Conditions: Pulmonary Disease, Chronic Obstructive
Keywords: COPD
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 974
Healthy volunteers: no

Brief summary:
This clinical study was designed to support the dose selection for future studies by evaluating efficacy and safety of different QBW251 doses in Chronic obstructive pulmonary disease (COPD) patients with chronic bronchitis and a history of exacerbations, compared to placebo, when added to a triple inhaled therapy of LABA, LAMA and ICS.

Detailed description:
This study used a 6 treatment arm, parallel-group, randomized, double-blind study design. 974 male and female COPD patients were randomized into the trial. The study consisted of four distinct study periods:

* Screening (Weeks -3 to -2): Participants underwent a screening period of 1 week where were assessed for eligibility and tapered off disallowed medications.
* Run-in (Days -14 to 1): Subsequently, participants entered the run-in period of up to 2 weeks to establish baseline values for symptom assessments, to standardize the COPD background therapy (triple combination LABA/LAMA/ICS), and to complete eligibility assessments.
* Treatment (Day 1 to Week 24): Eligible participants moved into the Day 1 visit where they were stratified according to their smoking status (current or ex-smoker) and severity of airflow limitation (FEV1 ≥ 30% to \< 50% and ≥ 50% to \< 80%) and then randomized into 1 of 6 treatment arms with a randomization ratio of 2:2:1:1:1:2 (450 mg b.i.d., 300 mg b.i.d., 150 mg b.i.d., 75 mg b.i.d., 25 mg b.i.d., placebo). The treatment period consisted of 24 weeks, during which the participant returned to the site for regular visits (Day 1 - Week 24). QBW251 450 mg arm was discontinued early based on a pre-defined pharmacokinetic exposure stopping rule.
* Follow-up (Weeks 25-28): Upon completion of the treatment period, participants were followed up for safety assessments for 30 days.

Arms:
arm 1: QBW251 was orally administered 450 mg b.i.d for 24 weeks arm 2: QBW251 was orally administered 300 mg b.i.d for 24 weeks arm 3: QBW251 was orally administered 150 mg b.i.d for 24 weeks arm 4: QBW251 was orally administered 75 mg b.i.d for 24 weeks arm 5: QBW251 was orally administered 25 mg b.i.d for 24 weeks arm 6: Placebo was orally administered b.i.d for 24 weeks

Interventions: intervention 1: QBW251 intervention 2: Placebo intervention 3: COPD maintenance background therapy
Intervention descriptions: intervention 1: QBW251 oral capsules (450, 300, 150, 75 and 25 mg) of identical appearance to ensure blinding administered twice a day (b.i.d) for 24 weeks intervention 2: Placebo oral capsules administered twice a day for 24 weeks intervention 3: Combination of fluticasone furoate, vilanterol and umeclidinium bromide

Protocol document:
Prot_000.pdf: 


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................11
Amendment 3 (10-Jun-2020) ............................................................................................13
Amendment 2 ....................................................................................................................16
Amendment 1 ....................................................................................................................18
Protocol summary..............................................................................................................20
1
Introduction .......................................................................................................................24
1.1
Background............................................................................................................24
1.2
Purpose ..................................................................................................................25
2
Objectives and endpoints...................................................................................................25
3
Study design ......................................................................................................................27
4
Rationale............................................................................................................................28
4.1
Rationale for study design .....................................................................................28
4.1.1
Rationale for choice of background therapy.........................................29
4.2
Rationale for dose/regimen and duration of treatment ..........................................29
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................30
4.4
Purpose and timing of interim analyses/design adaptations..................................30
4.4.1
Safety.....................................................................................................30
4.4.2
Efficacy .................................................................................................30
4.5
Risks and benefits..................................................................................................30
5
Population..........................................................................................................................33
5.1
Inclusion criteria ....................................................................................................33
5.2
Exclusion criteria...................................................................................................34
6
Treatment...........................................................................................................................38
6.1
Study treatment......................................................................................................38
6.1.1
Investigational and control drugs..........................................................38
6.1.2
Additional study treatments ..................................................................39
6.1.3
Treatment arms/group ...........................................................................39
6.1.4
Treatment duration................................................................................40
6.2
Other treatment(s)..................................................................................................40
6.2.1
Concomitant therapy.............................................................................40
6.2.2
Prohibited medication ...........................................................................45


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6.2.3
Rescue medication ................................................................................46
6.3
Subject numbering, treatment assignment, randomization....................................47
6.3.1
Subject numbering ................................................................................47
6.3.2
Treatment assignment, randomization ..................................................47
6.4
Treatment blinding.................................................................................................47
6.5
Dose escalation and dose modification..................................................................48
6.5.1
Dose modifications................................................................................48
6.5.2
Follow-up for toxicities.........................................................................49
6.6
Additional treatment guidance...............................................................................49
6.6.1
Treatment compliance...........................................................................49
6.6.2
Emergency breaking of assigned treatment code..................................49
6.7
Preparation and dispensation.................................................................................50
6.7.1
Handling of study treatment and additional treatment..........................50
6.7.2
Instruction for prescribing and taking study treatment .........................51
7
Informed consent procedures ............................................................................................52
8
Visit schedule and assessments .........................................................................................53
8.1
Screening ...............................................................................................................61
8.1.1
Information to be collected on screening failures.................................61
8.2
Subject demographics/other baseline characteristics.............................................61
8.3
Efficacy..................................................................................................................62
8.3.1
Appropriateness of efficacy assessments..............................................62
8.3.2
Spirometry.............................................................................................62
8.3.3
e-Diary...................................................................................................63
8.3.4
EXACT questionnaire...........................................................................63
8.3.5
St George's Respiratory Questionnaire (SGRQ)...................................64
8.3.6
Patient global impression of severity (PGI-S: general and specific) ....64
8.3.7
Cough And Sputum Assessment Questionnaire (CASA-Q).................64
65
65
66
66
8.4
Safety.....................................................................................................................67
8.4.1
Laboratory evaluations..........................................................................68
8.4.2
Electrocardiogram (ECG) .....................................................................69
8.4.3
Pregnancy and assessments of fertility .................................................69
8.5
Additional assessments..........................................................................................69
8.5.1
Pharmacokinetics ..................................................................................69


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70
70
71
9
Study discontinuation and completion ..............................................................................71
9.1
Discontinuation......................................................................................................71
9.1.1
Discontinuation of investigational treatment ........................................71
9.1.2
Withdrawal of informed consent...........................................................73
9.1.3
Lost to follow-up...................................................................................73
9.1.4
Early study termination by the sponsor.................................................74
9.2
Study completion and post-study treatment ..........................................................75
10 Safety monitoring and reporting........................................................................................75
10.1
Definition of adverse events and reporting requirements......................................75
10.1.1
Adverse events ......................................................................................75
10.1.2
Serious adverse events ..........................................................................77
10.1.3
SAE reporting........................................................................................78
10.1.4
Pregnancy reporting ..............................................................................79
10.1.5
Reporting of study treatment errors including misuse/abuse................79
10.2
Additional Safety Monitoring................................................................................80
10.2.1
Liver safety monitoring.........................................................................80
10.2.2
Renal safety monitoring........................................................................81
10.2.3
Data Monitoring Committee .................................................................81
11 Data Collection and Database management......................................................................81
11.1
Data collection.......................................................................................................81
11.2
Database management and quality control............................................................81
11.3
Site monitoring ......................................................................................................82
12 Data analysis and statistical methods ................................................................................83
12.1
Analysis sets ..........................................................................................................83
12.2
Subject demographics and other baseline characteristics......................................83
12.3
Treatments .............................................................................................................83
12.4
Analysis of the primary endpoint(s) ......................................................................84
12.4.1
Definition of primary endpoint(s).........................................................84
12.4.2
Statistical model, hypothesis, and method of analysis..........................85
12.4.3
Handling of missing values/censoring/discontinuations.......................87
12.4.4
Supportive analyses...............................................................................87
12.5
Analysis of secondary endpoints ...........................................................................88
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)....................................88
12.5.2
Safety endpoints....................................................................................90


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12.5.3
Pharmacokinetics ..................................................................................91
92
92
92
12.7
Interim analyses.....................................................................................................93
12.7.1
Safety.....................................................................................................93
12.7.2
Efficacy .................................................................................................94
12.8
Sample size calculation..........................................................................................94
13 Ethical considerations and administrative procedures ......................................................95
13.1
Regulatory and ethical compliance........................................................................95
13.2
Responsibilities of the investigator and IRB/IEC..................................................95
13.3
Publication of study protocol and results...............................................................95
13.4
Quality Control and Quality Assurance.................................................................96
14 Protocol adherence ............................................................................................................96
14.1
Protocol Amendments ...........................................................................................96
15 References .........................................................................................................................97
16 Appendices ......................................................................................................................101
16.1
Appendix 1: Clinically notable laboratory values and vital signs .......................101
16.2
Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.......................................................................................................102
16.3
Appendix 3 Spirometry guidance ........................................................................105
16.4
Appendix 4 CASA-Q...........................................................................................107
113
16.6
Appendix 6 EXACT questionnaire......................................................................114
117
16.8
Appendix 8 PGI...................................................................................................119
119
16.10 Appendix 10 CAT................................................................................................121
16.11 Appendix 11 e-Diary (for rescue medication).....................................................123
16.12 Appendix 12: SGRQ............................................................................................123
List of tables
Table 2-1
Objectives and related endpoints ..........................................................25
Table 6-1
Investigational and control drug............................................................38
Table 6-2
Medications permitted under certain conditions...................................41
Table 6-3
Medications the exposure of which may be modified by co-
administration with QBW251 ...............................................................42


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Table 6-4
Examples of contraceptives not recommended for systemic use 
(not acceptable as means of contraception as efficacy may be 
compromised by QBW251 administration) ..........................................44
Table 6-5
Prohibited medication ...........................................................................45
Table 6-6
Prohibited COPD-related medications..................................................46
Table 8-1
Assessment Schedule ............................................................................54
Table 8-2
Timed assessments for all visits............................................................58
Table 8-3
Timed assessments for Day 1 and Day 15 for subjects participating 
in the additional PK sampling sub-group (additional PK 
timepoints).............................................................................................60
Table 8-4
Assessments and Specifications............................................................67
Table 8-5
Laboratory parameters ..........................................................................68
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................79
Table 12-1
Power and Precision..............................................................................94
Table 16-1
Liver Event and Laboratory Trigger Definitions ................................102
Table 16-2
Follow Up Requirements for Liver Events and Laboratory Triggers.102
List of figures
Figure 3-1
Study design..........................................................................................28
Figure 5-1
Illustration of inclusion criteria 6. and 7. ..............................................34
Figure 12-1
Candidate Dose Response Curves.........................................................86


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List of abbreviations
AE
adverse event
AIC
Akaike information criterion
Alb
Albumin
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATS/ERS
American Thoracic Society (ATS)/European Respiratory Society (ERS)
AUC
Area under the plasma concentration-time curve
AUC0-24h
Area under the plasma concentration curve over 24 hours
b.i.d.
twice a day
BCRP
Breast Cancer Resistance Protein
BD
bronchodilator
BMI
Body Mass Index
BTPS
body temperature, pressure, saturated with water vapor
BUN
blood urea nitrogen
CASA-Q
Cough and sputum assessment questionnaire
CAT
COPD assessment test
CF
Cystic fibrosis
CFR
Code of Federal Regulation
CFTR
Cystic fibrosis transmembrane conductance regulator
Cmax
Maximum concentration
Cmin
Minimum concentration
CMO & PS
Novartis Chief Medical Office and Patient Safety
COPD
Chronic Obstructive Pulmonary Disease
COUI
cough impact domain
COUS
cough symptoms domain
COVID-19
Corona Virus Disease 2019
CRA
Clinical Research Associate
CRF
Case Report/Record Form (paper or electronic)
CRO
Commercial Research Organization
CT
computer-assisted tomography
CTT
Clinical Trial Team
CV
coefficient of variation
CYP1A2
Cytochrome P450 1A2 enzyme
CYP2B6
Cytochrome P450 2B6 enzyme
CYP3A4
Cytochrome P450 3A4 enzyme
DAR
Dose Administration Record
DDE
Direct Data Entry
DMC
Data Monitoring Committee


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DR
Dose response
EC
Ethics committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
ED50
efficacious dose in 50% of subjects
EDC
Electronic Data Capture
EDD
expected date of delivery
EMA
European Medicines Agency
E-RS
Evaluating Respiratory Symptoms in COPD
ER
emergency room
ERS
European Respiratory Society
eSAE
Electronic Serious Adverse Event
EU
European Union
EXACT
EXAcerbations of COPD Tool
FAS
Full analysis set
FDA
Food and Drug Administration
FEV1
Forced expiratory volume in one second
FVC
Forced vital capacity
GCP
Good Clinical Practice
GGT
gamma-glutamyltransferase
GOLD
The Global Initiative for Chronic Obstructive Lung Disease
h
Hour
hCG
Human chorionic gonadotropin
HCRU
Health care resource utilization
IA
Interim analysis
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ICS
Inhaled CorticoSteroid
IEC
Independent Ethics Committee
IN
Investigator Notification
IND
Investigational New Drug
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
intrauterine device
IUS
intrauterine system
IVRS/IWRS
interactive voice response system/interactive web-based response system
J2R
jump-to-reference
LABA
Long-Acting β2-Agonist


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LAMA
Long-Acting Muscarinic receptor Antagonist
LDH
lactate dehydrogenase
LFT
Liver function test
LLOQ
Lower limit of quantification
MAR
Missing at random
MCP-Mod
Multiple comparison procedure-modelling
MedDRA
Medical dictionary for regulatory activities
mg
milligram(s)
mL
milliliter(s)
mMRC
modified Medical Research Council scale
MMRM
Mixed-effect linear model for repeated measures
MRI
magnetic resonance imaging
mRNA
messenger Ribonucleic Acid
NDA
New Drug Application
ng
nanogram
NOAEL
No Adverse Event Level
NYHA
New York Heart Association
OAT3
Organic Anion Transporter 3
OATP1B1
Organic Anion Transporter 1B1
OATP1B3
Organic Anion Transporter 1B3
PD
pharmacodynamic(s)
PGI-S
Patient Global Impression of Severity
PK
pharmacokinetic(s)
pMDI
pressurized Metered Dose Inhaler
PRO
patient-reported outcome
PSW
premature subject withdrawal
PT/INR
Prothrombin time international normalized ratio
QMS
Quality Management System
QT
QT interval (measure between Q wave and T wave in the heart's electrical cycle)
QTc
corrected QT interval
QTcF
QT interval with Fridericia's correction
RAS
Randomized analysis set
RoW
rest of world
SABA
short-acting beta2-receptor agonist
SAE
serious adverse event
SAP
Statistical analysis plan
SCS
Systemic corticosteroids
SD
standard deviation
SGRQ
St George's Respiratory Questionnaire
SPUI
sputum impact domain
SPUS
sputum symptoms domain
SUSAR
Suspected Unexpected Serious Adverse Reactions


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t.i.d
3 times a day
TBL
total bilirubin
Tmax
time to reach maximum (peak) plasma concentration following drug administration
ug
microgram
UGT
UDP-glucuronosyltransferase
UGT1A1
Uridine Diphosphate-Glucuronosyltransferase 1A1
UGT2B7
Uridine Diphosphate-Glucuronosyltransferase 2B7
UK
United Kingdom of Great Britain and Northern Ireland
ULN
upper limit of normal
US
United States of America
WHO
World Health Organization


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Glossary of terms
Additional 
treatment
Medicinal products that may be used during the clinical trial as described in the 
protocol, but not as an investigational medicinal product (e.g. any background 
therapy).
Assessment
A procedure used to generate data required by the study.
Cohort
A specific group of subjects fulfilling certain criteria.
Control drug
Any drug (an active drug or an inactive drug, such as a placebo) which is used 
as a comparator to the investigational drug being tested in the trial.
Dosage
Dose of the study treatment given to the subject in a time unit (e.g. 100 mg 
once a day, 75 mg twice a day).
Electronic Data 
Capture (EDC)
Electronic Data Capture (EDC) is the electronic acquisition of clinical study 
data using data collection systems, such as Web-based applications, 
interactive voice response systems (IVRS) and clinical laboratory interfaces. 
EDC includes the use of Electronic Case Report Forms (eCRFs) which are 
used to capture data transcribed from paper source forms used at the point of 
care.
End of the study
The end of the clinical study is defined as the last visit of the last subject or at a 
later point in time as defined in the protocol
Enrollment
Point/time of subject entry into the study at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol)
Investigational 
drug
The study drug whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and Directive 2001/20/EC and is 
synonymous with “investigational new drug” or “test substance”.
Medication 
number
A unique identifier on the label of each study drug package in studies that 
dispense study drug using an IRT system.
Other treatment
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy)
Patient
An individual with the condition of interest.
Period
The subdivisions of the trial design (e.g.: Screening, Treatment, Follow-Up) 
which are described in the Protocol. Periods define the study phases and will 
be used in clinical trial database setup and eventually in analysis.
Personal data
Subject information collected by the investigator that is transferred to Novartis 
for the purpose of the clinical trial. This data includes subject identifier 
information, study information and biological samples.
Premature subject 
withdrawal
Point/time when the subject exits from the study prior to the planned 
completion of all study drug administration and assessments; at this time all 
study drug administration is discontinued and no further assessments are 
planned.
Randomization 
number
A unique identifier assigned to each randomized subject, corresponding to a 
specific treatment arm assignment.
Run-In Failure
A subject who is screened but not randomized/treated after the run-in period 
(where run-in period requires adjustment to subject's intervention or other 
treatment).
Screen Failure
A subject who is screened but is not treated or randomized.
Source 
Data/Document
Source data refers to the initial record, document or primary location from 
where the data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource.
Stage
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc.


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Start of the study
The start of the study is defined as the signature of the informed consent by 
the first subject.
Study completion
Point/time at which the subject came in for a final evaluation visit or when 
study drug was discontinued whichever is later.
Study drug 
discontinuation
Point/time when subject permanently stops taking study drug for any reason; 
may or may not also be the point/time of premature subject withdrawal.
Study 
drug/treatment
Any drug (or combination of drugs) administered to the subject as part of the 
required study procedures; includes investigational drug, active drug run-ins or 
background therapy.
Study treatment 
discontinuation
When the subject permanently stops taking study treatment prior to the defined 
study treatment completion date.
Subject
An individual who has consented to participate in this study. The term Subject 
may be used to describe either a healthy volunteer or a patient.
Subject number
A number assigned to each subject who enrolls in the study. When combined 
with the center number, a unique identifier is created for each subject in the 
study.
Treatment 
number
A unique identifier assigned in non-randomized studies to each dosed subject, 
corresponding to a specific treatment arm.
Variable
Information used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified timepoints.
Withdrawal of 
informed
consent (WoC)
Withdrawal of consent from the study occurs only when a subject does not 
want to participate in the study any longer and does not allow any further 
collection of personal data.
















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Protocol summary
Protocol number
CQBW251B2201
Full Title
A 24-week multi-center, double-blind, placebo controlled dose-range finding 
study to investigate the efficacy and safety of oral QBW251 in COPD patients 
on triple inhaled therapy (LABA/LAMA/ICS)
Brief title
Dose-range finding efficacy and safety study for QBW251 in COPD patients 
Sponsor and 
Clinical Phase
Novartis Pharma AG
Phase Iib
Investigation type
Drug
Study type
Interventional 
Purpose and 
rationale
The purpose of this study is to support the dose selection for the future 
development program of QBW251 by evaluating efficacy and safety of different 
QBW251 doses in patients with Chronic Obstructive pulmonary disease 
(COPD) with chronic bronchitis and a history of exacerbations. QBW251 
treatment will be added on top of a triple combination therapy of a long-active 
beta2-agonist (LABA), a long-acting muscarinic receptor-antagonist (LAMA) 
and an inhaled corticosteroid (ICS). 
The study has a parallel design with QBW251 doses ranging from 25 to 
450 mg administered twice daily (b.i.d.), which is expected to adequately 
describe the dose-response of QBW251. It is compared to placebo as a control 
in the absence of an approved COPD drug in this class. 
The study will standardize the COPD background therapy to a 
LABA/LAMA/ICS triple combination to limit its confounding potential on the 
study outcomes. The choice of the medications reflects their global availability, 
the convenience of once daily dosing, and the recommendation of The Global 
Initiative for chronic Obstructive Lung Disease (GOLD) strategy (GOLD 2018)
for use of triple inhaled therapy for exacerbating and symptomatic patients 
despite therapy with ICS/LABA or LABA/LAMA. This patient population closely 
mimics the patient population targeted by this study.
Primary 
Objective(s) 
The primary objective of this study is to characterize the dose-response 
relationship of QBW251 administered orally over 12 weeks on lung function, 
compared to placebo, when added to inhaled triple combination therapy 
(LABA/LAMA/ICS). Trough forced expiratory volume in one second (FEV1) will 
be assessed at Week 12 and evaluated as change from baseline after 12 
weeks of treatment.
Secondary 
Objectives
Objective 1: To evaluate symptoms (overall COPD symptoms, cough and 
sputum) across various dose levels of QBW251 administered orally over 24 
weeks, compared to placebo at Weeks 12 and 24.
Endpoints are

Change from baseline in the Evaluating Respiratory Symptoms in 
COPD (E-RS) weekly mean scores (total and subscale scores). 

Change from baseline in Patient Global Impression of Severity (PGI-
S) score.

Change from baseline in the Cough and Sputum Assessment 
Questionnaire (CASA-Q) domain scores - cough symptoms, cough 
impact, sputum symptoms, and sputum impact.


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Objective 2: To evaluate health-related quality of life across various dose levels 
of QBW251 administered orally over 24 weeks, compared to placebo, at 
Weeks 12 and 24. The endpoint assessed is the change from baseline in St. 
George's Respiratory Questionnaire (SGRQ) total and domain scores at 
Weeks 12 and 24.
Objective 3: To evaluate lung function across various dose levels of QBW251 
administered orally over 24 weeks, compared to placebo, over 4, 8, 16, 20 and 
24 weeks. Trough FEV1 change from baseline after 4, 8, 16, 20 and 24 weeks 
of treatment, respectively, will be evaluated.
Objective 4: To evaluate safety and tolerability across various dose levels of 
QBW251, administered orally over 24 weeks, compared to placebo, as assed 
by ECGs, laboratory tests (hematology and clinical chemistry, urinalysis), vital 
signs, and adverse events (AEs) per treatment group.
Objective 5: To assess the pharmacokinetics (PK) of QBW251 in COPD 
patients through measurement of
trough concentration
and
minimum 
concentration (Cmin) on all visits and around maximum concentration (Cmax) on 
Days 1, 15 and 169. The area under the plasma concentration-time curve
(AUC) and Cmax on Days 1 and 15 will be assessed in a sub-group of patients.
Study design
This study uses a 6 treatment arm, parallel-group, randomized, double-blind 
study design. One treatment arm (450 mg b.i.d.) has been discontinued. The 
study is placebo-controlled with a standardized COPD background treatment. 
The treatment period lasts 24 weeks, the total duration of study participation 
for a patient is 31 weeks.
Population
The study population will consist of approximately 956 male and female 
patients (≥40 years of age) with moderate to severe COPD (GOLD 2 and 3) 
and a smoking history of at least 10 pack years. It is expected that 
approximately 1500 patients will be screened globally to achieve the targeted 
number of randomized patients.
Key Inclusion 
criteria

Male and female COPD patients aged ≥ 40 years, who have signed 
an Informed Consent Form (ICF) prior to initiation of any study-
related procedure.

Current or ex-smokers who have a smoking history of at least 10 
pack years.

Patients who have been treated with a triple combination of 
LABA/LAMA/ICS for the last 3 months prior to screening.

A COPD Assessment Test (CAT) score of at least 10 at Run-In 1
visit.

Patients with a post-bronchodilator FEV1 to forced vital capacity 
(FVC) ratio (FEV1/FVC) < 0.70 at Run-In 1 visit.

Patients with airflow limitation indicated by
EITHER 
a post-bronchodilator FEV1 ≥ 30% and FEV1 < 50% of the predicted 
normal at Run-In 1, who must have had at least 1 documented 
moderate or severe healthcare resource utilization (HCRU) 
exacerbation in the 12 months prior to study entry (screening), 
OR 
a post-bronchodilator FEV1 ≥ 50% and < 80% of the predicted 
normal at Run-In 1, who must have had at least 2 documented 
moderate or at least 1 documented severe HCRU exacerbation(s) in 
the 12 months prior to study entry (screening)


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
Patients featuring chronic bronchitis, defined by the presence of 
cough and bronchial hypersecretion, that occurs for at least 3
consecutive months in each of 2 consecutive years prior to study 
entry (screening), documented in patient history.
Key Exclusion 
criteria

Patients who have a history of long-QT syndrome, or a clinically 
significant ECG abnormality at Run-In 1 or Run-In 2, or whose
corrected QT interval (QTc) measured at Run-In 1 is prolonged. 

Patients who have clinically significant renal, cardiovascular, 
neurological, endocrine, immunological, psychiatric, gastrointestinal, 
or hematological abnormalities, which could interfere with the 
assessment of the efficacy and safety of the study treatment, with a 
clinically significant laboratory abnormality at Run-In 1, or patients 
with Type I diabetes or uncontrolled Type II diabetes.

Patients who have had a COPD exacerbation that required treatment 
with antibiotics and/or oral corticosteroids and/or hospitalization, or a 
respiratory tract infection in the 4 weeks prior to screening, or 
between screening and Day 1. 

Patients with any documented history of asthma, or with an onset of 
chronic respiratory symptoms, including a COPD diagnosis, prior to 
age 40 years.

Patients with a body mass index (BMI) of more than 40 kg/m2.

Use of other investigational drugs (approved or unapproved) within 
30 days or 5 half-lives prior to screening, or until the expected 
pharmacodynamic (PD) effect has returned to baseline (e.g.
biologics), whichever is longer; or longer if required by local 
regulations.

Pregnant or nursing (lactating) women, and women of childbearing
potential not willing to use acceptable effective methods of 
contraception during study participation.
Study treatment

Treatment arm 1: QBW251, 450 mg, b.i.d. (discontinued)

Treatment arm 2: QBW251, 300 mg, b.i.d.

Treatment arm 3: QBW251, 150 mg, b.i.d.

Treatment arm 4: QBW251, 75 mg, b.i.d.

Treatment arm 5: QBW251, 25 mg, b.i.d.

Treatment arm 6: Placebo matching QBW251, b.i.d.
All patients are receiving standardized background COPD medication 
consisting of fluticasone furoate, umeclinidium and vilanterol.
Efficacy 
assessments

Spirometric assessments (forced spirometry)

Electronic diary/EXACT questionnaire

St. George’s Respiratory Questionnaire (SGRQ)

Patient global impression of severity questionnaires

Cough and Sputum Assessment Questionnaire (CASA-Q)
Pharmacokinetic 
assessments

Pharmacokinetic blood sampling




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1
Introduction
1.1
Background
Chronic obstructive pulmonary disease (COPD) is characterized by persistent respiratory 
symptoms (dyspnea, cough, sputum production) and airflow limitation (diagnosed using 
spirometry) that is due to airway and/or alveolar abnormalities usually caused by significant 
exposure to noxious particles/gases, in particular cigarette smoke. Chronic airflow limitation is 
caused by a mixture of small airways disease (obstructive bronchiolitis) and parenchymal 
destruction (emphysema).
COPD is a critically important disease, with a prevalence of 10% to 15% in Europe 
(Blanco et al 2018), approximately 10% in South East Asia and approximately 15% in the 
Americas (Adeloye et al 2015). COPD affects over 15 million people in the United States of 
America (US) alone (National Center for Health et al 2017), and is the third leading cause of 
death worldwide (World Health Organization 2018). COPD is associated with episodic periods 
of symptom deterioration termed exacerbations. Exacerbations are amongst the most common 
causes of medical admission to hospital and are also important events in the natural history of 
COPD that drive lung function decline (Donaldson et al 2002), increased risk of cardiovascular 
events (Donaldson et al 2010) and are responsible for much of the morbidity and mortality 
associated with this highly prevalent condition (Soler-Cataluña et al 2005).
COPD is also associated with significant healthcare expenditures with total economic costs in 
the US estimated at $49.9 billion in 2010, and total direct costs of medical care estimated at 
$29.5 billion annually. Direct costs associated with hospitalizations for COPD exacerbations in 
the US exceed $20 billion annually (Guarascio et al 2013). In the European Union, the annual 
costs of healthcare and lost productivity due to COPD are estimated at €48.4 billion (ERS 2013).
Chronic bronchitis, due to mucous hypersecretion and mucociliary dysfunction characterized 
by chronic cough and sputum, is a key phenotype amongst COPD patients. Bronchitic patients 
have higher exacerbation frequency (Seemungal et al 1998) and are more likely to be 
hospitalized (Vestbo et al 1996, Kim et al 2011). However, effective treatment options are 
extremely limited in this group. Current standard of care in the management of COPD consists 
of bronchodilators ± inhaled corticosteroids with triple inhaled therapy (long-acting β2-agonist 
+ long-acting muscarinic receptor antagonist + inhaled corticosteroid = LABA+LAMA+ICS) 
indicated in patients experiencing exacerbations with dual combination treatments 
(LAMA+LABA, LABA+ICS). The guidelines also consider macrolide antibiotics and 
roflumilast as additional add-on therapy to triple therapy in specific sub-groups of patients: in 
fact 30% to 40% of patients receiving triple inhaled therapy continue to have moderate or severe 
(hospitalized) exacerbations (Vestbo et al 2017, Mullerova et al 2017). However, long-term 
macrolide antibiotics are complicated by microbial resistance (Pomares et al 2018) and 
roflumilast, a non-bronchodilator (PDE4 inhibitor), has modest efficacy and poor tolerability 
(Chong et al 2017). Mucolytics have shown small and inconsistent benefits on exacerbation 
reduction and the efficacy of mucolytics on top of maximal inhaled treatment has yet to be 
clearly established (Wedzicha et al 2017). Thus despite currently available treatments almost 
70% of patients remain significantly limited by breathlessness (modified Medical Research 
Council scale (mMRC) ≥ 2) and 40% experience ≥ 2 moderate or ≥ 1 severe exacerbation per 
year (Mullerova et al 2017), therefore additional novel therapies are urgently needed.


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Research indicates that cigarette smoking induces an acquired state of cystic fibrosis 
transmembrane conductance regulator (CFTR) dysfunction in the respiratory tract 
(Cantin et al 2006), even in the absence of CFTR mutations, and may contribute to the 
pathogenesis of COPD. CFTR dysfunction due to smoke exposure adversely affects 
mucociliary transport and is strongly associated with symptoms of chronic bronchitis 
(Sloane et al 2012). Cigarette smokers and COPD patients exhibit reduced CFTR function by 
nasal potential difference measurements, accompanied by reduced CFTR mRNA levels 
(Cantin et al 2006, Sloane et al 2012, Dransfield et al 2013). Furthermore, current and former 
smokers with COPD have elevated sweat chloride levels compared with normal control subjects, 
indicating reduced CFTR activity (Raju et al 2013).
Modulation of CFTR function should improve airway hydration, decreasing mucus viscosity 
and so enhancing mucociliary clearance. CFTR also regulates bicarbonate secretion, whose 
effect on airway surface liquid pH is important in the fight against pathogens 
(Pezzulo et al 2012). This mechanism would support a reduction of the airway 
inflammation/infections and obstruction leading to clinical benefits such as improvement of 
respiratory function, symptoms of COPD, and a decrease in the rates of exacerbations and 
respiratory tract infections.
CFTR potentiators increase the activity of the CFTR channel that is present in the cell 
membrane of the lungs epithelium: this can include wild type CFTR. QBW251 is a novel 
potentiator of the CFTR channel that is safe and well-tolerated. In study CQBW251X2201, a 
28-day randomized, placebo-controlled trial, QBW251 in GOLD 2-3 COPD patients with 
chronic bronchitis and with various background inhaled therapies demonstrated improvement 
in lung function (FEV1) and sweat chloride over placebo, in addition to reducing systemic 
inflammation (measured by fibrinogen). Furthermore, exploratory sputum analyses have 
suggested a trend for decreased bacterial colonization with QBW251.
Therefore, QBW251 will be a first-in-class oral CFTR potentiator, with the capacity to reduce 
COPD exacerbations and improve symptoms, quality of life and lung function when added to 
inhaled therapies.
1.2
Purpose
The purpose of this Phase 2b study is to support the dose selection for future studies by 
evaluating efficacy and safety of different QBW251 doses in COPD patients with chronic 
bronchitis and a history of exacerbations, compared to placebo, when added to a triple 
combination therapy of LABA/LAMA/ICS. Lung function improvement will be the primary 
endpoint: trough FEV1 change from baseline after 12 weeks of treatment.
The study will also provide information on longitudinal spirometry assessments over 24 weeks, 
patient reported outcome (PRO) tools and safety.
2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)








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4.1.1
Rationale for choice of background therapy
The study will standardize the COPD background therapy to limit its confounding potential on 
the study outcomes. The selected standard background therapy will consist of a triple inhaled 
combination (LABA/LAMA/ICS): either a fixed combination of fluticasone furoate, vilanterol 
and umeclidinium, or, where not accessible, a free combination of fluticasone furoate/vilanterol 
and umeclidinium. The choice of these medications reflects their global availability and the 
convenience of once daily dosing. GOLD strategy (GOLD 2018) suggests the use of triple 
inhaled therapy for exacerbating and symptomatic patients despite therapy with ICS/LABA or 
LABA/LAMA. This patient population closely mimics the patient population targeted by this 
study.
4.2
Rationale for dose/regimen and duration of treatment
QBW251 is a small molecule intended for oral administration. Half-life of QBW251 following 
single dose ranges from 10 to16 hours. The twice-daily dosing regimen was chosen based on 
the half-life and the intent to have a sustained effect on the ion channel. Additionally a twice-
daily regimen would provide a reduced Cmax/trough fluctuation compared to once daily dosing. 
A twice-daily regimen was also tested in the proof of concept study (CQBW251X2201) and 
was shown to be effective in COPD patients at 300 mg b.i.d.
The study covers a dose range from 25 to 450 mg b.i.d., which is expected to adequately 
describe the dose-response of QBW251. While the COPD proof of concept study 
CQBW251X2201 has provided evidence of efficacy with a 300 mg b.i.d. regimen, there is no 
indication that this regimen may have reached the plateau of the dose-response. Therefore, the 
450 mg b.i.d. was also proposed. The 450 mg b.i.d. regimen was well tolerated in an earlier 
study in cystic fibrosis (CF) patients (CQBW251X2101). The respective treatment arm in this 
study has been stopped and patients on the 450 mg b.i.d. regimen have been prematurely 
discontinued from treatment after the Data Monitoring Committee (DMC) had found that the 
criterion for the pre-defined pharmacokinetic-based cohort stopping rule (Section 9.1.4.1) had 
been fulfilled. The DMC confirmed that the regimen was also well tolerated in this patient 
population and the stop was not based on adverse reactions to the 450 mg b.i.d. regimen. The 
lowest dose (25 mg b.i.d.) is intended to capture the location of the increasing part of the dose-
response curve (e.g. around the efficacious dose in 50% of subjects (ED50)) to ensure that the 
efficacy dose-response curve and the therapeutic margin of QBW251 are well characterized. 
Due to the limited available data, ED50 as low as 25 mg b.i.d. cannot be excluded, hence the 
selection of this dose. The 75 and 150 mg b.i.d. regimens have been selected to achieve uniform 
coverage of the exposure range between the lowest dose and the higher doses described above 
to enable a sufficiently granular description of the dose-response curve.
Twelve weeks of treatment are sufficient to detect a spirometric signal (FEV1) and are aligned 
with a symptomatic benefit reflective of the target profile of QBW251. A positive signal across 
these endpoints at this timepoint would enable an early decision making for a transition into 
confirmatory Phase 3.
The 24-week treatment enables a longer longitudinal assessment, which is more aligned with 
the intended chronic use of QBW251. The proposed exposure will also increase the robustness 
of the safety and tolerability assessment and may provide exploratory insights relative to the 
effect.


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4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
There is currently no approved CTFR potentiator for treatment of COPD on top of triple inhaled 
therapy of LABA/LAMA/ICS that could serve as a comparator. Therefore, QBW251 is tested 
against placebo on top of triple inhaled therapy, which is also in accordance with the robust 
method for the evaluation of an investigational agent, to standards meeting both regulatory 
requirements and accepted scientific principles. This includes optimizing the study design for 
high levels of confidence in the rigor and validity of the resulting data, and minimizing the risk 
of inconclusive results.
4.4
Purpose and timing of interim analyses/design adaptations
4.4.1
Safety
In addition to monitoring safety data, an independent external safety data monitoring committee 
(DMC) will evaluate the results of pre-specified interim PK to ensure that patients' exposures 
are generally consistent with an exposure threshold, see Section 9.1.4.1 and Section 12.7.1.
Based on their review, the DMC can make recommendations regarding the conduct of the trial. 
Recommendations from the DMC could trigger alteration of the current protocol, such as 
termination of a treatment arm. The communication flow process of the outcome of their 
reviews and any other recommendations by the DMC Chairman, on behalf of the members, will 
be outlined in the DMC charter. The planned interim analyses will be performed when the 
predefined amount of data are available; details are included in the DMC charter.
4.4.2
Efficacy
Up to 2 interim analyses (IAs) may be conducted on efficacy data. The purpose of the IA(s) is 
to have an early assessment of the efficacy data for planning future studies in the QBW251B 
program. The first IA will be triggered when approximately the first 645 to 680 randomized 
patients have either discontinued or completed 12 weeks of treatment. If the first IA does not 
lead to a clear decision for the planning of the QBW251B program, a second IA may be 
performed when all randomized patients have either discontinued or completed 12 weeks of 
treatment. The efficacy IA results will not trigger any design adaptations.
4.5
Risks and benefits
The risks to subjects in this trial will be minimized by compliance with all of the eligibility 
criteria and by close clinical monitoring which will include PK monitoring as well.
The inclusion and exclusion criteria are selected to enroll patients with COPD that are most 
likely to benefit from QBW251 while participating in the study: symptomatic patients at higher 
risk of exacerbations defined by the CAT score, presence of chronic bronchitis, and with a 
history of exacerbations in the 12 month prior to study entry. The study requires all patients to 
be on a triple combination (LABA/LAMA/ICS). The standardization of the concomitant COPD 
treatment aims at limiting the variability from this potential confounding source and ensures 
treatment of all patients, including those randomized to placebo. Accordingly, patients remain 
on the triple COPD background therapy throughout the study. 


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Potential risks of QBW251 are the common adverse events of QBW251 as noted in previous 
studies, comprising of gastrointestinal events (nausea, diarrhea, vomiting) and nervous system 
disorders (headache, fatigue and dizziness). There is also the possibility of hypersensitivity 
reactions against QBW251.
The most common adverse effects associated with the standardized triple COPD background 
therapy are headache, back pain, dysgeusia, diarrhea, cough, oropharyngeal pain, 
nasopharyngitis, upper respiratory tract infection, arthralgia, gastroenteritis, and oral 
candidiasis (approved labels for Trelegy Ellipta, Breo Ellipta (EU name Relvar Ellipta) and 
Incruse Ellipta). Recent data also suggests a potential increase of the risk of pneumonia 
(including fatal cases) related to the use of the inhaled corticosteroid (update to approved label 
for Trelegy Ellipta in September 2017).
Clinical monitoring includes the use of an electronic diary with the EXACT questionnaire to 
enable daily symptoms assessment, as well as safety assessments during visit days at the 
investigational site. These include a careful assessment of adverse events, as well as triplicate
ECGs, hematologic and clinical chemistry laboratory assessments, urinalysis and vital signs 
measurements. As a formal thorough QT assessment of QBW251 has not been completed, 
triplicate ECGs pre- and post-dose (at the time to reach maximum (peak) plasma concentration 
following drug administration (Tmax)) will be performed at Day 1, at Day 15 (when all patients 
have reached steady state concentration of the investigational drug), and at Day 169 (end of 
treatment). These assessments will be complemented by the corresponding PK sampling 
(trough and Cmax). The PK sampling is also part of a more granular PK monitoring (detailed in 
schedule of assessment Table 8-1), which has been put in place to ensure that patient exposures 
are in general consistent with a threshold (area under the plasma concentration curve over 24 
hours (AUC0-24h) = 91 700 ng×h/mL) that was established based on animal (monkey) data. As 
this threshold represents an average of the exposures observed in those animals after 39 weeks 
of treatment with QBW251, this limit is not absolute and few patients are expected to exceed it. 
In prior QBW251 studies, patients with exposures above this threshold reported either no 
adverse events or mild to moderate ones.
In addition to the sampling described above, the PK monitoring plan will generate Cmin data at 
all visits and additional PK samples are requested to be taken in case of treatment-emergent 
serious adverse events. Study drug discontinuation and cohort stopping rules related to exposure 
have been introduced into the protocol as well (see Section 9.1.4.1)
Finally a sub-group of approximately 48 patients will undergo serial PK assessments to further 
characterize the PK profile of QBW251 before transitioning into the confirmatory Phase 3.
Investigators and patients will be instructed how to react to worsening of COPD symptoms and 
exacerbations. For the worsening of COPD symptoms, a short-acting beta-2 agonist (SABA) is 
provided as rescue medication. With respect to the treatment of exacerbations, a suggested 
therapy consists of 5 days of oral prednisolone (or equivalent) 40 mg/day and/or an oral 7 day 
course of amoxicillin 500 mg three times per day (t.i.d.) (alternatively amoxicillin clavulanate 
625 mg t.i.d. or clarithromycin 500 mg b.i.d.), though investigators are free to treat COPD 
exacerbations according to the medical needs of the patients. The diary will also trigger alerts 
to both patients and investigators when an algorithm detects a deterioration of symptoms 
compatible with an exacerbation. The investigator will provide the patient with written 
instructions to contact them if symptoms of COPD worsen.


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Procedural risks in this clinical trial are local reactions to venipuncture, including pain, 
hematomas, fainting, swelling, infections, and erythema. Forced spirometry testing on visit days 
may furthermore induce cough, dyspnea and dizziness.
Women of childbearing potential must 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 requirements outlined in the 
exclusion criteria for the duration of their study participation. If withdrawing from the study 
prematurely, contraception as stipulated should be continued for at least 7 days following the 
last administration of investigational medicinal product. If there is any question that the subject 
will not reliably comply, she should not be entered or continue in the study. Based on a 
reproductive toxicity study, women of childbearing potential are allowed to enter the study as 
long as they are using an acceptable effective method of contraception (see also exclusion 
criteria). This group of patients is relevant for the targeted disease and their inclusion is aligned 
with the International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH) M3 (R2) guidance. However, in a 
hormonal contraception study, it was demonstrated that QBW251 enhances cytochrome 
pathways that lead to accelerated degradation of hormone levels; systemic hormones are 
therefore not approved as an acceptable effective method of contraception in this study.
Reflecting the currently limited characterization of QBW251 potential for clinical drug-drug 
interactions, the protocol uses cautionary language for drugs that may potentially interact with 
QBW251 based on available in vitro data. These drugs are sensitive substrates of CYP1A2, 
CYP2B6, CYP3A4, OAT3, BCRP, OATP1B1, OATP1B3, UGT1A1, and UGT2B7 (see List 
of abbreviations for full protein names). These drugs are not prohibited but their substitution 
with alternative agents is advised: when not possible closer monitoring is recommended.
Additionally use of sensitive substrates of CYP1A2 with a narrow therapeutic range is 
prohibited. Due to the involvement of multiple metabolic pathways in QBW251 metabolism, it 
is anticipated that the use of QBW251 with concomitant drugs will likely have no significant 
clinical 
impact 
on 
QBW251 
exposure.
However, 
as 
Uridine 
Diphosphate-
Glucuronosyltransferase (UGT) mediated glucuronidation is likely a significant elimination 
pathway, use of certain UGT inhibitors is prohibited.
QBW251 may also impact the systemic exposure of the individual components of inhaled triple 
therapy LABA/LAMA/ICS, whose most common adverse effects have been described above. 
However, efficacy of the triple therapy is not expected to be impacted due to the delivery 
directly to the lungs. Please refer to the respective labels of LABA/LAMA/ICS for additional 
information on drug interactions. Any concomitant medications should be noted in the 
electronic Case Report Form (eCRF). As additional information becomes available when 
clinical drug interaction studies are conducted during the QBW251 development program, this 
information will be further updated and reflected in the QBW251 Investigator's Brochure (IB).
With respect to clinical benefits, a proof of concept study showed an improvement of pulmonary 
function (FEV1) and provided additional observations that could be associated with a restoration 
of the mucociliary clearance (decrease in systemic fibrinogen and reduction of the bacterial load 
of selected pathogens). Nevertheless, the exploratory nature of the latter observations will 
require further assessment to confirm them.


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Finally, an independent Data Monitoring Committee will oversee the developing clinical 
database and ensure the well-being of the patients throughout the study.
5
Population
The study population will consist of approximately 956 male and female patients (≥ 40 years 
of age) with moderate to severe COPD (GOLD 2 and 3) and a smoking history of at least 10 
pack years. Assuming a screen-failure rate of 40%, it is expected that approximately 1500 
patients will be screened globally to achieve the targeted number of randomized patients. 
5.1
Inclusion criteria
Subjects eligible for inclusion in this study must meet all of the following criteria:
All patients in the study
The following criteria apply to all patients in the QBW251B2201 study.
1. Patients who have signed an Informed Consent Form prior to initiation of any study-
related procedure.
2. Male and female adults aged ≥ 40 years.
3. Patients with stable COPD according to the current GOLD strategy (GOLD 2018) at 
Screening visit.
4. Patients who have been treated with a triple combination of LABA/LAMA/ICS for the last 
3 months prior to screening. Fixed or free combinations are acceptable, but will be 
exchanged for standard combinations at Run-In 1.
At the Run-In 1 visit, the background treatment will be switched to a fixed combination of 
fluticasone furoate, vilanterol and umeclidinium, or, where not accessible, to a free 
combination of fluticasone furoate/vilanterol and umeclidinium.
5. A COPD Assessment Test (CAT) score of at least 10 at Run-In 1.
6. Patients with a post-bronchodilator FEV1/FVC < 0.70 at Run-In 1.
7. Patients with airflow limitation indicated by
EITHER 
a post-bronchodilator FEV1 ≥ 30% and FEV1 < 50% of the predicted normal at Run-In 1, 
who must have had at least 1 documented moderate or severe healthcare resource 
utilization (HCRU) exacerbation in the 12 months prior to study entry (screening), 
OR 
a post-bronchodilator FEV1 ≥ 50% and < 80% of the predicted normal at Run-In 1, who 
must have had at least 2 documented moderate or at least 1 documented severe HCRU 
exacerbation(s) in the 12 months prior to study entry (screening).
Notes:

Post-bronchodilator refers to 30 to 60 min after inhalation of 400 µg salbutamol/360 
µg albuterol (or equivalent dose).

HCRU exacerbations are defined as moderate if leading to treatment with systemic 
glucocorticosteroids and/or antibiotics, and as severe if leading to hospital admission 
or emergency room (ER) visit lasting > 24 h in addition to treatment with systemic 
glucocorticosteroids and/or antibiotics.




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All patients in the study
The following criteria apply to all patients in the QBW251B2201 study.
1. Patients with a history of long-QT syndrome or whose QTc measured at Run-In 1 is 
prolonged (QTc > 450 ms in males, > 460 ms in females; Fridericia method), confirmed 
by the central overreader.
2. Patients who have a clinically significant ECG abnormality at the start of Run-In 1 or at 
the end of run-in (Run-In 2).
Note: Clinically significant abnormalities may include but are not limited to the following: 
left bundle branch block, Wolff-Parkinson-White syndrome, clinically significant 
arrhythmias (e.g. atrial fibrillation, ventricular tachycardia).
Note: These patients must not be re-screened.
3. Patients who have a clinically significant laboratory abnormality at Run-In 1. For 
additional guidance on hepatic parameters see exclusion criterion #5.
4. Patients who have clinically significant renal, cardiovascular (such as but not limited to 
unstable ischemic heart disease, New York Heart Association (NYHA) Class III/IV left 
ventricular failure, myocardial infarction), neurological, endocrine, immunological, 
psychiatric, gastrointestinal, or hematological abnormalities, which could interfere with 
the assessment of the efficacy and safety of the study treatment, or patients with Type I 
diabetes or uncontrolled Type II diabetes.
Note: Clinically significant is defined as any disease that, in the opinion of the 
investigator, would put the safety of the patient at risk through participating, or which 
would affect the efficacy or safety analysis if the disease/condition exacerbated during the 
study, or would compromise patient compliance or preclude completion of the study.
5. Patients with a history or current treatment for hepatic disease including but not limited to 
acute or chronic hepatitis, cirrhosis or hepatic failure or prothrombin time international 
normalized ratio (PT/INR) of more than 1.5x upper limit of normal range (ULN) at 
Run-In 1. A history of resolved hepatitis A is not exclusionary.
Patients excluded for the PT/INR of more than 1.5x ULN can be re-screened when the 
values have returned to normal.
6. Patients contraindicated for treatment with, or having a history of 
reactions/hypersensitivity to any of the following inhaled drugs, drugs of a similar class or 
any component thereof:

Muscarinic antagonist agents,

Long- and short-acting β2-agonists,

Sympathomimetic amines,

Inhaled corticosteroids

Inhaled lactose or any of the other excipients of the trial medication, including any 
background or rescue medication.
7. Patients with a history of malignancy of any organ system, treated or untreated, within the 
past 5 years whether or not there is evidence of local recurrence or metastases, with the 
exception of localized basal cell carcinoma of the skin. Patients with a history of cancer 
and 5 years or more disease free survival time may be included in the study by agreement 
with Novartis Medical Monitor on a case-by-case basis.


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8. Patients who have not achieved an acceptable spirometry result at Run-In 1 in accordance 
with American Thoracic Society (ATS)/European Respiratory Society (ERS) criteria for 
acceptability and repeatability (refer to Section 16.3 Spirometry Guidance).
Note: one re-test may be performed in patients that do not meet the ATS/ERS criteria. 
Patients who have failed the test and re-test at Run-In 1 may be re-screened maximally 
twice.
9. Patients who have had a COPD exacerbation that required treatment with antibiotics 
and/or oral corticosteroids and/or hospitalization in the 4 weeks prior to screening. 
Patients can be re-screened after a minimum of 4 weeks after the resolution of the COPD 
exacerbation.
10. Patients who develop a COPD exacerbation that required treatment with antibiotics and/or 
oral corticosteroids and/or hospitalization between screening and prior to treatment Day 1 
will not be eligible, but will be permitted to be re-screened after a minimum of 4 weeks 
after the resolution of the COPD exacerbation.
11. Patients who have had a respiratory tract infection within 4 weeks prior to screening. 
Patients can be re-screened after a minimum of 4 weeks after resolution of the respiratory 
tract infection.
12. Patients who develop a respiratory tract infection between screening and prior to treatment 
Day 1 will not be eligible, but will be permitted to be re-screened 4 weeks after the 
resolution of the respiratory tract infection.
13. Patients requiring long term oxygen therapy prescribed for > 12 hours per day.
14. Patients with any documented history of asthma.
Note: Documented history refers to patient history recorded at screening, documented in 
source notes, pharmacy records, hospital records, chart records, referral records, or any 
other medical records of the patient.
15. Patients with an onset of chronic respiratory symptoms, including a COPD diagnosis, 
prior to age 40 years.
16. Patients with concomitant pulmonary disease (e.g. clinically significant bronchiectasis, 
lung fibrosis, sarcoidosis, interstitial lung disease, pulmonary hypertension, α-1 anti-
trypsin deficiency) or patients known to have CFTR mutation(s).
17. Patients with suspected active pulmonary tuberculosis or currently being treated for active 
pulmonary tuberculosis.
Note: Patients with a history of pulmonary tuberculosis can be enrolled if they meet the 
following requirements: history of appropriate drug treatment followed by negative 
imaging results within 12 months prior to screening suggesting low probability of 
recurrent active tuberculosis.
18. Patients with pulmonary lobectomy, lung volume reduction surgery, bronchoscopic lung 
volume reductions, or lung transplantation.
19. Patients participating in or planning to participate in the active phase of a supervised 
pulmonary rehabilitation program during the trial. Participation in a maintenance program 
is permitted. Note: the supervised pulmonary rehabilitation program as a maintenance 
program has to be ongoing for at least 3 months at the time of enrollment.
20. Patients with a body mass index (BMI) of more than 40 kg/m2.
21. Patients receiving any medications in the classes listed in Table 6-5.


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22. Patients receiving any COPD related medications in the classes specified in Table 6-6, 
unless they undergo the required washout period prior to screening and follow the 
adjustment to treatment program.
23. Patients receiving medications in the classes listed in Table 6-2 should be excluded unless 
the medication has been stabilized for the specified period and the stated conditions have 
been met.
24. Use of other investigational drugs (approved or unapproved) within 30 days or 5 half-lives 
prior to screening, or until the expected pharmacodynamic effect has returned to baseline 
(e.g. biologics), whichever is longer; or longer if required by local regulations.
25. Patients unable or unwilling to comply with study-related visits or procedures, including 
use of an electronic patient diary and EXACT pro diary.
26. Patients unable to use a dry powder inhaler device, metered dose inhaler, or a pressurized 
MDI (rescue medication) or comply with the study drug regimen.
27. Pregnant or nursing (lactating) women, where pregnancy was 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.
28. Women of childbearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using acceptable effective methods of contraception 
during study participation. Acceptable effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) total hysterectomy or bilateral tubal ligation at least 6 weeks before 
taking investigational drug. 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 subjects on the 
study, the vasectomized male partner should be the sole partner for that subject.

Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical 
/vault caps). For the United Kingdom of Great Britain and Northern Ireland (UK): 
with spermicidal foam/gel/film/cream/vaginal suppository.

Placement of an intrauterine device (IUD) or intrauterine system (IUS).

Note that systemic hormonal contraception (e.g. oral contraception or hormone 
vaginal ring) is not an acceptable means of contraception due to the potential 
influence of QBW251 in decreasing the systemic levels of these hormones and 
therefore making them ineffective (see Section 6.2.1.2).

If local regulations deviate from the contraception methods listed above to prevent 
pregnancy, local regulations apply and will be described in the ICF.
Women are considered post-menopausal and not of childbearing 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), total hysterectomy or bilateral tubal 




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Investigational/ 
Control Drug
(Name and 
Strength)
Pharmaceutical 
Dosage Form
Route of 
Administration
Supply Type
Sponsor (global 
or local)
QBW251 25 mg 
b.i.d.
Capsule
Oral use
Double-blind 
supply; bottles
Sponsor global
QBW251 Placebo 
b.i.d.
Capsule
Oral use
Double-blind 
supply; bottles
Sponsor global
All capsules are of identical appearance to ensure blinding. *Following discontinuation of the QBW251 
450 mg b.i.d. arm, this dose strength is not supplied to patients any more.
6.1.2
Additional study treatments
All patients will be required to have been on a triple therapy regimen (LABA/LAMA/ICS) for 
at least 3 months prior to screening. Patients will then be switched at the Run-In 1 visit to a 
standard background triple therapy:

Either a once daily fixed triple combination of fluticasone furoate1, vilanterol, and 
umeclidinium (100 µg/25 µg/62.5 µg, respectively) using a dry powder inhaler or

A once daily dual fixed combination of fluticasone furoate1/vilanterol (100 µg/25 µg, 
respectively) with once daily umeclidinium (62.5 µg), both using dry powder inhalers.
The selection of the standard background triple therapy will be determined by the availability 
in the country of the triple therapy option at study start. Either standard background triple 
therapy will be taken in the morning approximately between 7 and 10 a.m. Patients will be 
instructed not to take the triple therapy (LABA/LAMA/ICS) within 24 hours prior to any 
spirometric assessment visit. If a patient has to use triple therapy (LABA/LAMA/ICS) within 
24 hours prior to any spirometric assessment, the visit may need to be rescheduled.
The triple therapy will be supplied to the investigator sites locally by Novartis or provided by 
the study center and reimbursed by Novartis.
Sites will be instructed to record the triple therapy information in the corresponding COPD 
eCRF page.
In addition, patients are provided with a short acting beta agonist (salbutamol 100 µg or 
albuterol 90 µg) to use as rescue medication as needed (see Section 6.2.3 for rescue medication 
further information).
1 Fluticasone is a substrate of CYP3A and therefore systemic levels of fluticasone could be 
influenced by QBW251 administration. However, the efficacy of inhaled fluticasone is not 
expected to be impacted due to the delivery directly to the lungs.
6.1.3
Treatment arms/group
Subjects will be assigned at Day 1 to 1 of the following 6 treatment arms in a ratio of 2:2:1:1:1:2:

QBW251 450 mg b.i.d. (discontinued)

QBW251 300 mg b.i.d.

QBW251 150 mg b.i.d.

QBW251 75 mg b.i.d.


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
QBW251 25 mg b.i.d.

Matching placebo to QBW251 b.i.d.
Following discontinuation of the 450 mg b.i.d. treatment arm, subjects will no longer be 
randomized to this arm, resulting effectively in a 2:1:1:1:2 randomization ratio (300 mg b.i.d. : 
150 mg b.i.d. : 75 mg b.i.d. : 25 mg b.i.d. : placebo).
6.1.4
Treatment duration
The planned duration of treatment in the study with QBW251 or matching placebo is 24 weeks 
(Day 1 to Week 24). Subjects may be discontinued from treatment earlier at the discretion of 
the investigator if patient safety and well-being are compromised, if unacceptable side-effects 
occur, or if the subject withdraws informed consent (refer to Section 9.1.1 and Section 6.5.1
for more information).
Patients will be switched to a standardized COPD maintenance background therapy 
(LABA/LAMA/ICS) at the Run-In 1 visit and will continue throughout the study until the 
Follow-Up visit.
Patients will receive rescue medication SABA at Screening, which will be used as needed until 
the Follow-Up visit.
6.2
Other treatment(s)
6.2.1
Concomitant therapy
All medications, procedures and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the subject was enrolled into the study must be recorded 
in the concomitant medications/significant non-drug therapies or procedures eCRF page.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. Please note that the lists provided below may not be exhaustive. If in doubt the 
investigator should contact the Novartis Medical Monitor before randomizing a subject or 
allowing a new medication to be started. If the subject is already enrolled, contact Novartis to 
determine if the subject should continue participation in the study.
6.2.1.1
Permitted concomitant therapy requiring caution and/or action
Table 6-2 provides an overview of medications permitted under certain conditions, including 
bronchodilator medications, which need to be withheld for certain timeframes prior to 
spirometry assessments on visit days.


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Table 6-2
Medications permitted under certain conditions
Rationale/Group
Medication
Prohibition period /
Washout period
Action taken
Study-supplied COPD 
maintenance 
background therapy
Vilanterol, 
Umeclidinium, 
Fluticasone furoate
Hold treatment for 24 
hours (± 2 hours) prior 
to each 
FEV1/spirometry 
measurement on visit 
days.
If possible, postpone 
spirometry 
measurement on the 
same 
day until the washout 
criterion is 
fulfilled. Trough 
spirometry (-45 min 
and -15 min 
assessments) should 
be done within 10 to 
14 hours from dosing 
on the previous 
evening.
Otherwise, postpone 
visit to the next day 
where washout criteria 
can be fulfilled.
Study-supplied rescue 
medication only
Short-Acting Beta-2 
Agonists (SABA)
Hold treatment at least 
6 hours prior to each 
FEV1/spirometry 
measurement.
If possible, postpone 
spirometry 
measurement on the 
same day until the 
washout criterion is 
fulfilled. Trough 
spirometry (-45 min 
and -15 min 
assessments) should 
be done within 10 to 
14 hours from dosing 
of investigational drug 
on the previous 
evening.
Otherwise, postpone 
visit to the next day 
where washout criteria 
can be fulfilled.
Systemic antibiotics
Antibiotics
Systemic antibiotics 
are allowed for short-
term (up to 14 days) 
treatment of acute 
infections, or are 
allowed for the 
treatment of acute 
exacerbations (but not 
as permanent 
prophylactic 
treatment).
Discontinue study drug 
if permanent systemic 
antibiotic treatment 
cannot be 
discontinued.


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Rationale/Group
Medication
Prohibition period /
Washout period
Action taken
Topical treatment (e.g. 
use of intraocular, 
intraconjunctival 
antibiotic treatments, 
topical use of creams, 
etc.) is permitted.
QBW251 may inhibit the metabolic clearance of co-medications metabolized by CYP1A2 and 
induce CYP2B6. In addition, QBW251 is a time-dependent inhibitor and inducer of CYP3A4/5. 
Drugs that are sensitive substrates of CYP1A2 have potential for an increase in exposure with 
QBW251 due to inhibition of CYP1A2 and decrease in exposure due to induction of CYP2B6. 
The net effect of QBW251 on CYP3A4 is anticipated to be induction based on results of an oral 
contraceptive study resulting in a decrease in exposure.
Weak in vitro inhibition of BCRP, OAT1/3, OATP1B1, OATP1B3, UGT1A1 and UGT2B7 
was also observed. QBW251 may increase the exposure of drugs, which are substrates of the 
mentioned pathways.
These drugs are listed in Table 6-3 and can be used when indicated and no alternative treatment 
is available. Safety and efficacy of drugs should be monitored accordingly.
The following lists are not considered exhaustive and labels for individual drugs should be 
referred to.
Table 6-3
Medications the exposure of which may be modified by co-
administration with QBW251
Medications that may have decreased exposure due to co-administration with QBW251
Sensitive Substrates of CYP2B6
bupropion, efavirenz.
Narrow therapeutic index substrates of CYP3A
alfentanil1, astemizole, cisapride, cyclosporine, 
dihydroergotamine, ergotamine, fentanyl, 
pimozide, quinidine, sirolimus1, tacrolimus1, 
terfenadine1.
Sensitive substrates of CYP3A
alpha-dihydroergocryptine, alfentanil, 
almorexant, alisoporivir, aplaviroc, aprepitant, 
atazanavir, atorvastatin, avanafil, bosutinib, 
brecanavir, brotizolam, buspirone, capravirine, 
casopitant, cobimetinib, conivaptan, danoprevir, 
darifenacin, darunavir, dasatinib, dronedarone, 
ebastine, eletriptan, elvitegravir, eplerenone, 
everolimus, felodipine, grazoprevir, ibrutinib, 
indinavir, isavuconazole, ivabradine, ivacaftor, 
levomethadyl, lomitapide, lopinavir, lovastatin, 
lumefantrine, lurasidone, maraviroc, midazolam, 
midostaurin, naloxegol, neratinib, nisoldipine, 
paritaprevir, perospirone, quetiapine, 
ridaforolimus, saquinavir, sildenafil, simeprevir, 
simvastatin, sirolimus, tacrolimus, terfenadine, 
ticagrelor, tilidine,tipranavir, tolvaptan, triazolam, 
ulipristal, vardenafil, venetoclax, vicriviroc, 
voclosporin.


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Medications that may have increased exposure due to co-administration with QBW251
Sensitive Substrates of CYP1A2
alosetron, caffeine, duloxetine, melatonin, 
pirfenidone, ramelteon, selegiline, tacrine, 
tasimelteon.
BCRP substrates
atorvastatin daunorubicin, doxorubicin, ethinyl 
estradiol, hematoporphyrin, imatinib, 
methotrexate1, mitoxantrone, pitavastatin1, 
rosuvastatin1, SN-38 (irinotecan), simvastatin, 
sulfasalazine, sofosbuvir1, sulfasalazine1, 
tenofovir1, topotecan1.
OAT Substrates
acyclovir, adefovir, anagliptin, beta-lactam 
antibiotics, bumetanide, captopril, cefonicid, 
cefaclor, cephradine, cimetidine, 
chlorothiazide, cidofovir, dapagliflozin, 
famotidine, furosemide, ganciclovir, ibuprofen, 
methotrexate, olmesartan, pemetrexed, 
pravastatin, pitavastatin, quinaprilat, ranitidine,
rosuvastatin, tenofovir, tetracycline, topotecan-
hydroxyl acid, valsartan, zidovudine, 
zonampanel.
OATP substrates
aliskiren, ambrisentan, anacetrapib, asunaprevir, 
atenolol, atrasentan, atorvastatin, bosentan, 
bromociptine, caspofungin, cerivastatin, 
celiprolol, danoprevir, digoxin, docetaxel, 
eliglustat, empangliflozin, ezetimibe, fimasartan, 
fexofenadine, fluvastatin, glyburide, maraviroc, 
methotrexate, montelukast, olmesartan, 
paclitaxel, pirataprevir, pitavastatin, pravastatin, 
repaglinide, rifampin, rosuvastatin, saquinavir, 
simvastatin acid, simvastatin, SN-38 (irinotecan), 
telmisartan, ticlopidine, thyroxine, valsartan.
UGT1A1 Substrates
abacavir, acetaminophen, atorvastatin, axitinib, 
belinostat,buprenorphine, carvediol, diclofenac, 
dolutegravir, desvenlafaxine succinate, 
eltrombopag, elvitegravir, estradiol, etoposide,
ezetimibe, ezogabine, febuxostat, flurbiprofen, 
fluvastatin, furosemide gemfibrozil, indacaterol, 
indomethacin, irinotecan, ketoconazole, 
levothyroxine, losartan, lovastatin, morphine, 
muraglitazar, mycophenolate mofetil, 
mycophenolic acid, naltrexone, naproxen, 
paracetamol, raloxifene, raltegravir, rosuvastatin, 
simvastatin, irinotencan, suprofen, telmisartan.


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UGT2B7 Substrates
almokalan, ambrisentan, atorvastatin, 
buprenorphine, canagliflozin, carabamazepine, 
carvediolol, chloramphenicol, clofibric acid, 
codeine, cyclosporine, dabigatran etexilate, 
dapagliflozin, diclofenac, empagliflozin, 
entacapone, epirubicin, etodolac, ezetimibe, 
febuxostat, fenofibrate, fenoprofen, flurbiprofen, 
fluvastatin, furosemide, gemfibrozil, 
hydromorphone, ibuprofen, indomethacin, 
ketoprofen, lamotrigine, lorazepam, lorazepam, 
losartan, lovastatin, methadone, midazolam, 
mitiglinide, morphine, mycophenolate mofetil, 
mycophenolic acid, nalorphine, naloxone, 
naltrexone, naproxen, oxazepam, pitavastatin, 
sertraline, silodosin, simvastatin, suprofen, 
tacrolimus, tapentadol, temazepam, zaltoprofen, 
zidovudine.
Medications in this table were identified as substrates based on either in vivo or in vitro data. 
1 Also considered sensitive CYP3A substrates. Budesonide and fluticasone are also sensitive 
substrates of CYP3A, but have not been listed here since these are prohibited medications (except for 
study-supplied COPD background medication containing fluticasone, as specified in Section 6.1.2, or 
as systemic corticosteroids for the treatment of COPD exacerbations, as specified in Section 8.3.9). 
Furthermore, patients should be instructed not to take grapefruit, Seville oranges or their juice for 14 
days prior to dosing, during treatment and until 7 days following the last dose, due to an ingredient that 
is an inhibitor sensitive substrate of CYP3A.
6.2.1.2
Systemic contraceptives
Systemic contraceptives such as listed in Table 6-4 are not an acceptable means of contraception 
(refer also to definition of acceptable effective contraception methods in Section 5.2), since 
these drugs may be ineffective due to decreased exposure in combination with QBW251 and 
result in contraceptive failure. These drugs may be taken for other indications (e.g. osteoporosis 
prophylaxis); the efficacy of the treatment may be impaired by low systemic availability, though, 
and should be monitored.
Table 6-4
Examples of contraceptives not recommended for systemic use (not 
acceptable as means of contraception as efficacy may be 
compromised by QBW251 administration)
Medication
Period during which 
contraceptive effect may be 
compromised
Action taken


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Drospirenone
Ethinyl estradiol
Etonogestrel
Levonorgestrel
Medroxyprogesterone acetate
Norelgestromin
Norethindrone
Norgestimate
Norgestrel
Use of these drugs is not 
prohibited, but in combination 
with QBW251 these may no 
longer constitute means of 
contraception, and thus their 
use does not fulfill the 
requirements of contraception 
stipulated in the exclusion 
criteria (risk of contraceptive 
failure). Patient is at risk to 
experience a pregnancy due to 
the interaction between 
systemic contraceptive and 
QBW251.
Avoid concurrent 
administration; for alternative 
methods of contraception refer 
to exclusion criterion #28.
6.2.2
Prohibited medication
Use of the treatments displayed in the below table is NOT allowed after the onset of the 
prohibition period as indicated in Table 6-5 and Table 6-6. Should administration of one of 
these drugs during the course of the treatment period be required, study treatment should be 
discontinued as described in the “Action to be taken” column.
Table 6-5
Prohibited medication
Rationale/Group
Medication1
Prohibition period
Action to be taken
Medications with a 
narrow therapeutic 
range and potential for 
increased exposure 
with QBW251 due to 
inhibition of CYP1A2:
Theophylline2
Tizanidine
Discontinue treatment 
at least 1 week prior to 
Day 1
Discontinue study 
treatment.
Medications lacking 
information on 
metabolizing enzymes:
Pirbuterol
Discontinue treatment 
at least 1 week prior to 
Day 1
Discontinue study 
treatment.
Strong uridine 
diphosphate 
glucuronosyl 
transferase (UGT) 
inhibitors, which will 
potentially increase 
systemic 
concentrations of 
QBW251
Mefenamic acid
Probenecid
Valproic acid
Discontinue treatment 
at least 1 week prior to 
Day 1
Concurrent 
administration must be 
avoided; discontinue 
study treatment.
Mucolytics
Acetylcysteine
Ambroxol
Bromohexine
Erdosteine
Discontinue treatment 
prior to or on Run-In 1.
Concurrent 
administration must be 
avoided to ensure 
reliable assessment of 
symptoms.
Antibiotics (long-term 
maintenance)3
Azithromycin
Erythromycin
Doxycyline
Discontinue treatment 
at least 30 days prior 
to Run-In 1.
Discontinue study 
treatment.


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1 The medications listed here are prominent examples of the group of medications fulfilling the 
rationale, but all drugs fulfilling the rationale for exclusion are not allowed (e.g. any mucolytic drug).
2 Note that theophylline has to be terminated 7 days prior to Run-In 1 due to stipulations for prohibited 
COPD medications (Table 6-6) and is listed here for completeness of information only. 
3 Most frequently used antibiotics are listed only. However, all long-term systemic antibiotic treatment 
is excluded, regardless of the drug. For use of short term antibiotics for COPD exacerbations: prior to 
the study refer to the exclusion criteria 9 and 10, during the study, refer to Table 6-2. Any other use of 
short term antibiotics prior to the study does not require a wash-out.
Table 6-6
Prohibited COPD-related medications
Class of medication1
Minimum washout period prior to Run In 1 
Long-acting muscarinic antagonists (LAMA) 
(other than as ingredient of study background 
therapy)
12 hours for twice-daily LAMAs
24 hours for once-daily LAMAs
Short-acting muscarinic antagonists (SAMA)
6 hours
Fixed combinations of long-acting β2 agonists 
and inhaled corticosteroids (LABA/ICS)(other 
than as ingredient of study background therapy)
12 hours for twice-daily combinations
24 hours for once-daily combinations
Long-acting β2 agonists (LABA)(other than as 
ingredient of study background therapy)
12 hours for twice-daily LABAs
24 hours for once-daily LABAs
Short-acting β2 agonists (SABA) (other than trial 
rescue medication)
6 hours
Oral phosphodiesterase-IV inhibitor
7 days
Xanthines (any formulation)
7 days
Systemic corticosteroids
30 days
Inhaled corticosteroids (other than as ingredient 
of study-supplied background therapy)
12 hours
Intra-muscular depot corticosteroids
3 months
1 This table is not considered all-inclusive. Medications should be assessed for adherence to the 
indication and other inclusion/exclusion criteria. These medications are also prohibited if administered 
for other indications. This should be taken in the context of COPD severity as well as planned 
comparator arms. All these medication listed under Table 6-6 may be permitted for the treatment of a 
COPD exacerbation during the study except intra-muscular depot corticosteroids If intra-muscular 
depot corticosteroid treatment is required, the patient should be withdrawn from the study treatment. 
Medications under Table 6-5 are not permitted and should follow the action as listed in the table.
6.2.3
Rescue medication
At Screening and whenever needed thereafter, patients will be provided with a short acting beta 
agonist (salbutamol 100 µg or albuterol 90 µg) inhaler to use as rescue medication on an “as 
needed” basis throughout the study. Nebulized salbutamol/albuterol is not allowed as rescue 
medication throughout the trial. No other rescue medication is permitted.
The use of rescue medication (number of puffs taken in the previous 12 hours) will be recorded 
(once in the morning and once in the evening) by the patient, in the electronic patient diary. The 
rescue salbutamol/albuterol provided at Screening for use during the study should not be 
recorded on the COPD related prior concomitant page of the eCRF.
The rescue medication will be supplied to the investigator sites locally by Novartis or provided 
by the study center and reimbursed by Novartis.


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6.3
Subject numbering, treatment assignment, randomization
6.3.1
Subject numbering
Each subject is identified in the study by a Subject Number (Subject No.), that is assigned when 
the subject is first enrolled for screening and is retained as the primary identifier for the subject 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.) (assigned by Novartis to the investigative site) with a sequential subject 
number suffixed to it, so that each subject is numbered uniquely across the entire database. 
Upon signing the informed consent form, the subject is assigned to the next sequential Subject 
No. available.
6.3.2
Treatment assignment, randomization
At Day 1, all eligible patients will be randomized via Interactive Response 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 investigational treatment 
to be dispensed to the patient. The randomization number will not be communicated to the caller.
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 
randomization list will be produced by the IRT supplier 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 
Global Clinical Supply using a validated system that automates the random assignment of 
medication numbers to packs containing the investigational drug(s).
Randomization will be stratified by smoking status (current or ex-smoker) and severity of 
airflow limitation (FEV1 ≥ 30% to < 50% and ≥50% to < 80%), as assessed at Run-In 1.
The randomization scheme for patients will be reviewed and approved by a member of the 
Randomization Office.
6.4
Treatment blinding
Subjects, investigator staff, persons performing the assessments, and Clinical Trail Team (CTT)
will remain blind to the identity of the treatment from the time of randomization until database 
lock, using the following methods: 
(1) Randomization data are kept strictly confidential until the time of unblinding, and will not 
be accessible by anyone else involved in the study with the following exceptions: PK analyst, 
independent statistician and programmer supporting the DMC and, if deemed necessary by the 
DMC, the DMC members.
(2) the identity of the treatments will be concealed by the use of study treatment that are all 
identical in packaging, labeling, schedule of administration, appearance, taste and odor.


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The randomization codes associated with subjects from whom PK samples are taken will be 
disclosed to PK analysts who will keep PK results confidential until data base lock.
Unblinding will occur in the case of subject emergencies, in case of a DMC request as an 
outcome of their evaluation and at the conclusion of the study.
Unblinding of predetermined CTT members will occur at the time of the efficacy interim 
analysis. The study will then continue under the management of a separate blinded team. In 
order to maintain the integrity of the study data, separate blinded team members will not have 
access to any unblinded data. The detailed procedures will be described in a separate charter. 
The remainder of members including clinical study team, subjects, investigator staff, persons 
performing the assessments will remain blinded until the final database lock.
6.5
Dose escalation and dose modification
Investigational or other study treatment dose adjustments are not permitted. Dose temporary 
interruptions are permitted under specific circumstances described in Section 6.5.1.
6.5.1
Dose modifications
Study drug dose temporary interruptions are not permitted unless the investigator considers a 
temporary interruption is necessary for the treatment of an adverse event (if the adverse event 
grade is severe and suspected to be related to the investigational study drug should be 
permanently discontinued as described in Section 9.1.1).
Any interruption of study medication for more than 5 consecutive days during the treatment 
period should be discussed with the local Novartis Medical Monitor to review the patient’s 
eligibility to continue in the trial.
The study drug dose interruptions must be recorded in the Dosage Administration Record eCRF.
6.5.1.1
Dose adjustments for QTcF prolongation
In case of QTcF > 500 msec, (or QTcF prolongation > 60 msec from baseline)

Assess the quality of the ECG recording and the QT value and repeat, if needed.

Interrupt investigational treatment.

Determine the serum electrolyte levels (in particular hypokalemia, hypomagnesemia). If 
abnormal, correct abnormalities.

If possible, collect a time-matched PK sample on that visit (if not already scheduled/taken 
per Table 8-1) and record time and date of last study treatment intake.

If QTcF confirmed by the Central Reading > 500 msec: 

Permanently discontinue the investigational treatment.

Consult with a cardiologist (or qualified specialist).

Increase cardiac monitoring as indicated, until the QTcF returns to ≤ 480 msec.

Review concomitant medication use for other causes for QT prolongation (refer to 
http://www.qtdrugs.org for known QT prolonging drugs), and for drugs with the 
potential to increase the risk of drug exposure related QT prolongation.

Check the dosing schedule and treatment compliance.


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6.5.2
Follow-up for toxicities
Not applicable
6.6
Additional treatment guidance
6.6.1
Treatment compliance
Study drug compliance should be assessed by the investigator and/or center personnel at all 
visits. The Investigator or designee will collect, from the patient, the used/unused 
investigational study drug and packaging at all dispensing visits. Study drug compliance will 
be assessed from the capsule count (unused medication) and from information provided by the 
patient and/or caregiver. This information should be captured in the source documentation. The 
total number of doses of investigational treatment administered since the last dispensing visit 
should be captured in the source documentation, and the start and end date of investigational 
study drug and any interruptions of investigational treatment of more than 5 days or any 
interruption of investigational treatment due to an Adverse Event will be recorded on the eCRF. 
Patient will also be instructed to report any missing doses of investigational study drug in the 
eDiary.
The number of puffs of rescue medication inhaled will be recorded twice daily by the patient in 
the eDiary. The patient will be instructed accordingly at Screening (when he/she is provided 
with the eDiary and the use of rescue medication is discussed). The use of rescue medication 
will be reviewed at each visit and data from the eDiary downloaded at each visit. Where 
necessary, the Investigator will discuss compliance/documentation issues regarding rescue 
medication use with the patient.
The COPD maintenance background therapy compliance will also be monitored at all 
dispensing visits and information captured in the source documents at site. Information on the 
start date, end date and interruptions of more than 3 days or due to an Adverse Event must be 
captured in the eCRF. Any compliance issues must be discussed with the patient.
The investigator must promote compliance by instructing the subject to take the study treatment 
exactly as prescribed and by stating that compliance is necessary for the subject’s safety and 
the validity of the study. The subject must also be instructed to contact the investigator if he/she 
is unable for any reason to take the study treatment as prescribed. 
6.6.2
Emergency breaking of assigned treatment code
Emergency code breaks must only be undertaken when it is required to in order to treat the 
subject safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study subject who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a subject, he/she must provide the 
requested subject identifying information and confirm the necessity to break the treatment code 
for the subject. The investigator will then receive details of the investigational drug treatment 
for the specified subject and a fax or email confirming this information. The system will 
automatically inform the Novartis monitor for the site and the study team that the code has been 
broken.


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It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The investigator 
will provide:

protocol number

subject number
In addition, oral and written information to the subject must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that unblinding 
can be performed at any time.
Following emergency unblinding, the subject will be permanently discontinued from the study 
investigational treatment as described in Section 9.1.1.
6.7
Preparation and dispensation
Each study site will be supplied with investigational study drug in packaging as described under 
investigational and control drugs section.
A unique medication number is printed on the study medication label.
Investigator staff will identify the study medication kits to dispense to the subject by contacting 
the IRT and obtaining the medication number(s). The study medication has a 2-part label (base 
plus tear-off label), immediately before dispensing the medication kit to the subject, site 
personnel will detach the outer part of the label from the packaging and affix it to the source 
document.
Investigational study drug consists of oral dispensation capsules and no preparation prior to 
dispensation is required.
6.7.1
Handling of study treatment and additional treatment
6.7.1.1
Handling of study treatment
Investigational 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 designated site personnel have access. Upon receipt, all investigational study 
treatment must be stored according to the instructions specified on the labels and in the 
Investigator’s Brochure. Clinical supplies are to be dispensed only in accordance with the 
protocol. Technical complaints are to be reported to the respective Novartis Country 
Organization Quality Assurance.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the subject except for the medication number.
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Subjects will be asked 
to return all unused study treatment and packaging at the end of the clinical trial or at the time 
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At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused investigational study 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.
6.7.1.2
Handling of additional treatment
Additional study treatment (COPD maintenance background therapy and rescue medication) 
must be received by a designated person at the study site, handled and stored safely and properly 
and kept in a secured location to which only the investigator and designated site personnel have 
access. Upon receipt, the additional study treatment must be stored according to the instructions 
specified on the labels. Clinical supplies are to be dispensed only in accordance with the 
protocol.
The investigator must maintain a record of the shipment and dispensing of the additional study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Subjects will be asked 
to bring all unused study treatment to the site at all visits including the time of discontinuation 
of study treatment to allow for medication use review.
6.7.2
Instruction for prescribing and taking study treatment
The following are the instructions for the investigational drug (QBW251/placebo):

QBW251/ placebo is an oral capsule.

One capsule should be taken twice a day at approximately the same time each day, with 
about 12 hours between each dose administration (approximately in the morning between 
7 and 10 a.m. and in the evening between 8 and 11 p.m.).

It is recommended not to take the investigational drug in together with high-fat meals.
The definition of high-fat meals follows the definition suggested by the FDA in the draft 
guidance on Assessing the Effects of Food on Drugs in INDs and NDAs (FDA 2019): a 
meal containing at least 1000 kcal (4184 kJ), and at least 50% of that energy content from 
fat. 
An example of a high fat meal would be:
o
Total nutritional energy value: 1000 kcal

of which from proteins: 150 kcal

of which from carbohydrates: 250 kcal

of which from fats: 600 kcal.

Patients can drink water as needed.

Patients should be instructed not to take grapefruit, Seville oranges or their juice for 14 
days prior to dosing, during treatment and until 7 days following the last dose as these 
products are considered inhibitors of CYP3A.

If vomiting occurs during the course of treatment, patients should be instructed not to take 
the study drug again before the next scheduled dose.

Patients should be instructed not to make up missed doses.

Subjects should be instructed to swallow whole capsules and not to chew or open them.


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Instructions for the COPD maintenance background therapy and rescue medication should be 
according to the respective product label.
On study visit days, patients should be reminded not to take either the investigational drug 
(QBW251/placebo) or the COPD maintenance background therapy doses prior to the site visit 
to ensure compliance with the pre-dose PK sampling procedure and spirometry pre-dose 
measurements. The morning dose on the visit days should be taken after the pre-dose PK 
sampling and spirometry assessments have been completed within 15 min approximately.
Of note, spirometry on visit days shall be conducted

10-14 hours after the last intake of investigational drug on the evening before, and

22-26 hours after the last inhalation of COPD background medication on the morning
before (see also Section 8.3.2).
7
Informed consent procedures
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation), Institutional Review Board/Independent Ethics Committee (IRB/IEC)-
approved informed consent.
If applicable, in cases where the subject's representative(s) gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible given 
his/her understanding. If the subject is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document.
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the subject source documents.
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH Good Clinical Practice (GCP) guidelines and regulatory 
requirements and is considered appropriate for this study. Any changes to the proposed consent 
form suggested by the investigator must be agreed by Novartis before submission to the 
IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the subject 
informed consent and should be discussed with the subject during the study as needed. Any new 
information regarding the safety profile of the investigational drug that is identified between IB 
updates will be communicated as appropriate, for example, via an Investigator Notification (IN)
or an aggregate safety finding. New information might require an update to the informed 
consent and then must be discussed with the subject.
Women of childbearing potential must 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 requirements. They shall be 
informed that contraception should be continued for at least 7 days following the last intake of 
QBW251/placebo. Patients completing the study as planned are required to exercise acceptable 


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effective contraception during their entire study participation; thus, the above period is covered 
by the follow-up period.
The study includes optional assessments such as the additional pharmacokinetic sampling 
timepoints at Day 1 and Day 15 
. As previously described, 
each additional data collection activity may not be conducted in all countries, depending on 
regulatory acceptability, logistic considerations, and need of participants for the respective 
activity. Any additional data collections require a separate signature, if the subject agrees to 
participate. It is required as part of this protocol that the Investigator presents the available 
options to the subjects, as permitted by local governing regulations. The process for obtaining 
consent should be exactly the same as described above for the main informed consent.
Declining to participate in 1 or more of these optional assessments (
 additional 
pharmacokinetic sampling) will in no way affect the subject’s ability to participate in the main 
research study.
A copy of the approved version of all consent forms must be provided to Novartis/sponsor after 
IRB/IEC approval.
Subjects might be asked to complete an optional questionnaire to provide feedback on their 
clinical trial experience (see Section 8.5.4).
8
Visit schedule and assessments
The assessment schedule table (Table 8-1) lists all of the assessments and indicates with an “X”,
the visits when they are performed. All data obtained from these assessments must be supported 
in the subject’s source documentation.
Patients should be seen for all visits/assessments as outlined in the assessment schedule or as 
close to the designated day/time as possible. Missed or rescheduled visits should not lead to 
automatic discontinuation. Subjects who prematurely discontinue the study for any reason 
should be scheduled for a visit as soon as possible, at which time all of the assessments listed 
for the final visit will be performed. At this final visit, all dispensed investigational product 
should be reconciled, and the adverse event and concomitant medications recorded on the eCRF.
Below Table 8-2 will describe the order and timepoints for all the timed assessments in all the 
visits scheduled. If the subject is participating in the additional PK timepoints at Day 1 and Day 
15, refer to the Table 8-3 for these visits.


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Table 8-1
Assessment Schedule
Period Screening
Run-In
Treatment
Follow-Up
Unscheduled
Visit Name Screening
Run-In 
1
Run-In 
2
Day 
1
Week 
2
Week 
4
Week 
8
Week 
12
Week 
16
Week 
20
Week 24
PSW1
Follow-Up 
Unscheduled
Days
-21
-14
1
1
15
29
57
85
113
141
169
-
197
-
Informed consent
X
Demography
X
Physical Examination
X
X
X
Body Height
X
Body Weight
X
X
X
Vital Signs
X
X
X
(X)5
X
X
X
X
X
X
X
X
X
Medical history/current 
medical conditions2
X
COPD exacerbation 
history
X
Smoking history
X
Smoking status
(X)3
X
X
Inclusion/Exclusion 
criteria
X
X
X
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispensation of rescue 
medication
X
X
X
X
X
X
X
X
X
Dispensation of 
standard background 
triple therapy
X
X
X
X
X
X
X
X
Dispensation of study 
drug
X
X
X
X
X
X
Spirometry
X
X
X
X
X
X
X
X
X
X
Spirometry Reversibility 
Test
X


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Period Screening
Run-In
Treatment
Follow-Up
Unscheduled
Visit Name Screening
Run-In 
1
Run-In 
2
Day 
1
Week 
2
Week 
4
Week 
8
Week 
12
Week 
16
Week 
20
Week 24
PSW1
Follow-Up 
Unscheduled
Days
-21
-14
1
1
15
29
57
85
113
141
169
-
197
-
Electrocardiogram 
(ECG)4
X
X
X5
X6
X
X
X
X
X
X6
X
X
COPD Assessment Test 
(CAT)7
X
St. George's Respiratory 
Questionnaire7
X
X
X
X
Patients Global 
Impression of Severity 
Scale (PGI-S general 
question)7
X
X
X
X
Patients Global 
Impression of Severity 
Scale (PGI-S specific 
question)7
X
X
X
X
Cough And Sputum 
Assessment 
Questionnaire (CASA-
Q)7
X
X
X
X
e-Diary - rescue 
medication use
from
Day -21
X
X
X
X
X
X
X
X
X
until Day 
169
until 
PSW
e-Diary - EXACT 
Questionnaire8
from 
Day -14
X
X
X
X
X
X
X
X
until Day 
169
until 
PSW


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Period Screening
Run-In
Treatment
Follow-Up
Unscheduled
Visit Name Screening
Run-In 
1
Run-In 
2
Day 
1
Week 
2
Week 
4
Week 
8
Week 
12
Week 
16
Week 
20
Week 24
PSW1
Follow-Up 
Unscheduled
Days
-21
-14
1
1
15
29
57
85
113
141
169
-
197
-
Assessment of 
childbearing potential
S
Pregnancy Test 
(serum)10
X
Pregnancy Test (urine)10
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
Clinical Chemistry11
X
X
X
X
X
X
X
X
X
X
Urinalysis12
X
X
X
X
X
X
X
X
X
X
PK blood collection
X13
X13
X
X
X
X
X
X13
X
X14
PK Sub-group
(serial PK sampling)
X15
X15
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
Serious Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
Surgeries & procedures 
review
X
X
X
X
X
X
X
X
X
X
X
X
X
Contact IVRS/IWRS
X
X
X16
X
X
X
X
X
X
X
X
X
X
Study Disposition Page
X17
X18
X19
X19
X20
Study completion 
information
X21
X




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Table 8-2
Timed assessments for all visits
Time 
Point1
PROs at 
site
Urine 
Sample
ECG
Vital 
Signs3
Hemato
-logy/ 
Blood 
Chemis-
try
Spiro-
metry4
PK 
Blood 
Samp-
ling
Day 1
Prior to -
45 min
X
X
X2
X
Prior to -
45 min
Randomization
-45 min
X
-45 to -
20 min 
approxi
mately
X
X
-15 min
X
0
Study drug administered in clinic
3 h
X2
X
Week 2
Prior to 
Study 
drug
X2
X
Prior to 
Study 
drug
X
0
Study drug administered in clinic
3 h
X2
X
Week 4
Prior to -
45 min
X2
X
-45 min
X
-45 to -
20 min 
approxi
mately
X
X
-15 min
X
0
Study drug administered in clinic
Week 8
Prior to -
45 min
X2
X
-45 min
X
-45 to -
20 min 
approxi
mately
X
X
-15 min
X
0
Study drug administered in clinic


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Time 
Point1
PROs at 
site
Urine 
Sample
ECG
Vital 
Signs3
Hemato
-logy/ 
Blood 
Chemis-
try
Spiro-
metry4
PK 
Blood 
Samp-
ling
Week 12
Prior to -
45 min
X
Prior to -
45 min
X2
X
-45 min
X
-45 to -
20 min 
approxi
mately
X
X
-15 min
X
0
Study drug administered in clinic
Week 16
Prior to -
45 min
X2
X
-45 min
X
-45 to -
20 min 
approxi
mately
X
X
-15 min
X
0
Study drug administered in clinic
Week 20
Prior to -
45 min
X2
X
-45 min
X
-45 to -
20 min 
approxi
mately
X
X
-15 min
X
0
Study drug administered in clinic
Week 24
Prior to -
45 min
X
X
X2
X
-45 min
X
-45 to -
20 min 
approxi
mately
X
X
-15 min
X
0
Study drug administered in clinic
3 h
X2
X
PSW
Prior to -
45 min
X
X
X2
X


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Time 
Point1
PROs at 
site
Urine 
Sample
ECG
Vital 
Signs3
Hemato
-logy/ 
Blood 
Chemis-
try
Spiro-
metry4
PK 
Blood 
Samp-
ling
-45 min
X
-45 to -
20 min 
approxi
mately
X
X
-15 min
X
0
Theoretical study drug timepoint
3 h
1 Time relates to the dose given from spirometry device at visit unless otherwise specified.
2 Triplicate ECG measurements required.
3 Systolic/diastolic blood pressure and heart rate.
4 A minimum 3 minutes rest period from the beginning of ECG assessments to the start of spirometry 
maneuvers must be observed at all times.
Table 8-3
Timed assessments for Day 1 and Day 15 for subjects participating in 
the additional PK sampling sub-group (additional PK timepoints)
Time 
Point1
PROs at 
site
Urine 
Sample
ECG
Vital 
Signs3
Hemato
-logy/ 
Blood 
Chemis-
try
Spiro-
metry4
PK 
Blood 
Samp-
ling
Day 1
Prior to -
45 min
X
X
X2
X
Prior to -
45 min
Randomization
-45 min
X
-45 to -
20 min 
approxi
mately
X
X
-15 min
X
0
Study drug administered in clinic
1 h
X
2 h
X
4 h
X2
X
6 h
X
8 h
X
Week 2
Prior to 
Study 
drug
X2
X


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Time 
Point1
PROs at 
site
Urine 
Sample
ECG
Vital 
Signs3
Hemato
-logy/ 
Blood 
Chemis-
try
Spiro-
metry4
PK 
Blood 
Samp-
ling
Prior to 
Study 
drug
X
0
Study drug administered in clinic
1 h
X
2 h
X
4 h
X2
X
6 h
X
8 h
X
1 Time relates to the dose given from spirometry device at visit unless otherwise specified
2 Triplicate ECG measurements required.
3 Systolic/diastolic blood pressure and heart rate
4 A minimum 3 minutes rest period from the beginning of ECG assessments to the start of spirometry 
maneuvers must be observed at all times
8.1
Screening
Re-Screening
If a patient fails to meet the eligibility criteria, re-screening is allowed in the cases described in 
Section 5. Re-screening should occur after patient has failed screening. A new patient number 
will be assigned and the site must record the re-screening information in the corresponding 
eCRF and in IRT.
8.1.1
Information to be collected on screening failures
Patients who sign an informed consent but fail to continue into the Run-In period for any reason 
will be considered a screen failure. The reason for the screening failure will be entered on the 
screening phase disposition page. The demographic information, informed consent, and 
Inclusion/Exclusion pages must also be completed for screen failure patients. No other data will 
be entered into the clinical database for patients who are screen failures, unless the patient 
experienced a serious adverse event (SAE) during the screening phase (see SAE reporting 
details in Section 10.1.3). If the patient fails to be randomized, the IRT must be notified within 
2 days of the screen fail that the patient was not randomized.
8.2
Subject demographics/other baseline characteristics
Patient demographic and other baseline characteristic data to be collected on all subjects 
include:

Year of birth and age

Gender

Race






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8.3.5
St George's Respiratory Questionnaire (SGRQ)
The St. George Respiratory Questionnaire (SGRQ) will be used to provide the health status 
measurements in this study (Jones el al 1992). The SGRQ will be electronically completed by 
the patient at the investigator's site at the visits indicated in Table 8-1.
The SGRQ questionnaire should always be completed before any other assessments (including 
any other questionnaires) are made to avoid influencing the responses. A detailed guide relating 
to the administrative procedures of the questionnaire are given in Section 16.12.
Instrument scoring and handling of missing item data will be conducted in accordance with the 
user guide for the SGRQ (Section 16.12).
The SGRQ contains 50 items divided into 2 parts covering 3 aspects of health related to COPD: 
Part I covers "Symptoms" and is concerned with respiratory symptoms, their frequency and 
severity; Part II covers "Activity" and is concerned with activities that cause or are limited to 
breathlessness; Part II is also concerned with "Impacts", which covers a range of aspects 
concerned with social functioning and psychological disturbances resulting from airways 
disease. A score will be calculated for each of these 3 subscales and a "Total" score will also be 
calculated. In each case the lowest possible value is zero and the highest 100. Higher values 
correspond to greater impairment of health status.
8.3.6
Patient global impression of severity (PGI-S: general and specific)
The PGI-S questionnaire will rate the severity of the respiratory symptoms (general 
questionnaire) and of the cough and mucus (specific questionnaire) in the last 7 days and will 
be used to anchor the E-RS total score, E-RS cough and sputum subdomain and CASA-Q.
The PGI-S (a general and a specific question) will be completed electronically by the patient at 
the investigator's site at the visit schedule indicated in Table 8-1.
An example of the PGI-S is provided in Section 16.8.
8.3.7
Cough And Sputum Assessment Questionnaire (CASA-Q)
The CASA-Q is a validated questionnaire instrument used to measure cough and sputum 
production, and their impact in patients with chronic obstructive pulmonary disease (COPD) 
and/or chronic bronchitis (Crawford et al 2008). It contains a total of 20 items on a 5-step scale 
distributed in 4 domains: Cough symptoms (COUS; 3 items), Cough impact (COUI; 8 items), 
Sputum symptoms (SPUS; 3 items) and Sputum impact (SPUI; 6 items).
There are only domain scores and no overall score. The score in each domain ranges from 0 to 
100, with lower score indicating more severe symptoms or a higher impact.
The CASA-Q will be completed electronically by the patient at the investigator's site at the visit 
schedule indicated in Table 8-1.
An example of the CASA-Q is provided in Section 16.4.
Below are instructions for all the questionnaires administered at site, including the CASA-Q:
The appropriate language version of the questionnaires will be used in each participating 
country. The same language should be used by a particular patient throughout the study. The 
site personnel administering the questionnaire should be familiar with the measures and the 






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8.4
Safety
Safety assessments are specified below in with the assessment schedule detailing when each 
assessment is to be performed in Table 8-1.
For details on AE collection and reporting, refer to the AE reporting information 
in Section 10.1.
Physical assessments are defined in below table:
Table 8-4
Assessments and Specifications
Assessment
Specification
Physical examination
A complete physical examination will be 
performed at Screening and at Week 24 or 
premature discontinuation visit. It should include 
the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, 
lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular, and neurological. If 
indicated based on medical history and/or 
symptoms, rectal, external genitalia, breast, and 
pelvic exams will be performed.
Information for all physical examinations must be 
included in the source documentation at the 
study site. Clinically relevant findings that are 
present prior to signing informed consent must 
be included in the Medical History part of the 
eCRF. Significant findings made after signing 
informed consent which meet the definition of an 
Adverse Event must be recorded on the Adverse 
Event section of the eCRF.
Vital signs
Vital signs include blood pressure and pulse 
measurements. Vital signs are measured as per 
visit schedule indicated in Table 8-1.
After the subject has been sitting for 5 minutes, 
with back supported and both feet placed on the 
floor, systolic and diastolic blood pressure will be 
measured 3 times using an automated validated 
device, e.g. OMRON, with an appropriately sized 
cuff. The repeat sitting measurements will be 
made at 1 - 2 minute intervals and the mean of 
the 3 measurements will be used. In case the 
cuff sizes available are not large enough for the 
subject's arm circumference, a 
sphygmomanometer with an appropriately sized 
cuff may be used.
Clinically notable vital signs are defined in 
Section 16.1.


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Height and weight
Body height in centimeters (cm) and body weight 
(to the nearest 0.1 kilogram (kg) in indoor 
clothing, but without shoes) will be measured at 
Screening. Body weight will be measured in 
addition at Week 24 or premature 
discontinuation visit.
8.4.1
Laboratory evaluations
A central laboratory will be used for analysis of all specimens collected. Details on the 
collections, shipment of samples and reporting of results by the central laboratory are provided 
to investigators in the laboratory manual. Laboratory assessments will be performed in the visits 
specified in Table 8-1.
Clinically significant abnormalities must be recorded as either medical history or adverse events 
as appropriate. 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. Clinically notable laboratory values are defined in Section 16.1.
Table 8-5
Laboratory parameters
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, Platelets, Red blood 
cells, White blood cells, Differential (Basophils, 
Eosinophils, Lymphocytes, Monocytes, 
Neutrophils)
Clinical Chemistry
For all visits:
Albumin, Alkaline phosphatase, alanine 
aminotransferase (ALT), aspartate 
aminotransferase (AST), Blood Urea Nitrogen 
(BUN), Calcium, Creatinine, Gamma-
glutamyltransferase (GGT), Lactate 
dehydrogenase (LDH), Magnesium, 
Phosphorus, Potassium, Sodium, Total Bilirubin, 
If the total bilirubin concentration is increased 
above 1.5 times the upper limit of normal range, 
total bilirubin should be differentiated into the 
direct and indirect reacting bilirubin
At Day 1, Week 12 and Week 24/PSW only:
HbA1c will also be measured
Urinalysis
Microscopic Panel: Red Blood Cells, White 
Blood Cells, Casts, Crystals only if abnormalities 
on the macroscopic panel (dipstick) are 
detected.
Macroscopic Panel (Dipstick): Blood, pH, 
Protein, Specific Gravity
Coagulation
Prothrombin time international normalized ratio 
(PT/INR) at Run In 1 and at Week 24/PSW only


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Pregnancy Test
Serum/Urine pregnancy test for women of 
childbearing potential
Patient does not require fasting for the laboratory assessments
8.4.2
Electrocardiogram (ECG)
Triplicate ECGs (3 ECGs are collected within about a five-minute window) must be recorded 
after 10 minutes rest in the supine position to ensure a stable baseline/according to the ECG 
investigator manual. The preferred sequence of cardiovascular data collection during study
visits is ECG collection first, followed by vital signs, and blood sampling. A minimum 3 
minutes rest period from the beginning of ECG assessments to the start of spirometry maneuvers 
must be observed at all times.
Where clinical decisions are based on the QT interval, the length of the QT interval is to be 
calculated according to the Fridericia QT correction formula (QTcF). 
Triplicate ECGs are collected pre-dose and at 3 hours post-dose on Day 1, Day 15, and Day 
169 as indicated in Table 8-1. For patients participating in the optional additional PK sampling 
sub-group, is should be 4 h post-dose on Day 1 and Day 15 instead of 3 hours post-dose.
Triplicate ECGs are collected at pre-dose at visits indicated in Table 8-1. All ECGs must be 12-
lead ECGs. For each ECG performed, original traces and identical duplicate traces should be 
printed. Each ECG will be sent electronically for central review directly from the ECG machine. 
Two 'identical' duplicate print-outs will be generated and kept at the investigator site as source 
documentation and as back up for submission to the central laboratory in case of problems with 
the electronic transmission. Each print-out will be kept at the investigator site and will be dated 
and signed. The patient's number, the date, actual time of the tracing and study code must appear 
on each page of the tracing. Clinically significant abnormalities must be recorded on the eCRF 
as either medical history/current medical conditions or adverse events as appropriate.
8.4.3
Pregnancy and assessments of fertility
All pre-menopausal women who are not surgically sterile (women of childbearing potential) 
will have pregnancy testing. A serum or urine pregnancy test will be performed (urine test kits 
provided to the sites by the Central Laboratory/serum pregnancy tests conducted by the Central 
Laboratory) as per assessment schedule Table 8-1. A positive pregnancy test at any time during 
the study requires the patient to be discontinued from the study treatment. Refer to Section 9.1.1
for more details. Additional pregnancy testing can be performed if required by local authorities.
8.5
Additional assessments
8.5.1
Pharmacokinetics
Blood samples will be obtained from all subjects as per visits and timepoints indicated in
Table 8-1 and Table 8-2.
In approximately 48 subjects, additional PK samples at Day 1 and Day 15 will be collected, as 
per Table 8-3, to examine the time-concentration profiles of QBW251 after single dose and 
multiple doses in the COPD patients. Furthermore, additional PK samples will be collected, 






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
Emergence of a SAE that the Investigator suspects to be related to investigational drug 
shall lead to immediate stop of investigational treatment. A blood sample to assess the 
exposure level should be taken, where possible, for expedited assessment. Where no blood 
sample at the time of occurrence of the SAE can be obtained, the last sample taken prior to 
the start of the SAE will be assessed.

Emergence of an AE that is of severe intensity and that the Investigator suspects to be 
related to investigational drug shall lead to immediate stop of investigational treatment.

In case of emergence of a SAE that the Investigator does not suspect to be related to 
investigational drug, investigational treatment can be continued. A blood sample to assess 
the exposure level should be taken, where possible, for expedited assessment. If the SAE 
coincided with a verified exposure above the AUC threshold of AUC0-24h = 91 700
ng×h/mL, investigational drug needs to be permanently stopped as soon as possible upon 
receipt of the PK results.

A patient with a verified exposure above the upper range of the individual animal 
(monkey) model exposure (AUC0-24h = 159 000 ng×h/mL). The investigator must 
permanently discontinue the investigational drug as soon as possible upon receipt of the 
PK results.

Any laboratory abnormalities that in the judgment of the investigator, taking into 
consideration the subject’s overall status, prevents the subject from continuing 
participation in the study.

Any liver event requiring immediate discontinuation of study treatment, as specified in 
Table 16-2. 

In case of confirmed QTcF > 500 msec, as indicated in Section 6.5.1.1.
Investigational drug can be temporarily interrupted as a response to the occurrence of adverse 
events that do not fulfil the requirements above described for permanent discontinuation (refer 
to Section 6.5.1).
If permanent discontinuation of investigational treatment occurs, the investigator should make 
a reasonable effort to understand the primary reason for the subject’s premature discontinuation 
of investigational treatment and record this information. 
The investigator must also contact the IRT to register the subject’s discontinuation from 
investigational treatment.
If discontinuation occurs because treatment code has been broken, please refer to Emergency 
breaking of treatment code Section 6.6.2.
Subjects who have their investigational treatment permanently discontinued should NOT be 
considered withdrawn from the study UNLESS they withdraw their consent (see withdraw of 
informed consent section). Where possible, they should return for the assessments indicated 
in the assessment schedule in Table 8-1. If they fail to return for these assessments for unknown 
reasons, every effort (e.g. telephone, e-mail, letter) should be made to contact the subject/pre-
designated contact as specified in the lost to follow-up section. This contact should preferably 
be done according to the study visit schedule. If the subject cannot or is unwilling to attend any 
visit(s), the site staff should maintain regular telephone contact with the subject, or with a person 
pre-designated by the subject. This telephone contact should preferably be done according to 


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the study visit schedule and at a minimum information on new/ concomitant treatments and 
adverse events /serious adverse events should be obtained.
9.1.1.1
Replacement policy
Discontinued patients will not be replaced on study.
9.1.2
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject:

Does not want to participate in the study anymore
and

Does not allow further collection of personal data.
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table.
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject's samples until the time of withdrawal) according to applicable 
law.
For US and Japan: all biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form.
For EU and the rest of the world (RoW): all biological samples not yet analyzed at the time of 
withdrawal will no longer be used, unless permitted by applicable law. They will be stored 
according to applicable legal requirements.
9.1.3
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A subject should not be considered as lost to follow-up until due 
diligence has been completed.


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9.1.4
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. Exposure driven termination rules are 
described below in Section 9.1.4.1. In taking the decision to terminate, Novartis will always
consider the subject welfare and safety. Should early termination be necessary, subjects must 
be seen as soon as possible. The Investigator should ensure contact is made as quickly as 
possible by telephone and/or e-mail and/or letter. If the study is stopped for a change in the 
benefit/risk assessment or for medical reasons, patients may be instructed to stop taking the 
investigational drug QBW251 immediately. Else, patients may be instructed to continue 
QBW251 intake until they can return to the site for a final assessment. Background medication 
(LABA/LAMA/ICS) should be continued until the final visit. The patient should be treated as 
a prematurely withdrawn subject and undergo all assessments of the premature withdrawal visit. 
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 subject’s interests. The investigator 
or sponsor depending on the local regulation will be responsible for informing IRBs/IECs of
the early termination of the trial.
9.1.4.1
Criteria for premature termination of treatment arm(s)
As described in the risks and benefits section (Section 4.5), this protocol features a PK 
monitoring plan to ensure that patients' exposures are generally consistent with an exposure 
threshold (AUC0-24h = 91 700 ng×h/mL), which was established based on animal (monkey) data. 
Therefore, the cohort stopping rules have been developed to comply with this goal. The 
independent Data Monitoring Committee (Section 10.2.3) will periodically review the 
cumulating PK data against these rules.
The 2 rules described below support 2 aims:
- Limit the proportion of patients that exhibits exposures (AUC) above the threshold
- Limit the number of patients with exposures that are above the upper range of the exposures 
(AUC) observed in the animals.
Based on these goals, a treatment arm will be permanently discontinued if:
1. At predefined safety interim read outs the observed proportion of patients above the threshold 
(AUC0-24h = 91 700 ng×h/mL) is significant greater than expected. Statistical details of this rule 
are described in Section 12.7.1.
and/or
2. More than one patient exhibits a projected AUC above the upper range of the individual 
animal (monkey) exposures (AUC0-24h = 159 000 ng×h/mL). In case the 2 patients are in 
separate treatment arms, the treatment arm with the lowest dose will determine all the treatment 
arms to be prematurely terminated.
Any treatment arm* fulfilling either one of these criteria will lead to the permanent 
discontinuation of study investigational drug for the patients in such treatment arm. New 
patients would be randomized to the remaining treatment arms.


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PK exposure values above the threshold due to unverified sampling or analysis or the 
consequence of an accidental/voluntary overdosing will not be included in the determination of 
whether to stop a treatment arm.
* The affected treatment arm with the lowest dose will determine which treatment arm(s) will 
be discontinued (all the ones above it). For instance if the stopping rules impact the 300 mg 
b.i.d. treatment arm (but not the 450 mg b.i.d. treatment arm) both the 300 mg and the 450 mg
arms will be discontinued as described above.
9.2
Study completion and post-study treatment
Study completion is defined as when the last subject finishes his/her Follow-Up visit (study 
completion visit), and any repeat assessments associated with this visit have been documented 
and followed-up appropriately by the Investigator, or in the event of an early study termination 
decision, the date when the last patient completes his/her premature termination visit (see 
Section 9.1.4).
Upon completion of a patient's participation in the study, he/she should be treated according to 
his/her individual needs. It is not planned to provide QBW251 to study participants after the 
study is completed due to the early stage of development. Since this study is a Phase 2 study, 
the safety profile of the drug has not yet been established to the extent considered adequate for 
a provision of QBW251 with less stringent safety monitoring. Should there be patients with 
significant clinical benefit from QBW251 over approved treatment alternatives and the safety 
profile allow for treatment outside of the study, Novartis will consider to continue provision of 
the investigational treatment to these patients. Should there be a request from an investigator to 
provide post-trial treatment to a patient with evidence of significant clinical benefit from the 
use of QBW251 over the use of approved treatments, and the safety profile of the drug allow 
for treatment outside of the controlled environment of a study, Novartis will consider to 
continue providing the investigational treatment to this patient.
10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g. 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 investigator has the responsibility for managing the 
safety of individual subject and identifying adverse events. Novartis qualified medical 
personnel will be readily available to advise on trial related medical questions or problems.
The occurrence of adverse events must be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject during or between visits or through physical examination findings, laboratory test 
findings, or other assessments.


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Adverse events must be recorded in the Adverse Events eCRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information (as far as possible) 
(if the event is serious refer to Section 10.1.2):
1. The severity grade:
a. mild: usually transient in nature and generally not interfering with normal activities,
b. moderate: sufficiently discomforting to interfere with normal activities,
c. severe: prevents normal activities.
2. its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected’. The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single subject.
3. its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported.
4. whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met.
5. action taken regarding with study treatment.
All adverse events must be treated appropriately. Treatment may include one or more of 
the following:
a. Dose not changed,
b. Dose Reduced/increased,
c. Drug interrupted/withdrawn.
6. its outcome 
a. not recovered/not resolved,
b. recovered/resolved,
c. recovering/resolving,
d. recovered/resolved with sequelae,
e. fatal, or 
f.
unknown.
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the subject.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms.
Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment.
Once an adverse event is detected, it must be followed until its resolution or until it is judged to
be permanent (e.g. Continuing at the end of the clinical trial), and assessment must be made at 
each visit (or more frequently, if necessary) of any changes in severity, the suspected 
relationship to the interventions required to treat it, and the outcome.


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Information about adverse drug reactions for the investigational drug can be found in the 
Investigator’s Brochure (IB).
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms

they are considered clinically significant

they require therapy
Clinically significant abnormal laboratory values or test results must 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 subjects with 
the underlying disease. Alert ranges for laboratory and other test abnormalities are included in 
Section 16.1.
10.1.2
Serious adverse events
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing)
undesirable sign(s), symptom(s) or medical conditions(s)), which meets any one of the 
following criteria:

fatal

life-threatening
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might 
have caused death if it were more severe (please refer to the ICH-E2D Guidelines).

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

social reasons and respite care in the absence of any deterioration in the subject’s 
general condition

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

is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant”. Examples of such events are intensive treatment in an 


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emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred.
Upon reporting of an SAE, the investigator should make every attempt to bring the patient for 
an unscheduled visit to collect a PK blood sample at a minimum, unless a planned visit for this 
patient is occurring within a week time of the reported SAE.
10.1.3
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days following the last administration of study 
treatment if there are post-treatment Follow-Up visits with no required procedures must be 
reported to Novartis safety within 24 hours of learning of its occurrence. Detailed instructions 
regarding the submission process and requirements are to be found in the investigator folder 
provided to each site.
SAEs occurring after the subject has provided informed consent until the time the subject is 
deemed a screen failure or run-in failure must be reported to Novartis.
For randomized subjects, SAEs occurring after the subject has provided informed consent until 
30 days after the subject has discontinued or stopped study treatment (which usually would be 
the time of the Follow-Up visit) must be reported to Novartis.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a Novartis Chief Medical Office 
and Patient Safety (CMO & PS) department associate may urgently require further information 
from the investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study treatment 
that this SAE has been reported.
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries.
Any SAEs experienced after the 30 day period from the last treatment (usually marked by the 
Follow-Up visit) should only be reported to Novartis Safety if the investigator suspects a causal 
relationship to study treatment.


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10.1.4
Pregnancy reporting
To ensure subject safety, each pregnancy occurring after signing the informed consent 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 and reported by the investigator to the CMO&PS department. 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the investigational study drug and any pregnancy outcome. Any 
SAE experienced during pregnancy must be reported.
Follow up of pregnancies should be conducted as described below:

At expected date of delivery (EDD) +1 month: Mandatory to all pregnancy cases; 
pregnancy outcome, and other clinically relevant pregnancy data or changes in data, 
should be collected.

At EDD +2 months: Mandatory if no answer is obtained after request at EDD+1 month; 
same information as at EDD+1 month should be collected.

At EDD+3 months: Mandatory for all cases of live birth/unknown outcome; status of the 
baby 3 months after delivery, any development issue or abnormality that would not be 
seen at birth

EDD+12 months: Mandatory for all cases of live birth/unknown outcome; infant health 
status and development.
10.1.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the dose administration record (DAR) eCRF, irrespective of whether or not associated with an 
AE/SAE and reported to Safety only if associated with an SAE. Misuse or abuse will be 
collected and reported in the safety database irrespective of it being associated with an AE/SAE 
within 24 hours of Investigator’s awareness.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dose 
Administration (DAR) 
eCRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with 
an SAE


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Treatment error type
Document in Dose 
Administration (DAR) 
eCRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please see the, 
respective sections.
10.2
Additional Safety Monitoring
10.2.1
Liver safety monitoring
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.
The following 2 categories of abnormalities/adverse events have to be considered during the 
course of the study (irrespective of whether classified/reported as AE/SAE):

Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter

Liver events, which will require close observation, follow-up monitoring and completion 
of the respective eCRF pages as detailed in the CRF Completion Guidelines.
Please refer to Section 16.2 for complete definitions of liver laboratory triggers and liver events.
Every liver event defined in Table 16-1 should be followed up by the investigator or designated 
personnel at the trial site, as summarized below. Additional details on actions required in case 
of liver events are outlined in Table 16-2. Repeat liver chemistry tests (ALT, AST, total 
bilirubin (TBL), PT/INR, alkaline phosphatase (ALP) and GGT) to confirm elevation.

These liver chemistry repeats will be performed using the central laboratory. If results will 
not be available from the central laboratory, then the repeats can also be performed at a 
local laboratory to monitor the safety of the subject. If a liver event is subsequently 
reported, any local liver chemistry tests previously conducted that are associated with this 
event should have results reported on the local laboratory eCRF page,

If the initial elevation is confirmed, close observation of the subject will be initiated, 
including consideration of treatment interruption if deemed appropriate.

Discontinuation of the investigational drug (refer to the Discontinuation of study treatment 
section), if appropriate

Hospitalization of the subject if appropriate

Causality assessment of the liver event

An investigation of the liver event which needs to be followed until resolution. These 
investigations can include based on investigator’s discretion: serology tests, imaging and 
pathology assessments, hepatologist’s consultancy; obtaining more detailed history of 
symptoms and prior or concurrent diseases, history of concomitant drug use, exclusion of 
underlying liver disease and imaging such as abdominal ultrasound, computer tomography 
(CT) or magnetic resonance imaging (MRI), as appropriate.


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All follow-up information, and the procedures performed must be recorded as appropriate in 
the eCRF.
10.2.2
Renal safety monitoring
Renal safety monitoring for the investigational drug will be performed in the study. This 
includes baseline measurements of serum creatinine, calcium, potassium and urine dipstick and 
at subsequent visits as indicated in the Schedule of Assessments Table 8-1 and Laboratory 
parameters in Table 8-5.
10.2.3
Data Monitoring Committee
This study will include a data monitoring committee (DMC) which will function independently 
of all other individuals associated with the conduct of this clinical trial, including the site 
investigators participating in the study. The DMC will assess at defined intervals the progress 
of a clinical trial, safety data, and critical efficacy variables and recommend to the sponsor 
whether to continue, modify or terminate a trial. The DMC will furthermore assess at defined 
intervals the accumulating PK data and review these against the stopping rules (Section 9.1.4.1).
Specific details regarding composition, responsibilities, data monitoring and meeting frequency, 
and documentation of DMC reports, minutes, and recommendations will be described in a 
separate charter that is established between the sponsor and the DMC.
11
Data Collection and Database management
11.1
Data collection
Designated investigator staff will enter the data required by the protocol into the eCRF. The 
eCRFs have been built using fully validated secure web-enabled software that conforms to 21 
Code of Federal Regulations (CFR) Part 11 requirements, Investigator site staff will not be 
given access to the Electronic Data Capture (EDC) system until they have been trained. 
Automatic validation programs check for data discrepancies in the eCRFs, allow modification 
and/or verification of the entered data by the investigator staff.
The investigator/designee is responsible for assuring that the data entered into eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner. The Investigator must 
certify that the data entered are complete and accurate
After final database lock, the investigator will receive copies of the subject data for archiving 
at the investigational site.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
11.2
Database management and quality control
Novartis personnel (or designated Commercial Research Organization (CRO)) will review the 
data entered by investigational staff for completeness and accuracy. Electronic data queries 
stating the nature of the problem and requesting clarification will be created for discrepancies 
and missing values and sent to the investigational site via the EDC system. Designated 


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investigator site staff are required to respond promptly to queries and to make any necessary 
changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology.
Randomization codes and data about all study treatment (s) dispensed to the subject and all 
dosage changes will be tracked using an Interactive Response Technology (IRT). The system 
will be supplied by a vendor, who will also manage the database. The data will be sent 
electronically to Novartis (or a designated CRO) at specific timelines.
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of Novartis.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
available for data analysis. Any changes to the database after that time can only be made after 
written agreement by Novartis development management.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis/ 
representative will review the protocol and data capture requirements (i.e. eSource Direct Data 
Entry (DDE) or eCRFs) with the investigators and their staff. During the study, Novartis 
employs several methods of ensuring protocol and GCP compliance and the quality/integrity of 
the sites’ data. The field monitor will visit the site to check the completeness of subject records, 
the accuracy of data capture/data entry, the adherence to the protocol and to Good Clinical 
Practice, the progress of enrollment, and to ensure that study treatment is being stored, 
dispensed, and accounted for according to specifications. Key study personnel must be available 
to assist the field monitor during these visits. Continuous remote monitoring of each site’s data 
may be performed by a centralized Novartis Clinical Research Associate (CRA) organization. 
Additionally, a central analytics organization may analyze data & identify risks & trends for 
site operational parameters, and provide reports to Novartis clinical teams to assist with trial 
oversight.
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on eCRFs must be traceable to these source documents in the 
subject’s file. The investigator must also keep the original informed consent form signed by the 
subject (a signed copy is given to the subject).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. 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 


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study-specific monitoring plan. No information in source documents about the identity of the 
subjects will be disclosed.
12
Data analysis and statistical methods
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
If not stated otherwise, all inferential analyses will not include the 450 mg dose due to early 
termination of the 450 mg b.i.d arm, resulting in very few or no data in some of the strata 
(covariates/factors in the model) during the later visits. All descriptive summaries will include 
the 450 mg b.i.d. dose.
12.1
Analysis sets
The Randomized Analysis Set (RAS) consists of all randomized patients. Patients will be 
analyzed according to the treatment they were assigned to at randomization. 
The Full Analysis Set (FAS) will include all randomized patients who received at least one dose 
of randomized treatment. Following the intent-to-treat principle, patients will be analyzed 
according to the treatment they were assigned to at randomization. It is reasonable to require 
that patients took randomized treatment for inclusion in the FAS because the decision on 
whether or not randomized treatment is started will not be influenced by the treatment group 
assignment due to effective treatment blinding procedures. 
The Safety Set will include all patients who received at least one dose of double-blind treatment. 
Patients will be analyzed according to the treatment they received. 
Note that the FAS and Safety Set are the same except that the Safety Set allows the inclusion 
of non-randomized patients who receive double-blind treatment in error. In addition, analyses 
based on the FAS assigns randomized treatment while analyses based on the Safety Set assigns 
received treatment.
The PK set will include all patients with at least one evaluable drug concentration data sample. 
The PK serial sub-group will include all patients with at least one evaluable drug concentration 
data sample and who consented to participate in the PK serial sub-group. Patients will be 
analyzed according to the treatment received for both sets.
12.2
Subject demographics and other baseline characteristics
Demographic and other baseline data, including disease characteristics and relevant medical 
histories/current medical conditions, will be summarized descriptively by treatment group.
12.3
Treatments
The duration of exposure in days to each treatment group (QBW251 dose or placebo) will be 
summarized by means of descriptive statistics. The following summaries for COPD-related 
medications will be performed separately for medications prior to run-in (medications starting 
prior to screening and ending prior to or at the run-in visit) and for concomitant medications 
(medications which were taken anytime between the first dose and last dose of randomized 
treatment, inclusive). COPD-related medications will be summarized by pre-specified drug 


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categories, route of administration, preferred term, and treatment group. Non-COPD related 
medication prior to and after the start of randomized treatment will be summarized by route of 
administration, preferred term, and treatment group.
The number of patients who permanently discontinued from double blind treatment and the 
reasons will be summarized by treatment group.
12.4
Analysis of the primary endpoint(s)
The primary objective of this study is to characterize the DR (dose-response) efficacy 
relationship among QBW251 doses (25, 75, 150 and 300mg b.i.d.) and placebo with regards to 
the change from baseline in trough FEV1 after 12 weeks of treatment. The goals associated with 
this objective are below.

To confirm an overall DR signal

To estimate the dose(s) that corresponds to the target effect over placebo based on the 
estimated DR curve
12.4.1
Definition of primary endpoint(s)
The primary estimand, defined below, quantifies a hypothetical on-treatment Week 12 effect 
during stable periods (i.e. outside episodes of COPD worsening that require rescue medication 
or systemic corticosteroids). This estimand targets the maximum treatment effect for QBW251 
and allows selection of the best dose for those who take it for 12 weeks.

Population: patients with moderate to severe COPD enriched for presence of chronic 
bronchitis and a history of exacerbations and treated with LABA/LAMA/ICS background 
therapy

Variable: trough FEV1 (average of the 2 values taken 15 and 45 min pre-dose) change 
from baseline after 12 weeks of treatment

Intervention effect of interest: Effect of interventions initiated at randomization during 
stable periods (i.e. outside episodes of COPD worsening that require rescue medication or 
systemic corticosteroids) and that would have been observed had all patients remained on 
their assigned treatment for 12 weeks, with the following post-randomization events 
accounted for by assessing: 

Intake of rescue medication or systemic corticosteroids (SCS): the effect outside of 
periods of worsening disease that necessitate rescue medication or SCS

Discontinuation of study treatment or study participation: hypothetical on-treatment 
trough FEV1 value.

Missing data due to any reason prior to completion or discontinuation of treatment: 
on-treatment trough FEV1 values.

Summary measure: mean difference between treatment groups (QBW251 compared with 
placebo)
The baseline value is defined as the average of the FEV1 values taken approximately 45 and 15 
minutes prior to first dose of randomized treatment at Day 1. If one of the 2 values is missing 
(or is not confirmed to be pre-dose) then the remaining non-missing value will be taken as the 
baseline. If both values are missing (or are not confirmed to be pre-dose), then the 
measurements taken at the Run-In 1 visit will be used as the baseline.


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12.4.2
Statistical model, hypothesis, and method of analysis
The Multiple Comparison Procedure –
Modelling (MCP-Mod) methodology (see 
Bretz et al 2005 and Pinheiro et al 2014) will be employed to assess the primary objective. An 
overview of the steps for the MCP-Mod methodology is given below. Further details will be 
provided in the Statistical Analysis Plan (SAP).
Step 1 (Testing an overall dose-response signal - MCP part):
The (covariate) adjusted mean responses at each individual dose will be obtained from a mixed-
effect linear model for repeated measures (MMRM) with terms for baseline FEV1, visit, region, 
treatment, smoking status at screening, severity of airflow limitation, treatment-by-visit 
interaction, run-in post-bronchodilator FEV1, and baseline FEV1-by-visit interaction as fixed 
effects. To allow adjustment for correlations between timepoints within patients, an 
unstructured variance-covariance structure will be used.
The adjusted treatment means from the MMRM will be used to test the null hypothesis of a flat 
DR relationship for the primary efficacy endpoint at a one-sided significance level of 5% against 
the alternative hypothesis of a non-constant DR curve. The testing will be performed with a 
multiple contrast test described in the MCP-Mod methodology.
A wide range of possible dose-response relationship will be considered to take model 
uncertainty into account (Figure 12-1). A monotonic DR is assumed, supported by preclinical 
data and the observed DR of another CFTR-potentiator, ivacaftor. Eleven candidate DR curves 
(4 Emax, 4 Sigmoid Emax, 2 Exponential, and 1 Linear) will be used to derive the optimal 
model contrasts for the multiple contrast tests. Emax and sigmoidal Emax models are 
considered based on the observed DR of ivacaftor (FDA 2012). The ED50 values (the dose at 
which half of the maximum effect is reached) for the Emax models will be 25, 75, 150, and 300. 
The parameters of the sigmoidal Emax models (ED50, h) will be (25, 3), (75, 3), (150, 3) and 
(300, 3) where h is the Hill parameter that determines the steepness of the dose-response shape. 
Exponential models are considered since there is an over-proportional increase of exposures at 
the high end of the dose range tested. The parameter controlling the convexity of the 
Exponential models will be 150 and 300.
For each of the 11 candidate DR curves, a contrast test statistic will be derived that maximizes 
the power assuming the true mean response is the one assumed by the candidate DR curve. The 
detection of a significant DR signal is based on the maximum of the 11 contrast test statistics. 
The overall null hypothesis of no DR relationship is rejected if the multiplicity adjusted p-value 
for at least one contrast test is < 0.05 (one sided).


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Figure 12-1
Candidate Dose Response Curves
Step 2 (Estimation of the dose-response curve and target dose – Mod part):


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Once the DR signal is declared, the DR curve and the target dose(s) of interest will be estimated 
by model averaging. A large number of bootstrap samples from the multivariate normal 
distribution will be drawn with adjusted means from the MMRM and corresponding covariance 
matrix. For each sample:

DR models from the candidate families (Emax, Sigmoid Emax, Exponential, Linear) will 
be fitted to the data and the best model according to the generalized Akaike information 
criterion (AIC) will be chosen.

The predictions for dose-response will be obtained from the best model.
The final DR curve estimate is the median of these predictions while confidence intervals will 
be calculated from the quantiles. The final DR curve estimate with the model-based two-sided 
90% confidence interval will be presented graphically. In addition, the plot will include the 
mean responses from the MMRM and the associated 90% confidence intervals for each of the 
studied dose groups.
The target dose(s) that corresponds to a clinically relevant effect over placebo can be estimated 
using inverse regression techniques (Bretz et al 2005). All data related to safety, efficacy and 
other assessments including PK exposure will be taken into consideration to propose a dose for 
Phase 3.
12.4.3
Handling of missing values/censoring/discontinuations
Since the estimand is related to an effect outside of rescue med intake, spirometry measurements 
within 6 hours of rescue medication or within 7 days of intake of SCS use will be set to missing.. 
If one of the values contributing to the trough FEV1 variable is missing at a visit, the remaining 
non-missing value will be taken as trough FEV1. If both values are missing, then their trough 
FEV1 will be regarded as missing at that visit.
For the primary analysis, only on-treatment data (from date of first randomized dose up to 1 
day after date of last randomized dose) will be used as the estimand specifies a hypothetical on-
treatment effect. Missing on-treatment data will not be explicitly imputed as the MMRM model 
implicitly imputes missing data assuming the missing at random (MAR) mechanism.
The imputation procedure(s) related to the trough FEV1 supportive analyses (Section 12.4.4) 
are "jump-to-reference" (J2R) and MAR (Carpenter et al 2013). The imputations will be based 
on all available data (i.e. from all scheduled timepoints) using all covariates as specified in the 
MMRM. For J2R, only placebo (reference) data will be used. For MAR, data from the same 
treatment arm will be used for building the imputation model. Imputation of intermittent 
missing observations before treatment discontinuation will be carried out following a MAR 
mechanism for all treatment arms. Additional details will be available in the SAP.
12.4.4
Supportive analyses
A supplementary analysis will be performed that quantifies the treatment effect in all 
randomized patients during stable periods (i.e. outside episodes of COPD worsening that 
require rescue medication or SCS) with an adherence to treatment like we would see in clinical 
practice in a world without COVID-19, with the following post-randomization events 
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a. Intake of rescue medication or systemic corticosteroid: effect outside of periods of 
worsening disease that necessitate rescue med or systemic corticosteroid
b. Discontinuation of study treatment for non-COVID-19 reason with follow-up: actual off-
treatment value. If no data was retrieved after study treatment discontinuation, missing 
data will be multiply imputed based on placebo arm data: J2R assumption for the 
QBW251 arms and MAR assumption for placebo arm.
c. Discontinuation of study treatment due to a COVID-19 related reason: on-treatment value. 
Missing data will be multiply imputed based on the MAR assumption. 
d. Discontinuation of study participation due to any non-COVID-19 related reason: off-
treatment value. Missing data will be multiply imputed based on placebo arm data: J2R 
assumption for the QBW251 arms and MAR assumption for placebo arm.
e. Any other event leading to missing data prior to completion or discontinuation of study 
treatment: on-treatment value. Missing data will be multiply imputed based on the MAR 
assumption.
Additional sensitivity and/or supportive analyses may also be added to explore the impact of 
COVID-19 in the SAP.
A supportive exposure-response analysis may also be performed.
12.5
Analysis of secondary endpoints
No multiplicity adjustment will be carried out for secondary analyses described below. In 
addition, the treatment effect of QBW251 compared to placebo that would have been observed 
had all patients remained on their assigned treatment will be estimated. Only data obtained 
while patient is on-treatment (from date of first randomized dose up to 1 day after date of last 
randomized dose) will be used. Missing data for any reason will not be explicitly imputed and 
will be handled by the respective mixed effects model which implicitly imputes missing data 
assuming MAR.
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)
12.5.1.1 COPD symptoms
12.5.1.1.1
Respiratory symptoms from E-RS
The E-RS assesses both overall daily respiratory COPD symptoms (Total score) and specific 
respiratory symptoms using 3 subscales (Breathlessness, Cough & Sputum, and Chest 
Symptoms). Higher scores indicate more severe symptoms.
The mean baseline E-RS Total and subscale scores will be the average of the corresponding 
daily scores from the run-in period. The last 14 days of the run-in period, i.e. the scheduled 
duration of run-in period, will be considered. A patient needs to have at least 8 days of data 
from the run-in period in order for the mean baseline score to be calculated.
The daily scores post-randomization will be averaged for each week (Week 1, Week 2, etc.). A 
patient needs to have at least 4 days of data in any week in order for the mean score to be 
calculated.


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Monthly means over a 4-week period will also be calculated. A patient needs to have at least 3 
weekly means in that month in order for the monthly mean score to be calculated.
E-RS Cough & Sputum score
The change from baseline in the E-RS Week 12 Cough & Sputum mean scores will be analyzed 
using the same MCP-Mod approach described in Section 12.4 for the primary analysis of the 
primary variable. The change from baseline in the E-RS Cough & Sputum weekly mean scores
will be analyzed using a similar MMRM as described in Section 12.4 for the primary variable, 
with the appropriate baseline score replacing the baseline FEV1 value in the model. The 
estimated treatment difference (QBW251 – placebo) at each week will be reported along with 
the associated 90% confidence interval.
The proportion of patients who achieve a clinically important improvement (decrease) of at 
least 0.7 (Leidy et al 2014b) in the weekly mean score will be analyzed using a repeated 
measurements logistic regression. The model will include the same terms as for the MMRM 
analysis of the weekly scores. The estimated odds ratios will be displayed over time along with 
the associated 90% confidence intervals.
The change from baseline in the monthly mean scores will be analyzed using a similar MMRM 
as described above. The proportion of patients who achieve a clinically important improvement 
(decrease) in the monthly mean score will also be analyzed as described above.
E-RS Total, Breathlessness, and Chest Symptoms scores
The change from baseline in the E-RS weekly mean Total, Breathlessness, and Chest Symptom 
scores will be analyzed using a similar MMRM as described in Section 12.4 for the primary 
variable with the appropriate baseline E-RS score replacing the baseline FEV1 value. The 
estimated treatment difference (QBW251 – placebo) will be reported along with the associated 
90% confidence interval.
The minimum clinically important improvements (decrease) for the scores are defined below 
(Leidy et al 2014b).

Total ≥ 2.0

Breathlessness ≥ 1.0

Chest Symptoms ≥ 0.70
The proportion of patients who achieve a clinically important improvement in the weekly mean 
scores will be analyzed using a repeated measurements logistic regression. The model will 
include the same terms as for the MMRM analysis of the weekly mean scores. The estimated 
odds ratios will be displayed over time along with the associated 90% confidence intervals.
The change from baseline in the monthly mean scores will be analyzed using a similar MMRM 
as described above. The proportion of patients who achieve a clinically important improvement 
(decrease) in the monthly mean score will also be analyzed as described above.
12.5.1.1.2
Cough and sputum symptoms from CASA-Q
CASA-Q assesses cough and sputum symptoms and their impact with 4 domain scores (cough 
symptoms, cough impact, sputum symptoms, and sputum impact). The change from baseline in 
the domain scores will be analyzed using the MMRM described in Section 12.4 for the primary 


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variable with the appropriate baseline domain score replacing the baseline FEV1 value in the 
model. The estimated treatment difference (QBW251 – placebo) at each visit will be reported 
along with the associated 90% confidence interval.
12.5.1.1.3
Severity of symptoms from PGI-S
The PGI-S rates the severity of the respiratory symptoms and of cough and mucus. Shift tables 
will be used to compare baseline to Weeks 12 and 24 for each PGI-S value. The proportional 
odds model for repeated measures with the same terms as for the MMRM analysis described in 
Section 12.4 for the primary variable with the baseline PGI-S value replacing the baseline FEV1
value. The estimated odds ratios will be displayed over time along with the associated 90% 
confidence intervals.
12.5.1.2 Health-related quality of life from SGRQ
SGRQ measures health impairment. A total score is produced, along with the domain scores of 
symptoms, activity, and impacts. The Weeks 12 and 24 change from baseline in the SGRQ total 
and domain scores will be analyzed using the MMRM described in Section 12.4 for the primary 
variable with the appropriate baseline SGRQ score replacing the baseline FEV1 value in the 
model. The estimated treatment difference (QBW251 – placebo) at each visit will be reported 
along with the associated 90% confidence interval.
The proportion of patients who achieve a clinically important improvement (decrease) of at 
least 4 in the total score will be analyzed using a repeated measurements logistic regression. 
The model will include the same terms as for the MMRM analysis of the total scores. The 
estimated odds ratios will be displayed over time along with the associated 90% confidence 
intervals.
12.5.1.3 Lung function
The change from baseline in trough FEV1 at visits other than Week 12 will be analyzed using 
the same MMRM as described in Section 12.4 for the primary analysis of the primary variable. 
The estimated treatment difference (QBW251 – placebo) at each visit will be reported along 
with the associated 90% confidence interval. The change from baseline in trough FEV1 at Week 
24 will also be analyzed using the same MCP-Mod approach described in Section 12.4.
The change from baseline in trough FVC after 4, 8, 12, 16, 20, and 24 weeks of treatment will 
be analyzed using the MMRM model described in Section 12.4 for the primary variable. The 
estimated treatment difference (QBW251 – placebo) at each visit will be reported along with 
the associated 90% confidence interval.
12.5.2
Safety endpoints
Safety summaries include only data from the on-treatment period with the exception of baseline 
data which will also be summarized where appropriate (e.g. change from baseline summaries).
Adverse events
The on-treatment period for adverse events lasts from the date of first administration of double-
blind study treatment to 30 days after the date of the last actual administration of randomized 


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study treatment. Adverse events will be summarized by treatment group. Summary tables for 
AEs will summarize only on-treatment events (also known as treatment-emergent AEs).
The number (and percentage) of subjects with treatment-emergent adverse events will be 
summarized in the following ways:

by treatment, primary system organ class and preferred term.

by treatment, primary system organ class, preferred term and maximum severity.
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events and other significant adverse events leading to discontinuation.
A subject with multiple adverse events within a primary system organ class or preferred term 
is only counted once towards the total of the primary system organ class or preferred term.
In addition, treatment emergent AEs and SAEs will be presented by treatment, system organ 
class and preferred term, showing exposure adjusted event rates (i.e., the number of events 
expressed in rates per 100 patient years).
Vital signs
The on-treatment period for vital signs will be defined in the SAP. Summary statistics will be 
provided by treatment and visit/time for each vital signs variable. Notable values (to be defined 
in the SAP) and change from baseline will also be summarized. The baseline value is the last 
value prior to first dose of double-blind treatment.
12-lead ECG
The on-treatment period for ECG will be defined in the SAP. Summary statistics will be 
provided by treatment and visit/time for each ECG variable. Categorical analysis of QTc 
interval data based on the number of subjects meeting or exceeding predefined limits (to be 
defined in the SAP) in terms of absolute QTc intervals or changes from baseline will be 
presented. The baseline value is the last value prior to first dose of double-blind treatment.
Clinical laboratory evaluations
The on-treatment period for labs will be defined in the SAP. Summary statistics will be 
provided by treatment and visit/time by each lab variable.
For selected laboratory tests, the number and percentage of patients with newly occurring or 
worsening laboratory abnormalities meeting the clinically notable criteria (to be defined in the 
SAP) will be summarized by laboratory parameter. Change from baseline will also be 
summarized. The baseline value is the last value prior to first dose of double-blind treatment.
12.5.3
Pharmacokinetics
Descriptive summary statistics of QBW251B plasma concentration data will be provided by 
treatment and visit/sampling timepoint, including the frequency (n, %) of concentrations below 
the lower limit of quantification (LLOQ). Summary statistics will include mean (arithmetic and 
geometric), standard deviation, coefficient of variation (arithmetic and geometric), median, 




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12.7
Interim analyses
12.7.1
Safety
IAs are planned for the monitoring of PK and safety data and do not inflate the type I error for 
the primary efficacy hypothesis testing. Thus no adjustment for multiplicity is required. These 
analyses will be performed by an external Independent Statistician and an Independent 
Programmer for an independent external safety DMC. Persons directly involved in the conduct 
of the clinical trial will not be involved in performing the IA or reviewing the results. The DMC 
will be provided with reports which are semi-blinded. If necessary, the study treatment can be 
unblinded by the chair of the DMC. The DMC will review PK and safety data and make 
recommendations regarding the conduct of the trial and/or alteration of the current protocol, 
including termination of a treatment arm. As mentioned in Section 9.1.4.1, a treatment arm 
(along with all other treatment arms with higher doses administered) will be terminated if the 
observed proportion of patients above the exposure threshold (AUC0-24h = 91 700 ng×h/mL) is 
significant greater than expected. It is expected that < 5% of patients on 300 mg or 450 mg b.i.d.
will exceed the threshold based on a conservative scenario. An α-spending function with Pocock 
type stopping boundary (as implemented in East 6.4) will be used to construct the stopping 
boundaries (Lan et al 1983) using the p-value scale such that the overall significance level 
across all analyses is maintained at 0.05. At each interim analysis, an exact test on the proportion 
of subjects who exceed the exposure threshold will be performed to test the following 
hypotheses for these 2 treatment arms.

Null hypothesis (Ho): the proportion of patients exceeding the exposure threshold < 5% 

Alternative hypothesis (Ha): the proportion of patients exceeding the exposure threshold 
≥5% 
The interim analyses are proposed to occur when 20%, 40%, 60%, 80%, and 100% of subjects 
have completed at least 4 weeks of treatment, which should be long enough to determine if the 
patient's exposure will exceed the threshold or not. The corresponding stopping boundaries in 
the p-value scale are 0.015, 0.016, 0.017, 0.018, and 0.019 for the interim analyses. For example, 
when the first interim analysis is performed after 20% patients have completed 4 weeks of 
treatment in the 450 mg b.i.d. arm, the observed (i.e. nominal) p-value has to be equal to or 
smaller than 0.015 in order to reject Ho and terminate the treatment arm. 
If the true proportion of patients in the 300 mg or 450 mg b.i.d. treatment arm exceeding the 
exposure threshold is < 5%, then the probability of rejecting Ho would be very low (< 5%) with 
this group sequential test for the treatment arm. If the true proportion is 10% then the probability 
of rejecting Ho and stopping the treatment arm early would be high (≥77%). If the timing of the 
actual interim analyses deviate from the proposed schedule (20%, 40%, 60%, 80%, and 100% 
completed at least 4 weeks of treatment), stopping boundaries will need to be recalculated using 
the pre-specified α-spending function and based on the actual sample size at each interim 
analysis. The observed p-values at the interim analyses will then be compared against the re-
calculated stopping boundaries.
After reviewing the exposure data from the first interim analysis, the DMC informed the 
sponsor that the 450 mg b.i.d. arm had crossed the stopping boundary and recommended 
termination of the treatment arm. The DMC confirmed that the arm was well tolerated in this 
patient population and the stop was not based on adverse reactions to the 450 mg b.i.d. regimen.  


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The sponsor followed the DMC’s advice and discontinued investigational treatment from all 
patients randomized to the 450 mg b.i.d. arm.  
More detailed criteria will be outlined in the DMC charter.
12.7.2
Efficacy
Up to 2 IAs on efficacy data may be conducted and the timing will correspond to 1 or 2 safety 
DMC analyses. The purpose of these IA(s) is to have an early assessment of the data for 
planning future studies in the QBW251B program. The efficacy IA results will not trigger any 
change or decision in the conduct of this study.
An internal Novartis committee, external to the study team, will be set up to review the both the 
efficacy and safety data. Once team members are exposed to the unblinded IA data, they will 
no longer be involved in the further execution of the study. A charter will provide further details.
The first IA will be conducted when approximately 645 to 680 patients, including ~102 patients 
randomized to the 450 mg b.i.d. arm, have either discontinued or completed 12 weeks of 
treatment. This IA will have acceptable precision for the estimated trough FEV1 dose-response
curve. The average half-length of the 90% confidence interval is around 26 mL and 32 mL for 
the estimated dose-response curve and the estimated placebo-adjusted dose-response curve, 
respectively. If the first IA does not lead to a clear decision for the planning of the QBW251B 
program, a second IA may be performed when all randomized patients have either discontinued 
or completed 12 weeks of treatment.
12.8
Sample size calculation
A total of 956 patients will be randomized to one of the 6 groups including 5 QBW251 dose 
groups (450, 300, 150, 75, 25 mg b.i.d.) and placebo. This includes the ~102 patients 
randomized to the 450 mg b.i.d. arm prior to its discontinuation. Prior to the discontinuation of 
450mg b.i.d., patients were randomized to QBW251 450, 300, 150, 75, 25 mg b.i.d., or placebo 
with an allocation ratio of 2:2:1:1:1:2. After discontinuation of 450mg b.i.d., patients were 
randomized to QBW251 300, 150, 75, 25 mg b.i.d., or placebo with an allocation ratio of 
2:1:1:1:2. This sample size of 854 (956 total minus approximately 102 patients already 
randomized to 450 mg b.i.d.) achieves at least 80% power for dose-response signal detection 
on key endpoints for all models from the candidate set based on the MCP-Mod methodology 
and also to ensure an acceptable precision for the DR curve estimation. The calculations in 
Table 12-1 exclude 450 mg b.i.d. from the analysis and are based on a 20% dropout rate, a one-
sided significance level of 5%, and the following standard deviation assumptions.

Pre-dose trough FEV1: A common standard deviation of 200 mL based on previous 
Novartis COPD studies.

E-RS Cough & Sputum weekly mean score: A common standard deviation of 1.3 based on 
the FLAME study (Wedzicha et al 2016).
Table 12-1
Power and Precision
Variable
Power to detect a 
DR signal
Average half-length of 90% 
confidence interval


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Maximum 
improvement 
over placebo
Estimated DR 
curve
Estimated 
placebo-adjusted 
DR curve
Trough FEV1
60 mL
50 mL
92%
81%
21 mL
26 mL
E-RS Cough & 
Sputum
0.35
0.30
86%
76%
0.14
0.17
Power calculations were performed using ADDPLAN-DF-4.0 and the precision estimates (half-length 
of confidence interval) were obtained from simulations.
The randomization ratio was based generally on D-optimality criteria, which maximize the 
information on the dose response curve, for the MCP-Mod analysis. The D-optimal allocation 
ratio randomizes approximately twice as many patients to placebo and the highest dose, 
compared to the middle doses.  
13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki.
13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures (e.g.
advertisements) and any other written information to be provided to subjects. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made.
13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.).


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For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings.
13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.
14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented.
14.1
Protocol Amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation.
Only amendments that are required for subject safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations.










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16
Appendices
16.1
Appendix 1: Clinically notable laboratory values and vital signs
The central laboratory will flag laboratory values falling outside of the normal ranges on 
the central laboratory reports. Investigators are responsible for reviewing these abnormal values 
for clinical significance, signing the laboratory reports to indicate their review, and reporting 
values considered clinically significant in the appropriate eCRF.
Any clinically significant abnormal laboratory value should be evaluated and followed-up by 
the investigator until normal or a cause for the abnormality is determined.
See Section 16.2 for specific liver event and laboratory test trigger definitions and follow up 
requirements.
For ECGs, a notable QTc value is defined as a QTcF (Fridericia) interval of ≥ 450 msec for 
males or ≥ 460 msec for females – all such ECGs will be flagged by the Central ECG reading 
and require assessment for clinical relevance and continuance of the patient by the Investigator.


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16.2
Appendix 2: Liver event and Laboratory trigger Definitions and 
Follow-up Requirements
Table 16-1
Liver Event and Laboratory Trigger Definitions
Definition/ threshold
LIVER LABORATORY TRIGGERS

3 x ULN < ALT / AST < 5 x ULN
· 1.5 x ULN < TBL < 2 x ULN
LIVER EVENTS

ALT or AST > 5 × ULN

ALP > 2 × ULN (in the absence of known 
bone pathology)

TBL > 2 × ULN (in the absence of known 
Gilbert syndrome)

ALT or AST > 3 × ULN and PT/INR > 1.5

Potential Hy’s Law cases (defined as ALT or 
AST > 3 × ULN and TBL > 2 × ULN [mainly 
conjugated fraction] without notable increase 
in ALP to > 2 × ULN)

Any clinical event of jaundice (or equivalent 
term)

ALT or AST > 3 × ULN accompanied by 
(general) malaise, fatigue, abdominal pain, 
nausea, or vomiting, or rash with 
eosinophilia

Any adverse event potentially indicative of a 
liver toxicity*
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver 
neoplasms TBL: total bilirubin; ULN: upper limit of normal
Table 16-2
Follow Up Requirements for Liver Events and Laboratory Triggers
Criteria
Actions required
Follow-up monitoring
Potential Hy’s Law casea

Discontinue the study 
treatment immediately

Hospitalize, if clinically 
appropriate

Establish causality

Complete appropriate 
eCRFs
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc
(frequency at investigator 
discretion)
ALT or AST
> 8 × ULN

Discontinue the study 
treatment immediately

Hospitalize if clinically 
appropriate

Establish causality
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc
(frequency at investigator 
discretion)


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Criteria
Actions required
Follow-up monitoring

Complete appropriate 
eCRFs
> 3 × ULN and PT/INR > 1.5

Discontinue the study 
treatment immediately

Hospitalize, if clinically 
appropriate

Establish causality

Complete appropriate 
eCRFs
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc
(frequency at investigator 
discretion)
> 5 to ≤ 8 × ULN

Repeat LFT within 48 
hours

If elevation persists, 
continue follow-up 
monitoring

If elevation persists for 
more than 2 weeks, 
discontinue the study drug

Establish causality

Complete appropriate 
eCRFs
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc
(frequency at investigator 
discretion)
> 3 × ULN accompanied by 
symptomsb

Discontinue the study 
treatment immediately

Hospitalize if clinically 
appropriate

Establish causality

Complete appropriate 
eCRFs
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc
(frequency at investigator 
discretion)
> 3 to ≤ 5 × ULN (patient is 
asymptomatic)

Repeat LFT within the next 
week

If elevation is confirmed, 
initiate close observation of 
the patient
Investigator discretion
Monitor LFT within 1 to 4 
weeks
ALP (isolated)
> 2 × ULN (in the absence of 
known bone pathology)

Repeat LFT within 48 
hours

If elevation persists, 
establish causality

Complete appropriate 
eCRFs
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit
TBL (isolated)
> 2 × ULN (in the absence of 
known Gilbert syndrome)

Repeat LFT within 48 
hours

Fractionation into direct 
and indirect bilirubin is 
required
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc
(frequency at investigator 
discretion)


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Criteria
Actions required
Follow-up monitoring

Complete appropriate 
eCRFs
Test for hemolysis (e.g.
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin)
> 1.5 to ≤ 2 × ULN (patient is 
asymptomatic)

Repeat LFT within the next 
week

If elevation is confirmed, 
initiate close observation of 
the patient
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit
Jaundice

Discontinue the study 
treatment immediately

Hospitalize the patient

Establish causality

Complete appropriate 
eCRFs
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc
(frequency at investigator 
discretion)
Any AE potentially indicative of 
a liver toxicity*

Consider study treatment 
interruption or 
discontinuation

Hospitalization if clinically 
appropriate

Establish causality

Complete appropriate 
eCRFs
Investigator discretion
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN 
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable 
values at 3 subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level after a 
maximum of 6 months, (4) liver transplantation, and (5) death.


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16.3
Appendix 3 Spirometry guidance
Equipment
Spirometers must meet the specifications and performance criteria recommended in the 
American Thoracic Society (ATS)/European Respiratory Society (ERS) Standardization of 
Spirometry1. Spirometers must have the capacity to print FVC tracings. All spirometry values 
should be reported at body temperature, pressure, saturated with water vapor (BTPS) by the 
method established by the manufacturer.
Calibration
The spirometer should be calibrated every morning before any spirometric measurements for 
the study are performed. Calibration reports should be printed and stored as source data at the 
site.
Preparing the test subject
On study days when spirometry will be performed, patients should refrain from the following:

Coffee, tea, chocolate, cola and other caffeine-containing beverages and foods and ice-
cold beverages for 4 hours prior to spirometry

Alcohol for 4 hours prior to spirometry

Strenuous activity for 12 hours prior to spirometry

Smoking within at least 1 hour of testing

Exposure to environmental smoke, dust or areas with strong odors
Every effort should be made to assure consistent testing conditions throughout the study. A 
seated position with nose clips is recommended to reduce risks related to dizziness or syncope. 
When possible, spirometry should be conducted by the same technician using the same 
spirometer. To minimize the effects of diurnal variation on lung function, spirometry visits 
should start at approximately the same time of day at each visit.
Performing Spirometry
The subject’s age, height and gender will be entered into the spirometer. It is important that the 
height is measured accurately at the study site. Spirometry, an effort-dependent test, requires 
careful instruction and cooperation of the subject. The technician should ensure a good seal 
around the mouthpiece, and confirm that the subject’s posture is correct. The subject should be 
instructed to perform a maximal inspiration, followed by maximum forced expiration until no 
more air can be exhaled or for at least 6 seconds. Expiration must be rapid with exertion of 
maximal effort. The results of spirometry should meet the ATS/ERS criteria for acceptability 
(one retest may be performed for patients that don’t meet the acceptability criteria).
Number of trials
A minimum of 3 acceptable forced vital capacity (FVC) maneuvers should be performed. If a 
subject is unable to perform a single acceptable maneuver after 8 attempts, testing should be 
discontinued.
Acceptability
An acceptable maneuver has the following characteristics:


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
No hesitation or false start;

A rapid start;

No cough, especially during the first second of the maneuver;

No glottic closure or obstruction by tongue or dentures

No early termination of exhalation (minimum exhalation time of 6 seconds is 
recommended, or no volume change for at least 1 second) or the subject cannot continue 
to exhale further
Repeatibility
The 2 largest FVC and FEV1 values from 3 acceptable maneuvers should not vary by more than 
0.150 L.
Recording of data
The highest FEV1 and FVC from any of the acceptable curves are recorded. (The highest FEV1
and FVC may not necessarily result from the same acceptable curve).
Predicted normal
This study will utilize the spirometric predication equation standards for the European 
Community for Coal and Steel 2 or Nhanes3 or Japanese Respiratory Society4. Further details 
will be provided in a specification document for the central spirometry assessments.
Reversibility
All reversibility evaluations should follow the recommendations of the ATS/ERS Task force: 
Standardization of Lung Function Testing1.
Administer 400µg of salbutamol/albuterol following the completion of the pre-bronchodilator 
assessment. Post-bronchodilator spirometry assessment is then performed 30 - 60 minutes after 
administration of the salbumatol/albuterol.
Reversibility is calculated as:
100 x FEV1 (post-bronchodilator) – FEV1 (pre-bronchodilator)
FEV1 (pre-bronchodilator)
Following the reversibility testing assessment for post-bronchodilator FEV1, if lung function 
has been observed to have deteriorated (i.e. there is a decrease in post bronchodilator FEV1
compared to pre-bronchodilator FEV1 as opposed to an increase) after administration of 
salbutamol/albuterol, then the patient should repeat the visit, allowing at least 24 hours between 
visits (one retest may be performed in patients that demonstrate a deterioration in lung function 
post-bronchodilation).
Patients with COPD demonstrating a high reversibility may require further clinical evaluation
by the investigator to rule out a diagnosis of asthma.
References
1 Miller MR et al, Standardization of Lung Function Testing. Eur Resp J 2005;26:153-161.


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2 Quanjer PH at al. Lung volumes and forced ventilatory flows, Report Working Party 
Standardization of Lung Function Tests, European Community for Steel and Coal. Official 
Statement of the European Respiratory society. Eur Resp J 1993;6: Suppl. 16, 5-40.
3 Hankinson JL, Odencrantz JR, Fedan KB (1999) Spirometric reference values from a sample 
of the general US population. Am J Respir Crit Care Med 159:179–187.
4 Kubota, Kobayashi, Quanjer PH, et al. Reference values for spirometry, including vital 
capacity, in Japanese adults calculated with the LMS method and compared with previous 
values. Clinical Pulmonary Functions Committee of the Japanese Respiratory Society. 
Respiratory Investigations 2014, 242-250.
16.4
Appendix 4 CASA-Q
The sample provided here is for illustrative purposes only (US English version).


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16.6
Appendix 6 EXACT questionnaire
(The sample provided here is for illustrative purposes only)
The EXACT Total score is computed across 14 questions and has a theoretical range of 0 to 
100, with higher values indicating a more severe condition. The Total score is used in the 
determination of exacerbation frequency, severity and duration of exacerbation. Specifically, 
changes in the Total score are used to define onset and recovery from an exacerbation event and 
the magnitude of the event.
The EXACT provides information on 3 exacerbation-related outcomes: frequency (counts), 
severity (score) and duration (days). Time to first event may also be examined.
Study site and patient training
Study personnel should be trained on the following procedures to introduce a patient to the 
EXACT:

Sit down with the patient at the beginning of the study and show them an example of the 
EXACT diary in the device on which it is to be administered.

Inform the patient that the EXACT is to be completed every evening, just before going to 
bed.

Instruct patients to reflect on their day and answer the questions based on how they felt 
over the day.

Instruct a patient to respond in a way that is representative of the entire day.

Remind patients that there are no right or wrong answers.

Highlight for patients that the EXACT has 14 items.

All 14 items are to be answered daily for the study period, as specified in the protocol.

Point out that answers cannot be skipped.

If a patient is unsure how to answer an item, instruct the patient to select the answer that 
best describes how they feel.
The EXACT total score is the sum of the raw score of the EXACT 14 items.
The following lists the raw score values associated with each response category for the EXACT 
items.










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16.8
Appendix 8 PGI
The sample provided here is for illustrative purposes only.
The PGI-S consists of PGI-S - general question and PGI-S - specific question:
PGI-S - general question:
Overall, how would you rate the severity of your respiratory symptoms in the last 7 days? 
(Please check one only)
0 Not at all
1 Slightly
2 Moderately
3 Severely
4 Extremely
PGI-S - specific question:
Overall, how would you rate the severity of your cough and mucus in the last 7 days? (Please 
check one only)
0 No cough and mucus
1 Very Mild
2 Mild
3 Moderate
4 Severe
5 Very Severe






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16.11
Appendix 11 e-Diary (for rescue medication)
The following information will be captured twice daily before taking study medication. In 
addition, patient will register any study medication interruptions.
In the MORNING (pre-medication)
In the EVENING (pre-medication)
Number of puffs of rescue medication during the 
past 12 hours
Number of puffs of rescue medication during the 
past 12 hours
16.12
Appendix 12: SGRQ
The sample provided here is for illustrative purposes only.


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SAP_001.pdf: 






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Table of contents
Table of contents .................................................................................................................4
List of abbreviations............................................................................................................7
1
Introduction .........................................................................................................................9
1.1
Study design.............................................................................................................9
1.2
Study objectives and endpoints .............................................................................11
2
Statistical methods.............................................................................................................12
2.1
Data analysis general information .........................................................................12
2.1.1
General definitions................................................................................12
2.2
Analysis sets ..........................................................................................................13
2.2.1
Subgroup of interest ..............................................................................14
2.3
Patient disposition, demographics and other baseline characteristics ...................14
2.3.1
Patient disposition.................................................................................14
2.3.2
Patient demographics and other baseline characteristics ......................15
2.3.3
Medical history/current medical condition ...........................................15
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................16
2.4.1
Study treatment / compliance................................................................16
2.4.2
Prior, concomitant and post therapies...................................................16
2.5
Analysis of the primary objective..........................................................................16
2.5.1
Primary endpoint...................................................................................17
2.5.2
Statistical hypothesis, model, and method of analysis..........................17
2.5.3
Handling of missing values/censoring/discontinuations.......................20
2.5.4
Supportive analyses...............................................................................20
2.6
Analysis of the key secondary objective ...............................................................21
2.7
Analysis of secondary efficacy objective(s)..........................................................21
2.7.1
Secondary endpoints .............................................................................21
2.8
Handling of missing values for FVC will be similar to FEV1.Safety analyses.....24
2.8.1
Adverse events (AEs)............................................................................24
2.8.2
In addition, treatment emergent AEs of special interest will be 
presented by treatment and risk, showing exposure adjusted event 
rates (i.e., the number of events expressed in rates per 100 patient 
years).Deaths.........................................................................................26
2.8.3
Laboratory data .....................................................................................26
2.8.4
Other safety data ...................................................................................27
2.9
Pharmacokinetic endpoints....................................................................................28




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5.7.1
Primary analysis....................................................................................48
5.7.2
Key secondary analysis.........................................................................51
5.8
Rule of exclusion criteria of analysis sets..............................................................54
6
Reference...........................................................................................................................55


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List of abbreviations
AE
adverse event
AIC
Akaike information criterion
Alb
Albumin
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
Area under the plasma concentration-time curve
AUC0-Xh
Area under the plasma concentration curve over X hours
bid
bis in diem/twice a day
b.i.d.
twice a day
BMI
Body Mass Index
BUN
blood urea nitrogen
CASA-Q
Cough and sputum assessment questionnaire
Cmax
Maximum concentration
Cmin
Minimum concentration
COPD
Chronic Obstructive Pulmonary Disease
CSR
Clinical Study report
DMC
Data Monitoring Committee 
DR
Dose response
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
ED50
efficacious dose in 50% of subjects
E-RS
Evaluating Respiratory Symptoms in COPD
FAS
Full analysis set
FDA
Food and Drug Administration
FEV1
Forced expiratory volume in one second
FVC
Forced vital capacity
GOLD
The Global Initiative for Chronic Obstructive Lung Disease
GLM
generalized linear model
h
Hour
IA
Interim analysis
ICS
Inhaled CorticoSteroid
J2R
jump-to-reference
LABA
Long-Acting β2-Agonist
LAMA
Long-Acting Muscarinic receptor Antagonist


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LFT
Liver function test
LLOQ
Lower limit of quantification
MAR
Missing at random
MCP-Mod
Multiple comparison procedure-modelling
MED
Minimum effective dose
MedDRA
Medical dictionary for regulatory activities
MNAR
Missing not at random
mg
milligram(s)
mL
milliliter(s)
MMRM
Mixed-effect linear model for repeated measures
ng
nanogram
PD
pharmacodynamic(s)
PDS
Programming dataset specifications
PGI-S
Patient Global Impression of Severity
PK
pharmacokinetic(s)
PT
Preferred term
QTc
corrected QT interval
QTcF
QT interval with Fridericia's correction
RAS
Randomized analysis set
SAE
serious adverse event
SAP
Statistical analysis plan
SCS
Systemic corticosteroids
SD
standard deviation
SGRQ
St George's Respiratory Questionnaire
SOC
System Organ Class
TFLs
Tables, Figures, Listings
TBL
total bilirubin
Tmax
time to reach maximum (peak) plasma concentration following drug 
administration
ug
microgram
ULN
upper limit of normal
TFLs
Tables, Figures, Listings


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1
Introduction
This document contains details of the statistical methods that will be used in the Phase 2b
clinical trial CQBW251B2201. The purpose of this Phase 2b study is to support the dose 
selection for future studies by evaluating efficacy and safety of different QBW251 doses in 
COPD patients with chronic bronchitis and a history of exacerbations, compared to placebo, 
when added to a triple combination therapy of LABA/LAMA/ICS. Lung function improvement 
will be the primary endpoint: trough FEV1 change from baseline after 12 weeks of treatment.
Data will be analyzed according to Section 12 of the study protocol.
Important information is given in the following sections and details are provided, as applicable, 
in Section 5.
1.1
Study design
This study uses a 6 treatment arm, parallel-group, randomized, double-blind study design. One 
treatment arm (450 mg b.i.d.) was discontinued after reaching a pre-defined stopping criterion
(see Section 12.7.1 of the protocol) at the first DMC interim analysis.
Patients initially undergo a screening period of 1 week. This screening period (Weeks -3 to -2) 
serves to assess eligibility and to taper patients off disallowed medications. Subsequently, 
patients enter the run-in period (2 weeks; Days -14 to 1) to establish baseline values for 
symptom assessments, to standardize the COPD background therapy (triple combination 
LABA/LAMA/ICS), and to complete eligibility assessments. At visit Run-In 2 final eligibility 
will be assessed. Eligible patients will move into the Day 1 visit where they will be randomized. 
Day 1 also generates additional baseline data and study treatment is initiated. The treatment 
period consists of 24 weeks, during which the patient returns to the site for regular visits (Day 
1 – Week 24). Upon completion of the treatment period, patients are followed up for safety 
assessments during the Follow-Up period (Weeks 25 – 28).
Approximately 956 male and female COPD patients are randomized into 1 of 6 treatment arms 
with a randomization ratio of 2:2:1:1:1:2 (450 mg b.i.d. (discontinued), 300 mg b.i.d., 150 mg 
b.i.d., 75 mg b.i.d., 25 mg b.i.d., placebo). Detailed information regarding sample size 
calculation is provided in Section 3. After reaching the pre-defined exposure-based stopping 
criterion, patients were no longer randomized to the 450 mg b.i.d. treatment, resulting 
effectively in a 2:1:1:1:2 randomization ratio (300 mg b.i.d.:150 mg b.i.d.: 75 mg b.i.d.: 25 mg 
b.i.d.: placebo) from the day of 450 mg b.i.d. discontinuation (20-Apr-2020) onward.
Randomization will be stratified by smoking status (current or ex-smoker) and severity of 
airflow limitation (FEV1 ≥ 30% to < 50% and ≥ 50% to < 80%).


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Figure 1-1
Study design
The primary endpoint will be assessed after 12 weeks of treatment.
Interim analyses (IA) on safety data are planned for an independent external safety data 
monitoring committee (DMC) to evaluate the results of pre-specified interim PK and safety 
data. Up to 5 DMC IAs are proposed to occur. Detailed information regarding DMC analysis 
will be provided in the DMC charter and a separate DMC SAP. 
Up to 2 interim analyses (IAs) may be conducted on efficacy data. The purpose of the IA(s) is 
to have an early assessment of the efficacy data for planning future studies in the QBW251B 
program. The first IA will be triggered when approximately the first 645 to 680 randomized 
patients have either discontinued or completed 12 weeks of treatment. If the first IA does not 
lead to a clear decision for the planning of the QBW251B program, a second IA may be 
performed when all randomized patients have either discontinued or completed 12 weeks of 
treatment. The efficacy IA results will not trigger any design adaptations.


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1.2
Study objectives and endpoints
Section 2 of the study protocol lists the following primary, key secondary, other secondary 
 
objectives.
Table 1-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

Characterize the dose-response relationship of 
QBW251 administered orally over 12 weeks on 
lung function, compared to placebo when added to 
inhaled triple combination therapy (long-acting β2-
agonist/long-acting muscarinic receptor 
antagonist/inhaled corticosteroid; 
LABA/LAMA/ICS).

Trough FEV1 change from baseline 
after 12 weeks of treatment.
Secondary objective(s)
Endpoint(s) for secondary objective(s)

Evaluate symptoms (overall COPD symptoms, 
cough and sputum) across various dose levels of 
QBW251 administered orally over 24 weeks, 
compared to placebo at Weeks 12 and 24.

Change from baseline in the 
Evaluating Respiratory Symptoms in 
COPD (E-RS) weekly mean scores 
(total and subscale scores).

Change from baseline in Patient 
Global Impression of Severity (PGI-S) 
score.

Change from baseline in the Cough 
and Sputum Assessment 
Questionnaire (CASA-Q) domain 
scores - cough symptoms, cough 
impact, sputum symptoms, and 
sputum impact.

Evaluate health-related quality of life across 
various dose levels of QBW251 administered 
orally over 24 weeks, compared to placebo, at 
Weeks 12 and 24.

Change from baseline in St. George's 
Respiratory Questionnaire (SGRQ) 
total and domain scores at Weeks 12 
and 24.

Evaluate lung function across various dose levels 
of QBW251 administered orally over 24 weeks, 
compared to placebo, over 4, 8, 16, 20 and 24 
weeks.

Trough FEV1 change from baseline 
after 4, 8, 16, 20 and 24 weeks of 
treatment, respectively.

Evaluate safety and tolerability across various 
dose levels of QBW251, administered orally over 
24 weeks, compared to placebo.

Assessment of ECGs, laboratory 
tests, vital signs, and adverse events 
per treatment group.

Assess the pharmacokinetics of QBW251 in 
COPD patients. Additionally this information may 
be used to understand the relation between drug 
exposure and efficacy and/or safety.

Assessment of drug exposure (trough 
concentration; Cmin) on all visits and 
around Cmax on Days 1, 15 and 
169. AUC and Cmax on Days 1 and 15 
in a sub-group of patients.




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Study day = Assessment date – Date of first dose of double-blind treatment.
2.1.1.2
Baseline definition
In general, baseline is defined as the last measurement before the first dose of double-blind
treatment. Details on calculation of baseline will be provided in the latter sections.
2.1.1.3
Post-baseline measurement
Post-baseline measurements are defined as those assessments after the first dose of double-blind
treatment.
When change from baseline is of interest the following formula will be used for each scheduled 
visit and time-point where baseline and post-baseline values are both available:
Change from baseline = post-baseline value – baseline value.
If not stated otherwise for efficacy analyses on-treatment values are defined as values taken
post-baseline but no later than 1 day after last dose of double-blind treatment. Off-treatment 
values are defined as post-baseline values taken more than 1 day after last dose of double-blind 
treatment.
For safety analyses other than adverse events (AEs), e.g. laboratory, ECG, vital signs, on-
treatment values are defined as values taken post-baseline but no later than 30 days after last 
dose of double-blind treatment.
AEs will be considered as on-treatment if the event is starting on or after the time of first dose 
of double-blind treatment but not later than 30 days after last dose of double-blind treatment.
Details on calculation of post-baseline values are provided in the latter sections.
If not stated otherwise, visit-windows will be used for the data that is summarized by visit; they 
are based on the study evaluation schedule and comprise a set of days around the nominal visit 
day. For any assessment, there are the protocol defined scheduled visits around which visit 
windows were created to cover the complete range of days within the study. When visit 
windows are used, all visits will be re-aligned, i.e., they will be mapped into one of the visit 
windows. Details on calculation of visit windows will be provided in Section 5.
2.1.1.4
Handling early termination of the 450mg b.i.d arm
If not stated otherwise, all efficacy inferential analyses will not include the 450 mg dose due to 
early termination of the 450 mg b.i.d arm, resulting in very few or no data in some of the strata
(covariates/factors in the model) during the later visits. All descriptive summaries will include
the 450 mg b.i.d. dose.
2.2
Analysis sets
The Randomized Analysis Set (RAS) consists of all randomized patients. Patients will be 
analyzed according to the treatment they were assigned to at randomization. 
The Full Analysis Set (FAS) will include all randomized patients who received at least one dose 
of randomized treatment. Following the intent-to-treat principle, patients will be analyzed 






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2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
All summaries of treatments will be performed on the Safety Set.
2.4.1
Study treatment / compliance
The duration of exposure in days to each treatment group (QBW251 dose or placebo) will be 
summarized by means of descriptive statistics.
Duration of exposure to double-blind 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 double-blind treatment
– Date of first dose of double-blind treatment + 1).
The number of patients who permanently discontinued from double-blind treatment and the 
reasons will be summarized by treatment group. Patients who permanently discontinued from 
double-blind treatment will be listed including reason and date of discontinuation.
Compliance will be calculated as the percentage of the number of days where double-blind 
treatment was administered as per protocol (i.e., one dose in the morning and one dose in the 
evening) divided by the duration of exposure (i.e., the number of days between first and last 
dose).
Compliance will be categorized by < 80 % and 80 % - 100 % and summarized by treatment
group.
2.4.2
Prior, concomitant and post therapies
The following summaries for COPD-related medications will be performed separately for 
medications prior to run-in (medications starting prior to screening and ending prior to or at the 
run-in visit) and for concomitant medications (medications which were taken anytime between 
the first dose and last dose of randomized treatment, inclusive). COPD-related medications will 
be summarized by pre-specified drug categories, route of administration, preferred term, and 
treatment group. 
Non-COPD related medication prior to and after the start of randomized treatment will be 
summarized by route of administration, preferred term, and treatment group.
Surgical and medical procedures (non-drug therapies) are coded using MedDRA. Presentations 
will be done by MedDRA primary system organ class and preferred term, separately for prior 
and concomitant procedures.
2.5
Analysis of the primary objective
The primary objective of this study is to characterize the DR (dose-response) efficacy 
relationship among QBW251 doses (25, 75, 150, and 300 mg b.i.d.) and placebo with regards 
to the change from baseline in trough FEV1 after 12 weeks of treatment. The goals associated 
with this objective are below.

To confirm an overall DR signal


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
To estimate the dose(s) that corresponds to the target effect over placebo based on the 
estimated DR curve
Due to early termination of the 450 mg, analysis of the primary endpoint will not include the 
450 mg dose.
2.5.1
Primary endpoint
The primary estimand, defined below, quantifies a hypothetical on-treatment Week 12 effect 
during stable periods (i.e. outside episodes of COPD worsening that require rescue medication 
or systemic corticosteroids). This estimand targets the maximum treatment effect for QBW251 
and allows selection of the best dose for those who take it for 12 weeks.

Population: patients with moderate to severe COPD enriched for presence of chronic 
bronchitis and a history of exacerbations and treated with LABA/LAMA/ICS background 
therapy

Variable: trough FEV1 (average of the 2 values taken 15 and 45 min pre-dose ) change 
from baseline after 12 weeks of treatment

Intervention effect of interest: Effect of interventions initiated at randomization during 
stable periods (i.e. outside episodes of COPD worsening that require rescue medication or 
systemic corticosteroids) and that would have been observed had all patients remained on 
their assigned treatment for 12 weeks, with the following post-randomization events 
accounted for by assessing: 

Intake of rescue medication or systemic corticosteroids (SCS): the effect outside of 
periods of worsening disease that necessitate rescue medication or SCS

Discontinuation of study treatment or study participation: hypothetical on-treatment 
trough FEV1 value.

Missing data due to any reason prior to completion or discontinuation of treatment: 
on-treatment trough FEV1 values.

Summary measure: mean difference between treatment groups (QBW251 compared with 
placebo)
The baseline value is defined as the average of the FEV1 values taken approximately 45 and 15 
minutes prior to first dose of randomized treatment at Day 1. If one of the 2 values is missing
(or is not confirmed to be pre-dose) then the remaining non-missing value will be taken as the 
baseline. If both values are missing (or are not confirmed to be pre-dose), then the 
measurements taken at the Run-In 1 visit will be used as the baseline.
2.5.2
Statistical hypothesis, model, and method of analysis
The Multiple Comparison Procedure –
Modelling (MCP-Mod) methodology (see 
Bretz et al 2005 and Pinheiro et al 2014) will be employed to assess the primary objective. An 
overview of the steps for the MCP-Mod methodology is given below. 
Step 1 (Testing an overall dose-response signal - MCP part):
The (covariate) adjusted mean responses at each individual dose will be obtained from a mixed-
effect linear model for repeated measures (MMRM) with terms for baseline FEV1, visit, region, 


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treatment, smoking status at screening, severity of airflow limitation, run-in post-bronchodilator 
FEV1, treatment-by-visit interaction, and baseline FEV1-by-visit interaction as fixed effects. To 
allow adjustment for correlations between time points within patients, an unstructured variance-
covariance structure will be used. The estimated treatment difference and the associated 90% 
confidence intervals will be presented for the treatment contrast of each dose versus Placebo.
The adjusted treatment means from the MMRM will be used to test the null hypothesis of a flat 
DR relationship for the primary efficacy endpoint at a one-sided significance level of 5% against 
the alternative hypothesis of a non-constant DR curve. The testing will be performed with a 
multiple contrast test described in the MCP-Mod methodology.
A wide range of possible dose-response relationship will be considered to take model 
uncertainty into account (Figure 2-1). A monotonic DR is assumed, supported by preclinical 
data and the observed DR of another CFTR-potentiator, ivacaftor. Eleven candidate DR curves 
(4 Emax, 4 Sigmoid Emax, 2 Exponential, and 1 Linear) will be used to derive the optimal 
model contrasts for the multiple contrast tests. Emax and sigmoidal Emax models are 
considered based on the observed DR of ivacaftor (FDA 2012). The ED50 values (the dose at 
which half of the maximum effect is reached) for the Emax models will be 25, 75, 150, and 300. 
The parameters of the sigmoidal Emax models (ED50, h) will be (25, 3), (75, 3), (150, 3) and 
(300, 3) where h is the Hill parameter that determines the steepness of the dose-response shape. 
Exponential models are considered since there is an over-proportional increase of exposures at 
the high end of the dose range tested. The parameter controlling the convexity of the 
Exponential models will be 150 and 300.
For each of the 11 candidate DR curves, a contrast test statistic will be derived that maximizes 
the power assuming the true mean response is the one assumed by the candidate DR curve. The 
detection of a significant DR signal is based on the maximum of the 11 contrast test statistics. 
The overall null hypothesis of no DR relationship is rejected if the multiplicity adjusted p-value 
for at least one contrast test is < 0.05 (one sided).
For each candidate DR curve, the test statistics and corresponding adjusted p-values will be 
presented.


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Figure 2-1
Candidate Dose Response Curves
Due to termination of the 450 mg b.i.d. arm candidate curves Emax(ED50=300), 
SigEmax(ED50=300) and Exponential(delta=300) may no longer be appropriate for MCP-Mod 
analyses that do not include the 450 mg b.i.d. arm. These candidate curves will be removed and 
the Exponential(delta=75) will be added. 
Step 2 (Estimation of the dose-response curve and target dose – Mod part):
Once the DR signal is declared, the DR curve and the target dose(s) of interest will be estimated 
by model averaging. A large number of bootstrap samples from the multivariate normal 
distribution will be drawn with adjusted means from the MMRM and corresponding covariance 
matrix. For each sample:

DR models from the candidate families (Emax, Sigmoid Emax, Exponential, Linear) will 
be fitted to the data and the best model according to the generalized Akaike information 
criterion (AIC) will be chosen.

The predictions for dose-response will be obtained from the best model for each sample.
The final DR curve estimate is the median of these predictions while confidence intervals will 
be calculated from the quantiles. The final DR curve estimate with the model-based two-sided 
90% confidence interval will be presented graphically. In addition, the plot will include the 
mean responses from the MMRM and the associated 90% confidence intervals for each of the 
studied dose groups.


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The target dose(s) that corresponds to a clinically relevant effect over placebo can be estimated 
using inverse regression techniques (Bretz et al 2005). The target dose will be estimated for a 
delta of 50ml and presented graphically within the estimated DR curve.
All data related to safety, efficacy and other assessments including PK exposure will be taken 
into consideration to propose a dose for Phase 3.
2.5.3
Handling of missing values/censoring/discontinuations
Since the estimand is related to an effect outside of rescue med intake, spirometry measurements 
within 6 hours of rescue medication or within 7 days of intake of SCS use will be set to missing.    
If one of the values contributing to the trough FEV1 variable is missing at a visit, the remaining 
non-missing value will be taken as trough FEV1. If both values are missing, then their trough 
FEV1 will be regarded as missing at that visit.
For the primary analysis, only on-treatment data (from date of first randomized dose up to 1 
day after date of last randomized dose) will be used as the estimand specifies a hypothetical on-
treatment effect. Missing on-treatment data will not be explicitly imputed as the MMRM model 
implicitly imputes missing data assuming the missing at random (MAR) mechanism.
The imputation procedure(s) related to the trough FEV1 supportive analyses (Section 2.5.4) are 
"jump-to-reference" (J2R) and MAR (Carpenter et al 2013). The imputations will be based on 
all available data (i.e. from all scheduled time points) using all covariates as specified in the 
MMRM. For J2R, only placebo (reference) data will be used. For MAR, data from the same 
treatment arm will be used for building the imputation model. Imputation of intermittent 
missing observations before treatment discontinuation will be carried out following a MAR 
mechanism for all treatment arms. Additional details are provided in Section 5.7.
2.5.4
Supportive analyses
A supplementary analysis will be performed that quantifies the treatment effect in all 
randomized patients during stable periods (i.e. outside episodes of COPD worsening that 
require rescue medication or SCS) with an adherence to treatment like we would see in clinical 
practice in a world without COVID-19, with the following post-randomization events 
accounted for by assessing:
a. Intake of rescue medication or systemic corticosteroid: effect outside of periods of 
worsening disease that necessitate rescue med or systemic corticosteroid
b. Discontinuation of study treatment for non-COVID-19 related reason with follow-up: 
actual off-treatment value. If no data was retrieved after study treatment discontinuation, 
missing data will be multiply imputed based on placebo arm data: J2R assumption for the 
QBW251 arms and MAR assumption for placebo arm.
c. Discontinuation of study treatment due to a COVID-19 related reason: on-treatment value. 
Missing data will be multiply imputed based on the MAR assumption.
d. Discontinuation of study participation due to any non-COVID -19 related reason: off-
treatment value. Missing data will be multiply imputed based on placebo arm data: J2R 
assumption for the QBW251 arms and MAR assumption for placebo arm.


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e. Any other event leading to missing data prior to completion or discontinuation of study 
treatment: on-treatment value. Missing data will be multiply imputed based on the MAR 
assumption.
Results will be presented similarly to those of primary analyses. 
Details are provided in Section 5.7.
A supportive analysis will be performed including the 450mg dose and only data up to week 
12. This will be done similarly as the primary analysis, however in addition candidate curves
Emax(ED50=300), SigEmax(ED50=300) and Exponential(delta=300) will be considered.
A supportive exposure-response analysis may be performed outside the CSR.
2.6
Analysis of the key secondary objective
There is no key secondary objective defined in the protocol.
2.7
Analysis of secondary efficacy objective(s)
2.7.1
Secondary endpoints
No multiplicity adjustment will be carried out for secondary analyses described below. In 
addition, the treatment effect of QBW251 compared to placebo that would have been observed 
had all patients remained on their assigned treatment will be estimated. Only on-treatment data 
will be used. 
All analysis of secondary endpoints will be performed on the FAS.
Missing data for any reason will not be explicitly imputed and will be handled by the respective 
mixed effects model which implicitly imputes missing data assuming MAR.
If not stated otherwise, in the 450mg dose will be excluded from all inferential statistics. 
Descriptive analyses will include all doses. 
Details on statistical models are provided in Section 5.7.
2.7.1.1
COPD symptoms
2.7.1.1.1 Respiratory symptoms from E-RS
The E-RS assesses both overall daily respiratory COPD symptoms (Total score) and specific 
respiratory symptoms using 3 subscales (Breathlessness, Cough & Sputum, and Chest 
Symptoms). Higher scores indicate more severe symptoms. Details on derivation of scores and 
handling of missing data are provided in Section 5.6.
The mean baseline E-RS Total and subscale scores will be the average of the corresponding 
daily scores from the run-in period. The last 14 days of the run-in period, i.e. the scheduled 
duration of run-in period, will be considered. 
The daily scores post-randomization will be averaged for each week (Week 1, Week 2, etc.). 
Monthly means over a 4-week period will also be calculated. 


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E-RS Cough & Sputum score
The change from baseline in the E-RS Week 12 Cough & Sputum mean scores will be analyzed 
using the same MCP-Mod approach described in for the primary variable in Section 2.5. The 
change from baseline in the E-RS Cough & Sputum weekly mean scores will be analyzed using 
a similar MMRM as described in Section 2.5 for the primary variable, with the appropriate 
baseline score replacing the baseline FEV1 value in the model. The estimated treatment 
difference (QBW251 – placebo) at each week will be reported along with the associated 90% 
confidence interval. Results from MCP-Mod will be presented as described for primary variable 
in Section 2.5.
The proportion of patients who achieve a clinically important improvement (decrease) of at 
least 0.7 (Leidy et al 2014b) in the weekly mean score will be analyzed using a repeated 
measurements logistic regression. The model will include the same terms as for the MMRM 
analysis of the weekly scores. The estimated odds ratios will be displayed over time along with 
the associated 90% confidence intervals for treatment comparison of each dose versus Placebo.
The change from baseline in the monthly mean scores will be analyzed using a similar MMRM 
as described for weekly scores. The proportion of patients who achieve a clinically important 
improvement (decrease) in the monthly mean score will also be analyzed as described for 
weekly scores.
E-RS Cough & Sputum weekly mean and monthly mean scores will be summarized 
descriptively.
E-RS Total, Breathlessness, and Chest Symptoms scores
The change from baseline in the E-RS weekly mean Total, Breathlessness, and Chest Symptom 
scores will be analyzed using a similar MMRM as described in Section 2.5 for the primary 
variable with the appropriate baseline E-RS score replacing the baseline FEV1 value. The 
estimated treatment difference (QBW251 – placebo) will be reported along with the associated 
90% confidence interval.
E-RS mean weekly total score will be analyzed in addition using MCP-Mod as described for 
primary endpoint.
The minimum clinically important improvements (decrease) for the scores are defined below 
(Leidy et al 2014b).

Total ≥ 2.0

Breathlessness ≥ 1.0

Chest Symptoms ≥ 0.70
The proportion of patients who achieve a clinically important improvement in the weekly mean 
scores will be analyzed using a repeated measurements logistic regression. The model will 
include the same terms as for the MMRM analysis of the weekly mean scores. The estimated 
odds ratios will be displayed over time along with the associated 90% confidence intervals for 
treatment comparison of each dose versus Placebo.


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The change from baseline in the monthly mean scores will be analyzed using a similar MMRM 
as described above. The proportion of patients who achieve a clinically important improvement 
(decrease) in the monthly mean score will also be analyzed as described above.
E-RS Total, Breathlessness, and Chest Symptom weekly mean and monthly mean scores will 
be summarized descriptively.
2.7.1.1.2 Cough and sputum symptoms from CASA-Q
CASA-Q assesses cough and sputum symptoms and their impact with 4 domain scores (cough 
symptoms, cough impact, sputum symptoms, and sputum impact). Details on derivation of 
scores and handling of missing data are provided in Section 5.6.
The change from baseline in the domain scores will be analyzed using the MMRM described 
in Section 2.5 for the primary variable with the appropriate baseline domain score replacing the 
baseline FEV1 value in the model. The estimated treatment difference (QBW251 – placebo) at 
each visit will be reported along with the associated 90% confidence interval.
CASA-Q domain scores will be summarized descriptively by visit.
2.7.1.1.3 Severity of symptoms from PGI-S
The PGI-S rates the severity of the respiratory symptoms and of cough and mucus. Shift tables 
will be used to compare baseline to Weeks 12 and 24 for each PGI-S value. 
The PGI-S change from baseline will be analyzed using a proportional odds model for repeated 
measures with the same terms as for the MMRM analysis described in Section 2.5 for the 
primary variable with the baseline PGI-S value replacing the baseline FEV1 value. The 
estimated odds ratios will be displayed over time along with the associated 90% confidence 
intervals.  For the proportional odds analysis, the change in severity scores will first be grouped 
into the categories below, for cough and mucus categories -5 and 5 will be added. Further 
groupings of the change categories (such as better, no change, and worse) may be performed
prior to the proportional odds analysis, if the sample size for some of the categories are too 
small.
Change from baseline in severity score
Change category 
-4
Very much better
-3
Much better
-2
Better 
-1
Slightly better
0
No change
1
Slightly worse
2
Worse 
3
Much worse
4
Very much worse


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2.7.1.2
Health-related quality of life from SGRQ
SGRQ measures health impairment. A total score is produced, along with the domain scores of 
symptoms, activity, and impacts. Details on derivation of scores and handling of missing data 
are provided in Section 5.6.
The Weeks 12 and 24 change from baseline in the SGRQ total and domain scores will be 
analyzed using the MMRM described in Section 2.5 for the primary variable with the 
appropriate baseline SGRQ score replacing the baseline FEV1 value in the model. The estimated 
treatment difference (QBW251 – placebo) at each visit will be reported along with the 
associated 90% confidence interval.
The proportion of patients who achieve a clinically important improvement (decrease) of at 
least 4 in the total score will be analyzed using a repeated measurements logistic regression. 
The model will include the same terms as for the MMRM analysis of the total scores. The 
estimated odds ratios will be displayed over time along with the associated 90% confidence 
intervals.
SGRQ total and domain scores will be summarized descriptively by visit.
2.7.1.3
Lung function
The change from baseline in trough FEV1 at visits other than Week 12 will be analyzed using 
the same MMRM as described for the primary analysis. The estimated treatment difference 
(QBW251 – placebo) at each visit will be reported along with the associated 90% confidence 
interval. The change from baseline in trough FEV1 at Week 24 will also be analyzed using the 
same MCP-Mod approach. Supportive analyses as described for primary endpoint in Section 
2.5 will be performed for change from baseline in trough FEV1 at Week 24.
The change from baseline in trough FVC after 4, 8, 12, 16, 20, and 24 weeks of treatment will 
be analyzed using the MMRM model described in Section 2.5 for the primary variable with the 
appropriate baseline FVC value replacing the baseline FEV1 value in the model. The estimated 
treatment difference (QBW251 – placebo) at each visit will be reported along with the 
associated 90% confidence interval.
Trough FEV1 and trough FVC will be summarized descriptively by visit. 
2.8
Handling of missing values for FVC will be similar to FEV1.Safety 
analyses
Safety summaries include only data from the on-treatment period with the exception of baseline 
data which will also be summarized where appropriate (e.g. change from baseline summaries).
All safety analysis will be performed on the Safety Set.
2.8.1
Adverse events (AEs)
The on-treatment period for adverse events lasts from the date of first administration of double-
blind study treatment to 30 days after the date of the last actual administration of double-blind


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study treatment. Adverse events will be summarized by treatment group. Summary tables for 
AEs will summarize only on-treatment events (also known as treatment-emergent AEs).
The number (and percentage) of subjects with treatment-emergent adverse events will be 
summarized in the following ways:

by treatment and preferred term (PT).

by treatment, primary system organ class (SOC) and PT.

by treatment, SOC, PT and maximum severity.
Separate summaries by SOC and PT will be provided for:

AEs suspected to be study medication related 

fatal AEs

leading to treatment discontinuation

leading to dose interruptions and/or adjustments

serious adverse events (SAEs)
Further SAEs will be summarized by PT.
In addition, treatment emergent AEs and SAEs will be presented by treatment, system organ
class and preferred term, showing exposure adjusted event rates (i.e., the number of events
expressed in rates per 100 patient years).
Unless otherwise specified, SOCs will be sorted alphabetically and, within each SOC, the PTs 
will be sorted in descending order of frequency in the highest QBW251 dose. A subject with 
multiple adverse events within a SOC or PT is only counted once towards the total of the SOC 
or PT.
Listings will be provided for all AEs, SAEs and fatal AEs.
2.8.1.1
AE reporting for CT.gov and EudraCT
For the legal requirements of clinicaltrials.gov and EudraCT, two required tables on treatment 
emergent adverse events which are not serious adverse events with an incidence greater than 
2% and on treatment emergent serious adverse events and SAE suspected to be related to study 
treatment will be provided by system organ class and preferred term on the safety set population.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.


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The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.
2.8.1.2
Adverse events of special interest / grouping of AEs
The number and percentage of patients who reported treatment-emergent adverse events of 
special interest will be summarized by risk name, PT and treatment group.
Risk names will be sorted alphabetically and, within each risk name, the PTs will be sorted in 
descending order of frequency in the highest QBW251 dose. If a patient reported more than one 
adverse event with the same PT, the AE will be counted only once. If a patient reported more 
than one AE within the same risk, the patient will be counted only once at that risk.
The Compound Case Retrieval Strategy (CRS) will be used to determine the MedDRA search 
criteria to be used to identify events of special interest. The most recent list of adverse events 
of special interest at the time of database lock will be used.
SAEs of special interest will be summarized by risk name, PT and treatment group.
2.8.2
In addition, treatment emergent AEs of special interest will be 
presented by treatment and risk, showing exposure adjusted event 
rates (i.e., the number of events expressed in rates per 100 patient 
years).Deaths
Fatal AEs will be summarized and listed as specified in Section 2.8.1.
2.8.3
Laboratory data
Summaries of laboratory data will include on-treatment measurements, which are defined as 
measurements taken post-baseline but no later than 30 days after last dose of double-blind 
treatment.
Absolute values and change from baseline will be summarized for continuous laboratory 
parameters by visit, including the worst on-treatment value. The direction of interest for worst
on-treatment value for selected hematology and biochemistry parameters is shown in Section 
5.4. 
For selected laboratory tests, the number and percentage of patients with newly occurring or 
worsening laboratory abnormalities meeting the clinically notable criteria at any time on-
treatment, considering all on-treatment data from scheduled, unscheduled and premature 
discontinuation visits, will be summarized by laboratory parameter. Notable criteria are defined 
in Section 5.4.
Furthermore, the number and percentage of patients with newly occurring or worsening 
abnormalities in liver function tests (LFT) will be summarized by treatment and at any time on-
treatment considering all on-treatment data from scheduled, unscheduled and premature 
discontinuation visit. LFT criteria are defined in Section 5.4.
The baseline value is the last value prior to first dose of double-blind treatment.


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For selected laboratory parameter boxplots of laboratory values relative to the normal ranges 
will be provided.
Laboratory data of patients with notable values will be listed. Urinalysis will be listed for 
patients with abnormal urine dipstick.
2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
Summaries of ECG data will include on-treatment measurements, which are defined as 
measurements taken post-baseline but no later than 30 days after last dose of double-blind 
treatment.  Triplicate ECGs (3 ECGs are collected within about a five-minute window) will be 
performed. For the analysis of continuous ECG parameter the mean value of the 3 ECG 
measurements will be used, for ECG interpretation, all findings of the 3 ECGs will be 
considered.
Absolute values and change from baseline will be summarized for ECG parameters by visit and 
time point. The maximum on-treatment QTc value will be included in the summary.
The number and percentage of patients with newly occurring or worsening notable Fridericia’s 
QTc values will be summarized at any time on-treatment, considering all on-treatment data 
from scheduled, unscheduled and premature discontinuation visits. For derivation of notable 
values, the mean of the triplicate ECGs will be used. Notable criteria are defined in Section 5.5.
The number and percentage of patients with ECG abnormalities will be summarized by 
evaluation type, abnormality finding, visit and time point.
The baseline value is the last value prior to first dose of double-blind treatment.
ECG data of patients with notable Fridericia’s QTc values will be listed.
2.8.4.2
Vital signs
Summaries if vital signs data will include on-treatment measurements, which are defined as 
measurements taken post-baseline but no later than 30 days after last dose of double-blind 
treatment.  
Absolute values and change from baseline will be summarized for vital sign parameters by visit 
including the minimum and maximum on-treatment value.
The number and percentage of patients with newly occurring or worsening notable vital sign
values will be summarized at any time on-treatment, considering all on-treatment data from 
scheduled, unscheduled and premature discontinuation visits. Notable criteria are defined in 
Section 5.5.
The baseline value is the last value prior to first dose of double-blind treatment.
Vital sign data of patients with notable values will be listed.










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significance level across all analyses is maintained at 0.05. At each interim analysis, an exact 
test on the proportion of subjects who exceed the exposure threshold will be performed to test 
the following hypotheses for these 2 treatment arms.

Null hypothesis (Ho): the proportion of patients exceeding the exposure threshold < 5% 

Alternative hypothesis (Ha): the proportion of patients exceeding the exposure threshold 
≥5% 
The interim analyses are proposed to occur when approximately 20%, 40%, 60%, 80%, and 
100% of subjects have completed at least 4 weeks of treatment, which should be long enough 
to determine if the patient's exposure will exceed the threshold or not. The corresponding 
stopping boundaries in the p-value scale are 0.015, 0.016, 0.017, 0.018, and 0.019 for the interim 
analyses. For example, when the first interim analysis is performed after 20% patients have 
completed 4 weeks of treatment in the 450 mg b.i.d. arm, the observed (i.e. nominal) p-value 
has to be equal to or smaller than 0.015 in order to reject Ho and terminate the treatment arm. 
If the true proportion of patients in the 300mg or 450 mg b.i.d. treatment arm exceeding the 
exposure threshold is < 5%, then the probability of rejecting Ho would be very low (< 5%) with 
this group sequential test for the treatment arm. If the true proportion is 10% then the probability 
of rejecting Ho and stopping the treatment arm early would be high (>77%). If the timing of the 
actual interim analyses deviate from the proposed schedule (20%, 40%, 60%, 80%, and 100% 
completing at least 4 weeks of treatment), stopping boundaries will need to be recalculated 
using the pre-specified α-spending function and based on the actual sample size at each interim 
analysis. The observed p-values at the interim analyses will then be compared against the re-
calculated stopping boundaries. 
More details will be outlined in the DMC charter and a separate DMC SAP.
After reviewing the exposure data from the first interim analysis, the DMC informed the 
sponsor that the 450 mg b.i.d. arm had crossed the stopping boundary and recommended 
termination of the treatment arm. The DMC confirmed that the arm was well tolerated in this 
patient population and the stop was not based on adverse reactions to the 450 mg b.i.d. regimen. 
The sponsor followed the DMC’s recommendation and discontinued investigational treatment 
from all patients randomized to the 450 mg b.i.d. arm.
2.13.2
Efficacy
Up to 2 IAs on efficacy data may be conducted and the timing will correspond to 1 or 2 safety 
DMC analyses. The purpose of these IA(s) is to have an early assessment of the data for 
planning future studies in the QBW251B program. The efficacy IA results will not trigger any 
change or decision in the conduct of this study.
An internal Novartis committee, external to the study team, will be set up to review the both the 
efficacy and safety data. Once team members are exposed to the unblinded IA data, they will 
no longer be involved in the further execution of the study. A charter will provide further details.
The first IA will be conducted when approximately 645 to 680 patients, including the ~102 
patients randomized to the 450mg b.i.d. arm, have either discontinued or completed 12 weeks 
of treatment. This IA will have acceptable precision for the estimated trough FEV1 dose-


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response curve. The average half-length of the 90% confidence interval is around 26 mL and 
32 mL for the estimated dose-response curve and the estimated placebo-adjusted dose-response 
curve, respectively. If the first IA does not lead to a clear decision for the planning of the 
QBW251B program, a second IA may be performed when all randomized patients have either 
discontinued or completed 12 weeks of treatment.
For efficacy, the interim analyses will include all data up to the cut-off date for the IA.
An analysis may be planned and reported separately on the relationship between measured 
plasma trough concentrations and trough FEV1 change from baseline as described in Section 
2.10.
2.14
Additional analyses to assess the impact of COVID-19 pandemic
Number and percentage of patients enrolled (informed consent signed), discontinued double-
blind treatment, completed double-blind treatment and exposed to double-blind treatment
during the pre-COVID-19 pandemic period, the COVID-19 pandemic period and the post-
COVID-19 pandemic period (if applicable) will be summarized by region and country using
the FAS. 
The pandemic periods are defined based on the start and end date of the pandemic in the 
respective region/country. 
Demographics, baseline disease characteristics, and run-in spirometry will be summarized by 
time of enrollment (patients enrolled pre-COVID-19 pandemic, during COVD-19 pandemic, 
post- COVID-19 pandemic [if applicable]) to assess the impact of the COVID-19 pandemic on 
the study population.
Number and percentage of patients with COVID-19 related deviations will be summarized by 
deviation term and relationship to the COVID-19 pandemic. The PD process was used to 
identify COVID-19 related deviations even though these deviations were not true PDs.
To assess the impact of the COVID-19 pandemic on trough FEV1, the MMRM will be repeated 
for the following subgroups:
-
by region (Latin and South America, Eastern Europe, Western Europe, Asia and 
Australia, North America) 
-
by time of enrollment (patients enrolled pre-COVID-19 pandemic, patients enrolled
during COVD-19 pandemic)
The supplementary estimand considers differences between COVID-19 pandemic related and 
other discontinuations assuming missings related to COVID-19 pandemic are MAR. 
To assess the impact of COVID-19 on safety, and to assess possible regional differences in 
reporting of AEs, the 10 most frequent AEs (in total) will be summarized by preferred term and 
region.
3
Sample size calculation
A total of 956 patients will be randomized to one of the 6 groups including 5 QBW251 dose 
groups (450, 300, 150, 75, 25 mg b.i.d.) and placebo. This includes the ~102 patients 


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randomized to the 450 mg b.i.d. arm prior to its discontinuation. Prior to the discontinuation of 
450mg b.i.d., patients were randomized to QBW251 450, 300, 150, 75, 25 mg b.i.d., or placebo 
with an allocation ratio of 2:2:1:1:1:2. After discontinuation of 450mg b.i.d., patients were 
randomized to QBW251 300, 150, 75, 25 mg b.i.d., or placebo with an allocation ratio of 
2:1:1:1:2. This sample size of 854 (956 total minus approximately 102 patients already 
randomized to 450 mg b.i.d.) achieves at least 80% power for dose-response signal detection 
on key endpoints for all models from the candidate set based on the MCP-Mod methodology 
and also to ensure an acceptable precision for the DR curve estimation. The calculations in 
Table 3-1 exclude 450 mg b.i.d. from the analysis and are based on a 20% dropout rate, a one-
sided significance level of 5%, and the following standard deviation assumptions.

Pre-dose trough FEV1: A common standard deviation of 200 mL based on previous 
Novartis COPD studies.

E-RS Cough & Sputum weekly mean score: A common standard deviation of 1.3 based on 
the FLAME study (Wedzicha et al 2016).
Table 3-1
Power and Precision
Variable
Maximum 
improvement 
over placebo
Power to detect a 
DR signal
Average half-length of 90% 
confidence interval
Estimated DR 
curve
Estimated 
placebo-adjusted 
DR curve
Trough FEV1
60 mL
50 mL
92%
81%
21 mL
26 mL
E-RS Cough & 
Sputum
0.35
0.30
86%
76%
0.14
0.17
Power calculations were performed using ADDPLAN-DF-4.0 and the precision estimates (half-length 
of confidence interval) were obtained from simulations.
The randomization ratio was generally based on D-optimality criteria, which maximize the
information on the dose-response curve, for the MCP-Mod analysis. The D-optimal allocation
ratio randomizes approximately twice as many patients to placebo and the highest dose,
compared to the middle doses.
4
Change to protocol specified analyses
Analysis of the primary endpoint:
Due to termination of the 450 mg b.i.d. arm, candidate curves Emax(ED50=300), 
SigEmax(ED50=300) and Exponential(delta=300) may no longer be appropriate for MCP-Mod 
analyses that do not include the 450 mg b.i.d. arm. These candidate curves will be removed and 
the Exponential(delta=75) will be added.


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5
Appendix
5.1
Imputation rules
5.1.1
Study drug
Missing/partial start date or end date of double-blind treatment will not be imputed.
5.1.2
AE date imputation
Partial AE start and end dates will be imputed. If there is uncertainty whether an AE occurred 
on-treatment or not, imputation will be performed, such that AE will be considered as on-
treatment. Rules for imputing AE end date or start date will be provided in Programming 
Dataset Specification (PDS) document in details.
5.1.3
Concomitant medication date imputation
Rules for imputing the CM end date or start date will be provided in Programming Dataset 
Specification (PDS) document in details.
5.2
Visit windows
In general, if two consecutive visits Vt and Vs are x days apart, the upper limit of the visit 
window for Vt will be Vt+x/2 and the lower limit for the visit Vs will be Vs-x/2 (if x is even, the 
lower limit for Vs will be Vs-x/2+1, and the upper limit for Vt will be Vt+x/2). The algorithm 
needs to ensure that visit windows are not overlapping and that there are no gaps, such that each 
assessment can be uniquely allocated to one visit window. 
For ECG and spirometry assessments, unplanned visits will be ignored for the windowing as 
scheduled timing is not available. If there are multiple assessments within a visit window with 
different scheduled time points, the one with the planned scheduled time points of the target 
day will be used; if scheduled time points are the same, the visit closer to the target day will be 
used. 
For all other assessments, unplanned visits will also be considered for assigning visit windows.
If there are multiple assessments within a visit window the closest to the target day will be used.
Only on-treatment values will be considered for mapping of visit windows. For trough FEV1
visit windowing will be performed twice, once for primary analysis considering on-treatment 
measurements, and once for supportive analysis considering all post-baseline measurements 
whether being on-treatment or not.
The below table presents the visit windows for the respective assessments.
Analysis 
visit
Scheduled 
Day
Visit window –
assessments a)
Visit window –
assessments b)
Visit window 
– assessments
c)
Visit 
window 
–
assessments
d)
Visit 
window 
–
assessments
e)
Day 1 post 
dose
Day 1
Day 1 (post-
dose) - Day 7


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Week 2
Day 15
Day 8 - Day 22
Day 
1 
(post 
dose) - Day 22
Week 4
Day 29
Day 23 - Day 43
Day 23 - Day 43
Day 2 - Day 43
Week 8
Day 57
Day 44 - Day 71
Day 44 - Day 71
Day 44 - Day 
71
Week 12
Day 85
Day 72 - Day 99
Day 72 - Day 99
Day 72 - Day 
99
Day 2 - Day 
127
Week 16
Day 113
Day 100 - Day 
127
Day 100 - Day 
127
Day 100 - Day 
127
Week 20
Day 141
Day 128 - Day 
155
Day 128 - Day 
155
Day 128 - Day 
155
Week 24
Day 169
Day 156 - Day 
183
Day 156 - Day 
183
Day 156 - Day 
183
>Day 127
> Day 1 
Follow-up
Day 197
>= Day 184
>= Day 184
>= Day 184
a) ECG
b) Vital signs
c) Spirometry, Hematology, Chemistry, Urinalysis
d) SGRQ, PGI-S, CASA-Q
e) Weight, smoking status, 
5.3
AEs coding/grading
The MedDRA version which will be available at the time of database lock, will be used for the 
coding purpose of the adverse events.


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5.4
Laboratory parameters derivations
The following table shows the direction of interest when analyzing worst case values in form 
of maximum and/or minimum post-baseline values. If the direction of interest is given as "High" 
the maximum value will be calculated and used as worst value, if the direction is given as "Low" 
the minimum value will be taken, and if it is given as "Low and high", both the minimum value 
and the maximum value will be calculated and presented in summary tables.
Table 5.4-1
Directions of interest for worst case value for laboratory parameters
Laboratory Parameter
Direction of interest for worst case value
A. Hematology
Hemoglobin
Low
Hematocrit
Low
Erythrocytes
Low
WBC
Low and high
Basophils
High
Eosinophils
High
Lymphocytes
Low and high
Monocytes
High
Neutrophils
Low and high
Platelets
Low and high
B. Chemistry
Albumin
Low
Alkaline Phosphatase
High
ALT/SGPT
High
AST/SGOT
High
Bilirubin Total
High
Blood Urea Nitrogen (BUN)
High
Creatinine
High
Gamma GT
High
Potassium
Low and high
Magnesium
Low and high
Calcium
Low and high
LDH
High
Phosphorus
Low and high
Sodium
Low and high
HbA1c
Low and high
The following table shows the criteria for clinically notable laboratory values. Not all 
parameters have notable criteria defined:


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Table 5.4-2
Clinical notable criteria for selected laboratory tests
Laboratory parameter (unit)
Lower bound of 
clinically notable range
Upper bound of 
clinically notable range
Hematology
Hematocrit (v/v)
     Male
     Female
0.37
0.32
Hemoglobin (g/L)
    Male
    Female
115
95
Platelets (x10E9/L)
75 
700
WBC (x10E9/L)
2.8
16.0
Chemistry
Albumin (g/L)
25
-
Alkaline Phosphatase (U/L)
-
3xULN
ALT/SGPT (U/L)
-
3xULN
AST/SGOT (U/L)
-
3xULN
Bilirubin Total (mcmol/L)
-
34.2
BUN (mmol/L)
-
9.99
Creatinine (mcmol/L)
-
176.8
Gamma GT (U/L)
-
3 x ULN
Potassium (mmol/L)
3
6
Magnesium (mmol/L)
0.51
1.07
Sodium (mmol/L)
125
160
v = volume, ULN = upper limit of normal 


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Table 5.4-3
Notable liver function test values
Criterion
ALT > 3 x the upper limit of normal range (ULN)
ALT > 5 x ULN
ALT > 8 x ULN
ALT > 10 x ULN
ALT > 20 x ULN
ALT or AST > 3 x ULN
ALT or AST > 5 x ULN
ALT or AST > 8 x ULN
ALT or AST > 10 x ULN
ALT or AST > 20 x ULN
Total bilirubin > 1 x ULN
Total bilirubin > 1.5 x ULN
Total bilirubin > 2 x ULN
Total bilirubin > 3 x ULN
ALP > 1.5 x ULN
ALP > 2 x ULN
ALP > 3 x ULN
ALP > 5 x ULN
ALT or AST > 3 x ULN and total bilirubin > 1.5 x ULN
ALT or AST > 3 x ULN and total bilirubin > 2 x ULN
ALT or AST > 5 x ULN and total bilirubin > 2 x ULN
ALT or AST > 8 x ULN and total bilirubin > 2 x ULN
ALT or AST > 10 x ULN and total bilirubin > 2 x ULN
ALT or AST > 20 x ULN and total bilirubin > 2 x ULN
ALP > 3 x ULN and total bilirubin > 2 x ULN
ALP > 5 x ULN and total bilirubin > 2 x ULN
ALT or AST > 3 x ULN and Total Bilirubin > 2 x ULN and ALP < 2 x ULN (Hy's law)
ALT = alanine aminotransferase, AST = aspartate aminotransferase, ALP = alkaline phosphatase
When a criterion contains multiple laboratory parameters, the criterion will only be considered 
to have been met when all conditions occur within a 3-day window. A case where all criteria 
are met at a post-baseline time point will be considered as newly occurring if the criteria are not 
met at baseline and will be considered as worsening if the criteria are met at baseline and at 
least one component is worsening from baseline irrespective of whether the other(s) are better.


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5.5
Vital signs and ECG – definition of clinically notable values
The following two tables show the clinical notable criteria for vital signs and QTcF respectively.
Table 5.5-1
Clinical notable criteria for vital signs
Vital sign parameter (unit)
Lower bound of clinically 
notable range
Upper bound of clinically 
notable range
Notable value considering newly occurring or worsening cases
Systolic blood pressure (mmHg)
< 75
> 200
Diastolic blood pressure (mmHg)
< 40
> 115
Pulse rate (bpm)
< 40
> 130
Notable change from baseline
Systolic blood pressure (mmHg)
≤ 90 and decrease from 
baseline by ≥ 20 
≥ 180 and increase from 
baseline by ≥ 20
Diastolic blood pressure (mmHg)
≤ 50 and decrease from 
baseline by ≥ 15
≥ 105 and increase from 
baseline by ≥ 15
Pulse rate (bpm)
≤ 50 and decrease from 
baseline by ≥ 15
≥ 120 and increase from 
baseline by ≥ 15
Weight (kg)
Decrease > 7% from 
baseline
Increase > 7% from 
baseline
Table 5.5-2
Clinical notable criteria for QTcF (Fridericia's formula)
ECG parameter (unit)
Clinically notable range
Notable value considering newly occurring or worsening cases
QTc (msec)
> 450 
QTc (msec)
> 480
QTc (msec)
> 500 
Notable change from baseline
QTc (msec)
30 – 60
QTc (msec)
> 60
Combined criterion
QTc (msec)
> 500 & increase > 60
5.6
Details on derivation of variables
5.6.1
Derivation of baseline disease characteristics

Airflow limitation is classified based on % of predicted FEV1 and FEV1/FVC post 
bronchodilation (GOLD 2018): 

Mild (GOLD 1): FEV1/FVC < 70 % and % of predicted FEV1 ≥ 80 % 

Moderate (GOLD 2): FEV1/FVC < 70 % and 50% ≤ % of predicted FEV1 < 80 %

Severe (GOLD 3): FEV1/FVC < 70 % and 30% ≤ % of predicted FEV1 < 50 % 

Very Severe (GOLD 4): FEV1/FVC < 70 % and % of predicted FEV1 < 30 %


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
Patients will be classified based on a combined assessment of COPD using the number of 
COPD exacerbations and COPD exacerbations leading to hospital admission in the last 
year, and CAT at Run-In 1 visit. 
The following algorithm will be applied based on the standard in GOLD 2018:
–
Group A: 
history of exacerbation ≤ 1 not leading to hospital admission and CAT < 10
–
Group B: 
history of exacerbation ≤ 1 not leading to hospital admission and CAT ≥ 10
–
Group C: 
(history of exacerbation ≥ 2 or ≥ 1 leading to hospital admission) and CAT < 10
–
Group D:
(history of exacerbation ≥ 2 or ≥ 1 leading to hospital admission) and CAT ≥ 10

Duration of COPD is calculated from the date of COPD first diagnosed as recorded on 
the eCRF until the date of Visit 1. If the date is missing in day and month, the missing 
date part was imputed as 01-July if the year is before Visit 1 and as 01-January if the year 
is the same as the year of Visit 1. If the date is missing in day only, the missing day was 
imputed as 15 if month/year is before Visit 1 and as 01 if month/year is the same as of 
Visit 1.

Cardiovascular risk factors at baseline: Seven cardiovascular risk factors are defined. 
1. CCV history/condition = at least one out of: Myocardial infarction, Stroke, Peripheral 
arterial disease, Coronary artery bypass graft, or Percutaneous transluminal coronary 
angioplasty, as reported on the eCRF page of "Medical History – Protocol solicited events 
– Cardiovascular events". 
2. Hypertension, as reported on the eCRF page of "Medical History – Protocol solicited 
events – Cardiovascular events".
3. Hyperlipidemia = at least one out of: Hyperlipidemia, Hypercholesterolemia, as 
reported on the eCRF page of "Medical History – Protocol solicited events –
Cardiovascular events".
4. Diabetes mellitus = Type 1 or Type 2 diabetes mellitus, as reported on the eCRF page 
of "Medical History – Protocol solicited events – Cardiovascular events".
5. Obesity at baseline (i.e., BMI > 30 kg/m2). 
6. Age ≥ 65 years.
7. Current smoker at screening.
5.6.2
E-RS total and subscale scores
The E-RS total symptom score will be derived as the sum of items 1 to 11 (items 12 – 14 will 
not be used for the E-RS), the RS-Breathlessness score as the sum of items 7 - 11, the RS-Cough 
& Sputum scores as the sum of items 2 - 4 and the RS-Chest Symptoms score as the sum of 
items 1, 5, 6.
The mean baseline E-RS Total and subscale scores will be the average of the corresponding 
daily scores from the run-in period (which is usually a 14 day period), the last 14 days from 
Run-In 1 visit up to a day before the first dose of double-blind treatment will be included. A 
patient needs to have at least 8 days of data from the run-in period in order for the mean baseline 


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score to be calculated.  If there are less than 8 days of data available during the last 14 days 
from the run-in period, then use the last 7 days of data if there are at least 4 days of data available
to calculate the mean.  
For the derivation on-treatment mean weekly and mean monthly scores, only values from Day 
1 up to the date of last dose of double-blind treatment will be considered. Missing diary data 
will not be imputed. 
The daily scores will be averaged for each week (Week 1, Week 2, etc.). A patient needs to 
have at least 4 days of data in any week in order for the mean score to be calculated.
Monthly means over a 4-week period will also be calculated. A patient needs to have at least 3 
weekly means in that month in order for the monthly mean score to be calculated.
5.6.3
CASA-Q domain scores
The CASA-Q is a validated questionnaire instrument used to measure cough and sputum 
production, and their impact in patients with chronic obstructive pulmonary disease (COPD) 
and/or chronic bronchitis (Crawford et al 2008). It contains a total of 20 items on a 5-step scale 
distributed in 4 domains: Cough symptoms (3 items, question 1-3), Cough impact (8 items, 
question 4-11), Sputum symptoms (3 items, question 12-14) and Sputum impact (6 items, 
question 15-20).
Each item is answered on a scale from ‘never’ to ‘always’ (for frequency) or from ‘not at all’ 
to ‘a lot/extremely’ (for intensity), each type using five categories (1-5) as applicable. All items 
are rescored from 1-5 to 0-4 and then reverse scored such that better responses have higher 
scores.
There are only domain scores and no overall score. The four domains are Cough symptoms, 
cough impact, sputum symptoms and sputum impact with a range of 0-100. Higher scores 
associated with fewer symptoms/less impact due to cough or sputum.
Within each domain, items are summed and rescaled using the following algorithm:
CASA-Q domain scores= (sum of rescored items) / (range of rescored items) ×100
A domain score will only be derived if data of all corresponding items are available.
Baseline CASA-Q domain score is defined as the last CASA-Q measurement before first dose 
of double-blind treatment.  
5.6.4
SGRQ total and component scores
The algorithm below is based on SGRQ Manual Version 2.3, June 2009.
The St. George Respiratory Questionnaire (SGRQ) contains 50 items divided into three 
components: "Symptoms" concerned with respiratory symptoms, their frequency and severity; 
"Activity" concerned with activities that cause or are limited by breathlessness; and "Impacts" 
which covers a range of aspects concerned with social functioning and psychological 
disturbances resulting from airway disease. A score will be calculated for each component and 
a "Total" score will also be calculated. In each case the lowest possible value is zero and the 
highest 100. Higher values correspond to greater impairment of quality of life. 


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SGRQ scoring algorithm
Principle of calculation
Each response will be given a unique empirically derived weight between 0 and 100, the weights 
of all responses will be summed up and divided by the maximum possible score and expressed 
as a percentage.  
Each component of the questionnaire is scored separately in three steps:
1. The weights for all items with positive responses are summed. 
2. The weights for missed items are deducted from the maximum possible weight for each 
component. The weights for all missed items are deducted from the maximum possible 
weight for the Total score.
3. The score is calculated by dividing the summed weights by the adjusted maximum possible 
weight for that component and expressing the result as a percentage. The Total score is 
calculated in similar way.
Sum of maximum possible weights for each component and Total:
Symptoms
  662.5
Activity
1209.1
Impacts
2117.8
Total
3989.4
(Note: these are the maximum possible weights that could be obtained for the worst possible 
state of the patient).
Symptoms component is calculated from the summed weights for the positive responses to 
questions 1-8 (Part 1).
Activity component is calculated from the summed weights for the positive responses to 
questions 11 – 17 (Part 2, Section 2) and 36 – 44 (Part 2, Section 6) on the questionnaire. 
Impacts component is calculated from the summed weights for the positive responses to 
questions 9-10 (Part 2, Section 1), 18 – 35 (Part 2, Sections 3 - 5), and 45 – 50 (Part 2, Section 
7) on the questionnaire. 
Total score is calculated by summing all positive responses in the questionnaire and expressing 
the result as a percentage of the total weight for the questionnaire.
Handling of missing items
Symptoms:  The Symptoms component tolerates a maximum of 2 missed items.  The weight 
for the missed item is subtracted from the total possible weight for the Symptoms component 
(662.5) and from the Total weight (3989.4).
Activity:  The Activity component tolerates a maximum of 4 missed items.  The weight for the 
missed item is subtracted from the total possible weight for the Activity component (1209.1) 
and from the Total weight (3989.4). 










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AUC0-8h will be derived using a trapezoidal rule. If the 0h or the 8h concentration is missing 
the AUC0-8h will be set to missing.  AUC0-12hr will be based on the observed concentrations 
from 0 to 8hr and extrapolation up to 12h (using trapezoidal rule). The daily drug exposure 
AUC0-24hr will then be estimated as 2 x AUC0-12hr.
5.7
Statistical models
5.7.1
Primary analysis
The following MMRM ANCOVA will be used for trough FEV1:
Dependent variable = intercept + treatment + region + baseline FEV1 + smoking status at 
screening + severity of airflow limitation + run-in post-bronchodilator FEV1 + visit + 
treatment*visit + baseline value*visit + error.
The within-patient correlation will be modeled using an unstructured covariance matrix in the 
mixed model. The Kenward-Roger approximation will be used to estimate denominator degrees 
of freedom (Kenward and Roger, 1997). 
If the model fails to converge with unstructured covariance matrix, either a compound 
symmetry (first choice) or first order autoregressive (AR1) (second choice) covariance structure 
will be used. For the efficacy IA, if the model still fails to converge only data up to week 12 
will be included.
The SAS procedure PROC MIXED will be used for analysis. Results will be presented with 
LSM and standard error (SE) for treatment effects and LSM, SE, associated two-sided 90% 


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confidence interval, and two-sided p-value for treatment contrasts of each QBW251 dose versus 
Placebo.

MCP-Mod
The Multiple Comparison Procedure –
Modelling (MCP-Mod) methodology (see 
Bretz et al 2005 and Pinheiro et al 2014) will be employed to assess the primary objective. The 
following steps for the MCP-Mod methodology will be performed. The analysis will be 
implemented in SAS (used for MMRM) and R (MCP-Mod) using DoseFinding R package: 
Step 1 (Testing an overall dose-response signal - MCP part):
a.
Fit MMRM model. Extract estimates and variance-covariance matrix at Week 12 from 
fitted model.
b. Perform multiple contrast test with pre-defined model types and optimal contrasts, using 
variance-covariance matrix at Week 12 from the MMRM. 
Consider the following candidate models:
-
Emax (ED50=25)
-
Emax (ED50=75)
-
Emax (ED50=150)
-
sigEmax (ED50=25, h=3)
-
sigEmax (ED50=75, h=3)
-
sigEmax (ED50=150, h=3)
-
exponential (delta=75)
-
exponential (delta=150)
-
linear
Present T-statistics and corresponding adjusted p-values for each candidate model.
If there is at least one significant DR relationship, the DR signal is declared and Step 2 
will be performed.
Step 2 (Estimation of the dose-response curve and target dose – Mod part):
a.
Draw bootstrap samples (at least 1000) from a multivariate normal distributions N(µ,
sigma) with parameter µ and sigma populated with the corresponding estimates and 
variance-covariance from the MMRM of step 1a.  Fit each of the pre-defined models to 
the data of each sample. Select the model with the best fit based on generalized AIC and 
predict the dose-response curve with this model in each sample.
b. Derive median and other quantiles for predicted response over the dose range from the 
bootstrap samples. This will result in an averaged model.
c.
Estimate the target dose(s): the smallest dose which shows a clinical relevant effect of 
delta for each of the bootstrap samples using the best model. The target dose will be 


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estimated for a delta of 50ml using inverse regression techniques (Bretz et al 2005). The 
averaged target dose is the median of the target doses over the bootstrap samples. The
averaged target dose will only be derived if the estimated target dose of at least 50% of 
the bootstrap samples is within the investigated dose range.

Multiple imputation for supplementary analysis
For supplemental analysis the following imputation steps need to be performed for missing data. 
Off-treatment values will be considered for the analysis for patients discontinuing treatment not 
related to COVID-19, regardless of reason for discontinuing study. 
a) The following table provides an overview of the imputations rules for data after 
discontinuation:
Discontinuation of study
Discontinuation of study 
treatment
COVID-19-related
Non-COVID-19 related
COVID-19-related
no off-treatment data, 
MAR
no off-treatment data,
MAR during follow-up, 
J2R/MAR after study discontinuation
Non-COVID-19 related
off-treatment data, 
J2R/MAR
off-treatment data, J2R/MAR
J2R/MAR: Missing data after discontinuation of study treatment will be imputed using J2R assumption for 
the QBW251 arms and MAR assumption for placebo arm.
b) Any other event leading to missing data prior to completion or discontinuation of 
study treatment: on-treatment value. Missing data will be multiply imputed based on 
the MAR assumption.
A patient can have missing data for both situations a and b.
1. For patients discontinuing double-blind treatment prematurely due to COVID-19 set 
off-treatment values to missing after COVID-related discontinuation.
2. Impute missing data using MAR:
Select all patients, impute missing values at Week 4, 8, 12, 16, 20 and/or Week 24 using 
the MI approach based on the fully conditional specification (FCS) method for 100 time 
and obtain 100 imputed dataset. Missing Week 4 values will be imputed separately for 
treatment group using a model with the imputed values of baseline FEV1, region, 
smoking status, run-in pre-bronchodilator FEV1 and severity of airflow as predictors. 
Missing Week 8 values will be imputed separately for each treatment group using a 
model with the imputed values of Week 4, baseline FEV1, region, smoking status, run-
in pre-bronchodilator FEV1 and severity of airflow as predictors. Repeat the same for 
subsequent visits.
This results in 100 imputed datasets. 
For patients in the QBW251 treatment groups who discontinued double-blind treatment 
prematurely not related to COVID-19, set imputed values after discontinuation of 
treatment to missing, as these will be imputed using J2R in step 3. 


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For patients in the QBW251 treatment groups who discontinued double-blind treatment 
prematurely related to COVID-19 and discontinued study not related to COVID-19, set 
imputed values after discontinuation of study to missing, as these will be imputed using 
J2R in step 3.
3. Impute missing for patients in the QBW251 treatment groups using J2R: 
Select all patients, impute missing values at Week 4, 8, 12, 16, 20 and/or Week 24 using 
the MI approach, under assumption of missing not at random (MNAR) that patients in 
QBW251 treatment groups will behave as patients treated with Placebo, based on the 
fully conditional specification (FCS) method for 100 time and obtain 100 imputed 
dataset. Missing Week 4 values will be imputed using a model with the imputed values 
of baseline FEV1, region, smoking status, run-in pre-bronchodilator FEV1 and severity 
of airflow as predictors. Missing Week 8 values will be imputed using a model with the 
imputed values of Week 4, baseline FEV1, region, smoking status, run-in pre-
bronchodilator FEV1 and severity of airflow as predictors. Repeat the same for 
subsequent visits. 
This results in 100 imputed datasets. 
4. Merge datasets from step 2 and step 3. 
a.
For patients in QBW251 treatment groups discontinuing double-blind treatment 
prematurely not related to COVID-19 take imputed values after discontinuation
of treatment from step 3. 
b. For patients in the QBW251 treatment groups who discontinued double-blind 
treatment prematurely related to COVID-19 and discontinued study not related 
to COVID-19, take imputed values after discontinuation of study from step 3.
c.
For all other missing (including those for Placebo patients) values take imputed 
values from step 2. 
5. Week 12 data of the final multiply-imputed dataset where all missing values are filled 
will be analyzed (by imputed dataset) using a linear mixed model with treatment, region,
smoking status at screening, run-in pre-bronchodilator FEV1, severity of airflow 
limitation and baseline FEV1 as predictors.
6. The results for the treatment effect from the 100 datasets will then be combined using 
Rubin’s rule.
Step 1 to 4 will be implemented before MCP-Mod is used. 
Step 5 and 6 will be used within MCP-Mod for step 1a Step 1b and 2a of the MCP-Mod will 
use the combined estimate and variance-covariance matrix of step 6..
5.7.2
Key secondary analysis

Repeated measurements logistic regression analysis
The proportion of patients achieving a clinical important improvement, will be analyzed using 
a repeated measures logistic regression. The model is similar to the ANCOVA model: