Conditions: COPD
Keywords: COPD open-label QVA149 symptomatic tiotropium
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 379
Healthy volunteers: no

Brief summary:
To demonstrate superiority of QVA149 (110/50 μg) once daily compared to tiotropium 18 μg once daily in terms of trough forced expiratory volume in 1 second (FEV1) (mean of 45 min and 15 min pre-dose) following 12 weeks of treatment in mild to moderate symptomatic COPD patients

Detailed description:

Arms:
arm 1: QVA149 110/50 μg capsules for inhalation delivered once daily via single-dose dry powder inhaler (SDPPI) for 12 weeks arm 2: Tiotropium 18 μg capsules for inhalation delivered once daily via HandiHaler® device for 12 weeks

Interventions: intervention 1: Indacaterol and glycopyrronium (QVA149) intervention 2: Tiotropium
Intervention descriptions: intervention 1: Capsules for inhalation delivered via SDDPI intervention 2: Capsules for inhalation delivered via HandiHaler® device

Protocol document:
Prot_000.pdf: 
Clinical Development
QVA149/ indacaterol maleate/glycopyrronium bromide
Clinical Trial Protocol CQVA149AKR01/ NCT02566031
A randomized, multicenter, open-label, parallel-group, 
12-week study to assess the efficacy and safety of 
switching from tiotropium to QVA149 (indacaterol
maleate/glycopyrronium bromide) in symptomatic mild to 
moderate COPD patients
Authors:
Document type:
Amended Protocol Version
EUDRACT number:
Not applicable. 
Version number:
05 Clean
Development phase:
IV 
Release date:
12-Sep-2018
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis
NCDS Template Version 03-Feb-2012
 


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................5
List of abbreviations............................................................................................................6
Protocol synopsis.................................................................................................................9
1
Introduction .......................................................................................................................20
1.1
Background............................................................................................................20
1.2
Purpose ..................................................................................................................21
2
Study objectives.................................................................................................................21
2.1
Primary and key secondary objectives ..................................................................21
2.2
Secondary objectives .............................................................................................21
.21
3
Investigational plan ...........................................................................................................22
3.1
Study design...........................................................................................................22
3.2
Rationale of study design.......................................................................................24
3.3
Rationale of dose/regimen, route of administration and duration of treatment.....24
3.4
Rationale for choice of comparator .......................................................................24
3.5
Purpose and timing of interim analyses/design adaptations..................................25
3.6
Risks and benefits..................................................................................................25
4
Population..........................................................................................................................26
4.1
Inclusion criteria ....................................................................................................27
4.2
Exclusion criteria...................................................................................................27
5
Treatment...........................................................................................................................29
5.1
Protocol requested treatment .................................................................................29
5.1.1
Investigational treatment.......................................................................29
5.1.2
Reference treatment ..............................................................................30
5.1.3
Additional study treatment....................................................................30
5.2
Treatment arms......................................................................................................30
5.3
Treatment assignment, randomization...................................................................30
5.4
Treatment blinding.................................................................................................31
5.5
Treating the patient................................................................................................31
5.5.1
Patient numbering .................................................................................31
5.5.2
Dispensing the investigational treatment ..............................................31
5.5.3
Handling of study treatment..................................................................32
5.5.4
Instructions for prescribing and taking study treatment........................33
 


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5.5.5
Permitted dose adjustments and interruptions of study treatment ........33
5.5.6
Rescue medication ................................................................................34
5.5.7
Concomitant treatment..........................................................................34
5.5.8
Prohibited treatment..............................................................................34
5.5.9
Discontinuation of study treatment and premature patient 
withdrawal.............................................................................................35
5.5.10
Emergency breaking of treatment assignment ......................................36
5.5.11
Study completion and post-study treatment..........................................36
5.5.12
Early study termination.........................................................................37
6
Visit schedule and assessments .........................................................................................37
6.1
Information to be collected on screening failures..................................................40
6.2
Patient demographics/other baseline characteristics .............................................41
6.3
Treatment exposure and compliance .....................................................................41
6.4
Efficacy..................................................................................................................41
6.4.1
Spirometry measurements.....................................................................41
6.4.2
Baseline/transitional dyspnea index......................................................42
6.4.3
Chronic obstructive pulmonary disease assessment .............................42
43
6.4.5
Rescue medication use..........................................................................43
6.4.6
Chronic obstructive pulmonary disease exacerbations .........................43
6.4.7
Appropriateness of efficacy assessments..............................................44
6.5
Safety.....................................................................................................................44
6.5.1
Physical examination ............................................................................45
6.5.2
Vital signs..............................................................................................45
6.5.3
Height and weight .................................................................................45
6.5.4
Laboratory evaluations..........................................................................45
6.5.5
Electrocardiogram.................................................................................46
6.5.6
Pregnancy and assessments of fertility .................................................46
6.5.7
Appropriateness of safety measurements..............................................46
6.6
Other assessments..................................................................................................46
6.6.1
Resource utilization...............................................................................46
6.6.2
Health-related quality of life.................................................................47
6.6.3
Pharmacokinetics ..................................................................................47
6.6.4
Pharmacogenetics/pharmacogenomics .................................................47
6.6.5
Other biomarkers...................................................................................47
47
7
Safety monitoring..............................................................................................................48
 


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7.1
Adverse events.......................................................................................................48
7.2
Serious adverse event reporting.............................................................................50
7.3
Pregnancy reporting...............................................................................................51
7.4
Prospective suicidality assessment ........................................................................51
8
Data review and database management.............................................................................51
8.1
Site monitoring ......................................................................................................51
8.2
Data collection.......................................................................................................52
8.3
Database management and quality control............................................................52
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.......................................53
9.3
Treatments .............................................................................................................53
9.4
Analysis of the primary variable............................................................................54
9.4.1
Variable.................................................................................................54
9.4.2
Statistical model, hypothesis, and method of analysis..........................54
9.4.3
Handling of missing values/censoring/discontinuations.......................54
9.4.4
Supportive analyses...............................................................................55
9.5
Analysis of secondary variables ............................................................................55
9.5.1
Efficacy variables..................................................................................55
9.5.2
Safety variables .....................................................................................57
9.5.3
Resource utilization...............................................................................59
9.5.4
Health-related Quality of Life...............................................................59
9.5.5
Pharmacokinetics ..................................................................................59
9.5.6
Pharmacogenetics/pharmacogenomics .................................................59
9.5.7
Biomarkers............................................................................................59
9.5.8
PK/PD ...................................................................................................59
59
59
59
59
9.7
Interim analyses.....................................................................................................60
9.8
Sample size calculation..........................................................................................60
10 Ethical considerations........................................................................................................60
10.1
Regulatory and ethical compliance........................................................................60
 


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10.2
Informed consent procedures.................................................................................60
10.3
Responsibilities of the investigator and IRB/IEC/REB.........................................61
10.4
Publication of study protocol and results...............................................................61
11 Protocol adherence ............................................................................................................61
11.1
Protocol amendments.............................................................................................61
12 References .........................................................................................................................62
13 Appendices ........................................................................................................................63
13.1
Appendix 1: Baseline dyspnea index/transitional dyspnea index..........................63
13.2
Appendix 2: Spirometry guidance.........................................................................68
13.3
Appendix 3: Patient COPD treatment diary ..........................................................69
13.4
Appendix 4: GOLD guidelines..............................................................................71
72
13.6
Appendix 6: Instructions for use of the SDDPI for QVA149 
110/50 microgram..................................................................................................73
13.7
Appendix 7: Instructions for use of HandiHaler® for tiotropium 18 
microgram..............................................................................................................78
13.8
Appendix 8: COPD Assessment Test (CAT) ........................................................86
List of tables
Table 5-1
Prohibited medications..........................................................................34
Table 5-2
Medication allowed under certain conditions .......................................35
Table 6-1
Assessment schedule.............................................................................39
List of figures
Figure 3-1
Study design..........................................................................................22
47
48
 


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List of abbreviations
AE
Adverse Event
ALT
Alanine aminotransferase
ANCOVA
Analysis of Covariance
AST
Aspartate aminotransferase
ATS
American Thoracic Society
BDI
Baseline Dyspnea Index
BTPS
Normal body temperature (37°C), ambient pressure, saturated with water vapor
CAT
COPD Assessment Test
CCV
Cardio-cerebrovascular Event
COPD
Chronic Obstructive Pulmonary Disease
eCRF
Electronic Case Report/Record Form
DS&E
Drug Safety & Epidemiology
ECG
Electrocardiogram
EDC
Electronic Data Capture
ERS
European Respiratory Society
FEV1
Forced Expiratory Volume in 1 second
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GOLD
Global Initiative for Chronic Obstructive Lung Disease
hCG
Human Chorionic Gonadotropin
ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ICS
Inhaled Corticosteroid
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
Interactive Randomized Technology
IUD
Intrauterine Device 
IUS
Intrauterine System
LABA
Long Acting Beta-2 Agonist
LAMA
Long Acting Muscarinic Antagonist
 


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LOCF
Last Observation Carried Forward
MDI
Metered Dose Inhaler
mMRC
Modified Medical Research Council 
PSW
Premature Study Withdrawal
QoL
Quality of Life
QT
Time between start of Q wave and end of T wave in heart’s electrical cycle
QTc
Corrected QT
QTcF
Fridericia corrected QT formula
SABA
Short Acting Beta-2 Agonist
SAE
Serious Adverse Event
SDDPI
Single Dose Dry Powder Inhaler
SGRQ
St. George’s Respiratory Questionnaire
SmPC
Summary of Product Characteristics
SUSARs
Suspected Unexpected Serious Adverse Reactions
TDI
Transitional Dyspnea Index
TURP
Transurethral Resection of Prostate
 


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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).
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 interactive 
randomized technology (IRT) system.
Patient 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
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 drug 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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Protocol synopsis
Protocol number
CQVA149AKR01
Title
A randomized, multicenter, open-label, parallel-group, 12-week study to 
assess the efficacy and safety of switching from tiotropium to QVA149 
(indacaterol maleate/glycopyrronium bromide) in mild to moderate 
symptomatic COPD patients.
Brief title
Study of efficacy and safety of switching from tiotropium to QVA149 in 
patients with symptomatic mild to moderate COPD.
Sponsor and clinical 
phase
Novartis, Phase IV
Investigation type
Drug
Study type
Interventional
Purpose and rationale
Bronchodilator medications are central to symptom management in 
chronic obstructive pulmonary disease (COPD). According to local market 
research data in Korea, 70 to 80% of COPD patients using an inhaled 
mono-bronchodilator still have the same or more symptoms despite 
treatment compared to when they were first diagnosed. Tiotropium is the 
most widely used mono-bronchodilator in Korea.
Combining bronchodilators of different pharmacological classes may 
improve efficacy and decrease the risk of side effects compared to 
increasing the dose of a single bronchodilator. QVA149 is a novel, inhaled 
fixed dose combination of the
long acting beta-2 agonist (LABA)
indacaterol (QAB149) and the long acting muscarinic antagonist (LAMA)
glycopyrronium (NVA237) for once-daily maintenance treatment of COPD. 
QVA149 was first marketed in Europe and Japan in 2013 and has since 
been marketed in many other countries worldwide including South Korea 
(since May 2014). 
In this study, the efficacy and safety of QVA149 will be compared to that of 
tiotropium in COPD patients with mild to moderate airflow limitation with 
low exacerbation risk and who are currently receiving tiotropium but still 
symptomatic, which is defined as COPD assessment test (CAT) scores 
≥10. 
The main purpose of this study is to show that QVA149 (110/50 μg) once 
daily results in better lung function and airflow compared to tiotropium
18 μg once daily in patients with mild to moderate symptomatic COPD; 
and to assess the effect of both treatments on symptom burden, 
breathlessness, and use of rescue medication in these patients. 
Primary objective

To demonstrate superiority of QVA149 (110/50 μg) once daily 
compared to tiotropium 18 μg once daily in terms of trough forced 
expiratory volume in 1 second (FEV1) (mean of 45 min and 
15 min pre-dose) following 12 weeks of treatment in mild to 
moderate symptomatic COPD patients.
Secondary objectives
To evaluate the effect of QVA149 (110/50 μg) as compared to tiotropium
18 μg on:

Pre-dose trough FEV1 at Week 4.
 


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
Total transitional dyspnea index (TDI) focal score at Week 12.

Symptom control as assessed by total CAT score at Week 12.

Rescue medication used reported by the patients at Week 12. 

Safety and tolerability.
Study design
This is a randomized, multicenter, open-label, parallel-group, 12-week 
study
to assess the efficacy and safety of QVA149 (indacaterol 
maleate/glycopyrronium bromide) versus tiotropium in mild to moderate 
symptomatic COPD patients. 
Population
The study population will consist of approximately 389 male and female 
adults aged 40 or older, with a confirmed clinical diagnosis of COPD and 
post-bronchodilator FEV1 ≥50% of the predicted normal value and post-
bronchodilator FEV1/forced vital capacity (FVC) < 0.7 (COPD Grade 1 or 2 
by severity of airflow limitation (GOLD 2015) and a smoking history of at 
least 10 pack years. 
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 adults aged ≥40 years, who have signed an 
Informed Consent Form (ICF) prior to initiation of any study-
related procedure.
3.
Confirmed diagnosis of COPD and post-bronchodilator 
FEV1 ≥50% of the predicted normal value and post-
bronchodilator FEV1/FVC < 0.7 (COPD Grade 1 or 2 by severity 
of airflow limitation (GOLD 2015). 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.
Patients with CAT score ≥10 at Visit 0 and Visit 1.
5.
Patients who are on and have been on tiotropium 18 µg 
monotherapy for the past 3 months prior to Baseline (Visit 1).
6.
0 or 1 COPD exacerbation in the previous 12 months prior to 
baseline (Visit 1) (not leading to hospital admission). 
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.
General exclusion criteria
1.
Treatment with any inhaled corticosteroid (ICS) in the 3 months 
prior to Visit 1.
2.
Pregnant or nursing (lactating) women, where pregnancy is 
defined as the state of a female after conception and until the 
 


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termination of gestation, confirmed by a positive human chorionic 
gonadotropin (hCG) laboratory test. 
3.
Women of child-bearing potential, defined as all women 
physiologically capable of becoming pregnant, unless they are 
using effective methods of contraception during dosing of study 
treatment. Effective contraception methods include:

Total abstinence (when this is in line with the preferred and 
usual lifestyle) of the patient. Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception.

Female sterilization (have had surgical bilateral 
oophorectomy with or without hysterectomy) or tubal ligation 
at least 6 weeks before taking study treatment. In case of 
oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level 
assessment.

Male sterilization (at least 6 months prior to Screening). For 
female patients on the study, the vasectomized male partner 
should be the sole partner for that patient.

Barrier methods of contraception: condom or occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/ vaginal suppository.

Use of oral, injected or implanted hormonal methods of 
contraception or other forms of hormonal contraception that 
have comparable efficacy (failure rate < 1%), for example 
hormone vaginal ring or transdermal hormone contraception.

Placement of an intrauterine device (IUD) or intrauterine 
system (IUS).
In case of use of oral contraception, women should have been 
stable on the same pill for a minimum of 3 months before taking 
study treatment.
Women are considered post-menopausal and not of child bearing 
potential if they have had 12 months of natural (spontaneous) 
amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy) or tubal 
ligation at least 6 weeks ago. In the case of oophorectomy alone, 
only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment is she 
considered not of child bearing potential. 
4.
Presence of any contraindication, warning, precaution, 
hypersensitivity to LABA and LAMA.
5.
History or current diagnosis of clinically significant 
electrocardiogram (ECG) abnormalities including:

Concomitant clinically significant cardiac arrhythmias, e.g. 
sustained ventricular tachycardia, and clinically significant 
second or third degree AV block without a pacemaker.

History of familial long QT syndrome or known family history 
of Torsades de Pointes. 
6.
Patients who have not achieved an acceptable spirometry result 
at (Visit 10) in accordance with American Thoracic Society (ATS)/ 
European Respiratory Society (ERS) criteria for acceptability and 
 


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repeatability.
7.
Patients with Type I or uncontrolled Type II diabetes.
8.
Patients with narrow-angle glaucoma, symptomatic prostatic 
hyperplasia or bladder-neck obstruction or moderate to severe 
renal impairment or urinary retention. (Patients with a 
transurethral resection of prostate (TURP) are excluded from the 
study. Patients who have undergone full re-section of the prostate 
may be considered for the study, as well as patients who are 
asymptomatic and stable on pharmacological treatment for the 
condition).
9.
History of malignancy of any organ system, treated or untreated, 
within the past 5 years, regardless of whether there is evidence of 
local recurrence or metastases with the exception of localized 
basal cell carcinoma of the skin.
10. Patients with a history of clinically significant diseases that, in the 
opinion of the Investigator, would put the safety of the patients at 
risk through study participation, or would compromise patient 
compliance or preclude completion of the study.
11. Uncontrolled hypothyroidism and hyperthyroidism, hypokalemia.
12. Patients with neurological, endocrine, immunological, psychiatric, 
gastrointestinal, hepatic, or hematological abnormalities which, in 
the opinion of the Investigator, could interfere with the 
assessment of the efficacy and safety of the study treatment. 
13. Patients who are, in the opinion of the investigator, known to be 
unreliable or non-compliant. 
COPD specific exclusion criteria
1.
Patients requiring long-term oxygen therapy prescribed 
for > 12 hours per day. 
2.
COPD exacerbation between Visits 0 and 1. Patients can be 
re-screened after a minimum of 6 weeks after resolution of the 
exacerbation if the exacerbation did not require hospitalization. If 
a patient has an exacerbation that requires hospitalization 
between Visit 0 and Visit 1 then he/she is not eligible to re-
screen.
3.
Onset of respiratory symptoms, including a COPD diagnosis prior 
to age 40 years. 
4.
Patients with a history of respiratory infection within 4 weeks prior 
to Visit 0. Patients who develop a respiratory tract infection 
between Screening and prior to treatment will not be eligible but 
will be permitted to be re-enrolled 4 weeks after the resolution of 
the respiratory tract infection.
5.
Concomitant pulmonary disease (e.g. pulmonary tuberculosis 
(unless confirmed by chest X-ray to be no longer active), lung 
fibrosis, sarcoidosis, interstitial lung disease, primary pulmonary 
hypertension, clinically significant bronchiectasis). 
6.
Patients with lung lobectomy, or lung volume reduction or lung 
transplantation
7.
Prior or current diagnosis of asthma.
Medication exclusion
1.
Treatments for COPD and allied conditions: the following class of 
medications should be washed out prior to randomization (Visit 1)
or prohibited during the study period (Table 5-1 in main protocol).
 


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2.
Patients who need the following treatments for COPD and allied 
conditions unless they have been stabilized for the specified 
period and the stated conditions have been met (Table 5-2 in
main protocol). 
3.
Patients who have had live attenuated vaccinations within 
30 days prior to the screening visit. Inactivated influenza 
vaccination, pneumococcal vaccination or any other inactivated 
vaccine is acceptable provided it is not administered within 48 
hours prior to screening and randomization visits.
4.
Use of other investigational drugs at the time of enrollment, or 
within 30 days or 5 half-lives of Visit 1, whichever is longer.
5.
Patients unable to use a dry powder inhaler (e.g. single-dose dry 
powder inhaler (SDDPI), HandiHaler®) device or pressurized 
metered dose inhaler (MDI) (rescue medication).
Investigational and 
reference therapy
Investigational therapy:

QVA149 110/50 µg capsules once daily for inhalation supplied in 
blisters, delivered via manufacturer’s proprietary inhalation 
device. 
Reference therapy:

tiotropium 18 µg capsules once daily for inhalation supplied in 
commercially available blisters, delivered via proprietary inhaler 
(HandiHaler®). 
Efficacy assessments
Efficacy will be assessed using the following parameters:

Pre-dose (average of -45 min and -15 min) trough FEV1 following 
12-week treatment of QVA149 (110/50 μg) compared to 
tiotropium 18 μg.

Trough FEV1 (pre-dose) at Week 4 after treatment.

Mean number of puffs of rescue medication use per day and days 
without rescue medication over the 12-week treatment period 
using patient diary.

Baseline dyspnea index (BDI)/TDI focal score at Week 12.

CAT score at Week 12.

Safety assessments
Safety will be assessed by the monitoring of adverse events (AEs), serious 
adverse events (SAEs), ECGs, vital signs and routine laboratory analyses.
Data analysis
The primary objective of this study is to demonstrate the superiority of 
QVA 110/50 μg once daily compared to tiotropium 18 μg once daily in 
terms of trough forced expiratory volume in one second following 
12 weeks of treatment. This will be analyzed for the Full Analysis Set using 
an analysis of covariance (ANCOVA) model, with treatment, smoking 
status as fixed effects, baseline trough FEV1 as a covariate and center as 
a random effect.
The superiority of QVA to tiotropium will be demonstrated if the p-value is 
less than 0.05 and the confidence interval lies entirely to the right of 
(higher than) 0 mL.
 


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In addition, the following variables will also be analyzed in a similar 
manner: pre-dose trough FEV1 at Week 4; TDI focal score at Week 12;
symptom control as assessed by total CAT score 
 
; and rescue medication use reported by patients at Week 12. 
All safety endpoints (i.e. AEs, laboratory data, vital signs, and ECG) will be 
summarized by treatment for all patients in the safety set.
Key words
COPD, open-label, QVA149, symptomatic, tiotropium
 


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Rationale for Amendment 1 (09-September-2015)
This amendment has been prepared to clarify prohibited medications and allowable 
concurrent medications which were strongly recommended by the investigators. The study has 
not yet started and this will not have any major impact on the study population and study 
results. The opportunity was also taken to remove ICS use in statistical analysis plan which 
was erroneously included.
 


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Rationale for Amendment 2 (09-November-2015)
This amendment has been prepared to clarify some of the study procedures that would not 
affect primary and key secondary endpoints such as window period (Visit 2, 3), blood 
chemistry and SAE reporting details. 
The study has not yet started and this will not have any major impact on the study population
and study results. The opportunity was also taken to update patient diary in Appendix 3.
 


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Rationale for Amendment 3 (10-Dec-2015)
This amendment has been prepared to change several study procedures such as window 
period of visit 2/3, reversibility test and providing investigational drug. The study has not yet 
started patient recruitment and this will not have any major impact on the study population 
and study results.
 


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Rationale for Amendment 4 (18-Jun-2018)
This amendment has been prepared to reduce sample size due to low enrollment rate. 
This amendment also incorporated some minor typographical errors corrections.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions 
Changes to the Protocol:

Protocol author was changed.

Due to low enrollment rate, sample size will be reduced to 182 patients in each treatment 
arm to a total of 364 patients, and the expected treatment difference between QVA149 
110/50 µg once daily and tiotropium 18 µg was changed from 80 mL to 82 mL of pre-
dose trough FEV1(L) after 12 weeks of treatment , in order to achieve 80% power on a 2-
sided test with 5% level of significance. Assuming a dropout rate of 11%, approximately 
409 patients will be enrolled in the study. 

Visit number correction 

Screening period was changed from “Visit 1” to “Visit 0” 

Visit 1 was amended to Visit 0 in Exclusion criteria: “Patients who have not achieved 
an acceptable spirometry result at (Visit 10) in accordance with American Thoracic 
Society (ATS)/ European Respiratory Society (ERS) criteria for acceptability and 
repeatability.”

Abbreviations in blood chemistry section were defined 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. The changes described 
in this amended protocol are non-substantial and do not require IRB/IEC approval prior to 
implementation.
 


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Rationale for Amendment 5 (13-Aug-2018)
This amendment has been prepared to correct the sample size calculation error in amendment 
04. Changes to the Protocol:

Due to low enrollment rate, sample size will be reduced to 173 patients in each treatment 
arm to a total of 346 patients, and the expected treatment difference between QVA149 
110/50 µg once daily and tiotropium 18 µg was changed from 80 mL to 82 mL of pre-
dose trough FEV1 (L) after 12 weeks of treatment, in order to achieve 80% power on a 2-
sided test with 5% level of significance. Assuming a dropout rate of 11%, approximately 
389 patients will be enrolled in the study. 
 


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1
Introduction
1.1
Background 
Chronic Obstructive Pulmonary Disease (COPD) is characterized by persistent airflow 
limitation that is usually progressive and associated with an enhanced chronic inflammatory 
response in the airways and the lung to noxious particles or gases. It is a leading cause of 
morbidity and mortality worldwide and results in an economic and social burden that is both 
substantial and increasing. The prevalence and burden of COPD are projected to increase in 
the coming decades due to continued exposure to COPD risk factors and the changing age 
structure of the world’s population with more people living longer. Goals for treatment of 
stable COPD are to reduce symptoms and future risks. Pharmacological therapy in COPD is 
used to relieve symptoms, reduce the frequency and severity of exacerbations, and improve 
health status and exercise tolerance. The Global Initiative for Chronic Obstructive Lung 
Disease (GOLD) guidelines describe that the selection of treatment regimen needs to be 
patient-specific as the relationship between severity of symptoms, airflow limitation, and 
severity of exacerbations will differ between patients (GOLD Guidelines, 2015). 
Bronchodilator medications are central to symptom management in COPD. According to local 
market research data in Korea (Ipsos Korea 2014), 70 to 80% of COPD patients using an
inhaled mono-bronchodilator still have the same or more symptoms despite treatment 
compared to when they were first diagnosed. A similar observation was reported in a primary 
care setting in the United Kingdom (UK) where a high proportion of GOLD Stage 2 COPD 
patients were symptomatic on their current treatment management (Price et al 2014).
Tiotropium is the most widely used mono-bronchodilator in Korea. Combining 
bronchodilators of different pharmacological classes may improve efficacy and decrease the 
risk of side effects compared to increasing the dose of a single bronchodilator. The GOLD 
guidelines recommend the combined use of short-acting beta2 agonists (SABAs) or long-
acting beta2 agonists (LABAs) and anticholinergics if symptoms are not improved with single 
agents (GOLD Guidelines, 2015). 
QVA149 is a novel, inhaled fixed dose dual bronchodilator combination of the LABA
indacaterol (QAB149) and the long acting muscarinic antagonist (LAMA) glycopyrronium 
(NVA237) for once-daily maintenance treatment of COPD. QVA149 was first marketed in 
Europe and Japan in 2013 and has since been marketed in many other countries worldwide 
including South Korea (since May 2014). QVA149 was the first once-daily dual 
bronchodilator to gain European Commission approval in Sep 2013 as a maintenance 
bronchodilator treatment to relieve symptoms in adult patients with COPD. In Japan, once-
daily QVA149 (glycopyrronium 50 µg/indacaterol 110 µg) delivered through the Breezhaler®
device, was simultaneously approved in Sep 2013 for the relief of various symptoms due to 
airway obstruction in COPD. The approvals of QVA149 in Europe and Japan were based on 
the comprehensive IGNITE Phase III clinical trial program, one of the largest international 
trial programs in COPD comprising 11 studies in total with more than 10,000 patients from 
52 countries. 
 


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The Phase III clinical trials have shown that QVA149 provides significant and sustained 
improvement in lung function and health status compared with its mono components and 
tiotropium while having a similar safety profile (Bateman et al 2013, Beeh et al 2014,
Wedzicha et al 2013).
In this study, the efficacy and safety of QVA149 will be compared to that of tiotropium in 
COPD patients with mild to moderate airflow limitation with low exacerbation risk (Patient 
Group B by GOLD Guideline 2015) and who are currently receiving tiotropium but still 
symptomatic, which is defined as COPD assessment test (CAT) scores ≥10. According to 
GOLD guideline 2015, CAT scores ≥10 are associated with significantly impaired health
status. Patients will be randomized and treated with either QVA149 or tiotropium 
monotherapy for 12 weeks. 
1.2
Purpose 
The purpose of this Phase IV study is to show that QVA149 (110/50 μg) once daily results in 
better lung function and airflow compared to tiotropium 18 μg once daily in patients with mild 
to moderate symptomatic COPD; and to assess the effect of both treatments on symptom 
burden, breathlessness, and use of rescue medication in these patients.
2
Study objectives
2.1
Primary and key secondary objectives
To demonstrate superiority of QVA149 (110/50 μg) once daily compared to tiotropium 18 μg
once daily in terms of trough forced expiratory volume in 1 second (FEV1) (mean of 45 min 
and 15 min pre-dose) following 12 weeks of treatment in mild to moderate symptomatic 
COPD patients. 
2.2
Secondary objectives
To evaluate the effect of QVA149 (110/50 μg) as compared to tiotropium 18μg on:

Pre-dose trough FEV1 at Week 4.

Transitional dyspnea index (TDI) focal score at Week 12.

Symptom control as assessed by total CAT score at Week 12.

Rescue medication used reported by the patients at Week 12. 

Safety and tolerability.
 


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3
Investigational plan
3.1
Study design
This is a randomized, multicenter, open-label, parallel-group, 12-week study to assess the 
efficacy and safety of QVA149 (indacaterol maleate/glycopyrronium bromide) versus 
tiotropium in symptomatic mild to moderate COPD patients. A screening period of 3 weeks 
(21 days) will be used to assess patient eligibility. At the Baseline visit (Visit 1/ Day 1), 
eligible patients will be randomized to one of the following treatment groups and treated for 
12 weeks:

QVA149 (110/50 μg once daily)

tiotropium 18 μg once daily.
The assessment to address the primary objective will be performed at Week 12. The study 
design is presented in Figure 3-1. Further details are provided below. 
Figure 3-1
Study design
Screening Period (Day -21 to Day -1)
During the 21-day screening period (Visit 0), informed consent will be obtained and 
inclusion/exclusion criteria will be assessed. Current COPD medications will be reviewed. If 
the patient is taking a COPD therapy prohibited by the protocol, that COPD therapy will be 
adjusted to an allowable COPD therapy. Patient demographics, medical history including 
history of cardiovascular risk factors, COPD exacerbation history as well as smoking history 
will be collected. Vital signs will be checked and a 12-lead electrocardiogram (ECG) will be 
performed. Furthermore, blood and urine samples will be collected for analysis and a
Randomized Treatment Period
≥3 months of 
tiotropium 18 µg 
monotherapy for 
COPD treatment
tiotropium 18 µg once daily via Handihaler®
QVA149 110/50 µg once daily via Breezhaler®
Screening Period
Day -21 to Day -1 
ICF
Visit 2
Day 28 ± 7
Visit 3
Day 84 ± 7
Visit 1
Day 1
Randomization
 


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pregnancy test with urine sample will be applied at this visit. Patients are required to be taking 
tiotropium monotherapy for ≥ 3 months prior to randomization.
Spirometry measurements will be taken to assess patient eligibility for the study and to assess 
the post-bronchodilation FEV1 10 to 15 mins after inhalation of 4 x 100 μg puffs of 
salbutamol. 
To allow for a reliable reversibility test and classification of airflow limitation according to 
GOLD 2015 (Appendix 4), the test has to be performed 24 hours after the last dose inhalation 
of tiotropium.
At the start of screening (Visit 0), patients will be provided with salbutamol inhaler, which 
they will be instructed to use throughout the study as rescue medication. Patients will be 
asked, where possible, not to take rescue medication within the 6 hours prior to and during the 
study visit. If rescue medication is taken within 6 hours, the visit should be re-scheduled and 
the number of puffs of rescue medication taken recorded in the patient diary (Appendix 3). 
Any rescue medication taken within the study visit will be recorded in the spirometer and the 
number of puffs will be recorded in the patient diary. 
A patient diary (Appendix 3) will be distributed and patients will be asked to document the 
use of rescue medication throughout the study.
The CAT will be collected; patients must have a CAT score ≥10 to be included in this study.
The interval between Visit 0 and Visit 1 is an individual screening period used to determine 
eligibility of the patients for the study and is dependent on the current medication and the time 
it takes until the laboratory evaluation is available.
Randomization
At Visit 1 (Day 1), patient eligibility will be checked versus the study inclusion/exclusion 
criteria. Medical history and medication history will be checked and current medications will 
be reviewed and adjusted. A physical examination will be performed and vital signs will be 
checked. 
The CAT will be collected; patients must have a CAT score ≥10 to be included in this study.
At Visit 1 (Day 1), spirometry measurements will be taken to assess the FEV1 between 45 and 
15 minutes prior to dosing. The first dose of study drug will be administered in the clinic at 
Visit 1 (Day 1). Patients will be instructed not to take their study medication at home on the 
day of the clinic visit as this will be administered in the clinic.
All patients should refrain from strenuous activity, avoid caffeine and alcohol for 4 hours 
prior to spirometry and should not smoke at least 1 hour before spirometry.
A baseline dyspnea index (BDI) assessment
will also be performed. All patients 
who meet the inclusion/exclusion eligibility criteria will be randomized equally to receive 
either QVA149 or tiotropium. 
Patients will be required to take their study drug once a day between 08:00 am and 11:00 am. 
Subsequent clinic visits should be scheduled such that individual patients are re-assessed at 
approximately the same time each day. 
 


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Patients will attend a further 2 visits on Day 28 (Visit 2) and Day 84 (Visit 3) and should be 
seen for all visits on the designated day or as close as possible to that day. Visit window ±
7 days will be allowed. Spirometry tests to assess the FEV1 between 45 and 15 minutes prior 
to dosing will be performed for all patients at Visit 2 and Visit 3 (primary endpoint). In 
addition, TDI and CAT assessments will be performed at these visits. Other assessments will 
be performed as outlined in Table 6-1. 
 
 
3.2
Rationale of study design
QVA149 is marketed in Korea (as well as the UK, Japan and other countries worldwide) as a
once-daily bronchodilator for the maintenance treatment of COPD.
A multicenter, randomized, open-label parallel design was considered appropriate to 
demonstrate the superiority of QVA149 (110/50 µg once daily) versus tiotropium (18 µg once 
daily) in patients with mild to moderate symptomatic COPD in this Phase IV study. 
3.3
Rationale of dose/regimen, route of administration and 
duration of treatment
The dose/regimen and route of administration of QVA149 in this study is indacaterol
maleate/glycopyrronium bromide 110/50 µg for once-daily inhalation using a single-dose dry 
powder inhaler (SDDPI) device is in accordance with the clinical trial program with QVA149 
and with the product label (Summary of Product Characteristics for XOTERNA ™ 
BREEZHALER®). The selection of QVA149 dose in the clinical trial program (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 was reduced to 110 µg. 
The tiotropium dose of 18 µg once daily selected for this study is the licensed dose and the 
standard treatment for COPD. The duration of 12 weeks is considered an adequate time to 
establish the superiority of QVA149 over tiotropium as it is a clinically meaningful period to 
assess lung function. Furthermore, patients assigned to QVA149 will already have received 
tiotropium for at least 12 weeks prior to entering the study, which is long enough to allow
patient familiarization with both treatments 
 
.
3.4
Rationale for choice of comparator
According to the current GOLD guidelines (GOLD Guidelines, 2015) one of the first choice 
treatment options for COPD patients categorized in Group B is monotherapy with a LAMA. 
This study will test the effect of an alternative therapy as recommended in the guidelines 
 


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consisting of a LABA/LAMA combination (QVA149) in terms of lung function 
 
 in patients who are symptomatic despite maintenance treatment with a LAMA. As 
tiotropium is currently the most widely used LAMA in COPD treatment in Korea, this drug 
was chosen as the most suitable comparator in this study.
3.5
Purpose and timing of interim analyses/design adaptations
Not applicable.
3.6
Risks and benefits
The latest Developmental Safety Update Report (DSUR: Issue 004) indicated no new benefits 
or safety concerns during the reporting period (25-Oct-2013 to 24-Oct-2014). The key 
benefits of QVA149 in patients with COPD, as reported in the latest DSUR, are as follows:

Improvement of lung function/bronchodilation (increase in FEV1).

Improvement of dyspnea (TDI).

Reduction of COPD symptoms (over treatment period).

Reduction of COPD exacerbations.

Improvement of health status (St. George’s Respiratory Questionnaire (SGRQ) total score).

Use of rescue medication (over treatment period).
Combining 2 bronchodilators with different pharmacodynamics properties has demonstrated 
enhanced efficacy compared with single agents and placebo without increasing adverse effects. 
QVA149, administered once-daily, provided superior improvements in lung function in 
comparison with placebo as well as its mono-components, indacaterol and glycopyrronium. 
Improvement in pre-dose trough FEV1 was both statistically and clinically significant 
(ε100 mL in COPD) over placebo; versus active comparators, it approached clinical 
significance. Furthermore, lung function improvements with QVA149 were superior in terms 
of peak FEV1 and, in a subset of patients monitored over 24 hours, throughout the day.
Similar findings were observed in all relevant subgroups analyzed. Improvements in lung 
function versus placebo were greater in patients with moderate versus severe COPD; however, 
statistically and clinically significant improvements in trough FEV1 were seen for both 
moderate and severe patient subgroups. Improvements in lung function were not influenced 
by patient age, sex or concurrent use of inhaled corticosteroids. Furthermore, these 
improvements in lung function were maintained throughout the 26-week and up to a 64-week
treatment period. The onset of action of QVA149 was confirmed to be rapid, with effects seen 
at 5 minutes after the first dose, similar to that of SABAs.
These beneficial effects of QVA149 on lung function were paralleled by statistically 
significant improvements in other clinically important endpoints: dyspnea, patient symptoms, 
health status and reduced rescue medication use. QVA149 was significantly superior to 
placebo for both the TDI and quality of life (QoL) measured by the SGRQ total score at 
Week 26 and up to 64 weeks; no other active treatment achieved a significant improvement in 
SGRQ versus placebo. Furthermore, a significantly higher proportion of patients on QVA149 
achieved a clinically meaningful improvement in TDI (> 1 unit) and SGRQ (> 4 units) versus 
placebo. In a study specifically designed to examine the effect of QVA149 on exacerbations, 
QVA149 significantly reduced the rate of moderate to severe COPD exacerbations by 12% 
 


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compared with NVA237 (study CQVA149A2304). Furthermore, QVA149 significantly 
reduced the rate of all exacerbations (mild/moderate/severe) as compared to NVA237 by 15%. 
The ‘Number Needed to Treat’ to prevent one additional moderate or severe exacerbation 
over 1 year in the QVA149 group was determined as 8 versus NVA237. Reducing the number 
of exacerbations substantially impacts on patient’s overall well-being and may affect disease 
progression.
The safety profile of QVA149 is determined by the safety associated with its monotherapy 
components, indacaterol and glycopyrronium. Thus, a safety review needs to consider both 
pharmacological classes, i.e. β2-adrenergic agonists as well as antimuscarinics. A desired 
outcome in combining bronchodilators with different pharmacodynamic properties would be 
an increase in the degree of bronchodilation without an increase in adverse effects. Under 
consideration of the importance of the cardio-cerebrovascular (CCV) safety concerns 
associated with the use of both β2-adrenergic agonists and antimuscarinics, the key risks of 
QVA149 in patients with COPD are as follows:

Cardiac arrhythmia.

Cardiac failure.

Cerebrovascular events.

Ischemic heart disease.

Myocardial infarction.

Atrial fibrillation/flutter.
In the development program to date, the rates between QVA149 and placebo were found to be 
balanced across all risks. All CCV risks are identified risks (as per the Risk Management 
Plan).
QVA149 combines different pharmacological mechanisms resulting in greater and more 
sustained bronchodilation as compared to monotherapy. This therapeutic principle may also 
decrease the risk of AEs associated with increasing doses of single bronchodilators, or other 
treatment options such as combinations with inhaled corticosteroids (ICS).
The key benefits of QVA149 in COPD patients continue to be statistically significant and 
clinically meaningful with respect to improvements of airway obstruction, relief of dyspnea, 
reduction of rescue medication use, improvements in QoL, and the reduction of COPD 
exacerbations. The degree of CCV risk for QVA149 is comparable to those of the
monotherapy components; no additive or potentiating effects have been observed or reported.
In summary, strong evidence from clinical trials support the concept that dual bronchodilation 
via QVA149 provides significantly improved clinical efficacy in patients with COPD as 
compared to monotherapy with LABAs or LAMAs. Of note, the safety profile of the fixed-
dose combination is comparable to that of the monotherapy components, indacaterol and 
glycopyrronium, and often not different from placebo. 
4
Population
The study population will consist of approximately 389 male and female adults aged 40 or 
older, with a confirmed clinical diagnosis of COPD and post-bronchodilator FEV1 ≥ 50% of 
 


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the predicted normal value and post-bronchodilator FEV1/FVC < 0.7 (COPD Grade 1 or 2 by 
severity of airflow limitation (GOLD Guidelines, 2015)) and a smoking history of at least 
10 pack years. 
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 adults aged ≥40 years, who have signed an Informed Consent Form (ICF) 
prior to initiation of any study-related procedure.
3. Confirmed diagnosis of COPD and post-bronchodilator FEV1 ≥ 50% of the predicted 
normal value and post-bronchodilator FEV1/FVC < 0.7 (COPD Grade 1 or 2 by severity 
of airflow limitation (GOLD Guidelines, 2015). 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. Patients with CAT score ≥10 at Visit 0 and Visit 1.
5. Patients who are on and have been on tiotropium 18 µg monotherapy for the past 3 months
prior to baseline (Visit 1).
6. 0 or 1 COPD exacerbation in the previous 12 months prior to baseline (Visit 1) (not 
leading to hospital admission). 
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.
General exclusion criteria
1. Treatment with any ICS in the 3 months prior to Visit 1.
2. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive human 
chorionic gonadotropin (hCG) laboratory test. 
3. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using effective methods of contraception during 
dosing of study treatment. Effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle) of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least 6 weeks before taking study treatment. In case 
of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment.

Male sterilization (at least 6 months prior to Screening). For female patients on the 
study, the vasectomized male partner should be the sole partner for that patient.
 


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
Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository.

Use of oral, injected or implanted hormonal methods of contraception or other forms 
of hormonal contraception that have comparable efficacy (failure rate < 1%), for 
example hormone vaginal ring or transdermal hormone contraception.

Placement of an intrauterine device (IUD) or intrauterine system (IUS).
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy) or tubal ligation at least 6 weeks ago. In 
the case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment is she considered not of child 
bearing potential. 
4. Presence of any contraindication, warning, precaution, hypersensitivity to LABA and 
LAMA.
5. History or current diagnosis of clinically significant ECG abnormalities including:

Concomitant clinically significant cardiac arrhythmias, e.g. sustained ventricular 
tachycardia, and clinically significant second or third degree AV block without a 
pacemaker.

History of familial long QT syndrome or known family history of Torsades de 
Pointes. 
6. Patients who have not achieved an acceptable spirometry result at (Visit 0) in accordance 
with American Thoracic Society (ATS)/ European Respiratory Society (ERS) criteria for
acceptability and repeatability.
7. Patients with Type I or uncontrolled Type II diabetes.
8. Patients with narrow-angle glaucoma, symptomatic prostatic hyperplasia or bladder-neck 
obstruction or moderate to severe renal impairment or urinary retention. (Patients with a 
transurethral resection of prostate (TURP) are excluded from the study. Patients who have 
undergone full re-section of the prostate may be considered for the study, as well as 
patients who are asymptomatic and stable on pharmacological treatment for the condition).
9. History of malignancy of any organ system, treated or untreated, within the past 5 years, 
regardless of whether there is evidence of local recurrence or metastases with the 
exception of localized basal cell carcinoma of the skin.
10. Patients with a history of clinically significant diseases that, in the opinion of the 
Investigator, would put the safety of the patients at risk through study participation, or 
would compromise patient compliance or preclude completion of the study.
11. Uncontrolled hypothyroidism and hyperthyroidism, hypokalemia.
12. Patients with neurological, endocrine, immunological, psychiatric, gastrointestinal, hepatic, 
or hematological abnormalities which, in the opinion of the Investigator, could interfere 
with the assessment of the efficacy and safety of the study treatment. 
 


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13. Patients who are, in the opinion of the investigator, known to be unreliable or non-
compliant. 
COPD specific exclusion criteria
1. Patients requiring long-term oxygen therapy prescribed for > 12 hours per day. 
2. COPD exacerbation between Visit 0 and 1. Patients can be re-screened after a minimum of 
6 weeks after resolution of the exacerbation if the exacerbation did not require 
hospitalization. If a patient has an exacerbation that requires hospitalization between 
Visit 0 and Visit 1 then he/she is not eligible to re-screen.
3. Onset of respiratory symptoms, including a COPD diagnosis prior to age 40 years. 
4. Patients with a history of respiratory infection within 4 weeks prior to Visit 0. Patients 
who develop a respiratory tract infection between Screening and prior to treatment will not 
be eligible but will be permitted to be re-enrolled 4 weeks after the resolution of the 
respiratory tract infection.
5. Concomitant pulmonary disease (e.g. pulmonary tuberculosis (unless confirmed by chest 
X-ray to be no longer active), lung fibrosis, sarcoidosis, interstitial lung disease, primary 
pulmonary hypertension, clinically significant bronchiectasis). 
6. Patients with lung lobectomy, or lung volume reduction or lung transplantation
7. Prior or current diagnosis of asthma.
Medication exclusion
1. Treatments for COPD and allied conditions: the following class of medications should be 
washed out prior to randomization (Visit 1) or prohibited during the study period (see 
Table 5-1).
2. Patients who need the following treatments for COPD and allied conditions (e.g. allergic 
rhinitis) unless they have been stabilized for the specified period and the stated conditions 
have been met (see Table 5-2).
3. Patients who have had live attenuated vaccinations within 30 days prior to the screening 
visit. Inactivated influenza vaccination, pneumococcal vaccination or any other inactivated 
vaccine is acceptable provided it is not administered within 48 hours prior to screening 
and randomization visits.
4. Use of other investigational drugs at the time of enrollment, or within 30 days or 
5 half-lives of Visit 1, whichever is longer.
5. Patients unable to use a dry powder inhaler (e.g. SDDPI, HandiHaler®) device or 
pressurized metered dose inhaler (MDI) (rescue medication).
5
Treatment
5.1
Protocol requested treatment
5.1.1
Investigational treatment

QVA149 110/50 µg capsules once daily for inhalation supplied in blisters, delivered via 
the manufacturer’s proprietary inhalation device. 
 


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QVA149 capsules will be supplied by Novartis Drug Supply Management as open-label
medication packs, providing sufficient quantity of medication to ensure therapy according 
to the protocol. Under no circumstances is an alternative inhalation device to be used for the 
administration of QVA149 capsules; the manufacturer’s proprietary inhalation device.
5.1.2
Reference treatment

tiotropium 18 µg capsules once daily for inhalation supplied in commercially available 
blisters, delivered via proprietary inhaler (HandiHaler®). 
A sufficient quantity of open-label medication will be provided to each patient to ensure 
therapy according to the protocol. Only the HandiHaler® device should be used for the 
administration of tiotropium. 
5.1.3
Additional study treatment
Rescue medication with salbutamol, a SABA, is permitted in this study (Section 5.5.6). At
Visit 0, all patients will be provided with a SABA (salbutamol) which they will be instructed
to use throughout the study as rescue medication on an ‘as needed basis’. Patients should be 
instructed to abstain from taking rescue salbutamol within 6 hours of the start of each visit
unless absolutely necessary. If rescue medication is taken within 6 hours of a spirometry visit,
the visit should be re-scheduled and the number of puffs of rescue medication taken recorded
in the patient diary.
Use of rescue medication (number of puffs taken in the previous 24 hours) will be recorded 
daily in the morning by the patient in the patient diary. 
Salbutamol (100 µg will be supplied to the investigator sites locally by Novartis.
Concomitant medications and prohibited medications are described in Section 5.5.7 and 
Section 5.5.8, respectively. 
5.2
Treatment arms
Patients will be assigned to treatment for 12 weeks with either open-label QVA149 110/50 µg 
or tiotropium 18 µg in a 1:1 ratio as follows:

Open-label QVA149 110/50 µg once daily delivered via SDDPI.

tiotropium 18 µg once daily delivered via the manufacturer’s proprietary inhalation device 
(Handihaler®).
5.3
Treatment assignment, randomization
At Visit 1, all eligible patients will be randomized via the interactive randomized technology 
(IRT) to one of the treatment arms. The investigator or his/her delegate will contact the IRT 
after confirming that the patient fulfills all the inclusion/exclusion criteria. The IRT will 
assign a randomization number to the patient, which will be used to link the patient to a 
treatment arm and will specify a unique medication number for the first package of study drug 
to be dispensed to the patient. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
 


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randomization list will be produced by the IRT provider using a validated system that 
automates the random assignment of patient numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers.
A separate medication list will be produced by or under the responsibility of Novartis Drug 
Supply Management using a validated system that automates the random assignment of 
medication numbers to study drug packs containing each of the study drugs.
The randomization scheme for patients will be reviewed and approved by a qualified team 
member.
5.4
Treatment blinding 
Not applicable. 
5.5
Treating the patient
5.5.1
Patient numbering
Each patient is uniquely identified by a Patient Number which is composed by the center 
number assigned by Novartis and a sequential number assigned by the investigator. Once 
assigned to a patient, the Patient Number will not be reused. 
Upon signing the ICF, the patient is assigned the next sequential number by the investigator. 
The investigator or his/her staff will contact the IRT and provide the requested identifying 
information for the patient to register them into the IRT. The site should select the eCRF book 
with a matching Patient Number from the Electronic Data Capture (EDC) system to enter data. 
If the patient fails to be treated for any reason, the IRT must be notified within 2 days that the 
patient was not treated. The reason for not being treated will be recorded in the Screening 
Phase Disposition eCRF.
5.5.2
Dispensing the investigational treatment
Each study site will be supplied by Novartis with the following open-label study treatment:

QVA149 110/50 µg will be supplied as medication packs containing blister strips of 
capsules and one SDDPI device.

Tiotropium 18 µg will be supplied as medication packs containing blister strips of 
capsules and one HandiHaler® device.
Sufficient medication will be dispensed at Visit 1 (Day 1) and Visit 2 (Day 28) to cover the 
treatment period between patient visits and to allow for late visits and other unforeseen events.
The investigational treatment packaging has a 2-part label. A unique medication (kit) number 
is printed on each part of this label which corresponds to one of the 2 treatments. Investigator 
staff will identify the investigational treatment package(s) to dispense to the patient by 
contacting the IRT and obtaining the medication number(s). Immediately before dispensing 
the package to the patient, investigator staff will detach the outer part of the label from the 
packaging and affix it to the source document (Drug Label Form) for that patient’s unique 
patient number. 
 


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Capsules should only be removed from the blister immediately before dosing.
At randomization - Visit 1
Investigator staff will contact the IRT to randomize the patient and identify the specific 
medication pack number assigned to patients randomized to the QVA149 or tiotropium. 
One open-label medication box containing QVA149 or tiotropium will be dispensed at this 
visit for patients randomized to QVA149 or tiotropium, respectively.
Visit 2 and Visit 3
The patient’s study drug supplies should be checked at each visit and the Drug Accountability 
Log (Section 5.5.3) completed for that patient, as necessary.
Additional study drug should be dispensed when scheduled according to the Assessment 
Schedule (Table 6-1) and at other times, if required, due to unexpected events. Study center 
personnel should ensure that patients always have more than sufficient study medication to 
last until the next scheduled visit and must always call the IRT to obtain the specific 
medication pack numbers to be issued before dispensing supplies.
The duration between visits is 4 weeks (Visit 1 to Visit 2) and up to 8 weeks (Visit 2 to 
Visit 3). Sufficient tiotropium medication packs must be dispensed to last the duration 
between visits.
One SDDPI inhaler will be included in the QVA149 medication packs.
One Handihaler® inhaler will be included in the tiotropium medication packs.
At Visit 1 and Visit 2, all patients will be provided with 2 packs of study medication 
according to randomized treatment arms. At Visit 2, patients must bring back all used 
and unused study medication. After checking compliance, unused study medication will 
be returned to the patient. At Visit 3, all used and unused study medication must be 
returned.
5.5.3
Handling of study treatment
5.5.3.1
Handling of investigational treatment
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and 
designees have access. Upon receipt, all investigational treatment should be stored according 
to the instructions specified on the labels. Clinical supplies are to be dispensed only in 
accordance with the protocol.
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the study treatment but no information 
about the patient except for the medication number. Study treatment should not be stored 
above 25°C and should be protected from moisture.
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 
 


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will be asked to return all unused investigational treatment and packaging at the end of the 
study or at the time of discontinuation of investigational treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator will return all unused investigational treatment, packaging, drug labels, and a 
copy of the completed drug accountability log to the Novartis monitor or to the Novartis 
address provided in the investigator folder at each site.
5.5.4
Instructions for prescribing and taking study treatment
QVA149 110/50 µg and tiotropium bromide 18 µg will be provided as open-label study 
treatment.
Medication labels will comply with the legal requirements and be printed in the local 
language. They will supply no information about the patient. The storage conditions for study 
drug will be described on the medication label.
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 
08:00 and 11:00. Patients must be instructed to withhold the use of SABA (rescue medication) 
for at least 6 hours prior to all clinic visits, unless the use is absolutely necessary.
At Visit 1 (Day 1), patients will be randomized to one of the 2 treatment arms.
Patients will be instructed on how to use the study treatment SDDPIs. The instructions for use 
for the SDDPI for QVA149 110/50 µg administration are presented in Appendix 6. The 
instructions for use for the proprietary inhaler (Handihaler®) for tiotropium bromide 18 µg 
administration are presented in Appendix 7. 
At Visit 2 and Visit 3 (randomized treatment) the study medication will be administered in the 
clinic by the investigator between 08:00 and 11:00 h, after completion of all pre-dose 
procedures.
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 used and unused study medication must be returned by the patient at Visit 2 and Visit 3. 
The date and time of dose administration at each clinic visit will be recorded on the Dosage 
Administration Record eCRF.
All medication kits assigned by the IRT will be recorded in the IRT. 
5.5.5
Permitted dose adjustments and interruptions of study treatment
No adjustments to the study drug dosage or dosing scheme are permitted, other than 
temporarily interrupting study medication during the treatment period due to an AE (including 
mild COPD exacerbations), if necessary. 
However, any interruption of study medication should be for the shortest time period possible 
and any interruption of study medication for more than 5 consecutive days should be 
 


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discussed with the Novartis Medical Monitor to determine the patient’s eligibility to continue 
study participation.
These changes must be recorded on the Dosage Administration Record eCRF.
5.5.6
Rescue medication
At Visit 0, all patients will be provided with a salbutamol (containing chlorofluorocarbon-free 
propellant – hydrofluorocarbon 134a) inhaler, which they will be instructed to use throughout 
the study as rescue medication. Nebulized albuterol is not allowed as a rescue medication. 
Salbutamol (100 µg) will be supplied to the investigator sites locally by Novartis. Patients 
should be instructed to abstain from taking rescue salbutamol within 6 hours of the start of 
each visit unless absolutely necessary.
If rescue medication is taken within 6 hours prior to spirometry at Visit 1 or prior to 
administering study medication at any of the scheduled visits, the visit should be rescheduled 
to the next possible day. The investigator must use their judgment when deciding how many 
times a visit for an individual patient should be rescheduled for Visit 2 and Visit 3.
In the event that a patient uses a dose of rescue medication after taking study medication at 
that visit or during any other visits then the visit should continue as planned but the 
approximate time taken will be captured through the spirometer if taken during a study visit 
and the number of puffs collected in the Patient Diary.
5.5.7
Concomitant treatment
All medications and significant non-drug therapies administered 30 days prior to Visit 0 
(Day -21 to Day -1) and Visit 1 (Day 1) will be recorded in the eCRF. 
The Investigator should instruct the patient to notify the study site about any new medications 
he/she takes after the start of the study drug. All medications and significant non-drug 
therapies (including physical therapy and blood transfusions) administered after the patient 
starts treatment with study drug must be listed on the Concomitant medications/Significant 
non-drug therapies after start of study drug eCRF.
5.5.8
Prohibited treatment
The classes of medications listed in Table 5-1 are NOT allowed to be taken during the 
study unless part of the study medication e.g. tiotropium. Some medications (Table 5-2)
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 medications
Class of medication
Minimum washout period prior 
to Randomization (Visit 1)
Non-potassium sparing diuretics (unless administered as a 
fixed dose combination with a potassium conserving drug)
7 days
Cardiac antiarrhythmics class Ia, III
7 days, 
 


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Amiodarone 3 months
Any other drug with potential to significantly prolong the QT 
interval (e.g. mizolastin)
(macrolide antibiotics recommended under Section 6.4.6 for 
the treatment of COPD exacerbation are allowed)
14 days or 5 half-lives, whichever  
is longer 
Other investigational drugs
(Please note that investigational drugs should be washed out 
prior to V1)
30 days or 5 half-lives, whichever 
is longer
Systemic non-selective beta- blocking agents
7 days
Tricyclic antidepressants, Serotonin Norepinephrine reuptake 
inhibitors (SNRIs), Monoamine oxidase inhibitors
14 days
Other noradrenaline reuptake inhibitors
7 days
Theophylline and other Xanthines
7 days
Systemic anticholinergics
7 days
Short acting anticholinergics
8 hours
Short-acting β2 agonists (other than study rescue medication) 6 hours
Phosphodiesterase inhibitors (PDE-4), (e.g. roflumilast)
7 days
Parenteral or oral corticosteroids (allowed for the treatment of 
COPD exacerbation but should be discontinued at the 
resolution of the exacerbation)
30 days 
Intra-muscular depot corticosteroids 
3 months
Table 5-2
Medication allowed under certain conditions
Class of medication
Condition
Selective serotonin reuptake inhibitors
(SSRIs)
Treatment regimen has been stable for at least one 
month prior to screening visit and during the study
Screening ECG is normal with no clinical evidence of 
prior ECG abnormalities
Inactivated vaccine
Not administered within 48 hours prior to a study visit
Cromoglycate, Leukotriene antagonists, 
Ketotifen, Nedocromil
In constant doses and dose regimens for at least
5 days prior to Screening
5.5.9
Discontinuation of study treatment and premature patient withdrawal
Patients who discontinue their randomized study regimen should remain in the study, if 
possible, and receive standard therapy, according to local practice, until completing the study 
at Week 12. Visits and assessments for such patients are described in Table 6-1. 
The 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 the 
patient.
Study treatment must be discontinued and the patient withdrawn from the trial under the 
following circumstances:
 


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
Withdrawal of informed consent.

Adverse events for which continued inhalation of the study drug would be detrimental.

Abnormal test procedure results indicating risk for the patient on continued inhalation of 
the study drug.

Pregnancy.

If a COPD exacerbation is being treated with intra-muscular depot corticosteroids (e.g. 
Depo-Medirone®).
Protocol deviations should not lead to patient withdrawal unless they indicate a significant 
risk to the patient’s safety.
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.
If a patient experiences a COPD exacerbation he/she will be treated as deemed appropriate by 
the investigator. Guidance for treating exacerbations is described under Section 6.4.6.
Following treatment for the exacerbation the patient will be expected to continue in the study 
if, in the opinion of the investigator, he/she can be safely returned to their pre-exacerbation 
concomitant medications.
In addition to these requirements for study drug discontinuation, the Investigator should 
discontinue study treatment for a given patient and/or withdraw the patient from study if, on 
balance, he/she believes that continuation would be detrimental to the patient’s well-being.
Patients may voluntarily withdraw from the study for any reason at any time. They may be 
considered withdrawn if they state an intention to withdraw, or fail to return for visits, or 
become lost to follow up for any other reason.
The Investigator must also notify the IRT of the premature withdrawal.
For patients who are lost to follow-up (i.e. those patients whose status is unclear because they 
fail to appear for study visits without stating an intention to withdraw), the investigator should 
show “due diligence” by documenting in the source documents steps taken to contact the 
patient, e.g. dates of telephone calls, registered letters, etc.
Patients who are prematurely withdrawn from the study will not be replaced by an equal 
number of newly enrolled patients.
5.5.10
Emergency breaking of treatment assignment
Not applicable.
5.5.11
Study completion and post-study treatment
Completion of the study for an individual patient will be when he/she has completed 12 weeks 
of treatment (through Visit 3). Completion of the study will be when all randomized patients 
have completed the study or have been prematurely withdrawn. 
 


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Patients completing the 12-week treatment period will not be given further access to the study 
drug.
The Investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care.
When the patient has completed all scheduled study assessments, the Investigator must call 
the IRT to record the patient completion.
5.5.12
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and treated as described in Section 5.5.9
(premature patient withdrawal). The Investigator may be informed of additional procedures to 
be followed in order to ensure that adequate consideration is given to the protection of the 
patient’s interests. The investigator will be responsible for informing Institutional Review 
Board/Independent Ethics Committee/Research Ethics Board (IRB/IEC/REB) 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 or S” the visits at which they 
are performed. All data obtained from these assessments must be supported in the patient’s 
source documentation. At a minimum, patients will be contacted for safety evaluations 
(AEs/SAEs, death) during the 30 days following the last study visit. Documentation of 
attempts to contact the patient should be recorded in the source documentation. 
Patients should be seen for all visits on the designated day or as close to it as possible. Visit 
window±7 days will be allowed. These visits must be scheduled to start in the morning 
between 8:00 and 11:00 h. All data obtained from these assessments must be supported in the 
patient’s source documentation.
All patients are screened for study suitability. At Visit 0, informed consent is obtained and 
patients registered with the IRT by center personnel. The current COPD medications are 
reviewed and if necessary arrangements made to adjust prohibited COPD therapy to allowable 
COPD therapy. Medical history including history of cardiovascular risk factors will also be 
collected at this visit. Patients will undergo investigations including beta-2 agonist 
reversibility tests. 
Patients who meet the inclusion/exclusion criteria at the screening visit will be given a patient 
diary to capture daily symptoms and rescue medication use at Visit 0.
At Visit 1, patients who still fulfil the inclusion/exclusion criteria will be randomized to 
QVA149 110/50 µg or tiotropium 18 µg once daily via the IRT.
Patients must be reminded not to take study medication prior to ALL clinic visits, as this dose 
will be administered in clinic after all pre-dose measurements have been performed.
This data is to be captured on the eCRF.
The site must register the patient’s premature withdrawal with the IRT. 
 


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When the following assessments are scheduled to be performed at the same time point,
the order of priority will be as follows: CAT, ECG, pulse rate, blood pressure, and blood 
sample/urine samples, spirometry. Spirometry measurements should occur at the scheduled
time points and other tests should be performed as close as possible to the spirometry times.
Patients will be asked to refrain from the following prior to spirometry:

Caffeine-containing beverages (such as coffee, tea, cola) and food (such as chocolate), and 
ice cold beverage for 4 hours prior to spirometry.

Alcohol for 4 hours prior to spirometry.

Strenuous physical activity for 12 hours prior to spirometry.

Exposure to environmental smoke, dust or areas with strong odors.
Patients should not smoke for at least 1 hour before the scheduled time of the clinic visit 
and should be asked to refrain from smoking during the visit until all assessments are 
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Table 6-1
Assessment schedule
Study Period
Screen
RND
Treatment
PSW
Visit Number
0
1
2
3
Visit
SCR
BL
W4
W12
Day
-21 to -1
1
28 ±7
84 ± 7
Informed consent form1
X
Medical history and medication history
X
X
Height and Weight2
X
X
X
Smoking history
X
Review/adjustment of current medication
X
X
Pregnancy test3
X
X
X
Laboratory evaluations4
X
X
X
X
Demographics
X
Vital signs5
X
X
X
X
X
12-lead ECG
X
X
X
X
Inclusion/exclusion criteria
X
X
Reversibility test 
X
Issue & instruct on paper diary
X
Review diary 
X
X
X
X
Spirometry
X
X
X
X
Provide rescue medication
X
As needed
Check use of rescue medication
X
X
X
X
Randomization
X
Instruction on inhaler usage
X
Study drug dose administration record
X
X
X
BDI assessment
X
TDI assessment
X
X
X
CAT assessment
X
X
X
X
X
COPD exacerbation
X
X
X
X
X
Adverse events6
X
X
X
X
Concomitant medication
X
X
X
X
Surgical and medical procedures
As needed
Record any patient deaths
As applicable
Withdrawal of informed consent
As needed
Week 12 period completion7
As needed
X
Physical examination
S
S
S
IRT call
S
S
S
S
S
Dispense study treatment
S
S
 


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Abbreviations: BDI: baseline dyspnea index, CAT: COPD assessment test, COPD: chronic obstructive 
pulmonary disease, ECG: electrocardiogram, IRT: interactive randomized technology, 
 
, PSW: premature study withdrawal, RND: randomization, 
RDN: randomization, TDI: transitional dyspnea index
X=assessment for all patients in study regardless of on or off randomized study regimen, to be recorded in 
clinical data base
S=assessment to be recorded on source documentation
1. Informed consent should be obtained prior to performing any study-related procedures.
2. Height and weight will be recorded on Day 1. Weight will be recorded again at Week 12 and in the event of 
premature study withdrawal.
3. It will be conducted only in women of childbearing potential and the urine test can be performed according 
to local practice. Local result must be available and negative prior to randomization.
4. Laboratory evaluations: 
Hematology: white blood cells (WBC) (total and differential), red blood cells, hemoglobin, hematocrit, 
platelets.
Blood chemistry: Albumin, alkaline phosphatase, total bilirubin, blood urea nitrogen (BUN), calcium, total 
cholesterol, lactate dehydrogenase (LDH), magnesium, phosphate, sodium, potassium, creatinine, γ-GT, 
blood glucose, total protein, aspartate aminotransferase (AST), alanine aminotransferase (ALT), low-
density lipoprotein-cholesterol (LDL-C) and high-density lipoprotein-cholesterol (HDL-C).
Urinalysis: pH, specific gravity, protein, glucose, ketones, bilirubin, blood, urobilinogen, nitrate, and WBC.
5. For vital signs, systolic blood pressure, diastolic blood pressure and heart rate will be assessed.
6. Every SAE, occurring after 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).
7. All subjects are expected to continue in the study to Week12 regardless of whether they are on or off 
randomized study regimen, if subjects discontinue randomized study regimen they should continue on 
standard of care and attend study visits to W12, if possible. For all subjects completing the study to Week 
12 or discontinuing from the study prior to Week 12, the W12 Period completion form should be 
completed, regardless of on or off-treatment status.
6.1
Information to be collected on screening failures
All patients who have signed informed consent but not entered into the next period will have 
the study completion page for the Screening period, demographics (date of birth, age, sex, 
race and ethnicity), inclusion/exclusion and SAE data collected. The Patient Number and 
primary reason for not continuing the study will also be recorded. Adverse events that are not 
SAEs will be followed by the Investigator and collected only in the source data.
All patients who have signed informed consent and are entered into the next period of the 
study will have all AEs occurring after informed consent is signed recorded on the AE
eCRF.
Investigators will have the discretion to record abnormal test findings on the medical history 
eCRF whenever in their judgment, the test abnormality occurred prior to the informed consent 
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6.2
Patient demographics/other baseline characteristics
The following demographics / baseline characteristics will be collected and recorded in the 
eCRF:

Date of birth

Sex

Height

Weight

Date of diagnosis of COPD

Relevant medical history. History of cardiovascular risk factors will also be collected.

Smoking history (1 pack year = 20 cigarettes/day × 1 year or 10 cigarettes/day × 2 years)

Prior concomitant medications (COPD related and non-COPD related)

Baseline physical examination (not databased other than in the context of relevant medical 
history)

Vital signs

ECG findings

Screening spirometry (FEV1 and FVC).

FEV1 and FVC after reversibility test with 4 × 100 µg puffs of salbutamol.
6.3
Treatment exposure and compliance
The time of study drug administration at each dosing visit will be collected on the eCRF. For 
assessments where spirometry is performed, the time of dosing is to be taken from the 
spirometer. The date of last use of study drug will be recorded on the study phase 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 and HandiHaler® as well as from the information provided by the 
patient/caregiver. 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 Visit 2 and 3 for each patient on the eCRF.
In addition, the use of rescue medication will be documented in the patient diary and 
transferred at the following visit to the eCRF. All medications taken after the start of
study drug use, 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.
6.4
Efficacy
6.4.1
Spirometry measurements
All clinic visits will start in the morning. The following spirometry measurements will be 
taken: FEV1 and FVC. 
 


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
At Visit 0, spirometry measurements will be taken to assess patients eligibility for the 
study and to assess the post-bronchodilation  FEV1bronchodilation FEV1 10 to 15 min 
after inhalation of  4of 4 x 100 μg puffs of salbutamol.
The results of the spirometry measurement must meet ATS/ERS criteria for acceptability and 
repeatability for the patient to continue in the study (see Appendix 2).
A single spirometry manoeuver will be performed on those patients who withdraw 
prematurely.
All spirometry measurements taken after Visit 1 should be performed as close as possible, and 
ideally within 1 hour, of the time that they were performed at the randomization visit (Visit 1). 
For all clinic spirometry assessments, 3 acceptable maneuvers should be performed for each 
time-point. The FEV1 and FVC values recorded must be the highest values measured 
irrespective of whether or not they occur on the same curve. 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).
Pulmonary function assessments will be performed using spirometry. For this purpose the 
spirometer will be customized and programmed according to the requirements of the study 
protocol in accordance with ATS standards (Miller et al, 2005), including predicted reference 
values. In order to reduce the variability of observations, this equipment must be used for all 
measurements during the study. Whenever possible the same staff member should evaluate 
and coach a given patient at each visit throughout the study and be consistent in their patient 
handling. 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.
However, the deviation caused by a different equation of each participating center (Morris, 
Knudson, Korean equation, etc) will be accepted.
Refer to the Spirometry Guidance for further details on spirometry and reversibility testing
(Appendix 2).
6.4.2
Baseline/transitional dyspnea index 
Patients must be interviewed by a trained assessor who will grade the degree of impairment 
due to dyspnea at Visit 1 (BDI) and at Visit 2 and 3 and at the time of discontinuation for 
patients who discontinue prematurely (TDI). 
Preferably, the same assessor should complete all the BDI/TDI assessments for an individual 
patient. These assessments must be undertaken prior to the spirometry and study drug 
administration.
Details of the BDI and TDI (Mahler and Wells, 1988) are provided in Appendix 1. 
6.4.3
Chronic obstructive pulmonary disease assessment
The CAT is a short instrument used to quantify the symptom burden of COPD and will be 
used to assess the health status impairment of patients in this study (Jones et al, 2009) first at 
Visit 1 to determine patient eligibility (must have a score of at least 10). The CAT consists of 
8 items, each presented as a semantic 6-point differential scale, providing a total score out of 
 


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40. A higher score indicates a worse health status. The result is immediately available without 
the need for any calculation, apart from summing the scores of individual items. 
Scores of 0 to 10, 11 to 20, 21 to 30 and 31 to 40, respectively, represent a mild, moderate, 
severe, or very severe clinical impact of COPD on the patient.
The CAT questionnaire (see Appendix 8) is completed by the patient at the beginning of the 
study visit before any other assessment to avoid influencing the responses. Completed CAT 
questionnaires will be reviewed by the investigator and data entered into eCRF. The 
investigator should review not only the responses to the questions in the questionnaire but also 
for any unsolicited comments written by the patient. Investigators should not encourage the 
patients to change the responses reported in the questionnaire.
6.4.5
Rescue medication use
Each patient will be provided with salbutamol to use as rescue medication. If a patient 
requires the use of salbutamol as rescue medication due to an increase in COPD symptoms, 
the number of inhalations taken during the previous 24-hour period will be recorded in the 
paper diary. Instructions regarding the use of rescue medication are outlined in Section 5.5.6. 
6.4.6
Chronic obstructive pulmonary disease exacerbations
A COPD exacerbation is defined as:
A worsening of the following 2 or more major symptoms for at least 2 consecutive days:

dyspnea

sputum volume

sputum purulence
OR
A worsening of any 1 major symptom together with an increase in severity of any 1 of the 
following minor symptoms for at least 2 consecutive days:

sore throat

colds (nasal discharge and/or nasal congestion)

fever without other cause

cough

wheeze
 


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A COPD exacerbation is considered of moderate severity if treatment with systemic 
glucocorticosteroids or antibiotics or both was required and severe if hospitalization was 
required. An emergency room visit of longer than 24 hours will be considered a 
hospitalization. In the event of a COPD exacerbation matching the above definition occurring 
at any time after signing of informed consent, patients should be treated for the exacerbation 
as he/she deems appropriate. However, the following regimen is recommended for the 
treatment of an exacerbation:

A 2 week oral course of prednisolone (or equivalent), 30mg/day in Week 1, followed by 
20 mg/day in Week 2, and/or an oral 7 day course of amoxicillin 500 mg 3 times daily 
(alternatively augmentin 625 mg 3 times daily or clarithromycin 500 mg twice daily).
Following treatment for the exacerbation, the patient will be expected to continue in the study 
provided the investigator considers that the patient can safely return to their pre-exacerbation 
medications.
If systemic corticosteroids are taken within 7 days prior to any study visit, the visit must be 
rescheduled to allow a washout of 7 days.
The start date for a COPD exacerbation recorded in the eCRF should be the first day of 
symptom worsening of 2 or more major symptoms or 1 major and one minor symptom, as 
defined above. The end of a COPD exacerbation episode is marked by the return to 
pre-exacerbation symptom status. At the end of an exacerbation the patient should where 
possible attend the clinic for assessment of the episode.
In patients with multiple exacerbations, if the start date of an exacerbation was less than 
7 days after the end date of a previous episode, then this will be assumed to be one continuous 
exacerbation with the start date taken from the first episode and the end date from the second 
or last episode. The worst severity of these episodes will be taken as the severity of the 
collapsed exacerbation.
All COPD exacerbations should only be recorded on the COPD exacerbation eCRF and not 
on the AEs eCRF.
Any reported AEs or SAEs of pneumonia must be confirmed by chest X-ray.
6.4.7
Appropriateness of efficacy assessments 
The efficacy assessments (BDI/TDI, CAT, FEV1, rescue medication) planned for this study 
are standard efficacy assessments in COPD clinical trials.
6.5
Safety

Adverse events

Physical examination

Urine pregnancy test (females of childbearing potential)

ECG

Vital signs

Laboratory tests: biochemistry, hematology and urine.
 


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6.5.1
Physical examination
A complete physical examination will be performed at Visit 1 (Day 1) and Visit 3 (Day 84).
In case of early withdrawal, a physical examination should be performed at the premature 
study withdrawal visit. It will include the examination of general appearance, skin, neck 
(including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, and 
extremities; and vascular and neurological systems. If indicated based on medical history 
and/or symptoms, rectal, external genitalia, breast, and pelvic examinations will be performed.
Information for all physical examinations must be included in the source documentation at the 
study site. Significant findings that are present prior to the start of study drug must be 
included in the Relevant Medical History/Current Medical Conditions screen on the patient’s 
eCRF. Significant findings after the start of study drug which meet the definition of an AE
must be recorded on the AE screen of the patient’s eCRF.
6.5.2
Vital signs
Vital signs will include pulse rate (measured for 60 seconds) and systolic and diastolic blood 
pressure. Pulse rate and blood pressure will be assessed after the patient has rested in the 
sitting position for at least 10 minutes. The patient’s condition must be monitored to rule out 
any clinically relevant arrhythmia. The investigator needs to monitor the pulse rate for any 
missed beats or ectopics.
Vital signs will be obtained at Visit 0; Visit 1, 2 and 3; and once in the event of premature 
study withdrawal.
Clinically notable vital signs will be determined in accordance with the investigator’s decision. 
6.5.3
Height and weight
Height (in cm) and weight (to the nearest 0.1 kilogram (kg) in indoor clothing, but without 
shoes) will be recorded at Visit 1 (Day 1). Weight will be recorded again at Visit 3 (Day 84), 
and in the event of premature study withdrawal.
6.5.4
Laboratory evaluations
Laboratory evaluations and analyses will be performed locally at the site level.
In the event of premature study withdrawal, a laboratory sample for hematology, chemistry, 
and urinalysis will be obtained at the end of study visit. Clinically notable laboratory findings 
will be determined in accordance with the investigator’s decision.
6.5.4.1
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential, and 
platelet count will be measured at Visit 0 (Day -21 to Day -1), Visit 2 (Day 28) and Visit 3 
(Day 83). 
6.5.4.2
Clinical chemistry
Albumin, alkaline phosphatase, total bilirubin, blood urea nitrogen (BUN), calcium, total 
cholesterol, lactate dehydrogenase (LDH), magnesium, phosphate, sodium, potassium, 
 


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creatinine, γ-GT, blood glucose, total protein, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), low-density lipoprotein-cholesterol (LDL-C) and high-density 
lipoprotein-cholesterol (HDL-C) will be measured at Visit 0 (Day -21 to Day -1), Visit 2 
(Day 28) and Visit 3 (Day 83). If the total bilirubin concentration is increased above 1.5 times 
the upper limit of normal (ULN) range, direct bilirubin should be measured.
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.
6.5.4.3
Urinalysis
Urinalysis will be measured at Visit 0 (Day -21 to Day 1), Visit 2 (Day 28) and Visit 3 
(Day 83). 
Testing will include: pH, specific gravity, protein, glucose, ketones, bilirubin, blood, 
urobilinogen, nitrate, and WBC.
All patients with laboratory tests containing clinically significant abnormal values will be 
followed regularly until the values return to normal ranges or until a valid reason, other than 
drug-related AE, is identified.
6.5.5
Electrocardiogram
At Visit 0, a single screening ECG will be measured to test for eligibility for trial inclusion. 
ECGs will also be performed at Visit 2 and Visit 3. In the event of premature study 
withdrawal, a single ECG will be measured. All ECGs should include all 12 standard leads.
If a patient experiences a clinically significant change in cardiac rhythm or other clinically 
significant cardiovascular abnormality, the investigator should consider withdrawing the 
patient from the study.
6.5.6
Pregnancy and assessments of fertility
A urine pregnancy test will be performed in pre-menopausal women who are not surgically 
sterile (tests provided by the local laboratory at Visit 0 (Day -21 to Day -1) and Visit 3 
(Day 84) or at premature withdrawal. A positive urine pregnancy test requires the patient to be 
discontinued from the trial. No assessments of fertility will be performed. See Section 5.5.9
and Section 7.3 for more details.
6.5.7
Appropriateness of safety measurements
The safety assessments selected are standard for clinical trials in COPD.
6.6
Other assessments
No additional tests will be performed on patients entered into this study.
6.6.1
Resource utilization
Not applicable.
 


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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.
 


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7
Safety monitoring
7.1
Adverse events
An AE is any untoward medical occurrence (i.e., any unfavorable and unintended sign 
(including abnormal laboratory findings), symptom or disease) in a subject or clinical 
investigation subject after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The occurrence of AEs 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 AEs 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 AEs. 
Adverse events should be recorded in the AE 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 (suspected/not suspected).
 


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
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 AE (appearance of (or worsening of any pre-existing) undesirable sign(s), 
symptom(s) or medical conditions(s) which meets any one of the following criteria:

is fatal or life-threatening.

results in persistent or significant disability/incapacity.

constitutes a congenital anomaly/birth defect.

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition.

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent.

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission.

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition.

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 AEs 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 AE should be recorded on the AE eCRF. 
Once an AE 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 
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Information about common side effects already known about the investigational drug can be 
found in the Package Insert. 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 AE (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 this 30-day period should only be reported to Novartis if the 
investigator suspects a causal relationship to study treatment. 
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must be 
submitted within 24 hours of the investigator receiving the follow-up information. An SAE 
that is considered completely unrelated to a previously reported one should be reported 
separately as a new event.
Information about all SAEs (either initial or follow up information) is collected and recorded 
on the paper SAE Report Form. The investigator must assess the relationship to each specific 
component of study treatment, 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 (DS&E) Department. The telephone and fax number 
of the contact persons in the local DS&E Department, 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 eCRF documentation at the study site.
Follow-up information should be provided using a new paper SAE Report Form stating that 
this is a follow-up to a previously reported SAE. Information about all SAEs (either initial or 
follow up information) is collected and recorded in English on the paper SAE Report Form. 
The Investigator must assess the relationship to each specific component of the study 
treatment (if the study treatment consists of several components). 
SAEs (initial and follow-up) that are recorded on the paper SAE form should be faxed within
24 hours of awareness of the SAE to the local Novartis DS&E Department. The telephone and 
fax number of the contact persons in the local DS&E department specific to the site, are listed 
in the investigator folder provided to each site(site (Tel. 02-768-9007, Fax. 02-780-8487, 
Email. safety.kor@novartis.com). The original copy of the SAE Report Form and the fax 
confirmation sheet must be kept with the eCRF documentation at the study site. Follow-up 
information should be provided using a new paper SAE Report Form stating that this is a 
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SAEs (initial and follow-up) that are recorded electronically in the OC/RDC system should be 
entered, saved and e-signed within 24 hours of awareness of the SAE or changes to an 
existing 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 DS&E
Department associate may urgently require further information from the investigator for 
Health Authority reporting. All SAEs will be collected and reported to the competent 
authorities and relevant ethics committees in accordance with national regulatory 
requirements in participating countries.
7.3
Pregnancy reporting
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form in English and reported by 
the investigator to the local Novartis DS&E 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.
7.4
Prospective suicidality assessment
Not applicable.
8
Data review and database management
8.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative 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 
GCP, the progress of enrollment, and to ensure that study treatment is being stored, dispensed, 
and accounted for according to specifications. Key study personnel must be available to assist 
the field monitor during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
 


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information, laboratory data, ECGs, 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 ICF 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 of data that will be used for all primary 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 supply the investigator site with a computer loaded with 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 by Novartis personnel. 
Designated investigator staff will enter the data required by the protocol into the Novartis 
eCRFs using the Novartis-supplied computer. Automatic validation programs check for data 
discrepancies in the eCRFs and, by generating appropriate error messages, allow the data to 
be confirmed or corrected by the investigator staff before transfer of the data to Novartis via a 
secure Virtual Private Network. The investigator must certify that the data entered are 
complete and accurate by signing a memo generated at the end of the trial that will be sent to 
him by Novartis personnel. After database lock, the investigator will receive copies of the 
patient data for archiving at the investigational site.
8.3
Database management and quality control
Novartis staff will review the data entered into the CRFs by investigational staff for 
completeness and accuracy and instruct the site personnel to make any required corrections or 
additions. Queries are sent to the investigational site using an electronic data query. 
Designated investigator site staff is required to respond to the query and confirm or correct the 
data. If the electronic query system is not used, a paper Data Query Form will be faxed to the 
site. Site personnel will complete and sign the faxed copy and fax it back to Novartis staff that 
will make the correction to the database. The signed copy of the Data Query Form is kept at 
the investigator site.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Concomitant procedures, non-drug therapies and AEs will be coded using the Medical 
dictionary for regulatory activities (MedDRA) terminology.
Data about all study drugs dispensed to the patient and all dosage changes will be tracked 
using an IRT. The system will be supplied by a vendor, who will also manage the database. 
The database will be sent electronically to Novartis. 
 


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8.4
Data Monitoring Committee
Not required.
8.5
Adjudication Committee
Not required.
9
Data analysis
9.1
Analysis sets
The following sets will be used for the analysis of data:

The Randomized set (RAN), will include all randomized patients regardless of whether or 
not they actually received study treatment.

The Full analysis set (FAS) will include all randomized patients who received at least one 
dose of study treatment and have at least one evaluable post-baseline assessment.
Following the intent-to-treat principle, patients will be analyzed according to the treatment 
they were assigned to at randomization.

The Per-protocol set (PPS) will include all patients in the FAS without any major protocol 
deviations. Major protocol deviations will be defined prior to database lock. Patients will 
be analyzed according to the treatment they were assigned to at randomization.

The Safety set will include all patients who received at least one dose of study treatment. 
Patients will be analyzed according to the treatment they received.
The analysis of the primary objective will be performed on the FAS. The PPS will be used for 
the supportive analysis of the primary variable. The FAS will be used for the analysis of all 
other efficacy variables. The safety set will be used for 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 receive study treatment in error. Also the FAS assigns 
randomized treatment and the Safety set assigns received treatment.
9.2
Patient demographics and other baseline characteristics
Demographic and baseline characteristics including age, sex, race, ethnicity, height, weight, 
body mass index (BMI), relevant medical history, screening spirometry (FEV1, FVC, 
FEV1/FVC) including short acting bronchodilator reversibility, duration of COPD, baseline 
COPD severity (mild or moderate), smoking history, prior concomitant medications (COPD 
related and non-COPD related), vital signs (systolic and diastolic blood pressure, pulse rate), 
QT using Fridericia’s correction and ECG will be summarized for the randomized set by 
treatments.
9.3
Treatments
The number of patients and the length of time (in days) exposed to each study drug will be 
summarized by treatment for the Safety set.
 


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Concomitant medications will be summarized by treatment for the safety set. Concomitant
COPD related medications will be summarized by pre-specified categories recorded on the
CRF, route of administration and ingredient. Concomitant medications not related to COPD 
will be summarized by the preferred term. Furthermore, concomitant COPD-related and non
COPD-related medications were combined in one table and presented by Anatomical 
Therapeutic Chemical (ATC) class and preferred term.
Treatment compliance will be summarized by treatment for the safety set.
9.4
Analysis of the primary variable
The primary objective of this study is to demonstrate the superiority of QVA 110/50 μg once 
daily compared to tiotropium 18 μg once daily in terms of trough forced expiratory volume in 
one second (FEV1 in Liters) following 12 weeks of treatment.
9.4.1
Variable
The primary variable is pre-dose trough FEV1 (L) at Week 12, which is defined as the average
of FEV1 values taken at 45 and 15 min prior to the administration of study drug. 
The baseline FEV1 (L) measurement is defined as the average of the FEV1 values taken at 45 
and 15 min prior to the first dose of study drug at Visit 1 (Day 1).
9.4.2
Statistical model, hypothesis, and method of analysis
To demonstrate the superiority of QVA 110/50 µg once daily to tiotropium 18 µg once daily
in patients having COPD with mild to moderate airflow limitations, the following hypothesis 
will be tested using an analysis of covariance (ANCOVA) model for the full analysis set:
H0: There is no difference in trough FEV1 (L) at Week 12 for patients treated with QVA 
versus tiotropium 
HA: There is a difference in trough FEV1 (L) at Week 12 for patients treated with QVA versus
tiotropium 
The model will contain treatment and smoking status as fixed effects with baseline trough 
FEV1 as a covariate and center as a random effect.
Least squares means and the estimated treatment differences will be displayed along with the 
associated 95% confidence interval and p-value. The superiority of QVA to tiotropium will be 
demonstrated if the p-value is less than 0.05 and the confidence interval lies entirely to the 
right of (higher than) 0 mL. 
9.4.3
Handling of missing values/censoring/discontinuations
If any of the values contributing to the trough FEV1 are collected within 6 hours of rescue 
medication use or less than 7 days after systemic corticosteroid use then the individual FEV1
value will be set to missing or if the actual measurement times were outside the 22-25 hour
post-dose time window then the individual FEV1 value will be excluded from analyzed.
If any one of the 45 min or 15 min pre-dose values is missing at Week 12, the remaining non-
missing value will be considered as trough FEV1. If both values are missing, or if the patient 
 


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has withdrawn from the trial, regardless of the reason for discontinuation, then missing trough 
values will be imputed with the last observation carried forward (LOCF) method using the 
data at Visit 2. If the trough value at Visit 2 is missing, then patient will be excluded from this 
analysis.
9.4.4
Supportive analyses
Since some patients may discontinue the study prematurely affecting the sample size at 
Week 12, the following analyses will also be performed as supplementary to support the result 
of the primary analysis:
1. The primary analysis will be repeated only for patients who have a valid trough 
measurement at Week 12. Any missing observation at Week 12 will not be imputed.
2. The primary analysis will be repeated for the Per-protocol set. Missing FEV1 values will 
be imputed by LOCF method.
3. A sensitivity analysis of trough FEV1 at Week 12 (with and without imputation by LOCF 
method) will also be performed by allowing inclusion of values that fell within 6 hours of 
rescue medication use or within 7 days of systemic corticosteroid use.
4. The following exploratory subgroup analyses for the primary endpoint trough FEV1 at 
Week 12 will be performed (using the appropriate interaction term in the model and 
additional covariate as a fixed effect if necessary) for the full analysis set to explore the 
treatment effect in:

Age group.

Sex.

Severity of COPD (50% ≤FEV1 < 60%, FEV1 ≥60%).

Smoking status at baseline.

Exacerbation (exacerbation history in previous year; 0 or 1).

Patient’s larger value of FEV1 reversibility after SABA (12% & 200ml increase / 12% 
increase / 200 mL increase).

BMI.
5. In addition, analysis of the log-transformed trough FEV1 after 12 weeks of treatment for 
the FAS will be performed using the same ANCOVA model as specified for the primary 
analysis with the relevant covariates in the model log-transformed as appropriate.
9.5
Analysis of secondary variables
9.5.1
Efficacy variables
9.5.1.1
Trough FEV1 at Week 4
Trough FEV1 at Week 4 will be summarized using a similar ANCOVA model as specified in 
the primary analysis. Least squares means and the estimated treatment differences will be 
displayed along with the 95% confidence interval and p-value.
As an exploratory analysis, similar ANCOVA analysis will be performed for FVC and
FEV1/FVC at Week 4 and Week 12. The model will also contain visit and treatment by visit 
 


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interactions as fixed effects. Least squares means and the estimated treatment differences will 
be displayed along with the 95% confidence interval and p-value.
9.5.1.2
Rescue medication use
Diary data recorded between Visit 0 and Visit 1 will be used to calculate the baseline values. 
Patients will be considered as eligible for the analysis if they have at least 7 evaluable diary 
days in the baseline period and in the post baseline period they have at least 30% of their diary 
days evaluable and at least 40 evaluable diary days in total.
Daily rescue medication use (number of puffs) over 12 weeks 
The total number of puffs of rescue medication used over the last 24 hours will be recorded in 
the electronic patient diary in the morning. The total number of puffs of rescue medication per 
day over the full 12 weeks will be calculated and divided by the total number of days with 
non-missing rescue medication data to derive the mean daily number of puffs of rescue 
medication taken for the patient. The mean daily number of puffs of rescue medication used 
over 12 weeks will be summarized by treatments and analyzed using a negative binomial 
regression model with treatment and smoking status as fixed effects with baseline rescue 
medication use as a covariates and center as a random effect. Log of exposure to the study 
drug will be used as the offset variable. Least squares means will be displayed by treatments. 
The estimated difference between treatments, along with the 95% confidence interval and p-
value will also be displayed.
Percentage of ‘days with no rescue use’ over 12 weeks 
A ‘day with no rescue use’ is defined from diary data as any day where the patient does not 
use any puffs of rescue medication. The total number of ‘days with no rescue use’ over the 
12 weeks will be divided by the total number of days in order to derive the percentage of 
‘days with no rescue use’.
The percentage of ‘days with no rescue use’ will be summarized by treatment and analyzed 
using the same ANCOVA model as specified for the primary analysis, however, baseline 
percentage of ‘days with no rescue use’ will be used instead of baseline FEV1.
9.5.1.3
Dyspnea index
Dyspnea will be measured at baseline using the BDI and during the treatment period using the 
TDI, which captures changes from baseline. The BDI and TDI each have 3 domains-
functional impairment, magnitude of task and magnitude of effort. The BDI domains are rated 
from 0 (severe) to 4 (unimpaired) and the rates are summed for the baseline focal score 
ranging from 0 to 12; the lower the score the worse the severity of dyspnea. The TDI domains 
are rated from -3 (major deterioration) to 3 (major improvement) and the rates are summed for 
the transition focal score ranging from -9 to 9; minus scores indicate deterioration. A TDI 
focal score of 1 is considered to be a clinically significant improvement from baseline.
 


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TDI focal score 
The TDI focal score after 12 weeks of treatment will be analyzed using the same ANCOVA
model as specified for the primary analysis with the BDI focal score as the baseline covariate.
When the data are missing or insufficient for any one of the domains, a focal score cannot be 
calculated.
Proportion of patients with a clinically important improvement of at least 1 in 
the TDI focal score 
A TDI focal score of ≥1 is considered to be a clinically important improvement from baseline. 
The proportion of patients who achieve this clinically important improvement will be 
analyzed using logistic regression. The model will contain same terms as in the primary 
analysis, with BDI focal score as the baseline covariate. The estimated adjusted odds ratios 
will be displayed along with the associated 95% confidence intervals and two-sided p-values.
9.5.1.4
COPD Assessment Test
The CAT score at Week 12 will be summarized by treatment and analyzed using the same 
ANCOVA model as specified for the primary analysis, with the baseline covariate replaced by 
baseline CAT score. Least squares means will be displayed by treatments. The estimated 
difference between treatments, along with the 95% confidence interval and p-value will also 
be displayed.
9.5.2
Safety variables
All safety endpoints (i.e. AEs, laboratory data, vital signs, and ECG) will be summarized by 
treatment for all patients in the safety set. All data will be included in the summaries and/or 
analysis regardless of rescue medication use.
Adverse events
All study emergent AEs including COPD exacerbations will be recorded and listed. 
Adverse events starting on or after the time of the first dose of study drug and up to 7 days 
(30 days in case of SAEs) after the last dose of study drug will be classified as a treatment 
emergent AE and included in all summaries. Any AEs that started during the study before the 
time of the first dose of study drug will be listed only.
All treatment emergent AEs will be listed. 
The following treatment emergent AE summaries will be produced: overall by system organ 
class and preferred term, overall by system organ class, preferred term and maximum severity, 
suspected drug-related AEs by system organ class and preferred term, SAEs by system organ 
class and preferred term, and AEs leading to permanent discontinuation of study drug by 
system organ class and preferred term.
The number and percentage of patients with the most frequent AEs will be summarized by 
treatment.
The number and percentage of patient mortality and CCV SAE events will be summarized by
treatment.
 


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Deaths
All deaths occurring in the study will be listed by patient and summarized by treatments and 
investigator-reported principal cause. Deaths will be summarized separately based on 
(A) cases reported during the active treatment period only and (B) cases reported during the 
active treatment period plus the following 30 days. 
Electrocardiogram and vital signs
ECG data and vital signs (sitting systolic/diastolic blood pressures, sitting pulse rate) will be 
summarized by treatment for each visit separately. The baseline is defined as the measurement 
taken at Visit 1. The maximum (QTcF, systolic blood pressure, pulse rate) or minimum 
(diastolic blood pressure) post first dosing will also be summarized. Changes from baseline 
will also be summarized by treatment. 
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 treatments. 
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
QTc will be calculated from the QT interval and RR (in seconds) using Fridericia’s formula: 
QTc = QT / 3√ RR, where 3√ denotes the cube root. Notable QTc values and changes from 
baseline will be summarized. 
A notable value is defined as a QTc interval of greater than 450 ms. The categories used for 
the change from baseline in QTc are less than 30 ms, 30 to 60 ms and greater than 60 ms.
Laboratory Data
All laboratory data will be listed with abnormal values. The laboratory values and the change 
from baseline (Visit 0) for continuous laboratory parameters will be summarized for each visit. 
A frequency table of results for categorical laboratory parameters will be produced by visit. 
Shift tables relative to the normal reference ranges will be used to summarize the change from 
baseline to post-baseline for each laboratory parameter.
Laboratory data measured more than 7 days after last dose of study drug is regarded as post-
treatment data and will not be summarized, only listed.
 


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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.
 


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9.7
Interim analyses
Not applicable.
9.8
Sample size calculation
The primary objective is to demonstrate superiority of QVA149 110/50 µg once daily
compared to tiotropium 18 µg once daily in terms of pre-dose trough FEV1 (L) after 12 weeks 
of treatment. Based on the results of QVA149A2303 (SHINE) study, it was assumed that the 
estimated treatment difference between QVA149 and tiotropium is 80 mL and corresponding 
standard deviation is 271 mL (Bateman et al 2013). In this study, a sample size of 173 patients 
in each treatment arm with an estimated treatment difference between QVA149 and 
tiotropium of 82 mL would be required to achieve 80% power on a 2-sided test with 5% level 
of significance. Assuming a dropout rate of 11%, approximately 389 patients will be enrolled 
in the study.
10
Ethical considerations
10.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented and reported in accordance with 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practice (GCP), with applicable 
local regulations (including European Directive 2001/20/EC, US Code of Federal Regulations 
Title 21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles 
laid down in the Declaration of Helsinki.
10.2
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-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 a proposed ICF that complies 
with the ICH GCP guideline and regulatory requirements and is considered appropriate for 
this study. Any changes to the proposed consent form suggested by the investigator must be 
agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the approved 
version must be provided to the Novartis monitor after IRB/IEC/REB approval.
Women of child bearing potential should be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
 


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duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.
10.3
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed ICF must be reviewed and approved by a properly constituted 
IRB/IEC/REB before study start. A signed and dated statement that the protocol and informed 
consent have been approved by the IRB/IEC/REB 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/REBs, and regulatory authorities as 
required. If an inspection of the clinical site is requested by a regulatory authority, the 
investigator must inform Novartis immediately that this request has been made.
10.4
Publication of study protocol and results
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results.
11
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
trial to request approval of a protocol deviation, as requests to approve deviations will not be 
granted.
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Under no circumstances should an investigator collect additional data or 
conduct any additional procedures for any research related purpose involving any 
investigational drugs. 
If the investigator feels a protocol deviation would improve the conduct of the study this must 
be considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC/REB it cannot be implemented. All significant 
protocol deviations will be recorded and reported in the Clinical Study Report.
11.1
Protocol amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. 
Only amendments that are required for patient safety may be implemented prior to 
IRB/IEC/REB 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 
 


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protocol. In such cases, Novartis should be notified of this action and the IRB/IEC/REB at the 
study site should be informed within 10 working days or less, if required by local regulations. 
12
References
2015 Global Initiative for Chronic Obstructive Lung Disease (GOLD);
http://www.goldcopd.org
Beeh KM, Korn S, Beier J, et al (2014) Effect of QVA149 on lung volumes and exercise 
tolerance in COPD patients: The BRIGHT study. Respiratory Medicine; 108:584-592. 
Bateman ED, Ferguson GT, Barnes N et al (2013) Dual bronchodilation with QVA149 versus 
single bronchodilator therapy: the SHINE study. Eur Respir J; 42(6):1484-94. 
COPD Monitoring, Market research data from Ipsos Mar (2014). IPSOS Korea. 
http://www.ipsoskorea.com/Eng/healthcare.html 
Jones PW, Harding G, Berry P, et al (2009) Development and first validation of the COPD 
Assessment Test. Eur Respir J; 34:648-654.
Jones PW et al (on behalf of the CAT Development Steering Group), The COPD Assessment 
Test healthcare professional user guide: expert guidance on frequently asked questions. 
Issue 1: 2009.
Mahler DA and Wells CK (1988) Evaluation of clinical methods for rating dyspnea. 
Chest;93(3):580-6.
Miller MR, Crapo R, Hankinson J et al (2005) General considerations for lung function 
testing. Eur. Resp J; 26(1):153-161.
Price D, West D, Brusselle G et al (2014) Management of COPD in the UK primary-care 
setting: an analysis of real-life prescribing patterns. Int J Chron Obstruct Pulmon Dis;
9:889-905. 
Vogelmeier CF, Bateman ED, Pallante J et al (2013) Efficacy and safety of once-daily 
QVA149 compared with twice-daily salmeterol/fluticasone in patients with COPD 
(ILLUMINATE): a randomised, double-blind, parallel group study. Lancet Respir Med; 1(1): 
51-60.
Wedzicha JA, Decramer M, Ficker JH et al (2013) Analysis of chronic obstructive pulmonary 
disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium 
and tiotropium (SPARK): a randomised, double-blind, parallel-group study. Lancet Respir 
Med; 1(3):199–209.
 


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13
Appendices
13.1
Appendix 1: Baseline dyspnea index/transitional dyspnea 
index
 


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Source: Mahler DA and Wells CK, 1988
 


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13.2
Appendix 2: Spirometry guidance
Spirometry
Equipment
Spirometers must meet the specifications and performance criteria recommended in the 
American Thoracic Society (ATS)/European Respiratory Society (ERS) Standardization of 
Spirometry (Miller et al 2005). Spirometers must have the capacity to print FVC tracings. All 
spirometry values should be reported in liters (L) at the following conditions: normal body 
temperature (37°C), ambient pressure, saturated with water vapor (BTPS).
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 patient
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.

Exposure to environmental smoke, dust or areas with strong odors.
Every effort should be made to assure consistent testing conditions throughout the study. The 
patient should perform spirometry in the seated position with nose clips. When possible, 
spirometry should be conducted by the same technician using the same spirometer. To 
minimize the effects of diurnal variation on lung function, spirometry visits should start at 
approximately the same time of day at each visit.
Performing Spirometry
The patient’s age, height and gender will be entered into the spirometer. It is important that 
the height is measured accurately at the study site. Spirometry, an effort-dependent test, 
requires careful instruction and cooperation of the patient. The technician should ensure a 
good seal around the mouthpiece, and confirm that the patient’s posture is correct. The patient
should be instructed to perform a maximal inspiration, followed by maximum forced 
expiration until no more air can be exhaled or for at least 6 seconds. Expiration must be rapid 
with exertion of maximal effort. The results of spirometry should meet the ATS/ERS criteria 
for acceptability and repeatability. Acceptability criteria should be applied before repeatability 
is determined. 
Number of trials
A minimum of 3 acceptable forced vital capacity (FVC) maneuvers should be performed. If a 
patient is unable to perform a single acceptable maneuver after 8 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 early termination of exhalation (minimum exhalation time of 6 seconds is 
recommended, unless there is an obvious plateau of reasonable duration (i.e., no volume 
change for 1 second) or the patient 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
The study is using the spirometry at individual site therefore the predicted normal values will 
be handled at site level.
Reversibility
All reversibility evaluations should follow the recommendations of the ATS/ERS Task force: 
Standardization of Lung Function Testing (Miller et al, 2005). A baseline spirometry 
assessment should be performed after a washout period of at least 6 hours for 
short-acting-β2-agonists (SABAs), 48 hours for long-acting β2-agonists (LABAs) and 7 days 
for long-acting anticholinergics.
Following baseline assessment, perform post-bronchodilation FEV1 10 to 15 min after 
inhalation of  4of 4 x 100 µg puffs of Salbutamol.
.
Reversibility is calculated as:
100 × FEV1 (post β2-agonists) – FEV1 (baseline)
FEV1 (baseline)
13.3
Appendix 3: Patient COPD treatment diary
  Instructions for Completing the Diary:
Please use this diary to record the time when you take your COPD medication. 
 


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Please (√) check if you missed the dose. 
Each morning record the number of puffs of rescue medication taken during the past 24 
hours. 
Please bring this diary with you to the visit. 
PLEASE remember to not take any rescue medication 06 hours before a study visit. 
Visit 0 (Screening visit) to Visit 1 (Randomization visit)
Visit 1 (Randomization visit) to Visit 2 (Treatment visit)
Visit 2 (Treatment visit) to Visit 3 (Treatment visit)
 


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13.4
Appendix 4: 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
COPD groupings based on risk level and symptoms
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 no hospitalization for exacerbation; and CAT score 
< 10 or mMRC grade 0-1
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
Group C
High risk, less symptoms
Typically GOLD 3 or GOLD 4 (severe or very severe airflow limitation); and/or 
 


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≥2 exacerbations per year or ≥ 1 with hospitalization for exacerbation; and CAT 
score < 10 or mMRC grade 0-1
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
Abbreviations: CAT: COPD assessment test, GOLD: Global Initiative for Chronic Obstructive Lung Disease, 
mMRC: modified Medical Research Council
Source: GOLD Guidelines, 2015.
 


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13.6
Appendix 6: Instructions for use of the SDDPI for QVA149 
110/50 microgram
 


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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
Clear 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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13.7
Appendix 7: Instructions for use of HandiHaler® for tiotropium 
18 microgram
 


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13.8
Appendix 8: COPD Assessment Test (CAT)
 

SAP_001.pdf: 
Clinical Development
QVA149/ indacaterol maleate/glycopyrronium bromide
CQVA149AKR01/ NCT02566031
A randomized, multicenter, open-label, parallel-group, 
12-week study to assess the efficacy and safety of 
switching from tiotropium to QVA149 (indacaterol
maleate/glycopyrronium bromide) in symptomatic mild to 
moderate COPD patients
Statistical Analysis Plan (SAP)
Author:
Trial Statistician, 
Document type:
SAP Documentation
Document status:
Final V1.1
Release date:
04-Dec-2018
Number of pages:
32
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Document History – Changes compared to previous final version of SAP
Date
Reason for update
Section and 
title impacted 
(Current)
20-Nov-2018
Rule of exclusion criteria OTH06, OTH07, 
OTH08 were added.
Section 5.5
….


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Table of contents
Table of contents .................................................................................................................3
List of abbreviations............................................................................................................5
1
Introduction .........................................................................................................................7
1.1
Study design.............................................................................................................7
1.2
Study objectives and endpoints ...............................................................................8
2
Statistical methods...............................................................................................................9
2.1
Data analysis general information ...........................................................................9
2.1.1
General definitions................................................................................10
2.2
Analysis sets ..........................................................................................................10
2.2.1
Subgroup of interest ..............................................................................10
2.3
Patient disposition, demographics and other baseline characteristics ...................11
2.3.1
Patient disposition.................................................................................11
2.3.2
Protocol deviation .................................................................................11
2.3.3
Demographic characteristics.................................................................11
2.3.4
Medical history/ current medical condition ..........................................12
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................13
2.4.1
Study treatment / compliance................................................................13
2.4.2
Prior, concomitant and post therapies...................................................13
2.5
Analysis of the primary objective..........................................................................14
2.5.1
Primary endpoint...................................................................................14
2.5.2
Statistical hypothesis, model, and method of analysis..........................14
2.5.3
Handling of missing values/censoring/discontinuations.......................14
2.5.4
Supportive analyses...............................................................................15
2.6
Analysis of the key secondary objective ...............................................................16
2.6.1
Key secondary endpoint........................................................................16
2.6.2
Statistical hypothesis, model, and method of analysis..........................16
2.6.3
Handling of missing values/censoring/discontinuations.......................16
2.7
Analysis of secondary efficacy objective(s)..........................................................16
2.7.1
Secondary endpoints .............................................................................16
2.7.2
Statistical hypothesis, model, and method of analysis..........................16
Analysis of secondary endpoints:..........................................................................16
2.7.3
Handling of missing values/censoring/discontinuations.......................19
2.8
Safety analyses.......................................................................................................19
2.8.1
Adverse events (AEs)............................................................................19


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Serious adverse events (SAE)................................................................................20
2.8.2
Deaths....................................................................................................20
2.8.3
Laboratory data .....................................................................................20
2.8.4
Other safety data ...................................................................................21
2.9
Pharmacokinetic endpoints....................................................................................22
2.10
PD and PK/PD analyses.........................................................................................23
23
2.12
Biomarkers.............................................................................................................23
23
2.14
Interim analysis......................................................................................................23
3
Sample size calculation .....................................................................................................24
4
Change to protocol specified analyses ..............................................................................24
5
Appendix ...........................................................................................................................24
5.1
Imputation rules.....................................................................................................24
5.1.1
AE date imputation ...............................................................................24
5.1.2
Concomitant medication date imputation .............................................26
5.2
AEs coding/grading ...............................................................................................27
5.3
Laboratory parameters derivations ........................................................................27
5.4
Statistical models...................................................................................................28
5.4.1
Primary analysis....................................................................................28
5.4.2
Key secondary analysis.........................................................................28
5.5
Rule of exclusion criteria of analysis sets..............................................................30
6
Reference...........................................................................................................................32


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List of abbreviations
AE
Adverse event
ALT
Alanine aminotransferase
ATC
Anatomical Therapeutic Classification
ANCOVA
Analysis of Covariance
AST
Asprtate aminotransferase
ATS
American Thoracic Society
BDI
Baseline Dyspnea Index
BTPS
Normal body temperature (37°C), ambient pressure, saturated with water vapor
CAT
COPD Assessment Test
CCV
Cardio-cerebrovascular Event
COPD
Chronic Obstructive Pulmonary Disease
CSR
Clinical Study report
ECG
Electrocardiogram
ERS
European Respiratory Society
FAS
Full Analysis Set
FEV1
Forced Expiratory Volume in 1 second
FVC
Forced Vital Capacity
eCRF
Electronic Case Report Form
GOLD
Global Initiative for Chronic Obstructive Lung Disease
hCG
Human Chorionic Gonadotropin
ICS
Inhaled Corticosteroid
IRT
Interactive Randomized Technology
IUD
Intrauterine Device
IUS
Intrauterine System
LABA
Long Acting Beta-2 Agonist
LAMA
Long Acting Muscarinic Antagonist
LOCF
Last Observation Carried Forward
MDI
Metered Dose Inhaler
MedDRA
Medical Dictionary for Drug Regulatory Affairs
mMRC
Modified Medical Research Council
PPS
Per-Protocol Set
PRO
Patient-reported Outcomes
PSW
Premature Study Withdrawal
qd
Once Daily
QoL
Quality of Life
QT
Time between start of Q wave and end of T wave in heart’s electrical cycle
QTc
Corrected QT
QTcF
Fridericia corrected QT formula
RAP
Report and Analysis Process
SABA
Short Acting Beta-2 Agonist
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan


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SDDPI
Single Dose Dry Powder Inhaler
SGRQ
St. George’s Respiratory Questionnaire
SOC
System Organ Class
SUSARs
Suspected Unexpected Serious Adverse Reactions
TDI
Transitional Dyspnea Index
TFLs
Tables, Figures, Listings
TURP
Transurethral Resection of Prostate
WHO
World Health Organization


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1
Introduction
This document describes the planned statistical methods for all safety and efficacy analyses
which will be used in the phase IV clinical trial QVA149AKR01.
The main purpose of this document is to provide summary of the statistical methodology that 
will be used for this clinical study; this includes a detailed description of data summaries. 
Analyses plan in this document refers to the related statistical analysis sections in clinical 
study report.
Data will be analyzed by Novartis using statistical software SAS version 9.4 according to the 
data analysis section 9 of the study protocol which is available in Appendix 16.1.1 of the CSR.  
That statistical methodology is described below and any deviations from the protocol are
documented. Additional detailed information regarding the analysis methodology is contained
in the Appendix section 16.1.9 of CSR.
Please refer to the following document:
Clinical Protocol QVA149AKR01
1.1
Study design
This is a randomized, multicenter, open-label, parallel-group, 12-week study to assess the 
efficacy and safety of QVA149 (indacaterol maleate/glycopyrronium bromide) versus 
tiotropium in symptomatic mild to moderate COPD patients. 
The schematic of study design is is given in Figure 1.1 below.
Planned number of patients and randomization
It is intended that total of 404 patients will be recruited to compensate dropouts and protocol 
violaters.
Patient eligibility will be assessed during a 3-weeks (21 days) Screening period. At Baseline 
visit (Visit 1/ Day 1), eligible patients will be randomized to one of the following treatment 
groups and treated for 12 weeks:

QVA149 (110/50 μg once daily)

tiotropium 18 μg once daily.
Primary analysis time point 
The primary analyses will be performed at Week 12.
Interim analyses
No interim analysis is planned for this study.
Figure 1.1: Study Design


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1.2
Study objectives and endpoints
Table 1.2-1
Objectives and related endpoints
Objective
Endpoint
Primary objective
To demonstrate the superiority of QVA 
110/50 µg once daily to tiotropium 18 µg 
once daily
of trough
forced expiratory 
volume in 1 second (FEV1) at Week 12
Mean of pre-dose trough FEV1 (L) at Week 
12
Secondary objective
To evaluate the effect of QVA149 (110/50
μg) as compared to tiotropium 18μg of Pre-
dose trough FEV1 at Week 4
Mean of pre-dose trough FEV1 (L) at Week 4
To evaluate the effect of QVA149 (110/50
μg) as compared to tiotropium 18μg of 
Transitional dyspnea index (TDI) focal score
at Week 12
Mean Transitional dyspnea index (TDI) focal
score at Week 12
Proportion of patients with a clinically 
important improvement of TDI focal score at 
Week 12
To evaluate the effect of QVA149 (110/50
μg) as compared to tiotropium 18μg of 
symptom control by total CAT score at Week 
Mean of CAT score at Week 12
Randomized Treatment Period
≥3 months of 
tiotropium 18 µg 
monotherapy for 
COPD treatment
tiotropium 18 µg once daily via Handihaler®
QVA149 110/50 µg once daily via Breezhaler®
Screening Period
Day -21 to Day -1 
ICF
Visit 2
Day 28 ± 7
Visit 3
Day 84 ± 7
Visit 1
Day 1
Randomization


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12
To evaluate the effect QVA149 (110/50 μg)
as compared to tiotropium 18μg of rescue 
medication used reported by the patients at 
Week 12
Mean 
daily 
number 
of 
puffs 
(rescue 
medication) at Week 12
Mean percentage of days with no rescue 
medication 
To evaluate the safety and tolerability of 
QVA149
(110/50
μg)
as compared to 
tiotropium 18μg
Overall safety, as measured by frequency and 
severity of adverse events and changes in 
laboratory, vital signs and ECG values from 
baseline
2
Statistical methods
2.1
Data analysis general information
The data will be analyzed by Novartis and/or by the designated CRO. It is planned that the 
data from all centers that participate in this protocol will be used for analysis. Analysis 
datasets and statistical outputs will be produced using the most recent SAS® Version 9.4 (SAS 
Institute Inc., Cary, NC, USA), and stored in Novartis global programming & statistical 
environment (GPS).  
Summary statistics for continuous variables will include N, mean, standard deviation,
median, minimum and maximum. Summary statistics for discrete variables will be presented 
in the number and percent of patients in each category.
For descriptive statistics, the following number of decimal places will 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.


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The analysis will be conducted on all patients data at Week 12. Data will be presented by 
treatment group, Unless otherwise stated. 
2.1.1
General definitions
Study treatment: Study treatment refers to:  
QVA149 (110/50 μg once daily) or tiotropium 18 μg once daily.
Study treatment start and end date: Study treatment start date is defined as the first date of 
study drug is administered and recorded on the Drug Administration Record (DAR) CRF page. 
Similarly, study drug end date is defined as the last date of study drug is administered and 
recorded on the study phase completion CRF page.
Study day: Study day will be calculated as (event date – study drug start date + 1 day) for 
events that occurred on or after study drug start date (e.g.visit, lab samples, AEs). For events 
prior to study drug start date (e.g., time of diagnosis), study day will be negative and 
calculated as (event date – study drug start date). 
Baseline and post baseline: In general, a baseline value refers to the last measurement made 
prior to administration of the first dose of study treatment or the average values taken prior to 
administration of the first dose of study treatment. A post-baseline value refers to a 
measurement taken after the first dose of study treatment.
2.2
Analysis sets
The following analysis sets will be used in this trial:
The Randomized set (RAN) comprises all randomized patients regardless of whether or not 
they actually received study treatment.
The Full analysis set (FAS) will include all randomized patients who received at least one 
dose of study treatment and have at least one evaluable post-baseline assessment. Following 
the intent-to-treat principle, patients will be analyzed according to the treatment they were 
assigned at randomization. The FAS will be used for all efficacy analyses.
The Per-protocol set (PPS) 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. Patients 
will be analyzed according to the treatment they were assigned to at randomization. The PPS 
will be used to assess the robustness of the results drawn from the primary analysis using FAS 
set.
The Safety set (SAF) will include all patients who received at least one dose of study 
treatment. 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 treatment in error. In addition, the FAS 
assigns randomized treatment and the Safety set assigns received treatment.
2.2.1
Subgroup of interest
There is no planned subgroup of interest.


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2.3
Patient disposition, demographics and other baseline 
characteristics
2.3.1
Patient disposition
The randomized set will be used for summary and listing of patient disposition.
The number of patients who were screened, randomized, completed the study and 
discontinued from the study will be summarized by treatments with reasons for premature 
discontinuation for randomized set. In addition, number of screen failures with reasons will be 
presented for all screened patients. Patient identification number and whether they completed 
or discontinued from the study will be listed, with date of last dose and primary reason for 
premature discontinuation.
2.3.2
Protocol deviation
The number and percentage of patients with protocol deviations will be tabulated by category 
and deviation for randomized set. Patients with protocol deviations will be listed with date 
and study day of occurrence, deviation and severity codes for randomized set.
The number of patients included in each analysis set will be tabulated for all screened patients. 
Reasons for exclusions from analysis sets will be tabulated for randomized set. Patient 
exclusion from analysis sets will be listed for all patients with reasons for exclusion (i.e., both 
protocol and non-protocol deviation).
2.3.3
Demographic characteristics
Demographics and baseline characteristics will be summarized using the randomized set.
The following demographic variables collected in the CRF at screening (Visit 0) will be 
summarized:

age (in years)

sex (Male or Female)

race (Caucasian, Black, Asian, Native American, Pacific Islander, Unknown, Other)

ethnicity (Hispanic or Latino, East Asian, Southeast Asian, South Asian, West Asian, 
Russian, Mixed Ethnicity, Not Reported, Unknown, Other)

height (cm)

weight (kg)

body mass index (BMI) (kg/m2)
The following baseline disease characteristics collected at screening (Visit 0) will be 
summarized:

Duration of COPD (in years, formula specified in Section 16.1.9.3)

Spirometry at baseline Visit 0 including 
– both pre- and post- bronchodilator FEV1 percentage of predicted normal value, 
FEV1 and FVC; 
– post-bronchodilator: FEV1/FVC, FEV1 percentage of increase; 


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– pre- bronchodilatory: FEV1 predicted normal value;

severity of airflow limitation at baseline Visit 0 (COPD severity: mild and moderate)

smoking history 
– number of pack-years

smoking status (current smoker and ex-smoker)
– number of packs per year (for current and ex-smokers only)

Vital signs (sitting systolic/diastolic blood pressure (mmHg), sitting pulse rate (bpm))
at Visit 0.

ECG at Visit 0.
In addition, the following categorizations will be done:

Age into 40 - < 65 years, 65 - < 75 years, and ≥ 75 years;

BMI into ≤ 30.0 kg/m2 and > 30.0 kg/m2;

Duration of COPD into < 1 year, > 1 - 5 years, > 5 - 10 years, > 10 - 15 years, > 15 –
20 years, and > 20 years;
2.3.4
Medical history/ current medical condition
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
terminology (MedDRA). History/conditions will be summarized for the randomized set by 
primary system organ class and preferred term, and overall. Verbatim recorded 
history/conditions will be listed together with the coded terms, date of diagnosis/surgery and 
whether the problem was ongoing at start of the study. 
2.3.4.1
Cardiovascular risk factors
Number and percentage of patients with specific cardiovascular risk factors will be 
summarized. In addition, the number and percentage of patients with 0, 1, 2, 3, 4 or more 
cardiovascular risk factors will be summarized. Cardiovascular risk factors are defined as the
following 7 medical histories/conditions:

CCV history/condition

Hypertension

Hyperlipidemia

Diabetes mellitus of either type

Obesity at baseline (i.e. BMI > 30 kg/m2)

Age ≥ 65 years

Current smoker at baseline.
The algorithms to identify the presence of the cardiovascular risk factors CCV 
history/condition, hypertension, hyperlipidemia, and diabetes mellitus is described in 
Appendix 5.1.1.


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2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
Duration of exposure
Duration of exposure to the treatment will be calculated as the number of days between the 
first dose date and the last dose date exposed to that treatment over the specified period 
(expressed as: Duration of exposure = Date of last known dose of study drug – Date of first 
dose of study drug + 1).
The duration of exposure (in days) will be summarized for the safety set as 

a continuous variable with the standard descriptive statistics, and 

a categorical variable classified into ≤ 4 weeks, > 4 – 8 weeks, > 8 - 12 weeks,
with number and percentage of patients in each category.
Compliance
QVA149 110/50µg of blister strips of capsules with single dose dry powder inhaler device 
and /or Tiotropium 18 µg of blister strips of capsules with HandiHaler® device was prescribed 
to each patient once daily. 
The compliance is defined as the percentage of doses taken by the patient and will be 
calculated using the following formula:
Compliance (%) = 100 x number of doses taken / duration of exposure.
Compliance will be summarized with the standard descriptive statistics and by categories (i.e., 
<80 %, >= 80 % - < 100 %, >= 100% - < 120% and >= 120 %) for the safety set.
2.4.2
Prior, concomitant and post therapies
Each medication has the start and end dates recorded. Prior medications are defined as those 
medications which were taken and stopped prior to first dose of study treatment. Concomitant
medications are defined as those medications which were taken on or after the first dose of
study drug but not prior to the first dose of study treatment, also includes those which were 
taken prior to and continued after the first dose of the study treatment. All prior/concomitant 
medications will be summarized as concomitant medications, and will not be included in prior 
medication outputs.
All prior and concomitant medication will be coded using WHO drug dictionary with most 
updated version. COPD-related medications will be summarized by pre-specified drug 
categories, route of administration, and preferred term, as recorded on the eCRF. The 
summary will be repeated by showing ingredients instead of preferred terms. Non-COPD 
related medication will be summarized by route of administration and preferred term. Both 
COPD-related and non-COPD related medications will be summarized separately for prior 
and concomitant medications.
All summaries will be on the safety set.


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2.5
Analysis of the primary objective
The primary objective of the study is to demonstrate the superiority of QVA 110/50 μg once 
daily compared to tiotropium 18 μg once daily in terms of trough forced expiratory volume in 
one second (FEV1 in Liters) after 12 weeks treatment.
2.5.1
Primary endpoint
The primary efficacy endpoint is trough FEV1 (L) after 12 weeks treatment, will be defined as 
the average of 45 and 15 min values prior to the administration of study treatment. 
The analysis of the primary variable will be based on the FAS patients.
2.5.2
Statistical hypothesis, model, and method of analysis
The statistical hypothesis is to demonstrate the superiority of QVA 110/50 µg once daily to 
tiotropium 18 µg once daily in patients having COPD with mild to moderate airflow 
limitations, the following hypothesis will be tested using an analysis of covariance 
(ANCOVA) model for the full analysis set:
Baseline FEV1 is defined the average of the pre-dose FEV1 measured at -45 min and -15 min
at Visit 1 (Day 1).
H0: There is no difference in trough FEV1 (L) at Week 12 for patients treated with QVA 
110/50 versus tiotropium 
HA: There is a difference in trough FEV1 (L) at Week 12 for patients treated with QVA 
110/50versus tiotropium 
The primary analysis will be performed comparing treatment means with respect to trough 
FEV1 (L) at Week 12 using analysis of covariance (ANCOVA) model with treatment and 
smoking status as fixed effects, baseline trough FEV1 as a covariate and center 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. 
In addition, the primary variable trough FEV1 (L) will be summarized by treatment group.
The superiority of QVA to tiotropium will be demonstrated if the p-value is less than 0.05 and 
the confidence interval lies entirely to the right of (higher than) 0 mL.
2.5.3
Handling of missing values/censoring/discontinuations
If any of the values contributing to the trough FEV1 are collected within 6 hours of rescue 
medication use or less than 7 days after systemic corticosteroid use then the individual FEV1
value will be set to missing or if the actual measurement times were outside the 22-25 hour
post-dose time window then the individual FEV1 value will be excluded from analyzed.
If any one of the 45 min or 15 min pre-dose values is missing at Week 12, the remaining non-
missing value will be considered as trough FEV1. If both values are missing, or if the patient 
has withdrawn from the trial, regardless of the reason for discontinuation, then missing trough 
values will be imputed with the last observation carried forward (LOCF) method using the 


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data at Visit 2. If the trough value at Visit 2 is missing, then patient will be excluded from this 
analysis.
2.5.4
Supportive analyses
Supportive analyses will be performed for trough FEV1 at Week 12 using the FAS, Since 
some patients will discontinue the study prematurely will affecting the sample size at Week 
12. Therefore the following analyses will also be performed as supplementary to support the 
result of the primary analysis:
1. The primary variable will be analyzed for patients who have a valid trough measurement 
at Week 12, without any imputation for missing data at week 12 using the FAS. The 
analysis will be performed using analysis of covariance (ANCOVA) model with treatment 
and smoking status as fixed effects, baseline trough FEV1 as a covariate and center 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.
2. Missing value of FEV1 at Week 12 will be imputed using LOCF method. The primary 
analysis will be performed at Week 12 for FAS and PPS using analysis of covariance 
(ANCOVA) model with treatment and smoking status as fixed effects, baseline trough
FEV1 as a covariate and center 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.
3. The primary variable will also be analyzed for patients who have been allowing by 
inclusion of values that fell within 6 hours of rescue medication use or within 7 days of 
systemic corticosteroid use using the FAS. The analysis will be performed using analysis 
of covariance (ANCOVA) model with treatment and smoking status as fixed effects, 
baseline trough FEV1 as a covariate and center 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.
4. A sensitivity analysis of trough FEV1 at Week 12 (with and without imputation by LOCF 
method) will also be performed by allowing inclusion of values that fell within 6 hours of 
rescue medication use or within 7 days of systemic corticosteroid use.
5. The following exploratory subgroup analyses for trough FEV1 after 12 weeks of treatment 
will be performed (using the appropriate interaction term in the model and additional 
covariate as a fixed effect if necessary) for the FAS to explore the treatment effect in:

Age group (40 - < 65 years, 65 - < 75 years, and ≥ 75 years).

Sex (male, female).

Severity of COPD (50% ≤FEV1 < 60%, FEV1 ≥60%).

Baseline smoking status (current smoker, ex-smoker).

Exacerbation (exacerbation history in previous year; 0 or 1).

Patient’s larger value of FEV1 reversibility after SABA (12% increase of reversibility 
and 200ml increase in FEV1, 12% increase of reversibility, 200ml increase in FEV1).

BMI (≤ 30.0 kg/m2, > 30.0 kg/m2).


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Estimates of adjusted treatment means will be displayed for each treatment along with the 
difference between treatments means, 95% confidence interval for treatment difference and p-
value will be presented.
6. The log-transformed trough FEV1 after 12 weeks of treatment will be analyzed for the 
FAS using the ANCOVA model with treatment and smoking status as fixed effects, log 
transformed baseline trough FEV1 as a covariate and center as a random effect. The 
estimated adjusted treatment ratios, and the associated 95% confidence intervals and p-
values will be displayed.
2.6
Analysis of the key secondary objective
2.6.1
Key secondary endpoint
Not Applicable.
2.6.2
Statistical hypothesis, model, and method of analysis
Not Applicable.
2.6.3
Handling of missing values/censoring/discontinuations
Not Applicable.
2.7
Analysis of secondary efficacy objective(s)
Refer to Table 1.2-1 of Section 1 for the list of secondary objectives.
2.7.1
Secondary endpoints
All the secondary efficacy evaluation will be performed on FAS population.
Refer to Table 1.2-1 of Section 1 for the list of secondary endpoints.
2.7.2
Statistical hypothesis, model, and method of analysis
Analysis of secondary endpoints:
2.7.2.1
Trough FEV1 and FVC at Week 4 and Week 12

Trough FEV1 (L) at Week 4 is defined as the average of FEV1 values taken at 45 and 
15 min prior to the administration of study treatment at Week 4 will be analyzed using 
analysis of covariance (ANCOVA) model with treatment and smoking status as fixed 
effects, baseline trough FEV1 as a covariate and center 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.

Trough FVC (L) at Week 12 is defined as the average of FVC values taken at 45 and 
15 min prior to the administration of study treatment at Week 12 will be analyzed 
using analysis of covariance (ANCOVA) model with treatment and smoking status as 
fixed effects, baseline trough FVC as a covariate and center as a random effect. 


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Adjusted least square means, point estimate of difference between treatment means, 
95% confidence interval for treatment difference and p-value will be presented.

Trough FVC (L) at Week 4 (the average of FVC values taken at 45 and 15 min prior to 
the administration of study treatment) will be analyzed using analysis of covariance 
(ANCOVA) model with treatment and smoking status as fixed effects, baseline trough 
FVC (L) as a covariate and center 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.

FEV1 (L) at Week 4 and Week 12 will be analyzed using analysis of covariance 
(ANCOVA) model with treatment, smoking status, visit and treatment by visit 
interaction as fixed effects, baseline FEV1 as a covariate and center 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.

FVC at Week 4 and Week 12 will be analyzed using analysis of covariance 
(ANCOVA) model with treatment, smoking status, visit and treatment by visit 
interaction as fixed effects, baseline FVC as a covariate and center 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.

FEV1/FVC at Week 4 and Week 12 will be analyzed using analysis of covariance 
(ANCOVA) model with treatment, smoking status, visit and treatment by visit 
interaction as fixed effects, baseline FEV1/FVC as a covariate and center 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.
2.7.2.2
Daily rescue medication use (number of puffs) over 12 weeks
The number of puffs of rescue medication taken in the previous 24 hr is recorded in the
electronic patient diary in the morning.
The total number of puffs of rescue medication per day over the full 12 weeks will be
calculated and divided by the total number of days with non-missing rescue medication data
to derive the mean daily number of puffs of rescue medication taken for the patient.  
The mean daily number of puffs of rescue medication used over 12 weeks of treatment will be
analyzed using a negative binomial regression model with treatment and smoking status as 
fixed effects with baseline rescue medication use as a covariates and center as a random effect. 
The log (exposure time) will be used as the offset variable in the model. Adjusted least square
means, point estimate of difference between treatment means, 95% confidence interval for 
treatment difference and p-value will be presented.
In addition, the mean daily number of puffs of rescue medication used over 12 weeks of 
treatment will be summarized by treatment group.
2.7.2.3
Percentage of ‘days with no rescue medication use’ over 12 weeks
A ‘day with no rescue use’ is defined from diary data as any day where the patient does not


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use any puffs of rescue medication.
The total number of ‘days with no rescue use’ over the 12 weeks treatment will be divided by 
the total number of days in order to derive the percentage of ‘days with no rescue use’.
The percentage of ‘days with no rescue use’ will be analyzed using analysis of covariance 
(ANCOVA) model with treatment and smoking status as fixed effects, baseline percentage of 
‘days with no rescue use’ as a covariate and center 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.
In addition, the percentage of ‘days with no rescue use’ over 12 weeks of treatment will be 
summarized by treatment group.
2.7.2.4
Dyspnea index
Dyspnea is measured at baseline using the baseline dyspnea index (BDI) and at the end of the
treatment period (Week 12) using the transition dyspnea index (TDI), which captures changes
from baseline.
The BDI and TDI each have three domains: functional impairment, magnitude of task and
magnitude of effort. The BDI domains are rated from 0 (severe) to 4 (unimpaired) and the
rates are summed for the baseline focal score ranging from 0 to 12; the lower the score the
worse the severity of dyspnea. The TDI domains are rated from -3 (major deterioration) to 3
(major improvement) and the rates are summed for the transition focal score ranging from -9
to 9; minus scores indicate deterioration. A TDI focal score of 1 is considered to be a 
clinically significant improvement from baseline. If the data are missing or insufficient for 
any one of the domains, a focal score cannot be imputed.
TDI focal score
The TDI focal score after 12 weeks of treatment will be analyzed using analysis of covariance 
(ANCOVA) model with treatment and smoking status as fixed effects, BDI focal score as a 
covariate and center 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.
In addition, dyspnea index data will be summarized.
Proportion of patients with a clinically important improvement in TDI focal score at 
Week 12
A TDI focal score of ≥1 is defined a clinically important improvement from baseline. The
proportion of patients who achieve a clinically important improvement will be analyzed using 
logistic regression with treatment and smoking status as fixed effects, BDI focal score as a 
covariate and center as a random effect. Estimated odds ratio along with associated 95% 
confidence interval and p-value will be presented. 
2.7.2.5
COPD Assessment Test (CAT)
The CAT score at Week 12 will be analyzed using analysis of covariance (ANCOVA) model 
with treatment and smoking status as fixed effects, baseline CAT score as a covariate and 


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center 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.
In addition, CAT score data will be summarized by visit and category.
2.7.3
Handling of missing values/censoring/discontinuations
No missing imputation will be performed for secondary endpoint.
2.8
Safety analyses
Safety measurements include ECG, vital signs, laboratory data and adverse events. All safety 
endpoints will be summarized by treatment for the safety set. All safety data will be included 
in the summaries or analysis regardless of rescue medication.
2.8.1
Adverse events (AEs)
All adverse events including COPD exacerbations will be listed.
Events which start on or after the time of the first administration of study drug but not later
than 7 days (30 days in the case of a Serious Adverse Event (SAE)) after the last
administration of study drug will be classified as treatment emergent AEs.
AEs that start during the study before the first administration of study drug will be classified 
as pre-treatment and will be listed only. In addition, all the treatment emergent AEs will also 
be listed.
AEs by primary system organ class and preferred term
The number and percentage of patients who reported treatment emergent adverse events will 
be summarized by primary system organ class and preferred term. Primary system organ 
classes will be sorted alphabetically and, within each system organ class, the preferred terms 
will be sorted in descending frequency within the QVA 110/50 treatment arm. In addition, 
number and percentage of patients with the most frequent AEs with atleast 5% in each 
treatment arm will also be summarized.
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 primary system 
organ class level.
AEs by severity
All treatment emergent adverse events will be summarized by primary system organ class, 
preferred term and maximum 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 more than once within the same patient will be counted once by maximum 
severity and treatment.


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AEs suspected to be related to study drug
All treatment emergent adverse events suspected to be related to study drug (according to the 
investigators) will be summarized by primary system organ class and preferred term. 
Relationship to study treatment is considered as suspected for those events where 
"Relationship to study treatment" is answered by the investigator as "Suspected".
AEs leading to permanent study drug discontinuation
All treatment emergent adverse events leading to permanent study drug discontinuation, 
regardless of study drug relationship, will be summarized by primary system organ class and 
preferred term.
Serious adverse events (SAE)
Number and percentage of patients with treatment emergent serious adverse events, regardless 
of study drug relationship, will be presented by primary system organ class and preferred term.
In addition, number and percentage of patient mortality and CCV SAE events will also be 
summarized.
2.8.1.1
Adverse events of special interest / grouping of AEs
Not Applicable.
2.8.2
Deaths
All the deaths in the clinical database will be listed with the investigator-reported principal 
cause. Deaths occurring after the first dose of study treatment until 30 days after the date of 
last treatment will be summarized. In addition, deaths occurring after the first dose of study 
treatment till the date of last treatment will also be summarized.
2.8.3
Laboratory data
All laboratory data will be listed with abnormal values flagged.
Laboratory data measured more than 7 days after last dose of study drug is regarded as
post-treatment data and will not be summarized or analyzed, only listed.
For all continuous laboratory parameters, summary statistics for absolute and change from 
baseline at each scheduled visit and treatment will be provided and all laboratory data 
(including any unscheduled assessments) will be listed with abnormal values flagged. 
For categorical urinalysis laboratory parameters, a frequency table of results will be produced
by laboratory parameter, scheduled visit and treatment.
Shift tables for laboratory parameters will be provided in order to compare a subject’s 
baseline value to the value at each timepoint at each study visit, relative to the normal 
reference range for each lab parameter. Normal reference ranges provided by the local lab will 
be used to evaluate whether a particular laboratory test value for each timepoint at each visit is 
normal, low or high relative to the baseline value also categorized as normal, low or high. 
These summaries will be presented by laboratory parameter, visit, timepoint, and treatment 
group.


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In addition, shift tables relative to the normal reference ranges will be used to summarize the
change from baseline to the most extreme post-baseline for each laboratory parameter. For 
each laboratory test, the subjects will be classified into one of the four mutually exclusive 
groups (low, normal, high, and low + high), defined as follows:

Low: at least one post-baseline value below the normal range and none above the normal
range

High: at least one post-baseline value above the normal range and none below the normal
range

Normal: all the post-baseline values within the normal range

Low + High: at least one post-baseline value below the normal range and at least one
above the normal range
Categorical parameters in the urinalysis panel will also be summarized with shift tables
showing the shift from one categorical result to another. The shift from baseline to most
extreme post baseline value will also be summarized, with the least to most extreme scale
assumed to be negative, trace, +, ++, +++, ++++.
2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
Data from the electrocardiogram will be summarized by treatment at all time-points
Data measured more than 7 days after last dose of study drug will be regarded as 
posttreatment data and will not be summarized but listed only.
The following quantitative variables will be summarized by treatment at each scheduled 
postdose visit: ventricular rate, QT interval, RR interval, PR interval, QRS duration and 
Fridericia’s QTc (QTcF). The maximum QTcF will also be summarized.
The changes from baseline will be summarized by ECG parameter, scheduled visit and 
timepoint where baseline and post-baseline values are both available.
Notable value is defined as a QTc interval of greater than 450 ms. The categories used for the 
change from baseline in QTc are less than 30 ms, 30 to 60 ms and greater than 60 ms.
For a subject to meet the criterion of a newly occurring clinically notable value, the subject
needs to have a baseline value which is not clinically notable for that parameter. For a subject
to meet the criterion of a worsening clinically notable value, the subject needs to have a
baseline value which is clinically notable and also have a worse post-baseline value. For
subjects with a missing value at baseline, post-baseline values meeting the notable criterion
will be considered as newly occurring. The number and percentage of subjects who have
newly occurring or worsening clinically notable values, or notable changes from baseline, will
be presented by scheduled post-baseline visit. A listing of all newly occurring or worsening 
abnormalities will be provided.
2.8.4.2
Vital signs
Data measured more than 7 days after last dose of study drug will be regarded as 
posttreatment data and will not be summarized or analyzed, but listed only.


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Data from the vital signs (systolic blood pressure, diastolic blood pressure, pulse rate and 
weight) will be summarized by treatment at the scheduled visits. The maximum and minimum 
systolic blood pressure, diastolic blood pressure, and pulse rate post-baseline will also be 
summarized by treatment.
Vital signs will also be summarized by categories:
• systolic blood pressure: < 75 mmHg, 75 – 200 mmHg, and > 200 mmHg
• diastolic blood pressure: < 40 mmHg, 40 – 115 mmHg, and > 115 mmHg
• pulse rate: < 40 bpm, 40 – 130 bpm, and > 130 bpm
Notable values for vital signs will also be summarized by categories:
• 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
The change from baseline to each scheduled post-baseline visit will be summarized similarly
as the laboratory parameters where baseline and post-baseline values are both available. The
summary will be presented by vital sign parameter, scheduled visit, and treatment with 
standard descriptive statistics.
The number and percentage of subjects with newly occurring or worsening notable values,
including notable change from baseline, will be summarized by vital sign parameter,
scheduled post-baseline visit and treatment group. Subjects with any newly occurring or 
worsening value meeting the clinically notable criteria will be counted under the applicable 
criteria. 
For a subject to meet the criterion of a newly clinically notable occurrence, the subject needs
to have a baseline value which does not meet the criteria for categorizing a value as notable.
For a subject to meet the criterion of a worsening occurrence, the subject needs to have a
baseline value which is clinically notable and also have a worse post-baseline value. For
subjects with a missing value at baseline, post-baseline values meeting the notable criterion
will be considered as newly occurring. For subjects with both baseline and post-baseline
values which are clinically notable but in opposing directions (e.g. Low at baseline and high
at post-baseline, or vice versa), the post-baseline notable value will be considered as newly
occurring.
Absolute body weight and change from baseline will be summarized by visit and treatment
group.
2.9
Pharmacokinetic endpoints
Not Applicable.


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2.10
PD and PK/PD analyses
Not Applicable.
2.12
Biomarkers
Not Applicable.
2.14
Interim analysis
No interim analysis is planned for this study.


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3
Sample size calculation
The primary objective is to demonstrate superiority of QVA149 110/50 µg once daily
compared to tiotropium 18 µg once daily in terms of pre-dose trough FEV1 (L) after 12 weeks 
of treatment. Based on the results of QVA149A2303 (SHINE) study, it was assumed that the 
estimated treatment difference between QVA149 and tiotropium is 82 mL and corresponding 
standard deviation is 271 mL (Bateman et al 2013). With these estimates, a sample size of 173
patients in each treatment arm would be required to achieve 80% power on a 2-sided test with 
5% level of significance. 
Therefore assuming a dropout rate of 11%, approximately 404 patients will be enrolled in the 
study.
4
Change to protocol specified analyses
5
Appendix
5.1
Imputation rules
5.1.1
AE date imputation
The following table explains the notation used in the logic matrix. Please note that
missing start dates will not be imputed.
Day
Month
Year
Partial Adverse Event Start Date
Not used
MON
YYYY
Treatment Start Date (TRTSTD)
Not used
TRTM
TRTY
The following matrix explains the logic behind the imputation.
MON
MISSING
MON < TRTM
MON = TRTM
MON > TRTM
YYYY
MISSING
NC
Uncertain
NC
Uncertain
NC
Uncertain
NC
Uncertain
YYYY < TRTY
( D )
Before Treatment Start
( C )
Before Treatment Start
( C )
Before Treatment Start
( C )
Before Treatment Start
YYYY = TRTY
(B)
Uncertain
( C )
Before Treatment Start
(A)
Uncertain
(A)
After Treatment Start
YYYY > TRTY
(E)
After Treatment Start
(A)
After Treatment Start
(A)
After Treatment Start
(A)
After Treatment Start
The following table is the legend to the logic matrix.
If AE end date is complete and AE end date < Treatment start date or AE end date is partial 
and AE imputed end date < Treatment start date, then AE start reference = min (informed
consent date, earliest visit date from SV) Else if AE end date is partial,AE end date > = 
Treatment start date or AE is ongoing , then AE start reference = treatment start date.


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Relationship
Time imputation
Before AE start reference
Partial date indicates AE start 
date prior to AE start reference
After AE start reference
Partial date indicates AE start 
date after AE start reference
Uncertain
Partial date insufficient to 
determine relationship of AE 
start date to AE start reference
Imputation Calculation
NC/Blank
No convention
(A)
MAX( 01MONYYYY, AE start
reference+1 day)
(B)
AE start reference+1
(C)
15MONYYYY
(D)
01JULYYYY
(E)
01JANYYYY
Complete date
No date imputation
If time is cuptured for the study
Case1: if AE start date is not 
equal to AE start reference then 
do the following:
     If minutes missing then 
AESTMF = M and time is 
imputed to hh:00
    If minutes missing then 
AESTMF = H and time is 
imputed to 00:00
Case2: if AE start date = AE 
start reference then AESTMF = 
H and time is imputed to 
treatment start time + 1 hour
Adverse Event End Date Imputation
Imputed date = date part of original date, if complete date
Imputed date = min (completion/discontinuation visit date, DEC 31, date of death), if month 
is missing
Imputed date = min (completion/discontinuation visit date, last day of the month, date of 
death), if day is missing
Adverse Event End Time Imputation
If the AE end date is complete and time is captured in the study then:
Case 1. if AE end date is not equal to Treatment end date, then do the following:
if minutes missing then time is imputed to hh:00 if time missing then time is imputed to 00:00
Case 2: if AE end date = Treatment end date then time is imputed to treatment end time
If the AE end date is partial then end time is imputed to 00:00.


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Imputed Date Flag
If year of the imputed date is not equal to YYYY then date flag = Y
else if month of the imputed date is not equal to MON then date flag = M
else if day of the imputed date is not equal to day of original date then date_flag = D
else date flag = null
Imputed Time Flag
If hours of the imputed time is not equal to hours of original time then time flag = H
else if minutes of the imputed time is not equal to minutes of original time then time flag = M
else time flag = null.
Cardiovascular risk factors
Seven cardiovascular risk factors were defined. The first four, CCV history/condition,
hypertension, hyperlipidemia, type 2 diabetes are taken from the CRF page of Medical
History – Protocol solicited events – Cardiovascular events.
The remaining cardiovascular risk factors 5. Obesity at baseline (i.e. BMI > 30 kg/m2), 6. Age
≥ 65 years, and 7. Current smoker at baseline will be identified directly from the data recorded
in the eCRF.
5.1.2
Concomitant medication date imputation
This algorithm is used when event is the partial start date of the concomitant medication.
The following table explains the notation used in the logic matrix. Please note that
missing start dates will not be imputed.
Day
Month
Year
Partial CM Start Date
Not used
MON
YYYY
Treatment Start Date (TRTSDT)
Not used
TRTM
TRTY
The following matrix explains the logic behind the imputation.
MON 
MISSING
MON < TRTM
MON = TRTM
MON > TRTM
YYYY 
MISSING
(C2)
Uncertain
(C1)
Uncertain
(C1)
Uncertain
(C1)
Uncertain
YYYY < TRTY
(D)
Before Treatment Start
(A)
Before Treatment Start
(A)
Before Treatment Start
(A)
Before Treatment Start
YYYY = TRTY
(C2)
Uncertain
(A)
Before Treatment Start
(C1)
Uncertain
(B)
After Treatment Start
YYYY > TRTY
(E)
After Treatment Start
(B)
After Treatment Start
(B)
After Treatment Start
(B)
After Treatment Start
The following table is the legend to the logic matrix.
Relationship
Before Treatment Start
Partial date indicates CMD start date prior to Treatment Start Date
After Treatment Start
Partial date indicates CMD start date after Treatment Start Date


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Uncertain
Partial date insufficient to determine relationship of CMD start date relative to Treatment
Start Date
Imputation Calculation
(A)
15MONYYYY
(B)
01MONYYYY
(C1 or C2)
IF
relative reference start = before treatment start THEN TRTSDT-1
ELSE IF relative reference start = ‘ ’ THEN TRTSDT+1
(D)
01JULYYYY
(E)
01JANYYYY
Concomitant Medication End Date Imputation
If not ongoing then -
Imputed date = date part of CMENDTC, if complete date
Imputed date = min(completion/discontinuation visit date, DEC 31) , if month is missing,
(C2, D, E)
Imputed date = min(completion/discontinuation visit date, last day of the Month) , if day is
missing. (A, B, C1)
Concomitant Medication Date Flag
If not a complete date then
Y - If year of the imputed date is not equal to YYYY else M – If month of the imputed date is
not equal to MON else D.
5.1.2.1
Prior therapies date imputation
Same as above.
5.1.2.2
Post therapies date imputation
Same as above.
5.1.2.3
Other imputations
Same as above.
5.2
AEs coding/grading
NA
5.3
Laboratory parameters derivations
NA


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5.4
Statistical models
5.4.1
Primary analysis
The SAS procedure PROC MIXED, will be used to perform ANCOVA with the following 
SAS code:
PROC MIXED DATA = ....  ORDER = internal;
CLASS usubjid acenter trtpn smkst;
MODEL aval = trtpn smkst bl / DDFM=kr;
RANDOM acenter;
LSMEANS trtpn / CL DIFF;
ESTIMATE “QVA149 - Tiotropium” 1 -1/diff cl alpha=0.05;
RUN;
where aval
= dependent variable, e.g. Trough FEV1
trtpn
= Treatment 
smkst
= Smoking status
usubjid
= Patient identifier
bl
= Baseline value
acenter 
= Center
5.4.2
Key secondary analysis
The SAS procedure PROC MIXED, will be used to perform ANCOVA along with interaction 
term with the following SAS code:
PROC MIXED DATA = ....  ORDER = internal;
CLASS usubjid acenter trtpn smkst avisit;
MODEL aval = trtpn smkst avisit trtpn*avisit bl / DDFM=kr;
RANDOM acenter;
LSMEANS trtpn / CL DIFF;
ESTIMATE “QVA149 - Tiotropium” 1 -1/diff cl alpha=0.05;
RUN;
where aval
= dependent variable, e.g. FEV1
trtpn
= Treatment 
smkst
= Smoking status
avisit 
= Visit number
usubjid
= Patient identifier
bl
= Baseline value
acenter 
= Center
The SAS procedure PROC GENMOD, will be used to perform Negative Binomial model with 
the following SAS code:
PROC GENMOD DATA = ....  internal;
CLASS usubjid acenter trtpn smkst;
MODEL aval = trtpn smkst bl / dist=nb link=log offset=lrisk lrci type3 wald;
RANDOM acenter;
LSMEANS trtpn / CL DIFF EXP;


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ESTIMATE “QVA149 - Tiotropium” 1 -1/diff cl alpha=0.05;
RUN;
where aval
= dependent variable, e.g. Number of puffs of rescue medications
trtpn
= Treatment 
smkst
= Smoking status
avisit 
= Visit number
usubjid
= Patient identifier
bl
= Baseline value
lrisk 
= log (exposure time)
acenter 
= Center
The SAS procedure PROC LOGISTIC, will be used to perform Logistic regression with the 
following SAS code:
Certain binary outcome variables, e.g. response outcomes, will be evaluated using a logistic
regression model with treatment, smoking status, BDI focal score. Odds ratios will be
computed for comparisons of QVA149 versus Tiotropium utilizing the logistic regression 
model fitted.
PROC LOGISTIC DATA = .... ;
CLASS usubjid acenter trtpn smkst / param=glm;
MODEL aval = trtpn smkst bl;
RANDOM acenter;
LSMEANS trtpn / diff cl exp;
Ods output diffs=lsm_diff;
Run;
In cases where separation is a concern, e.g. 0% response in one treatment (sub)group, an exact
logistic regression model will be applied. To ensure convergence, this model will not include
any continuous covariates.
PROC LOGISTIC DATA = .... exactonly;
CLASS usubjid acenter trtpn smkst / param=glm;
MODEL aval = trtpn smkst;
EXACT trtpn / estimate=both;
Ods output exactoddsratio=exactoddsratio;
Run;
The SAS procedure PROC CORR, will be used to perform pearson’s product moment 
correlation with the following SAS code:
PROC CORR DATA = .... OUTP=CORR;
VAR VAR1 VAR2;
Run;


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5.5
Rule of exclusion criteria of analysis sets 
Table 1
Protocol deviations that cause subjects to be excluded
Deviation 
ID
Description of Deviation
Exclusion in Analyses
Severity 
code
INCL01
Signed informed consent not obtained
Excluded from PP analysis
1
INCL02
Patients' s age less than 40 years 
Or, DOB missing
Excluded from PP analysis
1
INCL03
COPD not diagnosed according to 
GOLD guidelines
Excluded from PP analysis
1
INCL03A
Post-bronchodilator FEV1 less than 50 
percentage of the predicted normal 
value Or,
post-bronchodilator FEV1 
value divided by FVC value is greater 
than or equal to 0.7
Excluded from PP analysis
1
INCL03B
Smoking history less than 10 pack 
years
Excluded from PP analysis
1
INCL04
CAT score less than 10 at  Visit 0 and 
Visit 1
Excluded from PP analysis
1
INCL05
Patients not on tiotropium monotherapy 
for the past 3 months
Excluded from PP analysis
1
INCL06
More than 1 COPD exacerbations in the 
previous 12 months or,
1 COPD 
exacerbations leading to hospitalization, 
in previous months
Excluded from PP analysis
1
EXCL01
Treatment with any ICS in the 3 months 
prior to Visit 1
Excluded from PP analysis
1
EXCL02
Pregnant or nursing (lactating) women.
Excluded from PP analysis
1
EXCL04
Presence 
of 
any 
contraindication, 
warning, precaution, hypersensitivity to 
LABA and LAMA
Excluded from PP analysis
1
EXCL05
History or current diagnosis of clinically 
significant ECG abnormalities.
Excluded from PP analysis
1
EXCL06
Patients not achieved an acceptable 
spirometry result at Visit 1
Excluded from PP analysis
1
EXCL07
Patients with Type I diabetes
Excluded from PP analysis
1
EXCL07A
Patients 
with uncontrolled Type II 
diabetes
Excluded from PP analysis
1
EXCL08
Patients with narrow angle glaucoma, 
symptomatic BPH or bladder neck 
obstruction, moderate or severe renal 
impairment or urinary retention.
Excluded from PP analysis
1
EXCL09
Patient has active cancer or has been 
cancer free for less than 5 years
Excluded from PP analysis
1
EXCL10
As per Investigator, History of clinically 
significant diseases will put safety of 
patients 
at 
risk 
through 
study 
participation or will compromise patient 
compliance or preclude completion of 
study.
Excluded from PP analysis
1
EXCL11
Uncontrolled 
hypothyroidism 
and 
hyperthyroidism, hypokalemia.
Excluded from PP analysis
1
EXCL12
Patients with neurological, endocrine, 
immunological,
psychiatric, 
Excluded from PP analysis
1


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gastrointestinal, 
hepatic, 
or
hematological abnormalities.
EXCL13
Patients who are, in the opinion of the 
investigator, known to be unreliable or 
non-compliant.
Excluded from PP analysis
1
EXCL14
Long term oxygen therapy of more than 
12 hrs. per day prescribed to patient.
Excluded from PP analysis
1
EXCL15
Patients 
reported 
with 
COPD 
exacerbation between Visit 0 and 1, can 
be re screened after a minimum of 6 
weeks 
after 
resolution 
of 
the 
exacerbation if the exacerbation did not 
require hospitalization.
Excluded from PP analysis
1
EXCL16
Onset 
of 
respiratory 
symptoms, 
including a COPD diagnosis prior to age 
40 years
Excluded from PP analysis
1
EXCL17
History of respiratory infection within 4 
weeks prior to Visit 0. 
Excluded from PP analysis
1
EXCL17A
Patients 
develops 
respiratory 
tract 
infection between Screening and prior 
to treatment will be permitted to be re-
enrolled 4 weeks after the resolution of 
the respiratory tract infection
Excluded from PP analysis
1
EXCL18
Patient with concomitant pulmonary 
diseases.
Excluded from PP analysis
1
EXCL19
Patients with lung lobectomy, or lung 
volume reduction or lung transplantation
Excluded from PP analysis
1
EXCL20
Patient has a history of Asthma
Excluded from PP analysis
1
EXCL21
Treatments 
for 
COPD 
and 
allied 
conditions: 
the 
following 
class 
of 
medications should be washed out prior 
to randomization (Visit 1) or prohibited 
during the study period.
Excluded from PP analysis
1
EXCL22
Patients 
with 
COPD 
and 
allied 
conditions.
Excluded from PP analysis
1
EXCL23
Patients 
had 
live 
attenuated 
vaccinations within 30 days prior to the 
screening visit.
Excluded from PP analysis
1
EXCL23A
Patients 
had 
inactivated 
influenza 
vaccination, pneumococcal vaccination 
or any other inactivated vaccine is 
administered within 48 hours prior to 
screening and randomization visits.
Excluded from PP analysis
1
EXCL24
Use of other investigational drugs at the 
time of enrollment, or within 30 days or 
5 half lives of Visit 1, whichever is 
longer.
Excluded from PP analysis
1
EXCL25
Patients unable to use a dry powder 
inhaler.
Excluded from PP analysis
1
EXCL25A
Patients unable to use a MDI.
Excluded from PP analysis
1
WITH01
Patients, who either become pregnant, 
while taking study medication.
Excluded from PP analysis
1
OTH02
Reversibility test not performed as 
required per protocol
Excluded from PP analysis
1
OTH03
Spirometry 
test 
not 
performed 
as 
Excluded from PP analysis
1


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Table 2
Subject Classification
Analysis Set
PD ID that
  
cause subjects to be excluded
Non-PD criteria that cause 
subjects to be excluded
RAN
NA
Not randomized
FAS
NA
Not in RAN;
Mistakenly randomized and no post-baseline
taken
PPS
All specified PD in Table 1
Not in FAS;
SAF
NA
No study drug taken
6
Reference
required per protocol
OTH04
Treatment Compliance less than 80 
percentage  or greater than 120 
percentage.
Excluded from PP analysis
1
OTH05
Time of spirometry outside of 22 to 25 
hrs.
Excluded from PP analysis
1
OTH06
Assigned IMP via NIRT but
subject took Non-IMP.
Excluded from PP analysis
1
OTH07
Time zone for treatment group
Xoterna is greater than 37hrs or
lesser than 22hrs.
Excluded from PP analysis
1
OTH08
Time zone for treatment group
Spiriva is greater than 25hrs or
lesser than 22hrs. 
Excluded from PP analysis
1