients with RVol>135% predicted as 
measured at Visit 3 
Exclusion criteria 
1. Patients on LABA or LAMA treatment at Visit 1. Those 
patients may enter the study after LABA or LAMA 
withdrawal during a 14-day wash-out period before Visit 3. 
2. History of one COPD exacerbation that required treatment 
with antibiotics, systemic steroids (oral or intravenous) or 
hospitalization 3 months prior to Visit 2.  
3. More than one COPD exacerbation that required treatment 
with antibiotics, systemic steroids (oral or intravenous) or 
hospitalization within 6 months prior to Visit 2. 
4. Patients who have clinically significant cardiovascular 
abnormalities, which could interfere with the assessment of 
the study treatment (such as but not limited to cardiac 
arrhythmias, heart failure  with left ventricular ejection 
fraction <40% as determined by MRI scan at Visit 4, 
unstable ischemic heart disease, NYHA Class III/IV left 
ventricular failure,  history of myocardial infarction 6 
months prior to Visit 2)  
5. Patients with a known history or current atrial fibrillation to 
be confirmed by ECG. 
6. Patients with pacemaker or bypass  
7. Patients with a mean sitting systolic blood pressure >160 
mmHg and/or mean sitting diastolic blood pressure > 90 
mmHg at Visit 3 


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8. Patients whose QTcF measured at Visit 3 is >450 ms for 
males and >470 ms for females 
Investigational and 
reference therapy 
 QVA149 capsules for inhalation 
 Placebo to QVA149 capsules for inhalation 
Efficacy assessments 
 Right and left ventricular enddiastolic volume 
 Right and left ventricular endsystolic volume 
 Right and left ventricular ejection fraction 
 Cardiac output 
 Lung function measured by spirometry and 
bodyplethysmography  
Safety assessments 
none 
Other assessments 
 Average physical activity level (as average number of steps 
at a time/day) 
 Regional lung ventilation and perfusion 
 Pulmonary parenchymal blood flow 
 Biventricular cardiac mass 
 Impulse oscillometry (IOS) 
 Health status (CAT) 
 Dyspnea (BDI/TDI) 
 Left and right ventricular diastolic function  
 Left and right ventricular systolic function  
 Pulmonary arterial pressures  
 Regional lung 19F gas wash-out time  
Data analysis 
The primary and secondary objectives will be analyzed by 
comparing treatments in an analysis of variance (ANOVA) model 
with the factors center, period, patient within center and treatment. 
Raw- as well as adjusted (LS-) means will be provided as point 
estimates for the pair wise treatment contrast. A two-sided, 95% 
confidence interval and a p-value for the null hypothesis of no 
treatment difference will be calculated. Additionally unadjusted 
descriptive statistics (mean, SD, range) will be provided for each 
treatment and for the treatment contrast. 
Key words 
QVA149, cardiac function, ventricular enddiastolic volume, 
hyperinflated COPD patients 
 


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1 
Introduction 
1.1 
Background  
Heart disease and chronic obstructive pulmonary disease (COPD) are leading causes of 
mortality that often co-exist: clinical or subclinical cardiovascular disease is increased in 
COPD patients, independently of risk factors shared by the two diseases [1]. 
In COPD patients, hyperinflation is a major lung functional abnormality, which is related to 
exercise limitations and mortality, with a higher RVol and a lower IC/TLC as independent 
predictors of all-cause and respiratory mortality in COPD [2, 3]. 
Hyperinflation can result from increase in airways resistance (e.g. airway narrowing), lung 
compliance (e.g., emphysema), or both [4]. FRC and TLC are thought to be more sensitive to 
changes in lung elastic recoil from emphysema [4, 5], whereas RVol is considered a better 
metric of hyperinflation with preserved lung elastic recoil but with airway narrowing [1]. As 
RVol is also the first lung volume to increase in COPD and is more sensitive to changes in the 
degree of airways obstruction than TLC, it may serve as an indicator for hyperinflation [6] 
and as an inclusion criterion for clinical trials.  
In a large, population-based cohort, that was free of clinical cardiovascular disease, it was 
shown, that airflow obstruction as measured by spirometry and extent of emphysema as 
measured by CT  are inversely related to left ventricular end-diastolic volumes, stroke volume 
and cardiac output. Relationships were linear across a spectrum from normal lung structure 
and function to moderately severe airflow obstruction and emphysema. Several potential 
mechanisms contribute to impaired left ventricular filling in COPD patients. Alveolar hypoxia 
has been described to cause pulmonary-artery vasoconstriction and vascular remodeling, 
leading to increased pulmonary vascular resistance and impaired left ventricular filling in 
COPD patients with severe airway obstruction. Hyperinflation is another mechanism in severe 
COPD, which can cause intrathoracic pressure to exceed venous pressure, with reductions in 
the blood volumes of both ventricles [7]. 
Smith et al. postulated also, that the intrathoracic pressure impairs the venous return to the 
right heart, resulting in underfilling of the pulmonary veins and leading to reduced pulmonary 
vein dimensions in COPD patients. Thus, impaired left ventricular filling may be 
predominantly due to reduced left ventricular preload from upstream pulmonary causes [8]. 
Jörgensen et al. described this as intrathoracic hypovolemia which decreases biventricular 
preload in patients with hyperinflated lungs and severe emphysema [9]. 
Consistent with this framework, Watz et al. described a significantly impaired left ventricular 
diastolic filling pattern and an impaired global right ventricular function in hyperinflated 
patients, characterized by IC/TLC<=0.25. This supports the concept of reduced preload 
condition in patients with COPD, as left ventricular isovolumetric relaxation time was 
unaffected by hyperinflation, indicating no relationship to left ventricular distensibility (i.e. 
stiff myocardium) [10]. 


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A very recent study showed that hyperinflated patients – defined as TLC>110% predicted – 
have lower cardiac output, LV end diastolic volume and RV end diastolic volume, whereas 
the ejection fraction remained unchanged [11].  
Until now, there is only very limited data available on the effect of bronchodilators, leading to 
reduced hyperinflation, on cardiac function. It has been shown, that treatment with tiotropium 
improved pulmonary arterial systolic pressure and E/e’ ratio measured with tissue Doppler 
imaging. This suggests attenuation of air trapping, being associated with an improvement of 
right ventricular overload and left ventricular diastolic dysfunction [12]. 
Ultibro® (indacaterol/glycopyrronium) is an inhaled, once-daily dual bronchodilator 
containing a fixed dose combination of the long-acting β2-agonist indacaterol and the long 
acting muscarinic antagonist glycopyrronium. It is prescribed for the treatment of chronic 
obstructive pulmonary disease (COPD).  
In phase III studies, Ultibro® significantly improved FEV1 compared to indacaterol, 
glycopyrronium or tiotropium alone. These improvements in lung function, which were rapid 
in onset and maintained during long-term treatment, were generally associated with 
significant improvements not only in dyspnea, health status, COPD exacerbation risk, patient 
symptoms, and rescue medication use [13], but also in reducing static hyperinflation as 
measured by static inspiratory capacity and residual volume [14]. 
The hypothesis of this study is that Ultibro® potentially has a positive effect on cardiac 
function by decreasing airflow obstruction. This might result in an improvement of 
hyperinflation, altered pulmonary parenchymal blood flow, which is associated with an 
improved LV enddiastolic volume. This study is designed to evaluate the effect of a 2-week-
treatment with Ultibro® on cardiac function evaluated by magnetic resonance imaging (MRI) 
[15; 16]. 
 
1.2 
Purpose  
The purpose of this mechanistic study is to determine whether QVA149 110/50 µg o.d. 
(compared to placebo) has a positive effect on cardiac function by decreasing airflow 
obstruction in hyperinflated COPD patients. Completion of the study will help to understand 
the effects of dual bronchodilation by QVA149 on cardiovascular parameters, which are 
impaired in COPD patients and are therefore co-existing risk factors. 
2 
Study objectives 
2.1 
Primary and key secondary objective 
To determine the effect of once-daily QVA149 (110/50 µg o.d.) compared with placebo on 
left ventricular enddiastolic volume as measured by MRI after 2 weeks of treatment in 
hyperinflated COPD patients. 
2.2 
Secondary objectives 
 To evaluate the effects of QVA149 compared to placebo on lung function parameters 
after 14 days of treatment, as measured by: 


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o Forced spirometry (75 min post-dose) 
- FEV1 and FVC 
o Bodyplethysmography (60 min post-dose): 
- inspiratory capacity (IC) 
- total lung capacity (TLC) 
- residual volume (RVol) 
- specific airway resistance (sRaw) 
- functional residual capacity (FRC) 
 
To evaluate the effects of QVA149 compared to placebo on cardiac parameters, as 
measured by MRI after 14 days of treatment: 
o right and left ventricular ejection fraction 
o right and left ventricular endsystolic volumes 
o right ventricular enddiastolic volume 
o cardiac output 
2.3 
Exploratory objectives  
To explore the change in: 
 health status (CAT questionnaire) 
 dyspnea (BDI/TDI questionnaire) 
 average physical activity level (as average number of steps at a time/day) 
 biventricular cardiac mass, measured by MRI 
 pulmonary parenchymal blood flow measured by MRI 
 regional lung ventilation and perfusion measures (OTF, oxygen transfer function) 
using oxygen-enhanced T1 mapping MRI 
 airway function using impulse oscillometry (IOS) 
 left and right ventricular diastolic function measured by echocardiography 
 left and right ventricular systolic function measured by echocardiography 
 pulmonary arterial pressures measured by echocardiography 
 regional lung 19F gas wash-out time measured by MRI (as optional measurement in a 
subgroup of patients) 


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3 
Investigational plan 
3.1 
Study design 
This will be a randomized, double-blinded, placebo controlled, single-center, two period 
crossover study to compare the effects of a 2 week therapy each with QVA149 versus 
placebo. The study duration will be about 13 weeks (see Figure 3-1 Study outline). The study 
consists of six epochs: a variable Pre-Screening epoch, a Screening epoch (depending on 
washout required for prior medications), a Baseline epoch necessary to collect baseline data, 
two cross-over treatment periods (Treatment I and II) separated by a wash-out epoch and a 
follow-up epoch.  
Figure 3-1 
Study outline 
 
Visit 1 (Pre-Screening) 
At Visit 1, the informed consent will be obtained to assess whether patients might be eligible 
for this study. Current COPD medications, inclusion/exclusion criteria, COPD exacerbation 
history as well as smoking history will be reviewed. Patient demographics and medical history 
including history of cardiovascular (CV) risk factors will be assessed. Forced spirometry will 
be performed after intake of salbutamol to assess reversibility. The interval between Visit 1 
and Visit 2 is variable and can take up to several months, depending on free MRI capacity 
slots. 
Visit 2 (Screening) 
At Visit 2 current COPD medications, inclusion/exclusion criteria as well as COPD 
exacerbation history will be reviewed. Medical history including history of cardiovascular 
(CV) risk factors will be assessed and if necessary, arrangements will be made to adjust 
prohibited COPD therapy (see Table 5-2). Patients on fixed-dose combination of long-acting 
beta2 agonists/inhaled corticosteroid (LABA/ICS) therapy must be switched to the equivalent 
dose of ICS monotherapy and salbutamol as rescue medication. This switch and wash-out of 
prior medication period has to be finished until Visit 3. However, during the treatment period 


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salbutamol is only to be applied for rescue (“when required”) use. The interval between Visit 
2 and Visit 3 is an individual run-in period (depending on the required wash-out time of the 
pre-medication), used to assess eligibility of patients for the study. Depending on the current 
medication the run-in period can be reduced to the wash-out period specified in Table 5-1 and 
Table 5-2. 
Visit 2 is optional (not mandatory) and can be omitted if the patient can already be washed-
out at Visit 1 and if subsequent MRI capacities are available. If Visit 2 is omitted, rescue 
medication should already be dispensed at Visit 1. All inclusion and exclusion criteria 
referring to Visit 2 are then related to Visit 1. 
Visit 3 (Baseline) 
Patients will commence a Baseline period for 7 days. The modified Medical Research Council 
(mMRC) as well as the COPD Assessment Test (CAT) will be collected. Patients will be re-
assessed for the inclusion/exclusion criteria. Physical examination, weight, vital signs, ECG 
and blood analysis will be collected and a urine pregnancy test applied for women with child-
bearing potential. Bodyplethysmography (before and after salbutamol inhalation) and impulse 
oscillometry will be performed to collect lung function data. Forced spirometry will be 
measured before and after salbutamol inhalation to assess reversibility. The Actibelt will be 
distributed to assess baseline physical activity (for 1 week) of patients after the wash-out 
period. 
Visit 4 (Randomization – Beginning of Treatment I) 
The questionnaires CAT and BDI will be completed prior to any other study assessment. The 
Actibelt will be returned and data will be transferred. ECG, vital signs and lung function 
measurements (impulse oscillometry, bodyplethysmography and spirometry) will be 
collected. Patients will undergo MRI investigation and inclusion/exclusion criteria will be re-
assessed. Echocardiography will be performed. Patients that are eligible for the study will first 
be trained on the device and correct inhalation technique and then be randomized to either 
receive QVA149 in treatment period I followed by placebo in treatment period II or the same 
treatment in reverse order in an allocation ratio of 1:1. Patients will again receive the Actibelt 
and will be asked to wear it to measure physical activity throughout the entire treatment 
period I. 
 
Patients must be instructed NOT to take their study medication at home on the day of 
the site visit as this will be administered at the site and – unless absolutely necessary – 
NOT to take rescue salbutamol within 6 hours of the start of each visit. 
Visit 5 (End of Treatment I) 
All questionnaires will be completed first. The Actibelt will be returned and data will be 
transferred. Vital signs, blood analysis and lung function measurements (impulse 
oscillometry, bodyplethysmography and spirometry) will be collected. Patients will undergo 
MRI and echocardiography investigations and receive their Actibelt for use during the wash-
out period. 


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Visit 6 (Beginning of Treatment II) 
All questionnaires will be completed first. The Actibelt will be returned and data will be 
transferred. Comparable to beginning of treatment I, ECG, vital signs, lung function 
measurements,  MRI and echocardiography will be performed. In the second treatment period, 
all subjects will receive the other treatment (i.e. patients receiving QVA149 in treatment 
period I will receive placebo in treatment period II and patients receiving placebo in treatment 
period I will receive QVA149 in treatment period II). Patients will be asked to wear the 
Actibelt throughout the entire treatment period II. 
Visit 7 (End of Treatment II) 
Questionnaires will be completed and the Actibelt returned for data transfer. Physical 
examination, vital signs, blood analysis and lung function measurements (impulse 
oscillometry, bodyplethysmography and spirometry) will be collected and a urine pregnancy 
test applied for women with child-bearing potential. Patients have to return unused medication 
and will undergo final MRI and echocardiography investigations. At the time of study 
completion or early termination, all patients will be placed on the appropriate COPD 
treatment as prescribed by the investigator. 
Visit 8 (Safety-Follow-up telephone call, 30 days after end of study) 
All adverse events with a date of onset up to 30 days following the last dose of study drug 
must be reported. 
 
The total time on study for each patient is (maximal 21 days screening/baseline) + (14 days 
treatment x 2=28 days) + (14 days washout) + safety follow-up (30 days) = 93 days plus the 
variable pre-screening period, where patients are maintained on their prior medication. 
Drop-out Visit (Patient who discontinue the study) 
Patient discontinuing the study shall perform all assessments as in Visit 7 marked with an 
asterix in the assessment schedule. 
 
3.2 
Rationale of study design 
A randomized, blinded, cross-over design (rather than a parallel group design) was chosen 
because within-patient variability for the parameters assessed in this trial is expected to be less 
than between-patient variability thus allowing greater precision to be achieved whilst 
exposing a smaller number of patients to trial treatment and assessments. All measured 
treatment effects are expected to be completely reversible, therefore a cross-over design is a 
feasible alternative. 
A washout period of 14 days between two treatment periods seems to be sufficient to avoid 
any “carry-over” effects and to restore potential structural changes of the heart.  
 


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3.3 
Rationale of dose/regimen, route of administration and duration 
of treatment 
The dose, dose regimen and route of administration of QVA149 (Ultibro®) is in accordance 
with product labeling. The selection of QVA149 dose (110/50 µg once daily) was based on 
data from the QAB149 and NVA237 monotherapy programs. Those programs identified the 
doses as 150 µg once daily for QAB149 and 50 µg once daily for NVA237. However, in 
formulating the QVA149 combination product, an increase in fine particle (respirable) 
fraction was observed for the QAB149 component (compared with the monotherapy). As a 
consequence, to ensure that the fine particle dose of QAB149 delivered to the lung from the 
combination matches that delivered from the monotherapy, the dose for the QAB149 
component of QVA149 has been reduced to 110 µg. 
A treatment duration of 2 weeks (14 days) was selected as the minimum required to detect 
functional changes in cardiac activity that are due to a decrease of intrathoracic pressure as a 
result of bronchodilation resulting in reduced hyperinflation. 
3.4 
Rationale for choice of comparator 
The use of placebo control is justifiable, as it is unknown whether the dual bronchodilator 
QVA149 will show an effect on cardiovascular parameters, such as right and left ventricular 
enddiastolic volumes. It is important to note that the term “placebo” used in the context of this 
study refers to a placebo control that will be added to the well-established COPD background 
therapy with salbutamol as rescue medication and inhaled corticosteroid treatment (if 
applicable). 
 
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 determined as inclusion/exclusion criteria and by close clinical monitoring. Although 
altering the current COPD medication regimen during the screening period at the beginning of 
the study carries an inherent risk of a decline in lung function, this period is short. Patients 
will be exposed to a placebo period and a washout period between treatments. Providing the 
patients with rescue medication for use as needed throughout study and permitting them to 
continue on ICS treatment throughout the study, mitigates these risks.  
Patients will be monitored closely by the investigator to ensure that the patients’ COPD 
remains adequately controlled. If patients experience a COPD exacerbation during the 
treatment period they will be treated as deemed appropriate by the investigator and 
discontinued from the study.  
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 


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to ensure availability of immediate aid if required. The assessments are infrequent, small in 
number, 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 compound 
QVA149. The most frequently reported side effects to date are upper respiratory tract 
infection, nasopharyngitis, cough, oropharyngeal pain and headache. Further information can 
be obtained from the QVA149 Investigator’s Brochure.  
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 will consist of 62 adult males and females aged 40 years and older, with 
a clinical diagnosis of COPD (GOLD 2014) and a smoking history of at least 10 pack years. It 
is anticipated that approximately 400 patients will need to be pre-screened in order to 
randomize 62 patients into 2 treatment sequences of the study with a randomization ration of 
1:1. Drop-outs will not be replaced. 
4.1 
Inclusion criteria 
Patients eligible for inclusion in this study have to fulfill all of the following criteria: 
1. 
Written informed consent must be obtained before any assessment is performed. 
2. 
Male or female subjects, aged ≥ 40 years, giving written Informed Consent and who are 
willing and capable to comply with all study procedures. 
3. 
Patients with stable COPD according to the current GOLD guidelines (GOLD 2014). 
4. 
Patients with airflow limitation indicated by a post-bronchodilator FEV1 <80% of the 
predicted normal value and a post-bronchodilator FEV1/FC<0.7 at Visit 3. Post-
bronchodilator refers to within 10-15 min after inhalation of 400 µg (4x100 µg) of 
salbutamol. 
5. 
Current or ex-smokers who have a smoking history of at least 10 pack years. (Ten pack-
years are defined as 20 cigarettes a day for 10 years, or 10 cigarettes a day for 20 years 
etc.) 
6. 
Hyperinflated patients with RVol>135% predicted as measured at Visit 3, before intake 
of salbutamol. 
 
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. 
 


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1. Patients with conditions contraindicated for treatment with, or having a history of 
reactions/hypersensitivity to any of the following inhaled drugs, drugs of a similar class or 
any component thereof  
 anticholinergics  
 long and short acting beta-2 agonists  
 sympathomimetic amines 
 lactose or any of the other excipients 
2. Patients with a history of long QT syndrome or whose QTcF (Fredericia method) 
measured at Visit 3 is prolonged (>450 ms for males and >470 ms for females). These 
patients should not be re-screened. 
3. Patients who have a clinically significant abnormality on the ECG at Visit 3, who in the 
judgment of the investigator would be at potential risk if enrolled into the study. These 
patients should not be re-screened.  
4. Patients who have clinically significant cardiovascular abnormalities, which could 
interfere with the assessment of the study treatment (such as but not limited to cardiac 
arrhythmias, heart failure  with left ventricular ejection fraction < 40 % as determined by 
MRI scan at Visit 4, unstable ischemic heart disease, NYHA Class III/IV left ventricular 
failure,  history of myocardial infarction 6 months prior to Visit 2) 
5. Patients with a known history or current atrial fibrillation to be confirmed by ECG at Visit 
3. 
6. Patients with pacemaker or bypass. 
7. Patients with a mean sitting systolic blood pressure >160 mmHg and/or mean sitting 
diastolic blood pressure > 90 mmHg at Visit 3. These patients will be permitted to be re-
screened after having achieved controlled disease status following initiation or 
intensification of antihypertensive therapy. Re-screening can start at Visit 2, 4 weeks after 
change of antihypertensive medication.   
8. Past or present disease, which as judged by the investigator, may affect the outcome of 
this study. These diseases include, but are not limited to history of hepatic disease, renal 
disease, hematological disease, neurological and psychiatric disease, endocrine disease or 
pulmonary disease other than COPD (including but not confined to tuberculosis, 
bronchiectasis, cystic fibrosis, pulmonary hypertension, sarcoidosis, interstitial lung 
disease or lung fibrosis). 
9. History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin), treated or untreated, within the past 5 years, regardless of whether there is 
evidence of local recurrence or metastases. 
10. Patients with narrow-angle glaucoma, symptomatic benign prostatic hyperplasia or 
bladder-neck obstruction or severe renal impairment (GFR<30 mL/min/1.73 m2) including 
those with end-stage renal disease requiring dialysis or urinary retention. Benign Prostatic 
Hyperplasia (BPH) patients who are stable on treatment can be considered. 
11. Patients with Type I or uncontrolled Type II diabetes.  
12. Patients with active/ clinical history of asthma. 


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13. Patients unable to undergo MRI scans, including claustrophobia or presence of any metal 
objects within the patient, preventing from MRI scan (e.g. pacemaker, aneurysm clips).  A 
separate MRI patient informed consent form including MRI safety will be signed by the 
patient before each MRI exam. 
14. History of lower respiratory tract infection within four weeks prior to Visit 2 and between 
Visit 2 and Visit 4. These patients will not be eligible, but will be permitted to be re-
screened 4 weeks after the resolution of the respiratory tract infection and can re-start at 
Visit 2. 
15. History of one COPD exacerbation that required treatment with antibiotics, systemic 
steroids (oral or intravenous) or hospitalization within 3 months prior to Visit 2. 
16. More than one COPD exacerbation that required treatment with antibiotics, systemic 
steroids (oral or intravenous) or hospitalization within 6 months prior Visit 2. 
17. Patients who develop a COPD exacerbation between Visit 2 and Visit 4 will not be 
eligible but will be permitted to be re-screened after a minimum of 3 months after the 
resolution of the COPD exacerbation and can re-start at Visit 2. 
18. Patients requiring long term oxygen therapy on a daily basis for chronic hypoxemia. 
19. Patients with active pulmonary tuberculosis, unless confirmed by imaging in the last year 
to be no longer active. 
20. Patients with pulmonary lobectomy or lung volume reduction surgery or lung 
transplantation. 
21. Patients with a diagnosis of alpha 1 anti-trypsin deficiency. 
22. Patients with a body mass index (BMI) of more than 40 kg/m2. 
23. Patients participating in or planning to participate in the active phase of a supervised 
pulmonary rehabilitation program during the study  
24. Patients who are, in the opinion of the investigator known to be unreliable or non-
compliant. 
25. Relevant history of drug or alcohol abuse as judged by the investigator. 
26. Suspected inability to understand the protocol requirements, instructions and study-related 
restrictions, the nature, scope, and possible consequences of the study 
27. Use of other investigational drug (approved or unapproved) at the time of enrollment, or 
within 30 days or 5 half-lives of Visit 1, whichever is longer. 
28. Patients receiving any medications in the classes listed in Table 5-1 and Table 5-2. 
29. Patients 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 have been 
met. 
30. Women who are pregnant or breast feeding (pregnancy defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test (> 5mIU/ml)). 
31. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using effective contraception (Pearl Index <1*) during 


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the study and up to at least 4 weeks after the end of treatment. UNLESS they meet the 
following definition of post-menopausal: 12 months of natural (spontaneous) amenorrhea 
OR 6 months of spontaneous amenorrhea with serum FSH levels >40mIU/m OR 6 weeks 
after 
surgical 
bilateral 
oophorectomy 
(with 
or 
without 
hysterectomy). 
* Examples of particularly reliable methods with Pearl Index (PI) <1, according to 
guidelines 
of 
Deutsche 
Gesellschaft 
für 
Gynäkologie 
und 
Geburtshilfe: 
- Combination pill with estrogen and gestagen (no mini-pill, PI=0.1-0.9) 
- Vaginal ring (NuvaRing®, PI=0.65 uncorr.; 0.4 corr.) 
- Contraceptive patch (EVRA®, PI=0.72 uncorr.; 0.9 corr.) 
- Estrogen-free ovulation inhibitors (Cerazette®, PI=0.14) 
- Progestin-containing contraceptives (Implanon®, PI=0-0.08) 
- Intra-uterine progestine device (Mirena®, PI=0.16) 
Oral contraceptives without estrogen (e.g. “mini-pills”), nonsynthetic progesterone only 
IUDs, female condoms, cervical shield, periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
Fertile males, defined as all males physiologically capable of conceiving offspring 
UNLESS the patient and his partner agree to comply with acceptable contraception, 
including 
a 
combination 
of 
male 
condom 
and 
spermicidal 
gel. 
 
5 
Treatment 
5.1 
Protocol requested treatment 
5.1.1 
Investigational treatment 
 
 QVA149 110/50 µg capsules for inhalation supplied in blisters, delivered via Novartis 
single dose dry powder inhaler (SDDPI). 
 Placebo to QVA149 capsules for inhalation supplied in blisters, delivered via Novartis 
single dose dry powder inhaler (SDDPI). Placebo QVA149 inhalation capsules will be 
equally matched in size, shape and color to QVA149 110/50 µg inhalation capsules. 
 
The use of spacers is not permitted for study medication at any time during the study 
However, assessment of reversibility at Visit 1 can be performed via spacer (not 
reversibility at Visit 3). 
 
Under no circumstances is an alternative inhalation device to be used for the 
administration of the above mentioned active or placebo capsules. 
 
All therapies will be supplied by Novartis, providing sufficient quantity of medication to last 
each patient between clinical visits. 
 


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5.1.2 
Additional study treatment 
No additional treatment beyond investigational treatment is requested for this trial. 
 
5.2 
Treatment arms 
Patients will be assigned to one of the following two treatment sequence arms in a ratio of 1:1.  
Treatment sequence I: QVA149 (110/50 µg) o.d. (Day 1-15) followed by Placebo o.d. (Day 
29-43).  
Treatment sequence II: Placebo o.d. (Day 1-15) followed by QVA149 (110/50 µg) o.d. (Day 
29-43).  
5.3 
Treatment assignment, randomization  
At Visit 4 an eligible patient will be given the lowest available randomization number. This 
number assigns the patient to one of the treatment sequences. The investigator will enter the 
randomization number on the eCRF. 
The randomization numbers will be generated using the following procedure to insure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A 
randomization list will be produced by or under the responsibility of Novartis Biometry using 
a validated system ensuring assignment of treatment sequences to randomization numbers in 
the specified ratio.  
The randomization scheme will be reviewed and approved by a member or delegate of the 
Novartis Biometry Randomization Group.  
 
5.4 
Treatment blinding  
Patients, investigator staff, persons performing the assessments, sponsor staff and data 
analysts will remain 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 will not be accessible by anyone else involved in 
the study. 2) The identity of the treatments will be concealed by the use of study drugs that are 
all identical in packaging, labeling, schedule of administration, appearance, taste.  
Unblinding will only occur in the case of patient emergencies (see Section 5.5.10), and at the 
conclusion of the study. 
 
5.5 
Treating the patient 
5.5.1 
Patient numbering  
Each patient is uniquely identified by a Patient-ID Number which is composed by the site 
number assigned by Novartis and a sequential subject number assigned by the investigator 


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(per allocation card or equivalently). Once assigned to a patient, the Patient-ID Number will 
not be reused.  
Upon signing the informed consent form, the patient is assigned the next sequential number as 
given by the investigator using the next blank CRF book available from the EDC system.  
If a screened patient fails to be randomized or enrolled for any reason, the reason will be 
entered on the Screening Failure Log CRF.  
If a patient will be re-screened, some visits have to be passed for the second time. In the eCRF 
system the respective data will be captured under the Visit number suffixed by “a”.  
 
5.5.2 
Dispensing the investigational treatment 
The site will be supplied by Novartis with study drug in identically-appearing packaging. 
QVA149 110/50 µg and matching placebo will be supplied as medication packs containing 
blister strips of capsules and SDDPI devices, as each SDDPI device should only be used for 
30 days. Each medication pack contains 2 blister strips à 20 capsules for inhalation and one 
SDDPI device, sufficient to last until the end of the respective treatment period. 
One component of the packaging has a 2-part label. Each part of this label contains 
sequentially increasing randomization numbers (corresponding to treatment sequences 
according to the confidential randomization list). Investigator staff will identify the study drug 
to dispense to the patient using the randomization number and the visit number on the label. 
Immediately before dispensing study drug 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) containing that patient’s unique patient number. 
 
5.5.3 
Handling of study treatment 
5.5.3.1 
Handling of investigational treatment 
Investigational treatment must be received by a designated person at the study site, handled 
and stored safely and properly, and kept in a secured location to which only the investigator 
and designated assistants have access. Upon receipt, all investigational treatment should be 
stored according to the instructions specified on the drug labels. Clinical supplies are to be 
dispensed only in accordance with the protocol. 
Medication labels will be in German and comply with the legal requirements of Germany. 
They will include storage conditions for the drug, but no information about the patient except 
for the randomization number. 
The investigator must maintain an accurate record of the shipment and dispensing of 
investigational treatment in a drug accountability log. Monitoring of drug accountability will 
be performed by the field monitor during site visits and at the completion of the trial. Patients 
will be asked to return all unused investigational treatment and packaging at the end of the 
study or at the time of discontinuation of investigational treatment.  


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At the conclusion of the study, and as appropriate during the course of the study, the 
investigator will return all unused investigational treatment, packaging, drug labels, and a 
copy of the completed drug accountability log to the Novartis monitor or to the Novartis 
address provided in the investigator folder at each site. 
 
5.5.3.2 
Handling of other study treatment 
Not applicable. 
5.5.4 
Instructions for prescribing and taking study treatment 
Patients will be required to take their study medication once a day between 7:00 and 11:30 +/- 
30 minutes. Patients will be instructed to come to the clinic in appropriate time to complete 
pre-dosing assessments and to allow randomized study medication to be taken in the morning 
between 07:00 and 13:30 (Visits 4 and 6) and between 07:00 and 11:30 (Visits 5 and 7), 
respectively. Patients must be instructed to withhold the use of short acting beta2 agonists 
(rescue medication) for at least 6 hours prior to all clinic visits, unless the use is absolutely 
necessary. 
Capsules should only be removed from the blister immediately before dosing. 
At Visit 4, patients will be randomized to one of two treatment sequences. 
Patients will be instructed on how to use the study treatment SDDPIs devices. Additional 
SDDPI devices and placebo capsules will be provided for training and demonstration 
purposes. 
At Visits 4, 5, 6 and 7 (randomized treatment) the study medication will be administered in 
the clinic by the site personnel after completion of all pre-dose procedures between 07:00 
and 13:30 (Visits 4 and 6) and between 07:00 and 11:30 (Visits 5 and 7),respectively. Patients 
shall refrain from the inhalation of study drug at home prior to each scheduled Visit. 
The site staff should call the patient two days prior to Visits 3, 4, 5, 6 and 7 to remind 
them to take their study medication only on the day before the scheduled visit (only 
relevant for Visits 4, 5, 6 and 7) and to abstain from taking rescue medication 
(salbutamol) within 6 hours of the start of the visit. 
If study drug is inhaled at home, at the day of Visit 4, 5, 6 and 7, the visit should be 
rescheduled to the next possible date.  
The investigator should promote compliance by instructing the patient to take the study drug 
exactly as prescribed and by stating that compliance is necessary for the patient’s safety and 
the validity of the study. The patient should be instructed to contact the investigator if he/she 
is unable for any reason to take the study drug as prescribed. 
All dosages prescribed and dispensed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record CRF (eCRF). 
The storage conditions for study drug will be described on the medication label 


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5.5.5 
Permitted dose adjustments and interruptions of study treatment 
No adjustments to the study drug dosage or schedule are permitted, other than temporarily 
interrupting study medication during the treatment period as a result of an adverse event 
(including mild COPD exacerbations), if necessary.  
Patients that experience a moderate to severe COPD exacerbation (see Section 5.5.9) must be 
discontinued from study medication and the trial immediately.   
Any interruption of study medication should be for the shortest time period possible and any 
interruption of study medication for more than 3 consecutive days should be discussed with 
the local Novartis Clinical Monitor to review the patient’s eligibility to continue in the trial.  
These changes must be recorded in the Dosage Administration Record CRF (eCRF).  
 
5.5.6 
Rescue medication 
At the start of screening (Visit 2), all patients will be provided with a short acting beta2 
agonist (salbutamol) which they will be instructed to use throughout the trial as rescue 
medication. Salbutamol (100 µg) will be supplied to the investigator sites locally by Novartis. 
In case Visit 2 is omitted, salbutamol will be dispensed at Visit 1. During the treatment period 
salbutamol should be taken as rescue (when required) purposes only. No other rescue 
treatment is permitted. Nebulized salbutamol is not allowed as rescue medication. 
In order to standardize measurements, patients must be instructed to abstain from taking 
rescue medication (salbutamol) within 6 hours of the start of each visit where spirometry is 
being performed unless absolutely necessary. If rescue medication is taken within 6 hours 
prior to spirometry at Visit 3, 4, 5, 6 and 7, 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.  
In the event that a patient uses a dose of rescue medication during any visit, but after 
echocardiography assessment was performed, the visit should continue as planned. If the 
patient uses a dose of rescue medication within 6 hours before MRI measurement, the visit 
should be rescheduled.  
The approximate time of rescue medication intake will be captured in the eCRF if taken 
during one of the above study visits. 
5.5.7 
Concomitant treatment 
The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) 
administered after the patient was enrolled into the study must be recorded on the 
Concomitant medications/Significant non-drug therapies eCRF page. 
The following adjustments to patients who are treated with ICS are required: 
 Patients taking inhalative corticosteroids (either as a monotherapy or as a fixed-dose 
combination of a LABA and ICS) for at least 30 days prior to Visit 2, shall continue 


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inhaling the ICS at an equivalent dose and dosing regimen for the duration of the 
study. The LABA-component, in case of a fixed-dose combination, must be 
discontinued at least 14 days prior to Visit 3. All other patients taking ICS 
intermittently or less than 30 days shall discontinue ICS inhalation. 
 If, in the judgment of the investigator, it is necessary to increase the ICS dose of a 
patient between Visit 2 and Visit 4 in order to stabilize the patient, this patient will be 
considered a screening failure. The patient may be re-screened when the ICS dose 
required for the stable maintenance of the patient’s condition has been established and 
he/she has been stable under this regimen for at least 1 month before being re-
screened. Patients being re-screened do not have to undergo Visit 1, but can 
immediately start with Visit 2. During the treatment period of the study (Visit 4 until 
Visit 7), patients shall be maintained on an unchanged ICS regimen. 
 
5.5.8 
Prohibited Treatment 
Use of the treatments displayed in Table 5-1 and Table 5-2 is NOT allowed to be taken 
during the study. The medications in Table 5-3 are only permitted under the circumstances 
given. Each concomitant drug must be individually assessed against all exclusion criteria and 
the tables below to see if it is allowed. If in doubt the investigator should contact the Novartis 
medical monitor before randomizing a patient or allowing a new medication to be started.  
 
Table 5-1 
Prohibited Concomitant  Medications1 
Class of Medication 
Minimum cessation period prior to  
baseline visit (Visit 3) 
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 
Cardiac anti-arrhythmics Class Ia 
7 days 
Cardiac anti-arrhythmics Class III 
7 days, amiodarone 3 months 
Other drug with potential to significantly prolong the QT 
interval 
14 days or 5 half-lives, whichever is 
longer 
Tricyclic antidepressants 
14 days 
All antipsychotic agents (first, second and third 
generation, inclusive of atypical antipsychotics) 
Combinations of antipsychotic agents with 
antidepressants are prohibited 
14 days 
Serotonin Noradrenaline Reuptake Inhibitors (SNRIs) 
Other noradrenaline reuptake inhibitors 
14 days 
14 days 
Monoamino-oxidase inhibitors 
14 days 
 
 
Live attenuated vaccine  
30 days  
 
 
Macrolide antibiotics  
30 days 


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Class of Medication 
Minimum cessation period prior to  
baseline visit (Visit 3) 
 
Systematic 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 to be used as a guide only and not considered all-inclusive. Medications should be 
assessed for adherence to the indication, compatibility with the study aims, study medication, study-
related procedures, and other inclusion/ exclusion criteria. 
2Selective ß1-blocking agents are permitted. 
The washout of these prohibited medications is not to be encouraged. 
 
Table 5-2 
Prohibited COPD related medications during the trial1 
Class of Medication 
Minimum washout period prior to 
baseline visit (Visit 3) 
Short-acting β2 agonists (SABA) (other than study rescue 
medication)  
6 hr 
Short acting anticholinergics (SAMA) 
8 hr 
Fixed combinations of short-acting β2 agonists and short-
acting anticholinergics (SABA/SAMA) 
Long-acting β2 agonists (LABA) 
Fixed combinations of long-acting β2 agonists and inhaled 
corticosteroids (LABA/ICS) 
 
Long-acting anticholinergics (LAMA) 
8 hr 
 
14 days 
14 days (LABA) - Must be switched to 
the nearest equivalent dose of  inhaled 
corticosteroid monotherapy 
14 days 
Inhaled corticosteroids (intermittent use) 
Oral Phosphodiesterase-IV inhibitor 
14 days 
7 days 
Xanthines (any formulation) 
7 days 
Parenteral or oral corticosteroids (allowed for the 
treatment of COPD exacerbation) 
30 days 
Intra-muscular depot corticosteroids 
3 months 
1These tables are to be used as a guide only and 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. 
 
 
Table 5-3 
Medications allowed under certain conditions1 
Class of Medication 
Condition under which medication is permitted 
Selective Serotonin Reuptake Inhibitors 
Stable dose for at least 30 days prior to 
screening (Visit 2) and during the study. 
Inhaled corticosteroids (stable long-term regimen) 
Stable dose for at least 30 days prior to 


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Class of Medication 
Condition under which medication is permitted 
screening (Visit 2) and during the study. 
Intra-nasal corticosteroids 
Stable dose for at least 30 days prior to 
screening (Visit 2) and during the study 
H1-antagonists  
Stable dose for at least 5 days prior to 
screening (Visit 2) and during the study.  
(except mizolastin or terfenadine) 
Inactivated influenza, pneumococcal or any other 
inactivated vaccine 
Not administered within 48 hours prior to a 
study visit 
1These tables are to be used as a guide only and 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 and premature patient withdrawal 
Study drug must be discontinued and the patient withdrawn from the trial if the investigator 
determines that continuing it would result in a significant safety risk for that patient. The 
following circumstances require study drug discontinuation: 
 Withdrawal of informed consent 
 Pregnancy 
 Adverse events for which continued inhalation of the study treatment would be 
detrimental  
 Abnormal test procedure results indicating risk for the patient on continued inhalation 
of the study drug  
 If patient experiences a moderate or severe COPD exacerbation during the study 
(i.e. between Visit 4-7)  
 If in the judgement of the investigator, the patient has had excessive use of rescue 
medication (more than 8 puffs a day), the investigator should assess whether it is safe 
for the patient to continue in the study. 
 
Protocol deviations should not lead to patient withdrawal unless they indicate a significant 
risk to the patient’s safety. 
In addition to these requirements for study drug discontinuation, the investigator should 
discontinue study drug for a given patient if, on balance, he/she believes that continuation 
would be detrimental to the patient’s well-being. 
Patients may voluntarily withdraw from the study for any reason at any time. Patients may be 
considered withdrawn, if they state an intention to withdraw, or fail to return for visits, or 
become lost to follow up for any other reason. 
If premature withdrawal occurs for any reason, the patient should return to the clinic as soon 
as possible for an End of Study Visit. The investigator must make every effort to determine 
the primary reason for a patient’s premature withdrawal from the study and record this 
information on the End of Treatment eCRF. 


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The last date of study treatment intake should be entered into the Study Completion CRF and 
the reason for discontinuing the study should be given on the comments page. If a patient who 
discontinued study treatment performed all scheduled study procedures and measurements (up 
to Visit 7), he/she will be counted as a study completer. 
Patients who are prematurely discontinued/ withdrawn from the study will not be replaced. 
 
5.5.10 
Emergency breaking of treatment assignment 
Emergency breaking of the assigned treatment code 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. Two complete sets of emergency 
code break cards are provided by Novartis Pharma GmbH. One set is to be retained by 
Novartis Pharma GmbH and one set is to be distributed to the investigator.  
They must be stored in a secure place but accessible in case of emergency. The investigator 
will receive a blinded code break card for each patient, with the details of drug treatment 
covered by a sealed tear-off cover. In an emergency, the tear-off cover can be removed to 
determine the treatment. The tear-off covers are not to be removed for any reason other than 
an emergency. When the investigator removes the tear-off cover he/she must note the date, 
time, and reason for removing it and retain this information with the case report form 
documentation. The unblinded treatment code should not be recorded on the eCRF. The 
investigator must also immediately inform the Novartis Monitor 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 emergency code breaks for his/her patients at the site. The investigator will inform the 
patient how to contact his/her backup in cases of emergency when he/she is unavailable. The 
protocol number, study drug name if available, patient number, and instructions for contacting 
the German Novartis affiliated company (or any entity to which it has delegated responsibility 
for emergency code breaks) will be provided to the patient in case emergency unblinding is 
required at a time when the investigator and backup are unavailable. As per Novartis SOPs it 
is one of the primary responsibilities of each investigator to be available in case of an urgent 
emergency unblinding for one of his/her patients. He or she need to provide a telephone 
number by which he or she can be reached throughout the trial in case of an emergency 
unblinding request for one of his patients (e.g. a mobile number). 
 
5.5.11 
Study completion and post-study treatment 
The study will be considered completed for an individual patient when he/she completes 
Study Visit 7. Completion of the study will be when all randomized patients have completed 
Study Visit 7 or have been withdrawn. 
Patients completing Visit 7 will not be given further access to study drug.  


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The investigator also must provide follow-up medical care for all patients who completed the 
study or who are prematurely withdrawn from the study, or must refer them for appropriate 
ongoing care. 
 
5.5.12 
Early study termination 
The study can be terminated at any time for any reason specified in the clinical trial study 
contract, 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 sponsor will be responsible for informing IRBs 
and/or ECs of the early termination of the trial. 
6 
 Visit schedule and assessments 
Table 6-1 lists all of the assessments and indicates with an “X” the visits when they are 
performed. Patients should be seen for all visits on the designated day or as close to it as 
possible. 
Patients who discontinue study treatment before completing the study should be scheduled for 
a visit as soon as possible, at which time all of the assessments listed for Visit 7 marked with 
an asterix in the assessment schedule will be performed. At a minimum, they will be 
contacted for safety evaluations during the 30 days following the last dose of study treatment, 
including final contact at the 30-day point. Documentation of attempts to contact the patient 
should be recorded in the patient record.  
All data obtained from the assessments listed in Table 6-1 and described in detail in the 
subsections below must be supported in the patient’s source documentation. Assessments that 
generate data for database entry and which are recorded on eCRFs are listed using the eCRF 
name. Assessments that are transferred to the database electronically (e.g., laboratory data) are 
listed by test name.   


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Table 6-1 
Assessment schedule 
Epoch 
Pre-
Screening 
Screening 
Baseline 
Treatment 
Period I 
Washout 
Treatment 
Period II 
FUP 
Study day 
variable 
-21 to -8 
-7  
1 
15
1 
16-28
1 
29 
43
1 
73±7 
Visit number 
1 
2 
3
2 
4
2 
5
2 
 
6
2 
7
2 
8
3 
Signed Informed 
consent 
X 
 
 
 
 
 
 
 
 
Medical history, 
demographics 
X 
X 
 
 
 
 
 
 
 
Incl./excl. criteria 
X 
X 
X 
X 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
 
 
 
 
X*,** 
 
Current medication 
review/ adjustment 
X 
X 
 
 
 
 
 
 
 
Review concomitant 
medications 
 
 
X 
X 
X 
 
X 
X*,** 
X 
Smoking history/status 
X 
 
 
 
 
 
 
 
 
Dispense ß2-agonist 
(rescue, as required) 
 
X
7 
X 
X 
X 
 
X 
 
 
Physical exam 
 
 
X 
 
 
 
 
X*,** 
 
Vital signs 
 
 
X 
X 
X 
 
X 
X*,** 
 
ECG 
 
 
X 
X 
 
 
X 
X*,**,
8
 
Hematology 
 
 
X 
 
X 
 
 
X*,** 
 
Blood chemistry 
 
 
X 
X 
X 
 
X 
X*,** 
 
Pregnancy Test (urine) 
 
 
X 
 
 
 
 
X*,** 
 
Impulse oscillometry 
 
 
X 
X 
X 
 
X 
X* 
 
Spirometry 
 
 
 
 X 
X 
 
X 
X* 
 
Reversibility 
X
4 
 
X 
 
 
 
 
 
 
Bodyplethysmography 
 
 
X
9 
 X 
X 
 
X 
X* 
 
Randomization 
 
 
 
X 
 
 
 
 
 
Device and inhalation 
training 
 
 
 
X 
 
 
 
 
 
Dispense study 
medication 
 
 
 
X 
 
 
X 
 
 
Administration study 
drug at visit 
 
 
 
X 
X 
 
X 
X* 
 
Collect study 
medication 
 
 
 
 
X 
 
 
X*,** 
 
Review use of study 
medication 
 
 
 
 
X 
 
 
X*,** 
 
MRI
5 
 
 
 
X 
X 
 
X 
X* 
 
19F MRI
10 
 
 
 
 
X 
 
 
X 
 
Echocardiography 
 
 
 
X 
X 
 
X 
X* 
 
Activity tool training 
 
 
X 
 
 
 
 
 
 
Provide activity 
measuring tool 
 
 
X 
X 
X 
 
X 
 
 
Return activity 
measuring tool 
 
 
 
X 
X 
 
X 
X*,** 
 


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Epoch 
Pre-
Screening 
Screening 
Baseline 
Treatment 
Period I 
Washout 
Treatment 
Period II 
FUP 
Study day 
variable 
-21 to -8 
-7  
1 
15
1 
16-28
1 
29 
43
1 
73±7 
Visit number 
1 
2 
3
2 
4
2 
5
2 
 
6
2 
7
2 
8
3 
mMRC
6 
 
 
X 
 
 
 
 
 
 
CAT
6 
 
 
X 
X 
X 
 
X 
X*,** 
 
BDI/ TDI 
6 
 
 
 
X 
X 
 
X 
X*,** 
 
Adverse events 
 
 
 
X 
X 
 
X 
X*,** 
X 
Serious adverse events 
X 
X 
X 
X 
X 
 
X 
X*,** 
X 
Call patient approx.-
2days: to remind them 
to abstain from rescue 
medication/not to take 
study drug at home
8 on 
the day of the next visit 
 
 
X 
X 
X 
 
X 
X* 
 
Study termination 
 
 
 
 
 
 
 
 
X 
* These assessments should be done for patients who prematurely withdraw, but are willing to perform end of study visit including 
all relevant assessments and study drug inhalation  
** These assessments should also be done for patients who discontinue study drug 
1 
Patients should be seen for all visits as close as possible, with a tolerance of ± 3 days. The treatment periods as well 
as the wash-out period have to be at least 14 days 
2 
Impulse oscillometry, bodyplethysmography, spirometry, MRI and echocardiography (can be performed on separate 
days within 48 hours); initial measurements at beginning of each treatment period (Visit 4 and Visit 6) shall be 
performed pre-dose (i.e. before study medication intake); whereas final measurements at the end of each treatment 
period (Visit 5 and Visit 7) shall be performed post-dose (i.e. after study medication intake), specifically 45 min (±15 
min) post-dose for impulse oscillometry, 60 min (±15 min) post-dose for bodyplethysmography, 75 min (±15 min) post-
dose for spirometry,2 hours (±30 min) post-dose for MRI and 4 hours (±30 min) post-dose for echocardiography. 
3 
Telephone call 
4 
Abbreviated reversibility only with post-dose measurement after inhalation of salbutamol (4*100 µg salbutamol or 
reduced dose, depending on prior medication intake of patient) 
5 
MRI will include the anatomical and functional assessment of the heart and lungs (i.e. right and left ventricular mass 
and function, and perfusion MRI of the lung parenchyma for pulmonary parenchymal blood flow and regional 
ventilation measures). 
6 
Questionnaires will include modified Medical Research Council (mMRC), COPD Assessment Test (CAT) and 
Baseline/Transition Dyspnea Index, which are to be completed before all other measurements. 
7 
Short-acting ß2-agonist will be dispensed as rescue medication on Visit 1 if Visit 2 is omitted. 
8 
ECG is no mandatory assessment at Visit 7 and should only be done for patients who prematurely withdrew or 
discontinued study drug intake. 
9 
Bodyplethysmography will be performed pre-and post-inhalation of salbutamol 
10 
19F-enhanced MRI sequence will be an optional measurement that require separate patient consent. The sequence 
will be captured after the MRI anatomical and functional assessment of the heart and lung. 
Table 6-2 
Timed Assessments  
 
Time-point
1 
CAT 
BDI/ 
TDI 
Impulse 
oscillometry 
Bodyplethys
mography 
Spirometry 
MRI 
Echocardio 
graphy 
Visit 4 
(Day 1) 
to be 
completed 
first 
X 
X 
 
 
 
 
 
 
before 
randomiza
tion 
 
 
X 
X 
X 
X 
X 
 
0 min 
 RANDOMIZATION 
 
 
 
 
 
 
 
 
 
 
Visit 5 
(Day 14) 
to be 
completed 
X 
X 
 
 
 
 
 


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Time-point
1 
CAT 
BDI/ 
TDI 
Impulse 
oscillometry 
Bodyplethys
mography 
Spirometry 
MRI 
Echocardio 
graphy 
first 
 
0 min 
Study drug intake 
 
 
45 min 
 
 
X 
 
 
 
 
 
1 h 
 
 
 
X 
 
 
 
 
1 h 15 min 
 
 
 
 
X 
 
 
 
2 h  
 
 
 
 
 
X 
 
 
4 h 
 
 
 
 
 
 
X 
 
1 Time-points relative to the scheduled dose at visit unless otherwise specified.  
 
6.1 
Information to be collected on screening failures 
Only demography data, the reason for failing (screening failure log) are collected for those 
patients who fail to enter the treatment phase.  
Potential serious adverse events and hospitalizations which may have occurred from time of 
signing informed consent until screening failure time should be documented in the patient 
medical records. Reporting of potential SAE during this time period should be followed as 
described in Section 7.2. 
6.2 
Patient demographics/other baseline characteristics 
The following demographics / baseline characteristics will be collected and recorded in the 
eCRF: 
 Year of birth 
 Age 
 
Time-point
1 
CAT 
BDI/ 
TDI 
Impulse 
oscillometry 
Bodyplethys
mography  
Spirometry 
MRI 
Echocardio 
graphy  
Visit 6 
(Day 29) 
to be 
completed 
first 
X 
X 
 
 
 
 
 
 
before 
study 
drug 
intake 
 
 
X 
X 
X 
X 
X 
 
0 min 
Study drug intake 
 
 
 
 
 
 
 
 
 
 
Visit 7 
(Day 42) 
to be 
completed 
first 
X 
X 
 
 
 
 
 
 
0 min 
Study drug intake 
 
 
45 min 
 
 
X 
 
 
 
 
 
1 h 
 
 
 
X 
 
 
 
 
1 h 15 min 
 
 
 
 
X 
 
 
 
2 h  
 
 
 
 
 
X 
 
 
4 h 
 
 
 
 
 
 
X 


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 Sex 
 Height 
 Weight 
 Date of diagnosis of COPD 
 Relevant medical history, including any documented exacerbation of COPD that occurred 
during the previous year 
 Smoking History (e.g., one pack year = 20 cigarettes/day x 1 year)  
 Prior concomitant medications (COPD related and non-COPD related) 
 Baseline physical examination (not databased other than in context of relevant medical 
history) 
 Vital signs at Visit 3 
 ECG finding at Visit 3 
 Laboratory: Hematology and blood chemistry at Visit 3 
 Pregnancy test (dipstick at Visit 3, if applicable) 
 Pre- and post-dose bronchodilator spirometry at Visit 3 (FEV1 and FVC) 
 Pre- and post-dose bodyplethysmography at Visit 3 (IC, FRC, sRAW, TLC, RVol) 
 
6.3 
Treatment exposure and compliance 
All medications taken after the start of study drug, the reason for prescribing the medication, 
and the start and end dates will be collected in the source documents and recorded on the 
respective pages of the eCRF. 
The time of study drug administration at each dosing visit will be collected on the eCRF. The 
date and time of the last use of study drug will be recorded on the study completion page. 
Study drug compliance will be assessed by the investigator and/or center personnel at 
designated visits by recording capsule counts from the previously dispensed blister strips for 
the Novartis SDDPI. This information should be captured in the source documentation at each 
visit. The total number of doses of study drug administered since the last dispensing visit will 
be recorded at Visits 5 and 7 for each patient on the eCRF. 
 
6.4 
Efficacy 
6.4.1 
Magnetic resonance imaging (MRI) 
The MRI exam will be conducted at a 1.5T system. The patient will change clothes and leave 
metallic belongings outside the scanner room. A G20 sized venous cannula (pink) will be 
placed in the antecubital fossa. MRI compatible ECG electrodes will be placed on the thoracic 
wall of the patient. During 100% oxygen delivery, O2 and CO2 will be continuously 
monitored. 


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The MRI assessment will include the anatomical (HASTE, VIBEUTE sequences) and 
functional assessment of the heart (SSFP cine MRI) and lungs (Dynamic contrast enhanced 
MRI, FLASH T1 mapping at room air and 100% oxygen, GRE MRI). 
The MRI protocol consists of: 
A detailed exam protocol including all scan parameters will be available on the MRI system at 
the CRC Hannover. The estimated total time for the MRI procedure is 1.5 h. 
The following parameters will be measured and evaluated with specific software: 
- Right and left ventricular enddiastolic volume 
- Right and left ventricular ejection fraction 
- Right and left ventricular endsystolic volumes 
- Cardiac output 
- Right and left ventricular cardiac mass 
- Pulmonary parenchymal blood flow 
- Regional lung ventilation and perfusion measures (oxygen transfer function) 
using oxygen-enhanced T1 mapping MRI 
All MRI parameters will be assessed by one radiologist blinded to procedure sequences. A list 
of parameters that will be captured in the eCRF is attached to this protocol in Appendix 8. The 
exclusion criteria 4 (patients with heart failure with left ventricular ejection fraction <40%) 
will be determined by MRI scan at Visit 4. This ejection fraction should be assessed by one 
MRI Sequence
Orientation
Breathing
Purpose
time (min)
T1 GRE
triplane
inspiration
localiser
1
True FISP
axial
free breathing
anatomy ECG gated
1
True FISP
coronal
free breathing
anatomy ECG gated
1
UTE (Siemens WIP)
3D
free breathing
anatomy
8
Measure blood pressure (1)
T1 GRE
oblique
inspiration
cardiac localiser
1
True FISP
4chamber view
inspiration
cardiac function ECG gated
1
True FISP
2 chamber view
inspiration
cardiac function ECG gated
1
True FISP
short axis view
inspiration
cardiac function ECG gated
10
GRE Phase contrast
Mitral valve
free breathing
flow venc 130
2
GRE Phase contrast
septum
free breathing
flow venc 30
2
GRE Phase contrast
main PA
free breathing
flow venc 150
2
Measure blood pressure (2)
T1 GRE
coronal
free breathing
ventilation 3 slices
3
T1 GRE
saggital
free breathing
ventilation 2 slices
2
T1 GRE FLASH
coronal
inspiration
T1 mapping room air 3 slices 1st time
1
T1 GRE FLASH
coronal
inspiration
T1 mapping room air 3 slices 2nd time
1
Oxygen mask on
2
HASTE
coronal
free breathing
wash in O2 (turn100% oxygen on )
5
T1 GRE FLASH
coronal
inspiration
T1 mapping oxygen 3 slices 1st time
1
GRE Phase contrast
main PA
free breathing
flow venc 150
2
T1 GRE FLASH
coronal
inspiration
T1 mapping oxygen 3 slices 2nd time
1
HASTE
coronal
free breathing
wash out O2 (turn oxygen off)
5
Measure blood pressure (3)
Oxygen mask off
2
TWIST‐VIBE
coronal
inspiration/shallow breathing lung perfusion
1
contrast agent 0.04 mmol/kg Dotarem© iv at 5cc/sec
TWIST‐VIBE
coronal
inspiration/shallow breathing lung perfusion
2
Measure blood pressure (4)
Sum (min)
58


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experienced radiologist, which not necessarily has to be the radiologist evaluating all MRI 
parameter.  
During MRI systolic and diastolic blood pressure will be measured 4 times as depicted in the 
MRI protocol above: at the beginning and the end of the cardiac sequence, after oxygen 
perfusion and finally at the end of all MRI sequences. 
In case a patient has a history of hypersensitivity to i.v. contrast medium, the last MRI 
sequence that require i.v. application of contrast medium will not be performed. 
 
Optional fluorine (19F) –enhanced MRI measurement  
The fluorine-enhanced MRI technique uses an inert perfluoropropane/oxygen (79%/21%) gas 
mixture as contrast agent to assess regional ventilation dynamics in the lungs during steady-
state breathing. It will be performed at Visit 5 and Visit 7 subsequent to the described 
anatomical and functional MRI measurements above.  
Every patient will receive a separate patient information on this MRI method and has to give 
separate written informed consent before this assessment is being performed. In case a patient 
would not fit into the specially equipped MRI-system due to the body size, the investigating 
radiologist will not perform the 19F MRI. 
During 19F MRI procedure, O2 and CO2 will be continuously monitored. 
The 19F MRI protocol is as follows: 
 
The estimated total time for the 19F MRI procedure is 25 min. 
The following parameter (see also Appendix 8) will be measured and evaluated with specific 
software by one radiologist blinded to procedure sequences: 
- regional lung 19F gas wash-out time  
 
6.4.2 
Bodyplethysmography 
Constant-volume bodyplethysmography will be used to assess the following parameters: 
- Total Lung Capacity (TLC) 
- Inspiratory Capacity (IC) 
- Residual Volume (RVol) 
- Specific Airway Resistance (sRaw) and  
- Functional Residual Capacity (FRC) 
19 F Protocol
Patient has a 7 min break outside the MRI scanner. During this time the 19F coil setup takes place.
MRI Sequence
Orientation
Breathing
Purpose
time (min)
T1 GRE
triplane
inspiration
localiser
1
3D Vibe
axial
inspiration
anatomy
1
3D Vibe
coronal
inspiration
anatomy
1
Mask on. Oxygen and carbon dioxide monitoring setup. 1 min 100 % oxygen breathing prior to 19F/oxygen gas mixture inhalation
4
3D GRE
coronal
inspiration
monitor 19F gas distribution in the lung
1
3D GRE
coronal
inspiration
monitor 19F gas distribution in the lung
1
3D GRE
coronal
inspiration
monitor 19F gas distribution in the lung
1
3D GRE
coronal
free beathing
19 F gas washout
5
Sum (min)
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Bodyplethysmography maneuvers must be first explained to the patient and then practiced 
until consistently reproducible efforts can be made by the patient. Further practices can be 
scheduled after the completion of all assessments at Visit 3 if required. 
 
The instructions for bodyplethysmography and the maximal flow-volume loop measurements 
are as follows: 
 
Specific airway resistance (sRaw) measurement: After having the maneuver 
explained to the subject, resting tidal breathing will commence. As soon as a stable 
end-expiratory lung volume level and a stable tidal volume are achieved at least five 
pressure-flow curves will be collected to determine the specific airway resistance 
(sRaw), which is entered as the effective resistance (sReff) in the eCRF. 
 
The slopes for the pressure-flow loops should be calculated such that the effective 
resistance is estimated (sReff). Artefacts will be deleted, but no corrections will be 
performed. At least 5 acceptable measurements should be taken. The median is 
reported as sReff in the eCRF. 
 
FRC measurements: After a few breaths, the shutter of the bodyplethysmograph will 
be closed and the subject will continue to breathe against the closed shutter at a 
breathing frequency of about 0.5 – 1 per second for an additional few breaths during 
which the pressure-volume loops will be collected and FRC obtained. Three 
acceptable shutter maneuvers will be performed. The difference of the FRC 
measurements should be ≤5% (difference between highest and lowest value, divided 
by the mean should be less than 0.05). 
 
Linked maneuvers to assess inspiratory capacity (IC) and slow vital capacity 
(SVC): Linked maneuver will be performed to assess IC and SVC. After a shutter, the 
patient should fill up his or her lungs slowly and completely to reach a plateau at the 
TLC level, and then exhale fully and slowly to the level of RVol with verbal 
encouragement. The exhaled volume is the slow vital capacity (SVC). The exhalation 
should be no longer than 15 s or fulfill the end-of-test criterion, which is less than 20 
ml volume change in two consecutive seconds. At least three linked maneuvers will be 
performed, with a difference of max. 150 ml between highest and second highest SVC 
measurement, as well as IC measurement. 
 
 
The following values are transferred to the eCRF: 
- sReff: median of five acceptable measurements  
- FRC: mean of three reproducible values (reproducible defined as: difference 
between highest and lowest value, divided by the mean should be less than 
0.05) 
- IC: highest of three reproducible values (reproducible defined as: difference of 
max. 150 ml between highest and second highest IC) 
- SVC: highest of three reproducible values (reproducible defined as: difference 
of max. 150 ml between highest and second highest SVC) 


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In case the values are not reproducible, three acceptable measurements should be 
taken instead. 
 
TLC will be calculated by the eCRF (TLC = FRC mean + highest IC) 
RVol will be calculated by the eCRF (RVol = TLC – highest SVC) 
 
All volumes will be reported in liters (L) under BTPS conditions (body temperature (37°C), 
ambient pressure, saturated with water vapor. 
 
To avoid exhaustion of the patients due to multiple lung function tests and potential influence 
on MRI assessment, at least 3 acceptable lung function tests up to a maximum of five lung 
function tests need to be performed only at each timepoint. 
Spirometry equipment and performance of spirometric testing must be in accordance with 
ATS/ERS standards [21]. The spirometer should be calibrated every morning before taking 
any spirometric measurements for this study. Calibration reports should be stored as source 
data. 
 
6.4.3 
Spirometry assessments 
Please refer to the latest version of the Spirometry Guidance, in Appendix 3 and Table 6-2 for 
full details on scheduling and performing spirometry. 
At Visit 3, spirometry measurements will be taken to assess patient’s eligibility for the study 
and to assess the post bronchodilation FEV1. The reversibility test should be performed as 
follows: 
A baseline spirometry assessment should be performed after a washout period of at least: 
- 6 h for short-acting ß2-agonist 
- 8 h for short-acting anticholinergic 
Administer 4*100 µg of salbutamol following the completion of the baseline assessment, 
which is pre-dose FEV1 measurement. A second spirometry assessment is then performed 15 
min thereafter. 
Spirometry performance should be in accordance with ATS standards [21]. For all clinic 
spirometry assessments, three acceptable maneuvers (a maximum of 5 maneuvers) should be 
performed for each time-point. The FEV1, FVC values recorded in the eCRF must be the 
highest values measured irrespective of whether or not they occur on the same curve. 
This study will utilize the spirometric predication equation standards for the European 
Community for Coal and Steel for predicted normal spirometry values [22].  
All displaceable volumes will be reported in liters (L) at the following conditions: normal 
body temperature (37°C), ambient pressure, saturated with water vapor (BTPS). In addition 
the spirometer should be calibrated every morning before taking any spirometric 
measurements for this study. Calibration reports should be stored as source data. 


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6.4.4 
Impulse oscillometry 
The impulse oscillometry system (IOS) is a sensitive and noninvasive method to assess 
pulmonary function during tidal breathing [23]. It is used to assess resistance and reactance in 
subjects with airway obstruction. It can provide separate measurements for both large and 
small airways function [24]. 
The following parameters will be assessed: 
- Resistance (R5, R20, R5-20, kPa L-1 s-1); 
- Reactance (X5, kPa L-1 s-1). 
- Area of reactance (AX, Hz kPa L-1 s-1). 
 
During the measurement, the patient sits upright, head straight or slightly extended. The 
patient should hold his hands tightly against his cheeks. The lips will be firmly closed around 
the mouthpiece and the mouthpiece will be held tightly between the teeth with the tongue kept 
beneath the mouthpiece.  
After about 15 to 30 seconds tidal breathing, measurement will be performed for at least 60 
seconds. At least three measurements will be performed. Spikes (indicative of glottis closure 
or swallowing) should be removed from the data manually prior to analysis but the data can 
still be analyzed.  
The variation for R5 and R20 should be < 15%. In case the variation is higher, up to 5 
measurements can be performed at the discretion of the investigator. The mean value of at 
least 3 measurements should be reported for R5, R20, R5-20, X5, AX. 
Daily calibration with the necessary standard resistors will be performed and information on 
temperature and humidity will be collected. Calibration reports will be stored as source data. 
6.4.5 
Echocardiography 
Echocardiography is the current standard examination tool for the diagnosis of diastolic 
dysfunction. An echocardiography will be performed at Visits 4, 5, 6, and 7 according to 
standard recommendations by the German Society of Cardiology.  
The following parameters will be assessed: 
• 
parameters of left and right ventricular diastolic function  
• 
parameters of left and right ventricular systolic function  
• 
parameters of pulmonary arterial pressure  
A detailed list of parameters that will be captured in the eCRF is attached to this protocol in 
Appendix 9.  
Due to an expected limitation in the acoustic window, examination of diameters, volumes, and 
ejection fraction will not be performed as this is part of analyzes done by MRI. All 
echocardiography investigations will be performed by the same investigator blinded to 
procedure sequences. The estimated total measurement time depending on the quality of 
acoustic window is about 20-40 min. 


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6.4.6 
Activity with Actibelt 
At Visits 3, 4, 5 and 6 each patient will be provided with an Actibelt device to measure 
physical activity. Patients may also require another, flexible Actibelt to wear in the evening/ at 
night. The Actibelt device to be used in this study is the Actibelt from TRIUM Analysis 
Online GmbH (München, Germany). Patient will be instructed to wear the accelerometer 
device continuously day and night with the exception of the time spent for personal hygiene. 
The Actibelt will be brought to the Visits 4, 5, 6 and 7 and the Actibelt recording box  has to 
be recharged. At the same time, the data from the Actibelt recording box will be downloaded 
to the local computer of the study site, copied to a SD-card and transferred to the data 
management system from TRIUM.  
 
6.4.7 
COPD Assessment Test (CAT)  
The COPD Assessment Test (CAT) is a short instrument used to quantify the symptom 
burden of COPD and will be used to assess the health status of patients in this study (Jones et 
al. 2009a, Jones et al 2009b). It is completed by the patient at the beginning of the study visit 
before any other assessment to avoid influencing the responses. The CAT will be completed 
by the patient at the investigator’s site at Visits 3, 4, 5, 6 and 7, or at the time of 
discontinuation for patients who prematurely withdraw from the study. There are 8 questions 
in the CAT. Patients should read the two statements for each item, and mark where on the 
scale (0-5) they fit. Scores for each of the eight items are summed to give an overall score (out 
of 40). A score of 0 indicates no impact of COPD on a person’s life and a maximum score of 
40 indicates a very high impact of COPD.  
An example of the COPD Assessment Test (CAT) is provided in Appendix 5. 
 
6.4.8 
Modified Medical Research Council (mMRC) Dyspnea Scale 
The modified Medical Research Council (mMRC) Dyspnea Scale (Mahler et al. 1984) is a 
five-item instrument to assess a patient’s degree of breathlessness in relation to physical 
activity. Participants will be required to read a brief description of an activity and then select a 
statement that best describes their experience with dyspnea at Visit 3. The mMRC will be 
used for characterizing COPD patients. 
An example of the mMRC Dyspnea Scale is provided in Appendix 6. 
6.4.9 
Baseline/Transition Dyspnea Indexes (BDI/TDI) 
Patients should be interviewed by a trained assessor (in accordance with training materials 
provided by Novartis) who will grade the degree of impairment due to dyspnea at Visits 4, 6 
(baseline dyspnea index) and at Visits 5, 7 (transition dyspnea index). If possible, the same 
assessor should complete both the BDI and TDI assessments for an individual patient, which 
should be undertaken prior to dosing at these visits. 


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The BDI must be administered at the beginning of the treatment period (Visits 4 and 6) and 
the TDI at the end of the treatment period (Visits 5 and 7). The BDI as well as the TDI must 
be completed prior to any spirometry assessment including taking of study medication. 
An example of the BDI/TDI Dyspnea Index is provided in Appendix 4. 
6.4.10 
Appropriateness of efficacy assessments  
The efficacy assessments planned for this study: spirometry, bodyplethysmography, impulse 
oscillometry, and patient symptoms (BDI/TDI, CAT) planned for this study are the standard 
ones in COPD clinical trials. 
MRI assessments are applied, due to their high accuracy and reproducibility compared to 
echocardiography, allowing for a smaller sample size of patients to prove the hypothesis of 
improved leftventricular enddiastolic filling. 
Echocardiography is applied as it is considered the current standard measure to particularly 
determine ventricular diastolic function and generates additional information on cardiac 
function complementary to MRI.   
The Actibelt accelerometer is applied to assess the activity of the patient with high accuracy, 
as it is worn at the body’s center of gravity. 
6.5 
Safety 
For details on adverse event collection and reporting, refer to Section 7. 
6.5.1 
Physical examination 
A physical examination is to be performed by the investigator at Visits 3 and 7 (or at early 
discontinuation) and will include the following: 
General appearance, skin, neck, (including thyroid), eyes, ears, nose, throat, lungs, heart, 
abdomen, back, lymph nodes, extremities, vascular, and neurological.  
Significant findings that are present prior to first intake of study drug must be included in the 
Relevant Medical History/Current medical Conditions screen on the patient’s eCRF. 
Significant findings made after first intake of  study drug which meet the definition of an 
Adverse Event must be recorded on the Adverse Event screen of the patient’s eCRF. Further 
information for all physical examinations must be included in the source documentation at the 
study site and will not be recorded in the eCRF. 
6.5.2 
Vital signs 
Vital signs will include pulse rate and systolic and diastolic blood pressure. All blood pressure 
measurements should be taken after the patient has rested for at least 5 min in a sitting 
position. At Visit 3 the mean sitting systolic and diastolic blood pressure of three consecutive 
measurements at 2 minute intervals will be captured to determine eligibility of the patient. 
Vital signs will be obtained at Visits 3, 4, 5, 6 and 7 or at premature discontinuation. 


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6.5.3 
Height and weight 
Height in centimeters (cm) will be measured at Visit 1 and body weight (to the nearest 0.1 
kilogram [kg] in indoor clothing, but without shoes) will be measured at Visit 1, Visit 3 and 
again at Visit 7. 
6.5.4 
Laboratory evaluations 
A blood sample will be collected for analysis at baseline Visit 3, Visits 4, 5, 6 and 7 or 
premature withdrawal. A central laboratory will be used for analysis of all specimens 
collected. Details on the collections, shipment of samples and reporting of results by the 
central laboratory are provided to investigators in the laboratory manual.  
Clinically notable laboratory findings are defined in Appendix 1. 
6.5.4.1 
Hematology 
Glycosylated Hemoglobin (HbA1c), Hemoglobin, hematocrit, red blood cell count, white 
blood cell count with differential (% and absolute), and platelet count will be measured at 
Visits 3, 5 and 7 or premature withdrawal.  
 
6.5.4.2 
Clinical chemistry 
Albumin, alkaline phosphate,  total bilirubin, BUN, calcium, total cholesterol, LDH, 
magnesium, phosphate, sodium, potassium, creatinine, creatinine clearance (measured by 
GFR (MDRD formula)), γ-GT, blood glucose, total protein, AST and ALT will be measured 
at Visits 3, 5 and 7 or premature withdrawal. TSH will be measured only at Visit 3 and NT-
proBNP will be measured at Visits 4, 5, 6, and 7 or premature withdrawal. 
If the total bilirubin concentration is increased above 1.5 times the upper limit of normal 
range, total bilirubin should be differentiated into the direct and indirect reacting bilirubin. 
The Laboratory will supply procedures for the preparation and collection of these samples. 
All patients with laboratory tests containing clinically significant abnormalities should be 
followed regularly until the values return to within the normal ranges or until a valid reason 
other than drug-related adverse experiences is identified, even after the medication has 
discontinued.  
6.5.5 
Electrocardiogram (ECG) 
ECGs should be free of baseline wander and noise. Prior to an ECG being performed, the 
ECG operator should check the tracing to ensure that it is of high quality. 
A standard 12 lead ECG will be performed at Visits 3, 4 and 6 or premature discontinuation 
visit. Interpretation of the tracing must be made by a qualified physician and documented on 
the ECG section of the eCRF. Each ECG tracing should be labeled with the study code, 
patient number, date and time, and kept in the source documents at the study site. Clinically 
significant abnormalities should also be recorded on the relevant medical history/Adverse 
Events eCRF page. Please refer to the relevant exclusion criteria prior to randomization 
(Section 4.2). Clinically significant findings must be discussed with the Novartis Clinical 


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Monitor prior to enrolling the patient in the study. Values of >450 ms for males and >470 ms 
for females or an increase of ECG value of >30ms during the course of the study shall be 
confirmed by the Investigator, a cardiologist at the site or a cardiologist employed by 
Novartis. 
ECGs must be performed only after subjects have been resting in the supine position for at 
least 5 minutes.  
6.5.6 
Pregnancy and assessments of fertility 
In pre-menopausal women who are not surgically sterile a urine pregnancy test will be 
performed at Visit 3 and Visit 7 (tests provided by the Central Laboratory). A positive 
pregnancy test requires the patient to be discontinued from the trial. No assessments of 
fertility will be performed. Refer to Section 5.5.9 and Section 7.4 for more details. A urine 
pregnancy test is also required in the event of premature study withdrawal. 
6.5.7 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/patient population. 
6.6 
Other assessments 
No additional tests will be performed on patients entered into this study. 
6.6.1 
Resource utilization 
Not applicable. 
6.6.2 
Health-related Quality of Life 
Not applicable. 
6.6.3 
Pharmacokinetics 
Not applicable. 
6.6.4 
Pharmacogenetics/pharmacogenomics 
Not applicable. 
6.6.5 
Other biomarkers 
Not applicable. 
7 
Safety monitoring 
7.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after first intake of study drug, even if the event is not considered 


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to be related to study drug. Therefore, an AE may or may not be temporally or causally 
associated with the use of an 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. Alert ranges for labs and other test abnormalities are 
included in Appendix 1. 
Adverse events should be recorded in the Adverse Events eCRF 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 
 its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved should be reported. 
 whether it constitutes a serious adverse event (SAE)  
 action taken regarding study treatment  
 whether other medication or therapies have been taken (concomitant medication/non-drug 
therapy) 
 its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown) 
An SAE is any adverse event (appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s) or medical conditions(s) which meets any one of the following criteria  
 is fatal or life-threatening  
 results in persistent or significant disability/incapacity 
 constitutes a congenital anomaly/birth defect 
 requires inpatient hospitalization or prolongation of existing hospitalization, unless 


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hospitalization is for: 
 routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
 elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent  
 treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission  
 social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
 is medically significant, i.e. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above. 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; see Section 7.2. 
All adverse events should be treated appropriately. Treatment may include one or more of the 
following: no action taken (i.e. further observation only); study treatment dosage 
adjusted/temporarily interrupted; study drug(s) permanently discontinued; concomitant 
medication given; non-drug therapy given. The action taken to treat the adverse event should 
be recorded on the Adverse Event CRF.  
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study treatment, the 
interventions required to treat it, and the outcome. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator’s 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 event reporting 
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days after the patient has stopped study participation 
(defined as time of last dose of study drug taken or last visit whichever is later) 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.  


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Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must be 
submitted within 24 hours of the investigator receiving the follow-up information. An SAE 
that is considered completely unrelated to a previously reported one should be reported 
separately as a new event. 
Information about all SAEs (either initial or follow up information)  is collected and recorded 
on the paper Serious Adverse Event Report Form. The investigator must assess the 
relationship to each specific component of study treatment (if study treatment consists of 
several drugs) complete the SAE Report Form in English, and send the completed, signed 
form by fax within 24 hours after awareness of the SAE to the local Novartis Drug Safety and 
Epidemiology Department. The telephone and fax number of the contact persons in the local 
department of Drug Safety and Epidemiology, specific to the site, are listed in the investigator 
folder provided to each site. The original copy of the SAE Report Form and the fax 
confirmation sheet must be kept with the case report form documentation at the study site. 
Follow-up information should be provided using a new paper SAE Report Form stating that 
this is a follow-up to a previously reported SAE 
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 investigational treatment a Drug Safety 
and Epidemiology Department associate may urgently require further information from the 
investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same 
investigational treatment that this SAE has been reported. Suspected Unexpected Serious 
Adverse Reactions (SUSARs) will be collected and reported to the competent authorities and 
relevant ethics committees in accordance with Directive 2001/20/EC or as per national 
regulatory requirements in participating countries. 
7.3 
COPD Exacerbation 
COPD exacerbations are defined as: 
Worsening of 2 or more of the following major symptoms for at least 2 consecutive days: 
• dyspnoea 
• sputum volume 
• sputum purulence 
• AND requiring treatment with systemic corticosteroids and/or antibiotic. 
OR 
Worsening of any 1 major symptom together with any 1 of the following minor symptoms for 
at least 2 consecutive days: 


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• sore throat 
• colds (nasal discharge and/or nasal congestion) 
• fever without other cause 
• increased cough 
• increased wheeze 
COPD exacerbations are considered of moderate severity if treatment with systemic 
corticosteroids and/or antibiotic was required and severe if hospitalization was required. An 
Emergency Room (ER) visit of longer than 24 hours will be considered a hospitalization.  
An increase in ICS dose will not be considered as an exacerbation. A worsening of symptoms 
that does not meet the above symptom definition but is treated by the investigator with 
systemic corticosteroids or antibiotics or meets the symptom definition and does not get 
treated by the investigator is not considered moderate or severe COPD exacerbation for the 
study.  
All COPD exacerbations, regardless of treatment, should only be recorded on the COPD 
exacerbation episode CRF and not on the Adverse Event Form CRF. In case of serious 
severity, it should be additionally reported on the Serious Adverse Event Form. Please refer to 
discontinuation criteria following moderate or severe exacerbations in Section 5.5.9. 
7.4 
Liver 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 a Clinical Trial Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment. 
Any SAE experienced during pregnancy must be reported on the SAE Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the female partner. 
7.6 
Prospective suicidality assessment 
Not applicable. 


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8 
Data review and database management 
8.1 
Site monitoring 
Before study initiation, at a site initiation visit, a Novartis representative will review the 
protocol and eCRFs with the investigators and their staff. During the study, the field monitor 
will visit the site regularly to check the completeness of patient records, the accuracy of 
entries on the eCRFs, the adherence to the protocol and to Good Clinical Practice, the 
progress of enrollment, and to ensure that study drug is being stored, dispensed, and 
accounted for according to specifications. Key study personnel must be available to assist the 
field monitor during these visits. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on eCRFs 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 eCRF entries. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion 
criteria, documentation of SAEs, and the recording of data that will be used for all primary 
and safety variables. Additional checks of the consistency of the source data with the eCRFs 
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 
Novartis will give the investigator site access to Electronic Data Capture (EDC) software that 
has been fully validated and conforms to 21 CFR Part 11 requirements.  
Investigator site staff will not be given access to the EDC system until they have been trained. 
Designated investigator staff will enter the data required by the protocol into the Novartis 
eCRFs. Automatic validation programs check for data discrepancies in the eCRFs and, by 
generating appropriate error messages, allow modification or verification of the entered data 
by the investigator staff. The investigator must certify that the data entered are complete and 
accurate. After database lock, the investigator will receive copies of the patient data for 
archiving at the investigational site.  
Data of the mMRC, the CAT and the BDI/TDI will be entered into the eCRF by investigator 
staff. The original version of the questionnaires will be stored at the investigational site as 
source documents. 
 


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8.3 
Database management and quality control 
Novartis staff or a designated CRO review the eCRFs entered 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 is required to respond to the query and make any necessary 
changes to 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 or a designated CRO who 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. 
Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO). 
At the conclusion of the study, the occurrence of any emergency code breaks will be 
determined after return of all code break reports and unused drug supplies to Novartis. The 
occurrence of any protocol violations 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 by Trial Statistician and Statistical Reporting 
and the Clinical Trial Leader. 
 
8.4 
Data Monitoring Committee 
Not required. 
8.5 
Adjudication Committee 
Not required. 
9 
Data analysis 
9.1 
Analysis sets 
The data will be analyzed by Novartis and/or by the designated CRO. Any data analysis 
carried out independently by the investigator should be submitted to Novartis before 
publication or presentation. 
The full analysis set (FAS) will include all randomized patients who received at least one 
dose of randomized study drug. FAS will be used for the efficacy variables related to lung 
function and QoL-parameters.  
The per-protocol set (PP) will include all patients in the FAS without any major protocol 
deviations. Major protocol deviations will be defined in the validation analysis plan (general) 
and in the protocol of the blind review meeting (details) prior to database lock and the un-


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blinding of the study. PP will be used for the primary analysis of cardiac function parameters, 
were the aim is to explore mechanistic effects rather than on an estimate of effects achievable 
in clinical practice. Additionally PP analyses will be used for lung function- and QoL- 
parameters to support the respective FAS-findings. 
The safety set (SAF) will include all patients who received at least one dose of study drug 
whether or not being randomized.  Patients will be analyzed according to the treatment they 
received. The safety set will be used in the analysis of all safety variables. 
Note that the FAS and safety set are the same except that the safety set allows the inclusion of 
non-randomized patients who received study drug in error. In addition, the FAS assigns 
randomized treatment and the safety set assigns received treatment. 
 
9.2 
Patient demographics and other baseline characteristics 
Summary statistics will be presented for continuous demographic and baseline characteristic 
variables by treatment sequence for all subjects in the FAS. The number and percentage of 
subjects in each category will be presented for categorical variables for each treatment 
sequence and for all subjects. 
9.3 
Treatments 
Duration of exposure to each of the study drugs during the treatment phase and compliance 
based on the returned medication will be summarized. 
Summary data listings will be provided for concomitant therapy both prior to and after start of 
study drug administration. The WHO Drug Reference dictionary will be used for coding of 
medications. 
9.4 
Analysis of the primary variable 
9.4.1 
Variable(s) 
The primary efficacy variable is the left ventricular enddiastolic volume assessed by MRI 
after 2 weeks of treatment (i.e. at visit 5 and 7 respectively). 
 
9.4.2 
Statistical model, hypothesis, and method of analysis 
The primary analysis will be performed comparing treatments with respect to the primary 
efficacy variable in an analysis of variance (ANOVA) model with the factors center, period, 
patient within center and treatment. Raw- as well as adjusted (LS-) means will be provided as 
point estimates for the pair wise treatment contrast. A two-sided, 95% confidence interval and 
a p-value for the null hypothesis of no treatment difference will be calculated. Additionally 
unadjusted descriptive statistics (mean, SD, range) will be provided for each treatment and for 
the treatment contrast. 


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9.4.3 
Significance Level: The significance level is 5% two-sided.Handling of 
missing values/censoring/discontinuations 
As the aim of this study is explore mechanistic effects rather than to estimate effects 
achievable in clinical practice, the primary analysis will be conducted for the PP-Set. No 
missing values for the primary endpoint are expected for this set. 
9.4.4 
Supportive analyses 
In case of serious deviations from the normality assumptions, a non-parametric comparison 
(signed-rank test) may be computed additionally. 
The primary endpoint, the left ventricular enddiastolic volume may be affected by the 
patient’s blood pressure. Blood pressure is not a ‘classical’ covariate, since it is measured 
after baseline and may itself be affected by the treatment given, therefore, this kind of 
confounding cannot validly be adjusted for in the primary analysis. However, as a secondary 
analysis and as an exploratory tool, the primary model will be re-calculated with systolic and 
diastolic blood pressure added as additional covariates. The mean over the four blood pressure 
measurements (beginning and the end of the cardiac sequence, after oxygen perfusion and 
finally at the end of all MRI sequences) will be used for this purpose. 
9.5 
Analysis of secondary variables 
9.5.1 
Efficacy variables 
All secondary endpoints (lung function- and other cardiac function parameters) will be 
analyzed analogous to the primary endpoint. Exploratory endpoints and Qol-measurements 
will be analyzed descriptively; appropriate statistical tests for treatment comparisons may be 
defined in the Statistical Analysis Plan (SAP). 
9.5.2 
Safety variables 
Safety assessments will be based mainly on the frequency of adverse events. Adverse events 
will be coded by primary system organ class and preferred term according to the Medical 
Dictionary for Regulatory Activities (MedDRA). All AEs will be assigned to the last 
treatment the patient received before AE start. In the data listings of adverse events, the 
severity of an AE, whether or not an AE is study drug related, and whether or not it is a 
serious AE, will be indicated. An adverse event related to study drug is defined as one 
considered by the investigator to have a suspected relationship with the study drug. The 
adverse events will be summarized by the number and percentage of patients in each primary 
system organ class and preferred term. For summaries by severity of event, the most severe 
occurrence for a particular preferred term will be used for a given patient. Summary tables of 
adverse events by treatment and severity will be provided. Multiple occurrences of the same 
AE or SAE in the same patient in one treatment period will be counted only once, using the 
worst severity and drug relationship. Data from other tests (e.g. ECG or vital signs) will be 
listed, notable values will be flagged, and any other information collected will be listed as 
appropriate. 
For a given treatment period in this crossover design, the only adverse event that will be 
counted for that treatment will be treatment-emergent events. These events are those that 


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started after the start of that treatment period, or were present prior to the start of the treatment 
period but increased in severity, change from being not suspected to being suspected to the 
due to study drug, or developed into an SAE after the start of the treatment period. 
9.5.3 
Resource utilization 
Not applicable. 
9.5.4 
Health-related Quality of Life 
Not applicable. 
9.5.5 
Pharmacokinetics 
Not applicable. 
9.5.6 
Pharmacogenetics/pharmacogenomics 
Not applicable 
9.5.7 
Biomarkers 
Not applicable 
9.5.8 
PK/PD 
Not applicable. 
9.6 
Interim analyses 
No interim analysis will be conducted. 
9.7 
Sample size calculation 
A QVA149-placebo treatment difference in left ventricular enddiastolic volume (primary 
endpoint) of 4 ml is considered a sufficient magnitude of effect to reveal mechanistic aspects 
relevant for COPD patients. The effect size of 4 ml is estimated based on different 
publications comparing COPD patients with non-COPD patients or with patients of different 
percentage emphysema, demonstrating differences in LVEDV between 4 – 25 ml [7, 8, 17, 
18].  
The intraindividual standard deviation of 10 ml is based on Bellenger et al, who describes the 
interstudy variability within 7 days with an SD of 7.4 ml [19]. As the reproducibility of the 
method itself (2 measurements with a minimal time interval) is given with a SD of 6.7 ml, an 
overall SD for this trial is assumed to be 10 ml [20].  
With a (within-patient-) standard deviation of 10 ml, 62 patients will be randomized initially 
with the intention that 52 patients complete the study with valid MRI-measurements. This 
samples size will provide 80% power to detect the difference as statistically significant at the 
5% significance level (2 sided).  
9.8 
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 


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regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 
21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid 
down in the Declaration of Helsinki. 
9.9 
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 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, he/she should indicate assent by personally signing and dating the written informed 
consent document or a separate assent form. Informed consent must be obtained before 
conducting any study-specific procedures (i.e. all of the procedures described in the protocol). 
The process of obtaining informed consent should be documented in the patient source 
documents.  
Novartis will provide to investigators in a separate document an informed consent form that 
complies with the ICH GCP guideline and regulatory requirements and is considered 
appropriate for this study. 
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. 
9.10 
Responsibilities of the investigator and IRB/IEC 
The protocol and the informed consent form must be reviewed and approved by a properly 
constituted Institutional Review Board/Independent Ethics Committee/Research Ethics Board 
(IRB/IEC) before study start. A signed and dated statement that the protocol and informed 
consent have been approved by the IRB/IEC must be given to Novartis before study initiation. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Clinical Quality Assurance representatives, 
designated agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an 
inspection of the clinical site is requested by a regulatory authority, the investigator must 
inform Novartis immediately that this request has been made. 
9.11 
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. 


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10 
Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
trial to request approval of a protocol deviation, as requests to approve deviations will not be 
granted. 
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants.  Under no circumstances should an investigator collect additional data 
or conduct any additional procedures for any research related purpose involving any 
investigational drugs.  
If the investigator feels a protocol deviation would improve the conduct of the study this must 
be considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR. 
10.1 
Protocol Amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC 
approval. Notwithstanding the need for approval of formal protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any patient 
included in this study, even if this action represents a deviation from the protocol. In such 
cases, Novartis should be notified of this action and the IRB/IEC at the study site should be 
informed within 10 working days or less, if required by local regulations.  
11 
References 
 
 1     Smith BM, Kawut SM, Bluemke DA, Baner RC, Gomes AS, Hoffman E, Kalhan R, 
Lima JA, Liu CY, Michos ED, Prince MR, Rabbani LR, Rabinowitz D, Shimbo D, Shea 
S, Barr RG: Pulmonary Hyperinflation and left ventricular mass. Circulation 2013; 
127(14): 1503-1511. 
 2     Martinez FJ, Foster G, Curtis JL, et al; NETT Research Group. Predictors of mortality 
in patients with emphysema and severe airflow obstruction. Am J Repir Crit Care Med. 
2006; 173(12):1326-1334. 
 3     Casanova C, Cote C, de Torres JP et al.: Inspiratory-to-total lung capacity ratio 
predicts mortality in patients with chronic obstructive pulmonary disease. Am J Respir 
Crit Care Med 2005; 171:591-597. 
 4     Leith DE, Brwon R. Human lung volumes and the mechanisms that set them. Eur 
Respir J. 1999;13:468-72. 


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 5     Petty TL, Silvers GW, Stanford RE. Mild emphysema is associated with reduced 
elastic recoil and increased lung size but not with air-flow limitation. Am Rev Respir 
Dis. 1987; 136:867-71.  
 6     Dykstra BJ, Scanlon PD, Kester MM, Beck KC, Enright PL. Lung volumes in 4,774 
patients with obstructive lung disease. Chest 1999; 115:68-74. 
 7     Barr RG, Bluemke DA, Ahmed FS, Carr JJ, Enright PL, Hoffman EA, Jiang R, Kawut 
SM, Kronmal RA, Lima JA, Shahar E, Smith LJ, Watson KE: Percent emphysema, 
airflow obstruction, and impaired left ventricular filling. N Engl J Med 2010;362:217-
227. 
 8     Smith BM, Prince MR, Hoffman EA, Bluemke DA, Liu CY, Rabinowitz D, Hueper K, 
Parikh MA, Gomes AS, Michos ED, Lima JAC, Barr RG: Impaired left ventricular 
filling in COPD and emphysema: is it the heart or the lungs? Chest 2013; 144: 1143-
1151. 
 9     Jörgensen K, Müller MF, Nel J, Upton RN, Houltz E, Ricksten SE: Reduced 
intrathoracic blood volume and left and right ventricular dimensions in patients with 
severe emphysema: an MRI study. Chest 2007; 1344): 1050-57. 
 10     Watz H, Waschki B, Meyer T, Kretschmar G, Kirsten A, Claussen M, Magnussen H. 
Decreasing cardiac chamber sizes and associated heart dysfunction in COPD: role of 
hyperinflation. Chest 2010;138:32-8. 
 11     Kohli P, Neilan TG, Natarajan P, Kwong RY, Malhotra A, Celli BR, Harris RS: 
Hyperinflation: a potential effect modifier of cardiovascular performance in individuals 
with chronic obstructive pulmonary disease and heart disease. ATS 2014. 
12    Nojiri T, Yamamoto K, Maeda H, Takeuchi Y, Funakoshi Y, Maekura R, Okumura M: 
Effects of inhaled tiotropium on left ventricular diastolic function in chronic obstructive 
pumonary disease patients after pulmonary resection. Ann Thorac Cardiovasc Surg 
2012; 18 (3): 206-211. 
13   Frampton JE: QVA149 (Indacaterol/Glycopyrronium Fixed-Dose Combination): A 
Review of Its Use in Patients with Chronic Obstructive Pulmonary Disease. Drugs 
2014;74:465-488. 
14   Beeh KM, Korn S, Beier J, Jadayel D, Henley W, D'Andrea P, Banerji D. Effect of 
QVA149 on lung volumes and exercise tolerance in COPD patients: the BRIGHT study. 
Respir Med. 2014; 108(4):584-92. 
15    Hueper K, Parikh MA, Prince MR, Schoenfeld C, Liu C, Bluemke DA, Dashnaw SM, 
Goldstein TA, Hoffman EA, Lima JA, Skrok J, Zheng J, Barr RG, Vogel-Claussen J: 
Quantitative and semiquantitative measures of regional pulmonary microvascular 
perfusion by magnetic resonance imaging and their relationships to global lung 
perfusion and lung diffusing capacity: the multiethnic study of atherosclerosis chronic 
obstructive pulmonary disease study. Invest Radiol 2013;48:223-230. 


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16   Thomashow MA, Shimbo D, Parikh MA, Hoffman EA, Vogel-Claussen J, Hueper K, Fu 
J, Liu CY, Bluemke DA, Ventetuolo CE, Doyle MF, Barr RG: Endothelial 
microparticles in mild chronic obstructive pulmonary disease and emphysema. The 
Multi-Ethnic Study of Atherosclerosis Chronic Obstructive Pulmonary Disease study. 
Am J Respir Crit Care Med 2013;188:60-68. 
 
17    Noordegraaf AV, Marcus JT, Roseboom B, Postmus PE, Faes TJ, Vries PM. The effect 
of right ventricular hypertrophy on left ventricular ejection fraction in pulmonary 
emphysema. Chest 1997; 112:640-45. 
 
18     Noordegraaf AV, Marcus JT, Hoverda S, Roseboom B, Postmus PE. Early changes of 
cardiac structure and function in COPD patients with mild hypoxemia. Chest 2005; 
127:1898-1903. 
 
19    Bellenger NG, Davies LC, Francis JM, Coats AJS, Pennell DJ. Reduction in sample size 
for studies of remodeling in heart failure by the use of cardiovasular magnetic 
resonance. J Cardiovasc Magnetic Reson. 2000. 2(4): 271-278. 
 
20     Grothues F, Smith GC, Moon JCC, Bellenger NCG, Collins P, Klein HU, Pennell DJ. 
Comparison of interstudy reproducibility of cardiovasular magnetic resonance with two-
dimensional echocardiography in normal subjects and in patients with heart failure or 
left ventricular hypertrophy. Am J Cardiol 2002; 90:29-34. 
 
21     Miller, M. R.; Hankinson, J.; Brusasco, V.; Burgos, F.; Casaburi, R.; Coates, A,; Crapo, 
R.; Enright, P.; van der Grinten, C. P.; Gustafsson, P.; Jensen, R.; Johnson, D. C.; 
MacIntyre, N.; McKay, R.; Navajas, D.; Pederson, O. F.; Pellegrino, R.; Viegi, G.; 
Wanger, J. Standardization of Spirometry. Eur. Respir. J. 2005, 26, 319-338. 
 
22     Quanjer, P. H.; Tammeling, G. J.; Cotes, J. E.; Pedersen, O. F.; Peslin, R.; Yernault, J. 
C. 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 Suppl 1993, 16, 5-40. 
 
23     Oostveen E, MacLeod D, Lorino H, Farré R, Hantos Z, Desager K, et al. The forced 
oscillation technique in clinical practice: Methodology, recommendations and future 
developments. Eur Respir J 2003; 22:1026 –1041. 
 
24     Goldman MD. Clinical application of forced oscillation. Pulm Pharmacol Ther. 
2001;14(5):341-50. 
 
 


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12 
Appendix 1: Clinically notable laboratory values and vital 
signs 
There are no specific criteria for this study, however, the Central Laboratory will flag 
laboratory values falling outside of the normal ranges on the Central Laboratory Report 
(which the investigator should review and sign off) and the investigator will report any values 
considered clinically significant in the eCRF. 
The number (%) of patients with pulse rate of <40 and >130 bpm; systolic blood pressure of 
<75 and >200 mmHg; diastolic blood pressure of <40 and >115 mmHg will be summarized 
by treatment group. 
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 
 
 
For ECGs a notable QTc value is defined as a QTc interval of greater than 450 ms for males 
and 470 ms for females.  
QTc will be calculated from the QT interval and RR (in seconds) using Fridericia’s formula: 
QTc = QT / cube root (RR).  


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13 
Appendix 2: GOLD guidelines (2014) 
 
 Patient Group A – Low Risk, Less Symptoms 
Typically GOLD 1 or GOLD 2 (mild or moderate airflow limitation); and/or 0-1 
exacerbation per year and not hospitalization for exacerbation; and CAT score <10 or 
mMRC grade 0-1. 
 
 Patient Group B – Low Risk, More Symptoms 
Typically GOLD 1 or GOLD 2 (mld or moderate airflow limitation); and/or 0-1 
exacerbation per year and no hospitalization for exacerbation; and CAT score ≥10 or 
mMRC grade ≥2. 
 
 Patient Group C – High Risk, Less Symptoms 
Typically GOLD 3 or GOLD 4 (severe or very severe airflow limitation); and/or ≥2 
exacerbations per year or ≥1 with hospitalization for exacerbation; and CAT score <10 
or mMRC grade 0-1. 
 
 Patient Group D – High Risk, More Symptoms 
Typically GOLD 3 or GOLD 4 (severe or very severe airflow limitation); and/or ≥2 
exacerbations per year or ≥1 with hospitalization for exacerbation; and CAT score ≥10 
or mMRC grade ≥2. 
 


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14 
Appendix 3: Spirometry Guidance 
Equipment 
Spirometers must meet the specifications and performance criteria recommended in the 
American Thoracic Society (ATS)/European Respiratory Society (ERS) Standardization of 
Spirometry. 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.   
Performing Spirometry 
The subject’s age, height and gender will be recorded and entered into the eCRF, where the 
predicted normal values are lodged. 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 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 
Spirometric assessments will be performed in triplicate according to ATS/ERS standards. If a 
subject is unable to perform a single acceptable maneuver after 5 attempts, testing may be 
discontinued. 


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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 glottis 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 highest FEV1 and FVC from any of the acceptable curves are recorded. (The highest 
FEV1 and FVC may not necessarily result from the same acceptable curve). 
Predicted normal 
This study will utilize the spirometric predication equation standards for the European 
Community for Coal and Steel (Quanjer et al 1993).  
Reversibility 
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 for short-acting anticholinergics 
 48 h for long-acting 2-agonist 
 7 days for long-acting anticholinergic 
 7 days for indacaterol 
Administer 400µg of salbutamol (4x100µg) following the completion of the pre-bronchdilator 
assessment. Post-bronchodilator spirometry assessment is then performed 10-15 minutes after 
administration of salbumatol. 
Reversibility is calculated as:  
100 x        FEV1 (post-bronchodilator) – FEV1 (pre-bronchodilator) 
                                     FEV1 (pre-bronchodilator) 
Patients with COPD demonstrating a high reversibility may require further clinical evaluation 
by the investigator to rule out a diagnosis of asthma.   


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References 
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. 
Miller MR et al,(2005) Standardization of Lung Function Testing. Eur Resp J;26:153-161. 
Polgar, G. & Promadhat, V. (1971) Pulmonary function testing in children: Techniques and 
Standards. WIB. Saunders, Philadelphia. 
Quanjer PH at al, (1993) 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;6: Suppl. 16, 5-40. 


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Appendix 4: Baseline Dyspnea Index and Transition 
Dyspnea Index 
 (Samples of questionnaires provided here are for illustrative purposes only) 
 


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Appendix 5: COPD Assessment Test (CAT) 
(Sample of test provided here are for illustrative purposes only) 
 
 


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Appendix 6: modified Medical Research Council (mMRC) 
Dyspnea Scale 
 
Medical Research Council (Mahler et al. 1984):  
 
Grade Symptoms 
 
0 
Not troubled by breathlessness except with strenuous exercise 
 
1 
Troubled by shortness of breath when hurrying on the level or walking up a slight hill 
 
2 
Walks slower than people of the same age on the level because of breathlessness or 
has to stop for breath when walking at own pace on the level 
 
3 
Stops for breath after walking about 100 yards (91 m) or after a few minutes on the 
level 
 
4 
Too breathless to leave the house or breathless when dressing or undressing 
 


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Appendix 7: Instructions for use of the SDDPI 
How to use the SDDPI 
Your inhaler 
 
 
Your inhaler is designed to administer the study 
drug contained in the capsules. The capsules are 
packaged in blisters.  
Do not swallow capsule.  
a 
Cap 
b 
Mouthpiece 
c 
Screen 
d 
Capsule cavity 
e 
Button 
f 
Base 
 
 
How to use your inhaler 


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Pull off cap. 
Open inhaler:  
Hold the base of the inhaler firmly and tilt the 
mouthpiece in the direction of the arrow to open 
the inhaler. 
Insert capsule:  
Immediately before use, with dry hands, 
remove one capsule from the blister. Place the 
capsule into the capsule cavity. 
 
Never place a capsule directly into the 
mouthpiece. 
1 
2 
3 


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Close the inhaler:  
Close the inhaler fully. You should hear a ‘click’ 
as it fully closes. 
Pierce the capsule:  
Hold 
the 
inhaler 
upright. 
Press both buttons fully one time. You should 
hear a ‘click’ as the capsule is being pierced. 
Release the buttons fully. 
Do not press the buttons repeatedly.  
Breathe out:  
Before placing the mouthpiece in your mouth, 
breathe out fully.  
Never blow into the mouthpiece. 
 
6 
5 
4 


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Administer study drug:  
Before breathing in, place the mouthpiece in 
your mouth and close your lips around the 
mouthpiece. Hold the inhaler with the buttons to 
the left and right (not up and down). 
Breathe in rapidly and steadily, as deeply as you 
can. Do not press the buttons. 
As you breathe in through the inhaler, the 
capsule spins around in the cavity and you 
should hear a whirring noise. You will 
experience a sweet taste as the medicine goes 
into your lungs.  
If you do not hear a whirring noise, the capsule 
may be stuck in the capsule cavity. If this occurs, 
open the inhaler and carefully loosen the capsule 
by tapping the base of the device. Do not press 
the buttons repeatedly to loosen the capsule. 
Repeat steps 6 and 7 if necessary. 
Continue to hold your breath as long as 
comfortably possible while removing the inhaler 
from your mouth. Then breathe out.  
Open the inhaler to see if any powder is left in 
the capsule. If there is powder left in the capsule, 
close the inhaler and repeat steps 6 to 8. Most 
people are able to empty the capsule in one or 
two inhalations. 
Remove capsule:  
After use, open the inhaler, remove the empty 
capsule by tipping it out, and discard it. Close the 
inhaler and replace the cap.  
Never leave a capsule in the inhaler. 
7 
8 
9 


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Additional information 
Occasionally, very small pieces of the capsule can get past the screen and enter your mouth. If 
this happens, you may be able to feel these pieces on your tongue. It is not harmful if these 
pieces are swallowed or inhaled. The chances of the capsule shattering will be increased if the 
capsule is pierced more than once (Step 5). Therefore it is recommended that you follow the 
storage directions, remove the capsule from the blister immediately before use and pierce 
each capsule only once. 
How to clean your inhaler 
Clean your inhaler every week. Wipe the mouthpiece inside and outside with a clean, dry lint-
free cloth to remove any powder residue. Alternatively, use a clean, dry, soft brush. 


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Appendix 8: List of MRI parameters captured in the eCRF 
 
 
 


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Appendix 9: List of echocardiography parameters captured 
in the eCRF 
 
 


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SAP_000.pdf: 
Clinical Development 
QVA149 
CQVA149ADE05 / NCT02442206
A randomized, double-blinded, single-center, placebo controlled, cross-
over study to assess the effect of QVA149 (indacaterol maleate / 
glycopyrronium bromide) on cardiac function in patients with chronic 
obstructive pulmonary disease (COPD) 
RAP Module 3 – Detailed Statistical Methodology 
Author: 
 
 
Document type: 
RAP Documentation 
Document status: 
Final version 2.0 
Release date: 
09-Nov-16
Number of pages: 
28 


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Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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


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Table of contents 
Document History – Changes compared to previous version of RAP module 3. ...................... 3 
1 
Introduction ......................................................................................................................... 6 
1.1 
Statistical and analytical plans ................................................................................. 6 
1.2 
Subjects and treatments ........................................................................................... 6 
1.2.1 
Analysis sets ............................................................................................ 6 
1.3 
Patient disposition and demographic characteristics ............................................... 7 
1.3.1 
Patient disposition ................................................................................... 7 
1.3.2 
Protocol deviations .................................................................................. 7 
1.3.3 
Patient demographics and other baseline characteristics ........................ 8 
1.3.4 
Medical history and current medical condition ....................................... 9 
1.4 
Study medication ..................................................................................................... 9 
1.4.1 
Study drug administration ....................................................................... 9 
1.4.2 
Compliance to study treatments .............................................................. 9 
1.5 
Prior and concomitant medications ....................................................................... 10 
1.6 
Efficacy evaluation ................................................................................................ 10 
1.6.1 
Primary variable .................................................................................... 10 
1.6.1.1 
Statistical model, hypothesis and method of analysis ........................... 10 
1.6.1.2 
Handling of missing values/censoring/discontinuations ....................... 11 
1.6.1.3 
Supportive analysis ............................................................................... 11 
1.6.2 
Secondary variables .............................................................................. 11 
1.6.2.1 
Analysis of spirometry outcomes .......................................................... 11 
1.6.2.2 
Analysis of bodyplethysmography outcomes ....................................... 12 
1.6.2.3 
Analysis of cardiac parameters ............................................................. 12 
1.6.3 
Analysis of exploratory parameters ...................................................... 13 
1.6.3.1 
COPD assessment test (CAT) ............................................................... 13 
1.6.3.2 
Baseline Dyspnea Index –Transitional Dyspnea Index (BDI‐TDI) ...... 13 
1.6.3.3 
Biventricular cardiac mass measures .................................................... 13 
1.6.3.4 
Pulmonary parenchymal blood flow measures ..................................... 14 
1.6.3.5 
Echocardiography assessments ............................................................. 14 
1.6.3.6 
Impulse oscillometry ............................................................................. 14 
1.6.3.7 
Regional lung ventilation, 19F washout time, perfusion measures and 
oxygen MRI 14 
1.6.3.8 
Rescue medication use .......................................................................... 14 
1.6.3.9 
Activity with Actibelt ............................................................................ 14 
1.7 
Safety evaluation ................................................................................................... 15 
1.7.1 
Adverse events (AE) ............................................................................. 15 


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1.7.2 
Serious adverse events (SAE) ............................................................... 16 
1.7.3 
Deaths .................................................................................................... 16 
1.7.4 
Vital signs.............................................................................................. 16 
1.7.5 
Weight ................................................................................................... 17 
1.7.6 
Laboratory data ..................................................................................... 17 
1.7.6.1 
Hematology ........................................................................................... 17 
1.7.6.2 
Clinical chemistry ................................................................................. 17 
1.7.7 
Electrocardiogram (ECG) ..................................................................... 17 
1.8 
Determination of sample size ................................................................................ 18 
1.9 
Changes in the conduct of the study or planned analysis ...................................... 18 
Clinical Study Report – ..................................................................................................... 19 
Appendix 16.1.9 Documentation of statistical methods .................................................... 19 
16.1.9.1 
Major protocol deviations and other exclusion criteria ......................... 19 
16.1.9.2 
Patient classification .............................................................................. 21 
16.1.9.3 
Derivations, Baseline and post-baseline definitions ............................. 22 
16.1.9.4 
Statistical methodology and assumptions ............................................. 24 
16.1.9.5 
Appendices ............................................................................................ 25 
Appendix 1: List of MRI Parameters ........................................................................... 25 
Appendix 2: GOLD guidelines ..................................................................................... 28 
Appendix 3: GOLD guidelines (2014) ......................................................................... 28 


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Statistical methods planned in the protocol and determination of sample size 
1 Introduction 
This document contains details of the statistical methods which will be used in the phase IV 
clinical trial CQVA149ADE05. This is a randomized, double-blinded, single-center, placebo 
controlled, cross-over study which is designed to evaluate the effectiveness of dual 
bronchodilation with QVA149 (indacaterol maleate/glycopyrronium bromide) on cardiac and 
lung function parameters in hyperinflated COPD patients. 
1.1 
Statistical and analytical plans 
Data will be analyzed by statistical analysis software (SAS) version 9.4 according to the data 
analysis section 9 of the study protocol which is available in Appendix 16.1.1 of the CSR. 
Important information is given in the following sections and details are provided, as 
applicable, in Appendix 16.1.9 of the CSR. 
Categorical data will be summarized as frequencies and percentages. For continuous data, 
mean, standard deviation, median, minimum, and maximum will be presented. 
For descriptive statistics, the following number of decimal places will be used: arithmetic 
mean, and median to 1 more decimal places than the raw data; minimum and maximum to the 
same number of decimal places as the raw data and SD to 2 more decimal places than the raw 
data. Percentages will be presented to 1 decimal place. Confidence interval(s) will be 
presented to the same decimal places as the estimate. 
1.2 
Subjects and treatments 
1.2.1 
Analysis sets 
 
Full analysis set (FAS) will include all randomized patients who received at least one dose of 
randomized study treatment. Patients will be analyzed according to the treatment assigned at 
randomization. The FAS will be used for summaries of patient disposition, analysis sets, 
protocol deviations, demographic and baseline characteristics, efficacy analyses relates to 
lung function- and QoL- parameters. 
 
Per protocol (PP) set will include all patients in the FAS who did not have any major 
protocol deviations. Major protocol deviations will be defined prior to database lock and the 
un-blinding of the study. The list of major protocol deviations is available in Appendix 16.1.9 
of this document. The PP set will also be used for the primary analysis of cardiac function 
parameters, where the aim is to explore mechanistic effects rather than on an estimate of 
effects achievable in clinical practice. Additionally PP analyses will be used for lung function- 
and QoL- parameters to support the respective FAS-findings. 
 


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Safety set (SAF) will include all patients who received at least one dose of the study 
treatment, whether or not being randomized. Patients will be analyzed according to the 
treatment they received. The SAF will be used for all safety analyses.  
Note that the FAS and safety set are the same except that the safety set allows the inclusion of 
non-randomized patients who received study drug in error. In addition, the FAS assigns 
randomized treatment and the safety set assigns received treatment. Unless otherwise stated, 
the actual and planned treatments are same. 
1.3 
Patient disposition and demographic characteristics 
1.3.1 
Patient disposition 
The FAS set will be used for the summary and listing of patient disposition. 
From the screening log, the overall number of patients who were screened, completed 
screening phase, discontinued from the screening phase with reason for not completing 
screening will be summarized. Only one attempt of rescreening is allowed in the study, the 
total patients screened will count individual patients and not attempts of screening. 
Using the screened patients and end of treatment CRF the number of patients randomized, 
completed the treatment phase and discontinued from the treatment phase will be summarized 
by treatment sequences with reasons for premature discontinuation for all patients in the FAS.  
Finally, using the end of study CRF, the number of patients completing and discontinuing the 
study, with reason for not completing the 30 day safety follow-up period will be summarized 
by treatment sequence for the FAS.  
In addition, the number of patients in each analysis set by treatment sequence will also be 
summarized for all randomized patients. Patient identification number, treatment sequence 
and whether they completed or discontinued from the different study phases will be listed, 
with date of last dose and primary reason for premature discontinuation. 
For patients who were rescreened at a certain visit, to avoid duplication of data in the 
database, all pages of previous visits were blanked, except the following pages which will be 
used for data summaries as appropriate: 
 
Visit 
CRF Page 
Visit 1 
Demography 
Visit 1 
Informed Consent 
Screen fail visit 
Visit date 
Screen fail visit 
Inclusion Exclusion Criteria (Screen Failure visit) 
Screen fail visit 
Screening Log (Screen Failure visit) 
For patients who passed the screening, data from the last completed visit where patient 
qualified the study eligibility criteria would be considered as screening assessments. 
1.3.2 
Protocol deviations 
The FAS set will be used for the summary by treatment and listing of protocol deviations. 


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The number and percentage of patients with protocol deviations will be tabulated by deviation 
category and treatment. The number of patients with protocol deviation that leads to exclusion 
in each analysis set will also be presented by treatment sequences. Subject exclusion from 
analysis sets will be listed for all patients with reasons of exclusion (i.e., both protocol and 
non-protocol deviation). Protocol deviations will be listed with date and study day of 
occurrence, deviation code and severity. 
1.3.3 
Patient demographics and other baseline characteristics 
Demographics and baseline characteristics will be summarized by treatment sequence using 
the FAS. Derivations related to demographic and baseline disease characteristics are defined 
in Section 16.1.9.3. 
The following demographic variables collected in the eCRF at Pre-screening (Visit 1) will be 
summarized: 
• age (in years) 
• sex (male or female) 
• race (Caucasian, Black, Asian, Other) 
• height (cm) 
• weight (kg) 
• body mass index (BMI) (kg/m2) 
 
Baseline characteristics (collected at Visit 1 for eCRF data, unless otherwise specified below) 
will be summarized: 
• Duration of COPD (in years, formula specified in Section 16.1.9.3) 
• History of exacerbation (number of any moderate or severe documented COPD 
exacerbation during the past 12 months). 
• Smoking status (never smoked, current smoker, ex-smoker) 
– estimated number of pack years (for current and ex-smokers only) 
– time since termination of smoking (for ex-smokers only) 
• Vital signs (sitting systolic/diastolic blood pressure (mmHg), sitting pulse rate (bpm)) 
at Visit 3. 
• Pre- and Post- bronchodilator (salbutamol) bodyplethysmography (sReff, IC, FRC, 
SVC, TLC, RVol and RVol %) at Visit 3. 
• Spirometry at screening including post- bronchodilator FEV1, FVC, FEV1/FVC, FEV1 
percentage of predicted normal value after bronchodilator and FVC percentage of 
predicted normal value after bronchodilator respectively at Visit 1 will be listed only. 
• Spirometry at baseline Visit 3 including  
– both pre- and post- bronchodilator FEV1 and FVC;  
– post-bronchodilator: FEV1 percentage of predicted normal value, FVC percentage 
of predicted normal value, FEV1/FVC;  
– FEV1 reversibility result. 


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• mMRC results (Grade 0, 1, 2, 3, 4) at Visit 3. 
• CAT total score at Visit 3. 
Baseline and demographic variables: continuous variables will be summarized using 
descriptive statistics (mean, median, standard deviation, minimum and maximum) and 
categorical variables will be summarized in terms of the number and percentage of patients in 
each category. 
1.3.4 
Medical history and current medical condition 
The number and percentages of patients with Cardio vascular (CV) related medical history 
will be tabulated by terms specified in the CRF page for the FAS.  
The number and percentages of patients with non-CV related medical history and current 
medical conditions will be summarized by primary system organ class and preferred terms. 
Verbatim recorded history/conditions will be listed together with the coded terms, date of 
diagnosis/surgery and whether the problem was ongoing at start of the study. 
1.4 
Study medication 
1.4.1 
Study drug administration 
Duration of exposure to each treatment will be calculated as the number of days between the 
first dose date and the last dose date exposed to that treatment over the specified period 
(expressed as: Duration of exposure = Date of last known dose of study drug – Date of first 
dose of study drug + 1).  
If by error a subject received the same in more than 1 period then the durations will be 
summed up. The duration of exposure (in days) will be summarized descriptively by treatment 
for the safety set. In addition, this duration will be summarized by categories of exposure (i.e., 
1-15 days and 29-43 days) and also cumulative categories (i.e., >=1, >=15, >= 29 and >= 43 
days) 
For each study treatment, the period, date, time, and dose of each single administration with 
reasons as per the CRF will be listed for the safety set. 
1.4.2 
Compliance to study treatments 
QVA149 110 mcg/50mcg and/or placebo of single dose dry powder inhaler per capsule with 
Ultibro® was prescribed to each patient once daily at two different periods.  
The compliance is defined as the percentage of doses taken by the patient at each period and 
will be calculated using the following formula:  
Compliance (%) = 100 x (total number of capsules administered / total number of capsules 
dispensed). 
The number of capsule administered is captured in the CRF pages. The number of capsules 
dispensed is same as the number of days dosed as per protocol assessment schedule in each 
period.  


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Compliance will be summarized with the standard descriptive statistics and by categories (i.e., 
<80% and 80-100%) for the safety set. 
1.5 
Prior and concomitant medications 
Prior medications are defined as treatments taken and stopped prior to first dose of study 
treatment at Visit 4. Any medication starting on or after the day of first dose of study 
treatment will be a concomitant medication, including those which were started pre-baseline 
and continued into the study period(s). 
Both COPD-related and non COPD-related medications will be coded using latest 
MedDRA version and summarized by ATC class and preferred term. The summaries will be 
provided separately for both prior and concomitant medication.   
All summaries will be on the safety set. 
1.6 
Efficacy evaluation 
Effectiveness analysis related to lung function will be performed on both FAS and PP set, 
whereas analysis related to cardiac function parameters will be performed only on PP set. 
Summary statistics by treatment will be provided for all efficacy outcome variables. 
Data within 6 hours of rescue medication use will be excluded from all efficacy analysis. 
1.6.1 
Primary variable  
The primary variable is left ventricular end-diastolic volume (LV-EDV in mL) collected after 
2 weeks of treatment at Visit 5 and Visit 7 from MRI eCRF. 
1.6.1.1 
Statistical model, hypothesis and method of analysis  
The comparison between QVA149 (110/50) and placebo in terms of LV-EDV (mL) for the PP 
set will be evaluated by testing the following null hypothesis (H0) versus the alternative 
hypothesis (Ha) at a two-sided 5% significance level: 
 
H0: There is no difference between QVA149 (110/50) compared to placebo in LV-EDV (mL) 
Ha: There is a difference between QVA149 (110/50) compared to placebo in LV-EDV (mL) 
 
The primary analysis will be performed comparing treatment means with respect to the LV-
EDV (mL) using analysis of variance (ANOVA) model with period and treatment as fixed 
effects and patient as a random effect.  
Adjusted least square means, point estimate of difference between treatment means, 95% 
confidence interval for treatment difference and p-value will be presented.  
Additionally unadjusted descriptive statistics (raw mean, SD, range) will be provided for each 
treatment and for the treatment contrast. 


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The absolute values and change from period baseline values in LV-EDV (mL) by visits will 
be provided for each treatment.  
Each of the above summary and analysis will be repeated for the FAS set. 
A Q-Q plot will be presented to verify the normality assumption of the primary variable. 
1.6.1.2 
Handling of missing values/censoring/discontinuations 
There will be no imputation for missing data, and the primary analysis will be based on only 
observed data. 
1.6.1.3 
Supportive analysis 
 
• If the observations of the primary variable does not follow the normality assumptions 
(confirmed by the QQ plot) then additional analysis of LV-EDV using the Wilcoxon 
signed rank test will be performed to test the difference between treatments.  
 
• Secondly, the primary variable, left ventricular end-diastolic volume will be affected by 
the patient’s blood pressure. However as the blood pressures are collected after baseline, 
their effects might be confounded with treatment effects and cannot be truly adjusted. 
Hence as a supportive exploratory analysis, the treatment means will be compared using 
an analysis of co-variance (ANCOVA) model with period, treatment as fixed effects, 
patient as a random effect and mean systolic blood pressure and mean diastolic blood 
pressure as additional continuous covariates. Where the mean systolic/diastolic blood 
pressure is calculated as the average over four measurements (beginning and the end of 
the cardiac sequence, after oxygen perfusion and finally at the end of all MRI sequences). 
Adjusted least square means, point estimates as difference between treatment means, 95% 
confidence interval for treatment difference and p-value will be presented. 
1.6.2 
Secondary variables 
1.6.2.1 
Analysis of spirometry outcomes  
The spirometry variables FEV1 (L) (Forced Expiratory Volume in 1 second) and FVC (L) 
(Forced Vital Capacity) are collected after 2 weeks of treatment at visit 5 and 7 (75 min post-
dose) in the spirometry eCRF. 
Each of these two variables will be analyzed using analysis of variance (ANOVA) model with 
period and treatment as fixed effects and patient as a random effect. 
Adjusted least square means, point estimate as difference between treatment means, 95% 
confidence interval for treatment difference and p-value will be presented. 
The absolute values and change from period baseline values for spirometry outcomes by visits 
will be summarized descriptively for each treatment. 
The above analysis will be performed on both PP and FAS set. 


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1.6.2.2 
Analysis of bodyplethysmography outcomes  
The bodyplethysmography variables such as  
• sReff (Effective resistance),  
• IC (inspiratory capacity),  
• TLC (Total lung capacity),  
• RVol (residual volume),   
• SVC (Slow Vital Capacity) and  
• FRC (functional residual capacity)  
are collected after 2 weeks of treatment at visit 5 and 7 in the bodyplethysmography eCRF. 
 
Each of the bodyplethysmography variables mentioned above will be analyzed using a similar 
analysis of variance (ANOVA) model with period and treatment as fixed effects and patient as 
a random effect.  
Adjusted least square means, point estimate as difference between treatment means, 95% 
confidence interval for treatment difference and p-value will be presented. 
The absolute values and change from period baseline values for bodyplethysmography 
outcomes by visits will be provided for each treatment. 
The above analysis will be performed on both PP set and FAS. 
1.6.2.3 
Analysis of cardiac parameters 
The cardiac variables right and left ventricular ejection fraction, right and left ventricular 
endsystolic volumes, right ventricular enddiastolic volume, and other cardiac outputs 
collected after 2 weeks of treatment at visit 5 and 7 from MRI in the eCRF. 
The following cardiac variables will be analyzed using analysis of variance (ANOVA) model 
with period and treatment as fixed effects and patient as a random effect. 
• right and left ventricular ejection fraction,  
• right and left ventricular end-systolic volumes,  
• right ventricular end-diastolic volume,  
• right and left cardiac outputs 
Adjusted least square means, point estimate of difference between treatment means, 95% 
confidence interval for treatment difference and p-value will be presented. 
Additionally, absolute values and change from period baseline values will be summarized 
using standard descriptive statistics for all the cardiac parameters for each treatment. Listings 
will also be presented. 
Cardiac output for both right and left ventricle is defined as CO [l/min] = (EDV-ESV 
[ml/beat]) * heart rate [bpm] /1000, and will also be summarized. 
The above analysis of cardiac parameters will be performed on PP set only. 


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1.6.3 
Analysis of exploratory parameters 
1.6.3.1 
COPD assessment test (CAT)  
The CAT is a short instrument used to quantify the symptom burden of COPD and will be 
used to assess the health status of patients in this study. It consists of eight items, each 
presented as a semantic 6-point differential scale (with scores from 0 to 5), providing a total 
score out of 40. A higher score indicates a worse health status. The total CAT score will be 
obtained by summing the scores on individual items. 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. 
Absolute values and change from period baseline values in the CAT total score by treatment 
period will be summarized using standard descriptive statistics. 
The absolute values and change from baseline in CAT total score at visit 5 and 7 will be 
analyzed using a similar analysis of variance (ANOVA) model as used for the primary 
analysis; with period and treatment as fixed effects and patient as a random effect. Adjusted 
least square means, point estimate of difference between treatment means, 95% confidence 
interval for treatment difference and p-value will be presented. 
The above analysis will be performed on FAS set only. 
1.6.3.2 
Baseline Dyspnea Index –Transitional Dyspnea Index (BDI‐TDI) 
Dyspnea is measured at baseline, Visit 4 and Visit 6 using the baseline dyspnea index (BDI) 
for Period I and Period II respectively and at Week 5 and Week 7 using the transition dyspnea 
index (TDI), which captures changes from baseline by period.  
The BDI and TDI grades will be summarized by treatment using number and percentage of 
each category.  
The TDI focal scores defined as the sum of scores of three domains (i.e., Functional 
impairment ranging from -3 to 3; Magnitude of task ranging from -3 to 3; Magnitude of effort 
ranging from -3 to 3), focal ranging between -9 to 9, will be analyzed using analysis of 
variance (ANOVA) model with period and treatment as fixed effects and patient as a random 
effect. Adjusted least square means, point estimate of difference between treatment means, 
95% confidence interval for treatment difference and p-value will be presented. 
The above summary will be presented on FAS set only. 
1.6.3.3 
Biventricular cardiac mass measures 
Absolute values and change from period baseline values in the right and left ventricular 
cardiac mass to end of each treatment period will be summarized using standard descriptive 
statistics.  
Each of the biventricular cardiac mass parameters will be analyzed using analysis of variance 
(ANOVA) model with period and treatment as fixed effects and patient as a random effect. 
Adjusted least square means, point estimate of difference between treatment means, 95% 
confidence interval for treatment difference and p-value will be presented. 


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The above summary will be presented on PP set only. 
1.6.3.4 
Pulmonary parenchymal blood flow measures 
Absolute values and change from period baseline values in the parameters related to 
pulmonary artery blood flow (room air) and pulmonary artery blood flow (100% oxygen) 
listed in Appendix 1 will be summarized using standard descriptive statistics to end of each 
treatment period.  
The above descriptive statistics will be presented on PP set only. 
1.6.3.5 
Echocardiography assessments 
Absolute values and change from period baseline values in the parameters of left and right 
ventricular of diastolic function, left and right ventricular of systolic function and pulmonary 
arterial pressures will be summarized using standard descriptive statistics to end of each 
treatment period.  
The above descriptive statistics will be presented on PP set only. 
1.6.3.6 
Impulse oscillometry 
Absolute values and change from period baseline values in the Resistance (R5, R20 and R5-
20), Reactance (X5) and Area of reactance (AX) will be summarized using standard 
descriptive statistics to end of each treatment period.  
The above descriptive statistics will be presented on FAS set only. 
1.6.3.7 
Regional lung ventilation, 19F washout time, perfusion measures and 
oxygen MRI 
Absolute values and change from period baseline values in the parameters related to lung 
ventilation, 19F washout time perfusion measures and oxygen MRI in Appendix 1 will be 
summarized using standard descriptive statistics to end of each treatment period.  
The above summary will be presented on FAS set only. 
1.6.3.8 
Rescue medication use 
Rescue medication (salbutamol) used during the study will be captured in dispense and 
administration of beta-2 agonist CRF page. The number of puffs of rescue medication use will 
be summarized descriptively by treatment on FAS set. 
1.6.3.9 
Activity with Actibelt 
Absolute value and change from baseline in the parameters related to the physical activity 
performed with Actibelt device will be summarized using standard descriptive statistics to end 
of each treatment period. The parameters collected using actibelt are: 
• Average time belt worn 
• Maximum coherent walking distance 


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• Mean velocity while walking/real world gait speed 
• Ratio of steps within sequences of 50 or more steps 
• Steps running 
• Steps walking 
• Total distance travelled 
• Total running time 
• Total walking time 
• Walking step frequency 
• Activity temperature raw 
• Activity temperature adherence 
• Walking step length 
The above descriptive summary statistics will be presented on FAS set only. 
1.7 
Safety evaluation 
All safety evaluations as a part of secondary objectives will be based on the safety set. 
1.7.1 
Adverse events (AE) 
 
All adverse events (including COPD exacerbations) will be coded with MedDRA version and 
included in tables and listings by treatment last administered.  
All AEs occurring prior to start of study treatment after signing of informed consent will be 
listed only. The following summaries of AEs will be presented. 
• AEs by primary system organ class and preferred term 
The number and percentage of patients who reported adverse events will be 
summarized by primary system organ class and preferred term. Primary system organ 
classes will be sorted alphabetically and, within each primary system organ class, the 
preferred terms will be sorted in descending frequency within the QVA149 (110/50) 
treatment 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.   
• AEs by severity 
All adverse events will be summarized by primary system organ class, preferred term 
and severity. If a patient reported more than one adverse event with the same preferred 
term, the highest (maximum) severity will be presented. If an adverse event occurs 


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more than once within the same patient in one treatment period will be counted once 
by maximum severity and treatment. A missing severity data will be considered as 
severe. 
• AEs suspected to be related to study drug 
All adverse events suspected to be related to study drug (according to the 
investigators) will be summarized by primary system organ class and preferred term. 
Relationship to study drug is considered as suspected for those events where 
"Relationship to study drug" is answered by the investigator as "Suspected". 
• AEs leading to permanent study drug discontinuation 
All adverse events leading to permanent study drug discontinuation, regardless of 
study drug relationship, will be summarized by primary system organ class and 
preferred term. 
In addition, adverse events resulting in dose adjustment or temporary interruption, use of 
concomitant medication, non-drug therapy, hospitalization or prolonged hospitalization will 
be summarized by treatment last administered. 
1.7.2 
Serious adverse events (SAE) 
Number and percentage of patients with serious adverse events by treatment last administered, 
regardless of study drug relationship, will be presented by primary system organ class and 
preferred term. 
1.7.3 
Deaths 
All the deaths in the clinical database will be listed with the investigator-reported principal 
cause. Deaths occurring after the first dose of study treatment will be summarized by 
treatment last administered. 
1.7.4 
Vital signs 
Summary statistics for absolute and change from baseline will be provided of vital signs 
(pulse rate and systolic and diastolic blood pressure) at baseline, start and end of Period I and 
start and end of Period II will be provided and all vital signs will be listed.  
The number (%) of patients with pulse rate of <40 and >130 bpm; systolic blood pressure of 
<75 and >200 mmHg; diastolic blood pressure of <40 and >115 mmHg will be summarized 
by treatment group. 
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 


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“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 
An additional listing will be provided for patients with notably abnormal vital signs. 
1.7.5 
Weight 
Summary statistics for weight at pre-screening, baseline and end of Period-II assessments will 
be provided. Listing will be provided for weight and height (pre-screening only). 
1.7.6 
Laboratory data 
1.7.6.1 
Hematology 
Laboratory assessments related to hematology are scheduled at baseline, end of Period I and 
end of Period II. 
Summary statistics for absolute and change from baseline will be provided and all laboratory 
data (including any unscheduled assessments) will be listed with abnormal values flagged. 
The listing will include the last treatment received before assessment (if any) and the number 
of days since last treatment. Any value considered as significantly notable will be reported by 
the investigator as an adverse event. 
1.7.6.2 
Clinical chemistry 
Laboratory assessments related to hematology are scheduled at baseline, start and end of 
Period I and start and end of Period II. 
Summary statistics for absolute and change from baseline will be provided and all laboratory 
data (including any unscheduled assessments) will be listed with abnormal values provided by 
central laboratory being flagged. The listing will include the last treatment received before 
assessment (if any) and the number of days since last treatment. Any value considered as 
significantly notable will be reported by the investigator as an adverse event. 
1.7.7 
Electrocardiogram (ECG) 
ECG assessments are scheduled at baseline, start of period I and start period II. Summary 
statistics of ECG parameters by sequence will be presented.  
The number and percentages of patients with clinically notable QTcF values will be 
summarized by treatment sequence and visits. 
Where QTc will be calculated from the QT interval and RR (in seconds) using Fridericia’s 
formula as QTcF = QT / 3√RR, where 3√ denotes the cube root. 
ECG results will be listed by patients. 


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Clinical notable criteria for QTcF (Fridericia's formula) 
 
ECG parameter 
(unit) 
Clinically notable range 
QTc (ms) 
> 450 for males 
QTc (ms) 
> 470 for females 
1.8 
Determination of sample size 
A QVA149-placebo treatment difference in left ventricular enddiastolic volume (primary 
endpoint) of 4 ml is considered a sufficient magnitude of effect to reveal mechanistic aspects 
relevant for COPD patients. The effect size of 4 ml is estimated based on different 
publications comparing COPD patients with non-COPD patients or with patients of different 
percentage emphysema, demonstrating differences in LVEDV between 4 – 25 ml [7, 8, 17, 
18].  
The intraindividual standard deviation of 10 ml is based on Bellenger et al, who describes the 
interstudy variability within 7 days with an SD of 7.4 ml [19]. As the reproducibility of the 
method itself (2 measurements with a minimal time interval) is given with a SD of 6.7 ml, an 
overall SD for this trial is assumed to be 10 ml [20].  
With a (within-patient-) standard deviation of 10 ml, 62 patients will be randomized initially 
with the intention that 52 patients complete the study with valid MRI-measurements. This 
samples size will provide 80% power to detect the difference as statistically significant at the 
5% significance level (2 sided). 
1.9 
Changes in the conduct of the study or planned analysis 
The terms center and patient within center is dropped from the primary analysis model due to 
the fact that there is only one center in the study. Patient is included in the model as a random 
effect. 
All statistical analyses models similar to primary analysis were modified similarly. 


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Clinical Study Report –  
Appendix 16.1.9 Documentation of statistical methods 
This appendix gives details about statistical methods in addition to the report text. All 
analyses will be performed by using SAS version 9.4. 
16.1.9.1 Major protocol deviations and other exclusion criteria 
 
Deviation code 
Text description 
Severity code 
I01 
Written informed consent was not obtained before performing any 
assessment. 
5 
I02 
Subject age is less than 40 or Subject age is missing 
age < 37 : 1 
Age >=37 : 49 
I03 
COPD is not stable according to the current GOLD guidelines 
(GOLD2014) and the subject was continuing in the study 
1 
I04 
"FEV1 of normal predicted value after inhalation of salbutamol"  is 
greater than or equal to 80% of the predicted normal value at Visit 
3 or Visit 3a 
1 
I04a 
Post-bronchodilator FEV1/FVC is greater than or equal to 0.7 at 
Visit 3 or V3a 
1 
I05 
Subject is Current or ex-smokers and Estimated number of pack 
years is less than 10 pack years 
1 
I05a 
Smoking history is Never smoked at visit 1 or 1a 
1 
I06 
RVol is less than or equal to 135% at Visit 3, before taking 
salbutamol. 
1 
E01 
Subject with conditions contraindicated for treatment with, or 
having a history of reactions/hypersensitivity to any of the 
anticholinergics or long and short acting beta-2 agonists or 
sympathomimetic amines or lactose or any of the other excipients 
inhaled drugs, drugs of a similar class and the subject was 
continuing in the study. 
1 
E02 
QTcF measured at Visit 3 or Visit 3a is greater than or equal to 
450 ms for males 
1 
E02a 
QTcF measured at Visit 3 or Visit 3a is greater than or equal to 
470 ms for females 
1 
E02b 
Subject with history of long QT syndrome at Visit 3 and the subject 
was continuing in the study 
1 
E03 
Clinically significant abnormality reported on the ECG at Visit 3 
would be at potential risk for patients by the Judgement of the 
investigator and the subject was continuing in the study. 
1 
E04 
Subject with clinically significant cardiovascular abnormalities, 
cardiac arrhythmias, heart failure with left ventricular ejection 
fraction equal to or less than 40% by MRI scan at Visit 4, unstable 
ischemic heart disease, NYHA Class III/IV left ventricular failure, 
history of myocardial infarction 6 months prior to Visit 2 and the 
subject was continuing in the study 
1 


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E05 
Subject with History or current atrial fibrillation confirmed by ECG 
at Visit 3 and the subject was continuing in the study 
1 
E06 
Subject having pacemaker or bypass and the subject was 
continuing in the study 
1 
E07 
Mean sitting systolic blood pressure is greater than160 mmHg 
and/or Mean sitting diastolic blood pressure is greater than 90 
mmHg at Visit 3 or Visit 3a 
1 
E08 
Past or present disease may affect the outcome of this study as 
judged by the investigator 
1 
E09 
History of malignancy of any organ system (other than localized 
basal cell carcinoma of the skin), treated or untreated, within the 
past 5 years, regardless of whether there is evidence of local 
recurrence or metastases and the subject was continuing in the 
study 
49 
E10 
Patients with narrow-angle glaucoma, symptomatic benign 
prostatic hyperplasia or bladder-neck obstruction or severe renal 
impairment (GFR equal to or less than 30 mL/min/1.73 m2) 
including those with end-stage renal disease requiring dialysis or 
urinary retention and the subject was continuing in the study 
49 
E11 
Subject reported with Type I Diabetes mellitus 
49 
E11a 
Subject is with uncontrolled Type II diabetes and the subject was 
continuing in the study 
49 
E12 
Patients with active/ clinical history of asthma and the subject was 
continuing in the study 
1 
E13 
Subject with claustrophobia or presence of any metal objects 
within the patient and unable to undergo MRI scan and the subject 
was continuing in the study 
49 
E14 
History of lower respiratory tract infection within four weeks prior to 
Visit 2 and between Visit 2 and Visit 4 and the subject was 
continuing in the study 
1 
E15 
History of one COPD exacerbation that required treatment with 
antibiotics and/or systemic steroids (oral or intravenous) and/or 
hospitalization within 3 months prior to Visit 2 or Visit 2a and the 
subject was continuing in the study 
1 
E16 
More than one COPD exacerbation that required treatment with 
antibiotics, systemic steroids (oral or intravenous) or 
hospitalization within 6 months prior Visit 2 and the subject was 
continuing in the study 
1 
E17 
Subject reported with COPD exacerbation between Visit 2 or Visit 
2a and Visit 4 or visit 4a and the subject was continuing in the 
study 
1 
E18 
Subject requiring long term oxygen therapy on a daily basis for 
chronic hypoxemia and the subject was continuing in the study 
1 
E19 
Patient with active pulmonary tuberculosis, unless confirmed by 
imaging in the last year to be no longer active and the subject was 
continuing in the study 
1 
E20 
Patient with pulmonary lobectomy or lung volume reduction 
surgery or lung transplantation and the subject was continuing in 
the study 
1 


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E21 
Patients with a diagnosis of alpha 1 anti-trypsin deficiency and the 
subject was continuing in the study 
1 
E22 
Body mass index (BMI) is greater than 40 kg/m2 at visit 3 or V3a 1 
E23 
Patients participating in or planning to participate in the active 
phase of a supervised pulmonary rehabilitation program during the 
study and the subject was continuing in the study 
1 
E24 
Patients are known to be unreliable or non-compliant as judged by 
the investigator and the subject was continuing in the study 
1 
E25 
Relevant history of drug or alcohol abuse as judged by the 
investigator and the subject was continuing in the study and the 
subject was continuing in the study 
49 
E26 
Suspected inability to understand the protocol requirements, 
instructions and study-related restrictions, the nature, scope, and 
possible consequences of the study and the subject was 
continuing in the study 
1 
E27 
Use of other investigational drugs at the time of enrollment, or 
within 30 days or 5 half-lives of Visit 1, whichever is longer and the 
subject was continuing in the study 
1 
E28 
Patients receiving any prohibited medications as per protocol and 
the subject was continuing in the study 
1 
E30 
Subject was pregnant or breast feeding (pregnancy defined as the 
state of a female after conception and until the termination of 
gestation, confirmed by a positive hCG test (less than 5mIU/ml)) 
and the subject was continuing in the study 
49 
E31 
Subject of child-bearing potential or capable of becoming 
pregnant, not using effective methods of contraception during 
dosing of study treatment and the subject was continuing in the 
study 
49 
S02 
An alternative inhalation device was used for the administration of 
the Study drug or placebo capsules during the study and the 
subject was continuing in the study 
1 
S03 
Patient taking Nebulized salbutamol and or other rescue treatment 
other than salbutamol and the subject was continuing in the study. 
1 
S04 
Subject received at least one pack of incorrect study drug at 
dispensing visit and the subject was continuing in the study 
1 
S15 
Written informed consent of 19F MRI Informed consent was not 
obtained before performing 19F MRI assessment. 
49 
D01 
Abnormal test procedure results indicating risk for the patient on 
continued inhalation of the study drug and the subject was 
continuing in the study 
49 
D02 
Codes broken accidentally 
1 
OTH01 
Premature discontinuation of study 
50 
OTH02 
Premature discontinuation of study drug 
50 
OTH03 
Compliance to study drug < 80% in any study period 
50 
16.1.9.2  Patient classification 
Protocol deviations severity codes leading to patient classification into the analysis sets are as 
follows: 


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Severity codes 
Actions 
0 
Exclude from all efficacy analysis (FAS, PP) 
1 
Exclude from Per-Protocol analysis (PP) 
5 
Exclude from all safety analyses (SAF) 
8 
Exclude from all analysis (FAS, PP, SAF) 
9 
Included in all efficacy analysis 
49 
Report relevant PD, include in all analysis 
50 
No PD, but affects data availability/validity, exclude from Per-
Protocol analysis (PP) 
Patient classification based on severity codes 
Analysis set 
PD severity codes that cause a subject to 
be excluded 
FAS  
0, (5*), 8 
SAF 
5, 8 
PP 
0, 1, (5*), 8, 50 
 
* Note: given that the PP is nested within the FAS set, which is itself nested within the SAF, 
severity code 5 implies exclusion from all three of these analysis sets (i.e. SAF, FAS and PP). 
Unless otherwise stated, summary tables, figures and listings will be on all subjects included 
in the analysis set under consideration. 
16.1.9.3 Derivations, Baseline and post-baseline definitions  
- 
Data from unplanned or unscheduled visits or the early treatment/study 
discontinuation visits will be listed. 
- 
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 
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. 
- 
BMI (kg/m2) = weight (kg) / [height (m)]^2 
- 
Time since termination of smoking is calculated from the date of smoking termination 
as recorded on the eCRF until the date of Visit 1. 
- 
When change from baseline is of interest then it will be calculated at each period using 
following formula, where baseline and post-baseline values are both available:  
Change from baseline at period x = post-baseline value at period x– baseline 
value at period x. 


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Study day 
Study day is defined as the number of days since the date of first dose of study medication. It 
is defined by statistical programming and reported in the CSR listings. 
Therefore, for a particular date, study day will be calculated as follows: 
• 
for dates on or after the first date of study medication, 
Study day = Assessment date – Date of first dose of study medication + 1; 
• 
for dates prior to the first date of study medication, 
Study day = Assessment date – Date of first dose of study medication. 
Baseline measurements 
In general, baseline is defined as the last measurement before the first dose of study treatment.  
Period baseline value is defined as value taken prior to first dose of study treatment at visit 4 
and visit 6 for period I and period II respectively.  
If the value is missing at visit, then the baseline value will be imputed by the non-missing last 
available pre-dose value.  
Post-baseline assessments 
Post-baseline values are defined as assessment taken after first dose of study treatment at each 
period.  
For safety data, all AEs starting on or after the first dose of study treatment will be 
summarized as post-baseline observations. 
 
 


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16.1.9.4 Statistical methodology and assumptions 
SAS codes to perform ANOVA 
The SAS procedure PROC MIXED will be used with the following SAS code: 
 
PROC MIXED DATA = ....  ORDER =internal; 
 CLASS usubjid aperiod trtpn; 
 MODEL aval = aperiod trtpn / DDFM=kr; 
 RANDOM usubjid; 
  LSMEANS trtpn; 
 ESTIMATE “QVA149 - Placebo” 1 -1/ CL ALPHA=0.05; 
RUN; 
 
where aval 
 
= dependent variable, e.g. left ventricular enddiastolic volume 
 
trtpn 
 
= Treatment within period as randomized 
 
aperiod 
= Period 
 
usubjid 
= Patient identifier 
 
 
Model fit will be identified by a QQ plot of residuals. 
SAS code to perform ANCOVA 
The SAS procedure PROC MIXED will be used with the following SAS code: 
 
PROC MIXED DATA = ....  ORDER =internal; 
 CLASS usubjid aperiod trtpn; 
 MODEL aval = aperiod trtpn msystolic mdiastolic/ DDFM=kr; 
 RANDOM usubjid; 
 LSMEANS trtpn; 
 ESTIMATE “QVA149 - Placebo” 1 -1/CL ALPHA=0.05; 
RUN; 
 
where aval 
 
= dependent variable, e.g. left ventricular enddiastolic volume 
 
trtpn 
 
= Treatment within period as randomized 
 
aperiod 
= Period 
 
usubjid 
= Patient identifier 
 
msystolic  
= Mean systolic BP 
 
mdiastolic 
= Mean diastolic BP 
 
 
SAS code to perform Wilcoxon signed rank test 
 
PROC NPAR1WAY DATA = … WILCOXON hl alpha=.05; 
 
CLASS trtpn; 
   
VAR aval; 
 
EXACT hl; 
RUN; 
 
where aval 
 
= dependent variable, e.g. left ventricular enddiastolic volume 
            trtpn                = Treatment within period as randomized 


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16.1.9.5 Appendices 
Appendix 1: List of MRI Parameters 
 
 
 
 


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Appendix 2: GOLD guidelines 
 
Classification of severity of airflow limitation in COPD based 
on post-bronchodilator FEV1 
In patients with FEV1/FVC < 0.7 
GOLD 1 
• FEV1 ≥ 80% predicted 
GOLD 2 
• 50% ≤ FEV1 < 80% predicted 
GOLD 3 
• 30% ≤ FEV1 < 50% predicted 
GOLD 4 
• FEV1 < 30% predicted 
 
Appendix 3: GOLD guidelines (2014) 
 
• Patient Group A – Low Risk, Less Symptoms 
Typically GOLD 1 or GOLD 2 (mild or moderate airflow limitation); and/or 0-1 
exacerbation per year and not hospitalization for exacerbation; and CAT score <10 or 
mMRC grade 0-1. 
• Patient Group B – Low Risk, More Symptoms 
Typically GOLD 1 or GOLD 2 (mild or moderate airflow limitation); and/or 0-1 
exacerbation per year and no hospitalization for exacerbation; and CAT score ≥10 or 
mMRC grade ≥2. 
• Patient Group C – High Risk, Less Symptoms 
Typically GOLD 3 or GOLD 4 (severe or very severe airflow limitation); and/or ≥2 
exacerbations per year or ≥1 with hospitalization for exacerbation; and CAT score <10 
or mMRC grade 0-1. 
• Patient Group D – High Risk, More Symptoms 
Typically GOLD 3 or GOLD 4 (severe or very severe airflow limitation); and/or ≥2 
exacerbations per year or ≥1 with hospitalization for exacerbation; and CAT score ≥10 
or mMRC grade ≥2.