Clinical trial NCT04396366
Conditions: Bronchiectasis
Keywords: Bronchiectasis QBW251 colony forming units
Sponsor: Novartis Pharmaceuticals
Start date: 2021-02-02; Completion date: 2023-06-21
Enrollment: 42 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine whether potentiating the cystic fibrosis transmembrane conductance regulator (CFTR) with QBW251 in patients with bronchiectasis will demonstrate clinical safety and efficacy related to improved mucociliary clearance with reduced bacterial colonization as potential drivers of airway obstruction, reduced airway inflammation, exacerbations and mucus load, improved lung function, clinical symptoms and quality of life to support further development in bronchiectasis.

Detailed description:
This was a randomized, participant- and investigator-blinded, placebo-controlled, parallel-group study investigating the preliminary efficacy and safety of QBW251 administered orally for 12 weeks in participants with bronchiectasis. Approximately 72 subjects were planned to be randomized in a 1:1 ratio to receive either QBW251 or placebo in order to achieve 60 subjects to complete the treatment period based on the assumption of a 16% drop-out rate. However, the study was prematurely terminated due to a Novartis strategic decision. As a result, only 42 participants were randomized to either the QBW251 300 mg b.i.d group or the placebo group.

The study consisted of the screening, baseline/Day 1, treatment period, and end of study assessments (EOS) visit followed by an additional post-treatment safety follow up via phone call. The total duration for each patient in the study was up to approximately 19 weeks.

Arms: arm 1: Participants received QBW251 300 mg orally, twice daily (b.i.d.), for 12 weeks. arm 2: Participants received matching placebo, b.i.d., for 12 weeks.
Interventions: intervention 1: QBW251 intervention 2: Placebo
Intervention descriptions: intervention 1: QBW251, 300 mg, oral use, one capsule, twice daily. intervention 2: Matching placebo, 300 mg, oral use, one capsule, twice daily.

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development
QBW251
Clinical Trial Protocol CQBW251C12201
ClinicalTrials.gov Identifier: NCT04396366
A randomized, subject- and investigator-blinded, 
placebo-controlled, parallel group study to 
assess the safety, tolerability, pharmacokinetics 
and pharmacodynamics of QBW251 in patients 
with bronchiectasis
Document type:
Amended Protocol Version
EUDRACT number:
2019-002840-26
Version number:
v03 (Clean)
Clinical Trial Phase:
II
Release date:
02-Dec-2022
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 2.0 dated 01-Aug-2018


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Site Operations Manual (SOM)
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study procedures. Note: The SOM will not be a part of the Clinical Study Report.


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Table of contents
Site Operations Manual (SOM)...........................................................................................2
Table of contents .................................................................................................................3
List of tables ........................................................................................................................7
List of figures ......................................................................................................................7
List of abbreviations............................................................................................................8
Glossary of terms...............................................................................................................11
Amendment 03 (December 2022) .....................................................................................13
Amendment 02 (November 2021).....................................................................................17
Amendment 01 (March 2021) ...........................................................................................19
Protocol summary..............................................................................................................22
1
Introduction .......................................................................................................................29
1.1
Background............................................................................................................29
1.2
Purpose ..................................................................................................................31
2
Objectives and endpoints...................................................................................................31
3
Study design ......................................................................................................................34
3.1
Study visits.............................................................................................................34
4
Rationale............................................................................................................................37
4.1
Rationale for study design .....................................................................................37
4.1.1
Rationale for choice of background therapy.........................................38
4.2
Rationale for dose/regimen and duration of treatment ..........................................38
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................39
4.4
Purpose and timing of interim analyses/design adaptations..................................40
4.5
Risks and benefits..................................................................................................40
4.5.1
Blood sample volume............................................................................43
5
Population..........................................................................................................................43
5.1
Inclusion criteria ....................................................................................................43
5.2
Exclusion criteria...................................................................................................44
6
Treatment...........................................................................................................................47
6.1
Study treatment......................................................................................................47
6.1.1
Investigational and control drugs..........................................................48
6.1.2
Additional study treatments ..................................................................48
6.1.3
Treatment arms/group ...........................................................................48
6.2
Other treatment(s)..................................................................................................48
6.2.1
Concomitant therapy.............................................................................48
6.2.2
Prohibited medication ...........................................................................52


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6.2.3
Treatment for exacerbations and for bronchospasm.............................54
6.2.4
Restriction for study subjects................................................................54
6.3
Subject numbering, treatment assignment, randomization....................................55
6.3.1
Subject numbering ................................................................................55
6.3.2
Treatment assignment, randomization ..................................................55
6.4
Treatment blinding.................................................................................................56
6.5
Dose escalation and dose modification..................................................................57
6.5.1
Dose Interruptions.................................................................................57
6.5.2
Dose Adjustments for QTcF Prolongation............................................57
6.6
Additional treatment guidance...............................................................................58
6.6.1
Treatment compliance...........................................................................58
6.6.2
Recommended treatment of adverse events..........................................58
6.6.3
Emergency breaking of assigned treatment code..................................59
6.7
Preparation and dispensation.................................................................................59
6.7.1
Instruction of prescribing and taking study medication........................59
7
Informed consent procedures ............................................................................................60
8
Visit schedule and assessments .........................................................................................62
8.1
Screening ...............................................................................................................67
8.1.1
Information to be collected on screening failures.................................67
8.2
Subject demographics/other baseline characteristics.............................................67
8.3
Efficacy..................................................................................................................68
8.3.1
Microbiological assessment ..................................................................68
8.3.2
Spirometry.............................................................................................69
8.3.3
Fibrinogen .............................................................................................69
8.3.4
High Resolution Computed Tomography (HRCT)...............................69
8.3.5
High-sensitivity C-reactive protein (hsCRP) ........................................70
8.3.6
Appropriateness of efficacy assessments..............................................70
8.4
Safety.....................................................................................................................70
8.4.1
Laboratory evaluations..........................................................................71
8.4.2
Electrocardiogram (ECG) .....................................................................72
8.4.3
Pregnancy and assessments of fertility .................................................72
8.4.4
Bronchiectasis exacerbation..................................................................72
8.4.5
Appropriateness of safety measurements..............................................73
8.5
Additional assessments..........................................................................................73
8.5.1
Clinical Outcome Assessments (COAs) ...............................................73
8.5.2
Pharmacokinetics ..................................................................................76


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8.5.3
Biomarkers............................................................................................77
9
Study discontinuation and completion ..............................................................................78
9.1
Discontinuation......................................................................................................78
9.1.1
Discontinuation of study treatment .......................................................78
9.1.2
Withdrawal of informed consent...........................................................80
9.1.3
Lost to follow-up...................................................................................80
9.1.4
Study stopping rules..............................................................................80
9.1.5
Early study termination by the sponsor.................................................81
9.2
Study completion and post-study treatment ..........................................................81
10 Safety monitoring and reporting........................................................................................82
10.1
Definition of adverse events and reporting requirements......................................82
10.1.1
Adverse events ......................................................................................82
10.1.2
Serious adverse events ..........................................................................83
10.1.3
SAE reporting........................................................................................84
10.1.4
Pregnancy reporting ..............................................................................85
10.1.5
Reporting of study treatment errors including misuse/abuse................86
10.2
Additional Safety Monitoring................................................................................86
10.2.1
Liver safety monitoring.........................................................................86
10.2.2
Renal safety monitoring........................................................................87
10.2.3
Data Monitoring Committee .................................................................87
10.2.4
Steering Committee...............................................................................88
11 Data Collection and Database management......................................................................88
11.1
Data collection.......................................................................................................88
11.2
Database management and quality control............................................................88
11.3
Site monitoring ......................................................................................................89
12 Data analysis and statistical methods ................................................................................90
12.1
Analysis sets ..........................................................................................................90
12.2
Subject demographics and other baseline characteristics......................................90
12.3
Treatments .............................................................................................................90
12.4
Analysis of the primary endpoint(s) ......................................................................90
12.4.1
Definition of primary endpoint(s).........................................................91
12.4.2
Statistical model, hypothesis, and method of analysis..........................91
12.4.3
Handling of missing values/censoring/discontinuations.......................92
12.4.4
Sensitivity and Supportive analyses......................................................92
12.5
Analysis of secondary endpoints ...........................................................................93
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)....................................93


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12.5.2
Safety endpoints....................................................................................94
12.5.3
Pharmacokinetics ..................................................................................95
12.5.4
PK/PD relationships..............................................................................95
12.5.5
Patient reported outcomes.....................................................................95
12.6
Analysis of exploratory endpoints.........................................................................95
12.6.1
Changes from baseline in SGRQ, and EQ-5D-3L ................................95
12.6.2
Bronchiectasis exacerbation..................................................................96
12.6.3
Biomarkers............................................................................................96
12.6.4
DNA......................................................................................................96
12.7
Interim analyses.....................................................................................................97
12.8
Sample size calculation..........................................................................................97
12.8.1
Primary endpoint(s)...............................................................................97
13 Ethical considerations and administrative procedures ......................................................97
13.1
Regulatory and ethical compliance........................................................................97
13.2
Responsibilities of the investigator and IRB/IEC..................................................98
13.3
Publication of study protocol and results...............................................................98
13.4
Quality Control and Quality Assurance.................................................................98
14 Protocol adherence ............................................................................................................98
14.1
Protocol amendments.............................................................................................99
15 References .......................................................................................................................100
16 Appendices ......................................................................................................................102
16.1
Appendix 1: Clinically notable laboratory values and vital signs .......................102
16.2
Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.......................................................................................................103
16.3
Appendix 3: Specific Renal Alert Criteria and Actions and Event Follow-up....106


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List of tables
Table 2-1
Objectives and related endpoints ..........................................................31
Table 6-1
Investigational and control drug............................................................48
Table 6-2
Medications permitted under certain conditions...................................49
Table 6-3
Medications which may be co-administered with QBW251 (if no 
alternative treatment is available) .........................................................50
Table 6-4
Examples of contraceptives not recommended for systemic use as 
acceptable means of contraception as efficacy may be 
compromised by QBW251 administration............................................52
Table 6-5
Prohibited medication ...........................................................................52
Table 6-6
Respiratory related medications and required washout periods............53
Table 6-7
Blinding levels ......................................................................................56
Table 8-1
Assessment Schedule ............................................................................62
Table 8-2
Assessments and Specifications............................................................71
Table 8-3
Laboratory evaluations..........................................................................72
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................86
Table 16-1
Liver event and laboratory trigger definitions ....................................103
Table 16-2
Follow up requirements for liver events and laboratory triggers........103
Table 16-3
Specific Renal Alert Criteria and Actions...........................................106
Table 16-4
Renal Event Follow Up.......................................................................107
List of figures
Figure 3-1
Study Flowchart ....................................................................................34


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List of abbreviations
AE
adverse event
AEMPS
Spanish Agency for Medicines and Medical Devices
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATS
American Thoracic Society
b.i.d.
twice a day
BCRP
Breast Cancer Resistance Protein
BE
Bronchiectasis
BfArM
Federal Institute for Drugs and Medical Devices (Germany)
BMI
Body Mass Index
BUN
blood urea nitrogen
Cmin
Minimum concentration
CF
cystic fibrosis
CFR
Code of Federal Regulation
CFTR
Cystic fibrosis transmembrane conductance regulator
CFU
Colony-Forming-Unit
CMO&PS
Chief Medical Office & Patient Safety
COA
Clinical Outcome Assessments
COPD
Chronic obstructive pulmonary disease
COVID-19
Coronavirus identified in 2019
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CRP
C-reactive protein
CRA
Clinical Research Associate
CSR
Clinical study report
CV
coefficient of variation
DBP
Diastolic Blood Pressure
DDE
Direct Data Entry
DDI
Drug-Drug Interaction
DIN
Drug Inducted Nephrotoxicity
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DRF
dose range finding
ECG
Electrocardiogram
EDC
Electronic Data Capture
EFPIA
European Federation of Pharmaceutical Industries and Associations
EMA
European Medicines Agency
EoS
End of Study
EQ-5D-3L
Euro Quality of Life-5 Dimensions-3 level
E-RS
Evaluating Respiratory Symptoms in COPD


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EU
European Union
eCRF
Electronic Case Report Form
eSAE
Electronic Serious Adverse Event
eSource
Electronic Source
EXACT-PRO
EXAcerbations of COPD Tool - Patient Reported Outcome
FDA
Food and Drug Administration
FEV1
Forced Expiratory Volume in 1 second
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GCS
Global Clinical Supply
GGT
Gamma-glutamyl transferase
h
hour
HA
Health Authorities
hsCRP
High-sensitivity C-reactive Protein
HbsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
hCG
Human Chorionic gonadotropin
HCV
Hepatitis C virus
HDL
high-density lipoproteins
HIV
human immunodeficiency virus
HRCT
High Resolution Computed Tomography
iABC
inhaled Antibiotics in Bronchiectasis and Cystic Fibrosis
IB
Investigator's Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ICS
Inhaled Corticosteroids
IEC
Independent Ethics Committee
IL-6
Interleukin 6
IL-8
Interleukin 8
IN
Investigator Notification
IND
Investigational New Drug
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
LABA
Long-acting β2 agonist
LAMA
Long-acting muscarinic antagonist
LDH
lactate dehydrogenase
LDL
low-density lipoproteins
LFT
Liver function test
LLOQ
lower limit of quantification
MCC
mucociliary clearance


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MedDRA
Medical dictionary for regulatory activities
MHRA
The Medicines and Healthcare products Regulatory Agency (UK)
mg
milligram(s)
mL
milliliter(s)
NCFBE
non-CF bronchiectasis
NDA
New Drug Application
NOAEL
no-observed-adverse-effect-level
NTM
nontuberculous mycobacterial
NYHA
New York Heart Association
PCR
protein-creatinine ratio
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PoC
Proof of concept
PPM
potential pathogenic microorganisms
PRO
Patient Reported Outcomes
PT
prothrombin time
QMS
Quality Management System
QOL-B
Quality of Life Questionnaire for Bronchiectasis
QTcF
QT interval corrected by Fridericia’s formula
rRNA
ribosomal ribonucleic acid
RoW
Rest of World
SABA 
Short-Acting Beta-2 Agonists
SAE
Serious Adverse Event
SAR
Serious Adverse Reaction
SBP
Systolic Blood Pressure
SD
standard deviation
SGRQ
St. George's Respiratory Questionnaire
SMQ
Standardized MedDRA Query
SOC
Standard of care
SOM
Site Operations Manual
SOP
Standard Operation Procedure
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBL
total bilirubin
ULN
upper limit of normal
US
United States of America
WHO
World Health Organization
WoC
Withdrawal of Consent


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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
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study subject
Cohort
A specific group of subjects fulfilling certain criteria
Control drug
A study drug (active or placebo) used as a comparator to reduce assessment 
bias, preserve blinding of investigational drug, assess internal study validity, 
and/or evaluate comparative effects of the investigational drug
Cycles
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g., q28 days)
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 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 clinical 
trial
The end of the clinical trial is defined as the last visit of the last subject or at a 
later point in time as defined by 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)
eSource
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource combines source documents and 
case report forms (eCRFs) into one application, allowing for the real time 
collection of clinical trial information to sponsors and other oversight 
authorities, as appropriate.
Healthy volunteer
A person with no known significant health problems who volunteers to be 
a study participant 
Investigational 
drug/treatment
The drug whose properties are being tested in the study
Medication pack 
number
A unique identifier on the label of each drug package in studies that dispense 
study treatment using an IRT system
Part
A single component of a study that contains different objectives or populations 
within that single study. Common parts within a study are a single dose part 
and a multiple dose part, or a part in patients with established disease and in 
those with newly diagnosed disease.
Patient
An individual with the condition of interest
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.
Randomization 
number
A unique identifier assigned to each randomized subject, corresponding to 
a specific treatment arm assignment


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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 medications or other 
intervention)
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 data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource
Study treatment
Any drug or combination of drugs administered to the study participants as 
part of the required study procedures; includes investigational drug(s), 
control(s) or background therapy
Study treatment 
discontinuation
When the subject permanently stops taking study treatment prior to 
the defined study treatment completion date
Subject
A trial participant (can be a healthy volunteer or a patient)
Subject number
A unique number assigned to each subject upon signing the informed consent. 
This number is the definitive, unique identifier for the subject and should be 
used to identify the subject throughout the study for all data collected, sample 
labels, etc.
Treatment number
A unique identifier assigned in non-randomized studies to each dosed subject, 
corresponding to a specific treatment arm 
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested in 
the study
Withdrawal of 
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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Amendment 03 (December 2022)
Amendment Rationale
This amendment removes the stopping rules for NOAEL threshold limits as recommended by 
both the sponsor and the Data Monitoring Committee (DMC) upon review of the full safety 
data set from all completed studies with QBW251 to date. No apparent correlation between 
drug exposure above the NOAEL threshold limits and safety signals has been observed in 
this safety review.
Further, this amendment discontinues the DMC involvement in the trial.  The DMC was 
established as an independent review committee to monitor the exposure safety relationship and 
the benefit of the chosen exposure threshold. As the PK threshold monitoring has been 
eliminated given the lack of correlation with safety signals, the DMC is no longer required.
This protocol amendment clarifies the requirement of patient’s completion of 
the EXAcerbations of COPD Tool - Patient Reported Outcome (EXACT-PRO) during 
screening/baseline period for the purpose of EXACT-PRO baseline score calculation to 
correctly set up EXACT-PRO alert after patient’s being randomized. In addition, 
the exploratory objective and endpoints related to mucus burden are updated to be more specific. 
This change is made to ensure a baseline score can be correctly calculated and to ensure 
participants fully understand how to complete the EXACT-PRO, a questionnaire in place to 
measure exacerbations during the trial.
This amendment reduces the number of ECGs to one per visit versus in triplicate as results from 
the thorough QT study (CQBW251A2105) indicated that QBW251 at 300 mg b.i.d. did not 
have clinically relevant effects on studied ECG parameters, and reduction of ECGs will 
minimize time at study visits for participants.
This amendment updates the co-medication lists to include the most updated drug-drug 
interaction (DDI) information based on clinical DDI study (CQBW251A2107) and in vitro data.
This amendment also clarifies the inclusion/exclusion criteria, allowing patients with Primary 
Ciliary Dyskinesia (PCD) to participate which may facilitate recruitment to the study. 
Additional inclusion criteria are clarified, including the use of screening HRCT to satisfy 
inclusion in the study and the clarification that Haemophilus parainfluenzae alone is NOT 
permitted for inclusion as a pathogenic organism. These changes are made to increase 
understanding and simplify inclusion criteria in the study to facilitate recruitment.
This amendment introduces flexibility in the number of attempts for spontaneous sputum 
collection for each visit before attempting induced sputum collection.
This amendment allows participants at selected sites, upon approval of the sponsor, to forgo 
HRCT scanning. This change may facilitate participant recruitment at selected sites.
Additionally, this amendment made some other administrative and minor modifications to 
clarify or correct certain points, improving readability and to assure alignment between different 
protocol sections.


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Changes to the protocol

Protocol summary was updated to align with the changes in the protocol text.

Table 2-1 Objectives and endpoints is updated to expand on the endpoints for the effect of 
QBW251 on HRCT outcome measures and to clarify biomarker endpoints.

Section 3.1 Study visits and subsections are updated. Screening Visit subsection is 
updated to clarify the possibility to use the screening HRCT for diagnosis confirmation
and to add the possibility for HRCT assessment to be optional at selected sites.
Baseline/Randomization Day 1 subsection is updated to include information about mucous 
clearance regimen changes. Treatment period subsection is updated to provide flexibility 
in the number of attempts allowed for sputum collection and provide guidance on induced 
sputum, as well as to remove the need for triplicate ECGs based on CQBW251A2105 QT 
study results.

Section 4.2 Rationale for dose/regimen and duration of treatment is updated to add DMC 
review conclusion and to remove PK threshold limits.

Section 4.4 Purpose and timing of interim analyses/design adaptations is updated to 
remove the reference to the DMC.

Section 4.5 Risks and benefits is updated to add advice for cautionary use of narrow 
therapeutic index substrates of CYP2C8, sensitive substrates of CYP2B6, CYP2C8, 
CYP2C19, OCT1, and MRP2, and prohibit use of narrow therapeutic index substrates of 
CYP2C19 and strong inducers mediating enzyme levels via PXR according to the updated 
information from CQBW251A2107 results and in vitro data. The triplicate ECGs were 
removed based on CQBW251A2105 QT study results. The PK threshold limits were 
removed, and more information was added about the DDI study CQBW251A2107.

Section 5.1 Inclusion criteria is updated to clarify the possibility to use the screening 
HRCT for diagnosis confirmation and to exclude H. parainfluenzae alone as an acceptable 
pathogenic organism for inclusion.

Section 5.2 Exclusion criteria is updated to clarify who determines certain exclusion 
criteria and to allow inclusion of patients with PCD with approval of Sponsor. 
The definition of an exacerbation in Excl #12 was updated. And Excl #22 was updated to 
clarify that only uncontrolled Type I and Type II diabetes are exclusionary. The timeframe 
for receiving medication that may influence treatment response was updated to within 
4 weeks from Day 1.

Section 6.2.1.1 Permitted concomitant therapy requiring caution and/or action is updated 
to include the most updated DDI information. The prohibition periods and action taken 
columns are reworded for more clarity and to remove the reference to -45min and -15min 
spirometry as the double spirometry is not required at each visit, only at screening.

Table 6-4 is updated to clarify the action to be taken in case of the use of prohibited 
contraception methods.

Table 6-5 Prohibited medication is updated to include additional prohibited medications 
that may influence the response to treatment and to clarify the duration of the prohibition 
period.

Table 6-6 Prohibited Respiratory related medications and required washout periods prior 
to Day 1 is updated to remove redundancy with other tables.


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
Section 6.4 Treatment blinding is updated to remove DMC-related activities.

Table 6-7 Blinding levels is updated to remove DMC-related activities.

Table 8-1 Assessment schedule is reformatted for all the visits to fit on the same page. It is 
also updated to clarify that patients need to complete the EXACT-PRO on at least 4 out of 
the past 7 days before patients begin the Baseline visit to calculate the EXACT-PRO 
baseline score. The Sparse PK Sample collection is removed at unscheduled visits. 
The footnotes have been updated to provide clarity and consistency with the rest of 
the document. The HRCT assessment is also made optional at selected sites with approval 
of Sponsor. For clarity, Concomitant medication and Adverse events were marked as 
assessments to be recorded in clinical database. Comments were marked as to be recorded 
in the source documentation. 

Section 8.1 Screening is updated to clarify that the sputum bacterial load assessment may 
be repeated twice prior to randomization if sputum bacterial load at screening is outside of 
the eligibility range.

Section 8.3.1 Microbiological assessment is updated to allow participants to provide 
flexibility in the number of attempts allowed for sputum collection and provide guidance 
on induced sputum collection.

Section 8.3.4 High Resolution Computed Tomography (HRCT) is updated to allow HRCT 
assessment to be optional at selected sites with approval of Sponsor. Additional details 
about secondary and exploratory HRCT assessments have also been included.

Section 8.4.4 Bronchiectasis exacerbation is updated to include steroids as possible 
treatment for BE exacerbation treatment to be considered.

Section 8.5.1 Clinical Outcome Assessment (COAs) was updated to remove that it should 
be completed before all other assessments for consistency with other recommendations in 
the protocol

Section 8.5.2 Pharmacokinetics is updated to remove the need to collect additional PK 
samples for treatment-emergent SAEs.

Section 8.5.3.1 Sputum biomarkers is updated to allow analysis flexibility depending on 
methods availability and emerging scientific knowledge.

Section 8.5.3.2 Serum protein signatures is updated to add the description of serum protein 
profiling analysis

Section 9.1.1 Discontinuation of study treatment is updated for discontinuation due to PK 
threshold-related SAEs. The EoS visit is specified for the assessments to be completed in 
case of discontinuation.

Section 9.1.5 Early Termination by the sponsor is updated to remove exposure-driven 
decision.

Section 10.2.3 Data Monitoring Committee is updated to specify that the DMC is no 
longer required.

References were updated according to the latest guidance on Harvard style format
Changes to specific sections of the protocol are shown in the track changes version of 
the protocol using strike through red font for deletions and red underlined for insertions.


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Amended Protocol Version v03 (Clean)
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IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC and Health Authority 
approval according to local regulation prior to implementation. In addition, the changes herein 
will affect the Informed Consent, sites are required to update and submit for approval a revised 
Informed Consent that takes into account the changes described in this amended protocol.


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Amended Protocol Version v03 (Clean)
Protocol No. CQBW251C12201
Amendment 02 (November 2021)
Amendment rationale
This protocol amendment addresses the following changes: two inclusion and one exclusion
criteria were amended following investigators’ feedback to improve study feasibility and 
recruitment. These changes will expand the number of eligible participants, but will not change 
the overall patient profile for the study.
1. Subjects with one documented exacerbation between January 2019 and study 
screening will be permitted. This will extend the window for historical exacerbations 
to pre-COVID-19 when subjects were potentially having exacerbations more typical of 
their disease state.
2. Subjects who are using mucolytics and hyperosmolar agents will be permitted.
The study drug has a different mechanism of action compared to mucolytics and 
hyperosmolar agents, so use of mucolytics and hyperosmolar agents will not interfere 
with assessment of the study drug.
Additionally, this amendment made some other administrative and minor modifications to 
clarify or correct certain points, improving readability and to assure alignment between different 
protocol sections.
Changes to the protocol

Key inclusion criteria in Protocol Summary, Section 5.1 Inclusion Criteria were updated 
to expanded timeframe for subject to have had defined, documented exacerbations 
between Jan 2019 and screening instead of 12 months prior to screening. This accounts for 
the reported reduction in exacerbations in this population due to presumed fewer 
exposures to triggers of exacerbation during the COVID-19 pandemic.

Key inclusion criteria in Protocol Summary, Section 5.1 Inclusion Criteria were updated 
to allow patients to use mucolytics or hyperosmolar agents as maintenance therapy if they 
were treated with them before study start.

Key exclusion criteria in Protocol Summary, Section 5.2 Exclusion Criteria and Table 6-6
Prohibited respiratory related medications and washout period prior to Day 1 were 
updated to remove mucolytics and hyperosmolar agents from the prohibited medication 
list.

Section 3.1 Study visits and Section 8 Visit schedule and assessments and throughout 
the document were updated to extend the screening period from 35 days to 42 days to 
accommodate turn-around times for sputum in case of need to re-test during screening.

Section 4.5 Risks and benefits was updated to remove advice for cautionary use of 
sensitive substrates of CYP2B6 and OATP1B3 according to the updated assessment based 
on the highest dose of 300 mg b.i.d. in IB version 13.

Section 5.2 Exclusion criteria was updated to split exclusion criterion #18 into 3 separate 
criteria #18, #24 and #25, which was accidentally combined as one criterion.

Section 6.2.4.1 Dietary restrictions and smoking was updated to allow smoking as 
smokers without severe emphysema are allowed to be enrolled.


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
Section 8.1 Screening was updated to clarify in case of rescreening, patient does not need 
to retest HRCT at baseline if it has been done in the previous screening period within
the past 12 months.

Section 10.1.3 SAE reporting has been updated to include the latest requirement from 
BfArM in Germany.
Changes to specific sections of the protocol are shown in the track changes version of 
the protocol using strike through red font for deletions and red underlined for insertions.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC and Health Authority 
approval according to local regulation prior to implementation. In addition, the changes herein 
will affect the Informed Consent, sites are required to update and submit for approval a revised 
Informed Consent that takes into account the changes described in this amended protocol.


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Amended Protocol Version v03 (Clean)
Protocol No. CQBW251C12201
Amendment 01 (March 2021)
Amendment rationale
This protocol amendment addresses the following changes as requested by MHRA, BfArM, 
AEMPS and the EC in Germany:
1. To clarify that the dose to be used in the study is 300 mg and the respective dose 
rationale. During the independent Data Monitoring Committee (DMC) meeting held 
on 16-Apr-2020 for the QBW251 studies, the DMC recommended treatment with 
the 450 mg b.i.d. dose be discontinued in the ongoing dose-range-finding study, based 
on the statistical stopping rule pre-specified in the protocols (Section 10.2.3). 
Importantly, no safety findings contributed to this DMC recommendation. 
Accordingly, Novartis decided to use 300 mg b.i.d. dose in the present study instead of 
450 mg b.i.d.
2. Remove the requirement for the serious adverse reactions to be similar in nature as 
a pre-requisite to put the study on hold.
3. Include a statement that any restart following a temporary hold due to stopping rules 
being met will require the Competent Authorities and Ethic Committees approval, as 
required per country regulations.
4. To clarify the primary analysis strategy as requested by the EC in Germany.
Additionally, this amendment made some other administrative and minor modifications to 
clarify or correct certain points, improving readability and to assure alignment between different 
protocol sections.
Changes to the protocol

List of abbreviations was updated to include new abbreviations.

Primary objective in protocol summary Section 2 and Section 8.3.1 were updated to 
clarify 1 CFU/mL = 1 CFU/g.

Study design in protocol summary, Section 3.1 and Section 8.3.1 were updated to 
allow retesting of bacteria load during the screening period.

Inclusion criteria in protocol summary and Section 5.1 was updated to clarify that 
chest CT (not only the chest HRCT) are acceptable for diagnosis of bronchiectasis 
(inclusion criterion #3).

Inclusion criteria in protocol summary and Section 5.1 were updated to remove 
the requirement of steering committee’s approval for including additional organisms to 
be measured and counted in the bacterial load (inclusion criterion #4).

Exclusion criteria in protocol summary and Section 5.2 were updated to clarify 
the hepatitis exclusion criterion and requirements on liver function tests (exclusion 
criterion #5).

Section 2 secondary objectives, Section 8.5.2 and Section 12.5.3 were updated to 
reflect the most accurate PK parameters to be assessed in this study.

Section 3.1 was updated to clarify the requirement of HRCT assessment during 
screening.


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
Further sections were updated throughout the document to emphasize the use of 
the dose of 300 mg b.i.d. and that the dose of 450 mg b.i.d. will not be used in this 
study.

Figure 3-1 was updated to remove the dose of 450 mg.

Section 4.2 Rationale for dose/regimen and duration of treatment was updated to 
clarify the reasons for using the dose of 300 mg b.i.d.

The original Section 6.5.2 Dose Modifications and Section 9.1.4.1 Dose Reduction are 
integrated into Section 4.2, Section 4.5, Section 9.1.1 and Section 10.2.3. Redundant 
information related to the 450 mg dose was removed. Section 6.5.2.1 Dose 
Adjustments for QTcF Prolongation is promoted to the new Section 6.5.2.

Section 6.2.1.1 was updated to reflect that induction of QBW251 by CYP2B6 and 
relevant change in exposure due to concomitant medicines are not expected at the 
anticipated exposure of QBW251 300 mg b.i.d. and remove sensitive substrates of 
CYP2B6 from Table 6-3.

Section 6.2.3 was updated to accurately reflect the treatment for exacerbations instead 
of the rescue medication only.

Section 6.4 was updated to clarify the blinding strategy.

Table 8-1 was updated to include below changes to be aligned with the protocol body:

Add week number for each visit

Change time point “dose” to “0”.

List the requirement of drug accountability

List the assessment of coagulation

List sputum 16s rRNA PCR in a separate row

Add SGRQ, EQ-5D-3L, QOL-B and eDiary, EXACT-PRO to Unscheduled visit

Add respiratory assessment on Day 56

Combined individual cells for EXACT-PRO in to one for the treatment period to 
reflect that it needs to be completed every evening

Changed data capture requirement for telephone follow-up on day 14 from 
requiring in clinical database to only requiring in source data

Footer was updated to be aligned with the changes.

Section 8.3.1 was updated to move the 16s rRNA PCR test to the Section 8.5.3.1.

In Section 8.3.3, the method for fibrinogen analysis is removed as it will be defined by 
the central lab.

Section 8.4.1 was updated to move fibrinogen from chemistry panel to coagulation 
panel; and to remove PTT from coagulation panel according to lab settings.

Multiple sections throughout the document were updated to remove the mandatory 
serial PK sampling for selected sites. Now at selected sites, serial PK sampling is also 
optional to patients.

Section 8.5.3.1 was updated to list all sputum biomarkers, including 16S rRNA PCR 
for bacterial load and 16S rRNA gene sequencing for bacterial profile, which are both 
optional to China.


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
A statement for the restart of the study following a temporary hold due to stopping 
rules being met will require HA and EC approval as required per local regulations is 
added in Section 9.1.4 Study stopping rules.

Section 9.1.4 was updated to remove the requirement for the serious adverse reactions 
to be similar in nature.

Section 10.1.4 was updated to remove the requirement of following up male subject’s 
female partner’s pregnancy.

Section 10.2.3 was updated to correct a typo in bullet point 1 from “The proportion of 
subjects” to “The number of subjects”.

Section 12.4.1, Section 12.4.2 and Section 12.4.3 were updated to clarify the analysis 
strategy for the primary estimand.

Section 12.5.1 was updated to reflect the analysis plan for the secondary efficacy 
endpoints.

Updated the analysis in Section 12.5.1.3

Moved the description of the endpoint from Section 12.6.1 to Section 12.5.1.5.

Reference was updated to reflect the correct URL for ICH-E2E.
Only the information referring to 450 mg has been deleted. All information that still concerns 
the 300 mg has been kept in the protocol. Sections that previously described the dose reduction 
and the steps to be taken have been distributed to other sections, as applicable (i.e. Section 4.2 
and Section 9.1.1). 
Changes to specific sections of the protocol are shown in the track changes version of 
the protocol using strike through red font for deletions and red underlined for insertions.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC and Health Authority 
approval according to local regulation prior to implementation. In addition, the changes herein 
will affect the Informed Consent, sites are required to update and submit for approval a revised 
Informed Consent that takes into account the changes described in this amended protocol.


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Protocol No. CQBW251C12201
Protocol summary
Protocol number
CQBW251C12201
Full Title
A randomized, subject- and investigator-blinded, placebo-controlled, parallel 
group study to assess the safety, tolerability, pharmacokinetics 
and pharmacodynamics of QBW251 in subjects with bronchiectasis
Brief title
Study of safety, tolerability, pharmacokinetics and pharmacodynamics of 
QBW251 in subjects with bronchiectasis
Sponsor and 
Clinical Phase
Novartis
Phase II
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
The purpose of this study is to determine whether potentiating the cystic 
fibrosis transmembrane conductance regulator (CFTR) with QBW251 in 
patients with bronchiectasis will demonstrate clinical safety and efficacy 
related to improved mucociliary clearance with reduced bacterial colonization 
as potential drivers of airway obstruction, reduced airway inflammation, 
exacerbations and mucus load, improved lung function, clinical symptoms and 
quality of life to support further development in bronchiectasis.
Primary 
Objective(s)
The primary objective for this study is to determine the efficacy of QBW251 
compared to placebo with respect to change from baseline in bacterial load of 
colony forming units (CFU/mL, 1 CFU/mL = 1 CFU/g) of potentially pathogenic 
microorganisms in spontaneous sputum at week 12.
Secondary 
Objectives
Objective 1: to assess the change on sputum bacterial clearance of QBW251 
compared to placebo with respect to proportion of patients with absence of any CFU 
of potentially pathogenic bacteria in sputum culture after 12 weeks of treatment.
Objective 2: to assess the change on patient reported outcomes on 
bronchiectasis symptom assessment of QBW251 compared to placebo with 
respect to change from baseline in Quality of Life Questionnaire for 
Bronchiectasis (QOL-B) after 12 weeks of treatment.
Objective 3: to assess the change of fibrinogen plasma concentration of 
QBW251 compared to placebo after 12 weeks of treatment.
Objective 4: to assess the change in rescue medication use of QBW251 
compared to placebo after 12 weeks of treatment.
Objective 5: to assess the effect of QBW251 after 12 weeks of treatment, on 
the change from baseline in lung function from measurement by spirometry of 
pre-bronchodilator FEV1 and FVC.
Objective 6: to assess the effect of QBW251, after 12 weeks of treatment, on 
the change from baseline in airway structure and function from measurements 
by HRCT of airway wall, lumen parameters and the extent of global and 
regional air trapping.
Objective 7: to assess the pharmacokinetic profile of QBW251 in subjects by 
measurement of concentrations of QBW251 in plasma and calculation of 
relevant PK parameters including Cmax, AUC on Days 1 and 28 (for a subset 
of patients at selected sites). Pre- and post- dose concentration (Ctrough and 
around Cmax) on Days 1, 28, 56 and 84 (for all patients).


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Objective 8: to assess the safety and tolerability of QBW251 by reporting 
the occurrence of adverse events, vital signs, ECG and safety laboratory 
changes during the study
Study design
This is a randomized, subject- and investigator-blinded, placebo-controlled, 
parallel-group study investigating the preliminary efficacy and safety of 
QBW251 administered orally for 12 weeks in subjects with bronchiectasis. 
Approximately 72 subjects will be randomized in a 1:1 ratio to receive either 
QBW251 or placebo in order to achieve 60 subjects who complete 
the treatment period based on the assumption of a 16% drop-out rate. 
The sample size assumptions will be reviewed in an interim analysis in 
a blinded manner when approximately 14 subjects complete the treatment 
period.
The study consists of the following periods: Screening, baseline/Day 1, 
treatment period, and end of study assessments (EOS) visit followed by 
an additional post-treatment safety follow up via phone call. The total duration 
for each subject in the study is up to approximately 19 weeks.
Study visits
The study employs the following visits:
Screening visit (Day -42 to Day -1):
Screening assessments can be performed over a 6-week period maximum (up 
to 42 days).
Informed consent must be obtained prior to implementing any study specific 
procedure. Inclusion and exclusion criteria will be checked to confirm patient's 
eligibility.
Sputum will be collected once within the screening window to confirm bacterial 
load with at least one strain of potentially pathogenic bacteria (refer to 
Section 5.1). The sputum microbiology results at screening will need to be 
available prior to randomization. Retesting is allowed once.
At screening, all subjects will be provided with an electronic diary (eDiary) and 
be trained on its use on how to record information about their rescue 
medication (salbutamol/albuterol), other concomitant medication use, how to 
complete questionnaires, how to record study medication intake (from Day 1 
onwards) as well as symptoms.
A HRCT assessment will be performed during screening period except at 
selected sites where HRCT is optional with Sponsor approval.
Baseline/Randomization Day 1:
Subjects who meet the eligibility criteria will be admitted to baseline/Day1 
safety and efficacy evaluations before randomization.
During baseline, sputum samples will be collected at the same time of the day 
(sputum collection procedure and timing will be detailed in the SOM and 
laboratory manual) for biomarker assessments (bacterial load and colonization 
as well as inflammatory markers). Subjects will be also asked to complete 
various scales and questionnaires (refer to Assessment Schedule type of 
questionnaires and time-points).


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There is no antibiotic intervention allowed between screening and baseline 
except for the use of macrolides for subjects who are on this medication before 
enrolment. In this case, macrolides are to be continued at the same dose and 
regimen during the study.
Once all baseline assessments have been completed and subjects are again 
confirmed as being eligible for the study, they can be randomized on the same 
day (baseline/randomization Day 1). In the case that sputum sample cannot 
be collected or other assessments can't be completed at baseline visit for 
various reasons, the site must not randomize the subject on the same day.
An unscheduled visit needs to be planned for sputum collection prior to 
randomization and treatment allocation. Once sputum is collected and other 
required assessments are completed, the subject can be randomized on 
the same day of the unscheduled visit.
Treatment Period (Day 1 to Day 84):
The treatment period will be 84 days (Day 1 to Day 84), with dosing occurring 
on Days 1 through 84, and will include a Day 1 Visit, a Day 14 visit (via 
telephone check), a Day 28 Visit, a Day 56 Visit, and a Day 84 Visit.
On Day 1, after completion of all pre-dose assessments (including 
the Concomitant medication therapy as per Table 6-2 and Table 6-6), eligible 
subjects will be randomized in a 1:1 ratio to receive QBW251 300 mg b.i.d. or 
matching placebo for 84 consecutive days.
At randomization, stratification will be done according to the status of 
macrolides use and geographic region (sites from China/sites outside China) 
in order to balance patient distribution in treatment and placebo group. The first 
study medication for this treatment period should be administered in the clinic 
in the morning of Day 1, following the pre-dose pharmacokinetic blood sample 
collection as indicated in the Assessment Schedule.
(NOTE: all PK sampling times are relative to the first dose of the treatment day).
During treatment period, subjects will return to the site for scheduled visits for 
biomarker blood/sputum sample collections, PK, safety and efficacy assessments 
including completion of the questionnaires. On visit days, subjects will take 
their morning dose in the clinic after completion of pre-dose assessments.
On scheduled sputum collection visits, sputum specimens are recommended 
to be collected in the morning at pre-dose time point and if possible before 
breakfast. In case subjects can’t produce enough sputum on the individual 
scheduled visits, they can come back to site up to 3 days after the scheduled 
visit to try to produce a sputum sample. If spontaneous sputum collection 
attempts are still not satisfactory, investigator may take decision to collect 
sputum sample after induction by the inhalation of saline.
At Day 14, site will call the subject to evaluate the compliance and to check 
patient well-being.
Pharmacokinetic blood sampling (pre-dose and 3 hr post dose) will be done at 
Day 1, Day 28, Day 56 and Day 84 visits. Additionally, although serial PK 
sampling is optional, efforts will be made to have a subset of approximately 
30-40 subjects undergo serial PK sampling at pre- and up to 8 hours post-dose 
on Day 1 and Day 28.


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ECGs pre- and post-dose at Tmax will be performed at visits on Day 1, Day 28, 
Day 56 and Day 84 (end of treatment). These assessments will 
be complemented by PK sampling (trough and Cmax) on the matching time-
points, at visits on Day 1, Day 28, Day 56 and Day 84.
The morning dose on Day 84 will be the final dose administration for 
this treatment period. End of treatment assessment, e.g., safety assessment, 
lung function assessments and PROs will be performed on Day 84.
If spontaneous sputum collection is not possible at Day 84, site needs to 
reschedule the visit within 3 days after Day 84 and subject has to continue to 
take study medication. Other assessments which have been completed on 
Day 84 do not need to be repeated.
A second HRCT will be performed at Day 84 after the morning dose of study 
medication at site. If the HRCT can't be performed at Day 84 for any reason, 
the assessment needs to be planned within approximately the 3 coming days 
and patient must continue to take study medication.
In case of symptom deterioration (via e-diary alert), subjects have to visit
their study center to determine whether exacerbation criteria have been met 
and an immediate antibiotic treatment may be necessary (e.g. CRP increase 
over normal laboratory level). In addition, other markers of inflammation such 
as fibrinogen in blood will be taken to gain more information on systemic 
inflammation and sputum sample collection in order to determine if there are 
changes in pathogen or bacterial load that may have resulted in 
the exacerbation. Subjects experiencing an exacerbation during the treatment 
period will continue with the study treatment along with the standard of care 
(SOC) therapy for an exacerbation (i.e. antibiotics).
End of Study (EoS) visit (Day 91):
Approximately one week upon completion of the treatment period, subjects will 
be invited to the center for study visit completion (EOS) assessments.
Safety follow-up call (Day 114)
A follow-up phone call for safety will occur 30 days after the last dose 
administration. The safety follow-up includes adverse events safety 
monitoring. For a complete list of assessments, refer to the Assessment 
Schedule in Table 8-1.
Population
The study population will consist of approximately 72 male and female 
patients with bronchiectasis
Key Inclusion 
criteria

Male or female patients aged ≥18 years at screening.

Proven diagnosis of bronchiectasis by chest CT at screening as 
determined by investigator

Evidence of sputum bacterial load of ≥106 CFU/mL with at least one 
potentially pathogenic microorganism (H. Influenzae, M catarrhalis, 
S aureus, S pneumoniae, Enterobacteriaceae, P aeruginosa, 
Stenotrophomonous maltophilia, or any potential pathogenic non-
fermenting Gram-negative bacteria measured by dilution/outgrowth).

Documented history of at least one bronchiectasis exacerbation between 
January 2019 and study screening.


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
Patients with bronchial hypersecretion, defined as productive cough that 
occurs on most days (defined as >50% days) for at least three 
consecutive months within 12 months prior to screening, as assessed by 
documentation of patient recollection (anamnesis) or documented in 
patients' record.

Patients are allowed to stay on fixed or free combinations of LABA/LAMA 
or LABA/ICS or LABA/LAMA/ICS as maintenance therapy if they are 
treated with them at a stable dose for the last 3 months prior to 
screening. Patients are also allowed to stay on macrolides as 
maintenance therapy if they are treated with them at a stable doses 
3 months before screening. Patients will be allowed to use mucolytics or 
hyperosmolar agents if they were treated with them before study start.

If prescribed, patients are included in the study with unchanged chest 
physiotherapy for at least 4 weeks prior to screening.

Clinically stable pulmonary status in the opinion of the investigator and 
unlikely to require any change in the standard regimen of care during 
the course of the study
Key Exclusion 
criteria

Patients with a history of long-QT syndrome or the QTcF interval at Screening 
and baseline is prolonged (QTcF >450 ms in males, >460 ms in females).

Patients with a history or current treatment for hepatic disease including 
but not limited to acute or chronic hepatitis, cirrhosis or hepatic failure. 
A history of resolved Hepatitis A is not exclusionary. Patients with 
a prothrombin time international normalized ratio (PT/INR) of more than 
1.5xULN at screening. Patients excluded for the PT/INR of more than 
1.5xULN can be re-screened when the values have returned to normal.

History of lung transplant or malignancy of any organ system (other than 
localized basal cell carcinoma of the skin), treated or untreated, within 
the past 5 years, regardless of whether there is evidence of local 
recurrence or metastases, with the exception of localized basal cell 
carcinoma of the skin. Patients with segmentectomy for other reasons 
than cancer are allowed to be included in the study. 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.

Patients requiring long-term oxygen therapy for chronic hypoxemia. 
This is typically patients requiring oxygen therapy >12 h per day delivered by 
home oxygen cylinder or concentrator. Note: Nocturnal oxygen therapy for 
transient oxygen desaturations during sleep is allowed.

Patients with bronchiectasis who have had a pulmonary exacerbation with 
a deterioration in three or more of the following key symptoms for at least 48 h:

cough;

sputum volume and/or consistency;

sputum purulence;

breathlessness and/or exercise tolerance;

fatigue and/or malaise;

haemoptysis
AND
A clinician determines that a change in bronchiectasis treatment is required 
(e.g. requiring systemic glucocorticosteroid treatment and/or systemic or 
inhaled antibiotics) within 4 weeks prior to screening.


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In the event of an exacerbation occurring 4 weeks before screening, or 
between the screening and baseline (please see definition above), the patient 
must NOT be enrolled. The patient may be rescreened once, 4 weeks after 
the resolution of exacerbation.

Patients with bronchiectasis requiring therapy that may interfere with 
the assessment of QBW251 efficiency or that are unlikely to respond to 
QBW251 as follows:

Patients with suspected active pulmonary tuberculosis or currently 
being treated for active pulmonary tuberculosis are not allowed. 
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 baseline visit suggesting low probability of 
recurrent active tuberculosis

Patients with active allergic bronchopulmonary aspergillosis and 
asthma as primary diagnosis.

Patients with cystic fibrosis

Current or ex-smokers with severe emphysema.

Patients with another concomitant pulmonary disease according to 
the definition of the International ERS/ATS guidelines, including but not 
limited to interstitial pulmonary fibrosis (IPF), sarcoidosis or other 
granulomatous or infectious process. Concomitant COPD and asthma 
with characteristics of airway hyperresponsiveness as well as COPD-
Asthma overlap syndrome are allowed as long as it is not the main, 
primary diagnosis in the opinion of the investigator. Primary ciliary 
dyskinesia (PCD) is allowed.

Patients currently receiving treatment for nontuberculous mycobacterial 
(NTM) pulmonary disease. If performed, patients with one or more 
positive cultures in the last 12 months for M. avium complex, 
M. abscessus complex, M. kansasii, M. malmoense, M. xenopi, 
M. simiae or M. chelonae, unless all subsequent NTM cultures (at least 
two) are negative and in the opinion of the investigator the patient does 
not meet ATS criteria for NTM-pulmonary disease.

Patients receiving any medication that may influence the response to 
treatment within 4 weeks prior to screening including systemic or inhaled 
steroids (ICS alone), or other systemic immunomodulators, recombinant 
human DNAse, any systemic or inhaled antibiotics.

Patients with a body mass index (BMI) of more than 40 kg/m2
Study treatment
investigational and control drugs

QBW251 dose of 300 mg

Matching placebo
Efficacy 
assessments

Microbiological assessment: Spontaneous sputum (if possible) will be 
collected for analysis of pathogenic bacterial colonization (CFU/mL) 
(e.g. H influenzae, M catarrhalis, S aureus, S pneumoniae, 
Enterobacteriaceae, P aeruginosa, Stenotrophomonous Maltophilia, or 
any potential pathogenic non-fermenting Gram negative bacteria). 
In addition, 16S rRNA PCR will be performed to measure the bacterial 
load.

Spirometry: FEV1, FVC

Plasma Fibrinogen


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
HRCT assessment on airway structure and function, mucus load

hsCRP
Pharmacokinetic
assessments

Cmax, Tmax, AUClast, AUC0-12h, T1/2, eff when feasible.
Key safety 
assessments

Physical examinations

Vital signs

ECG

Safety laboratory

Adverse events, serious adverse events
Other 
assessments

Bronchiectasis exacerbation

PROs: QOL-B, SGRQ, EQ-5D-3L, EXACT-PRO, eDiary

Sputum biomarkers: including but not limited to IL-6 and IL-8

If feasible, sputum bacterial profile measured by 16s rRNA gene 
sequencing

Serum protein levels measured by SomaScan 
Data Analysis
The primary endpoint will be analyzed using a Bayesian repeated measures 
model with change from baseline in CFU as response, adjusting for effect of 
treatment* visit interaction, status of macrolides use at screening as factor, and 
baseline CFU counts. In absence of informative data, non-informative priors 
for the model parameters will be used. The prior for placebo may be updated 
as a weakly informative prior and will be specified in the statistical analysis 
plan, should new relevant data become available before the database lock of 
this study.

A comparison of QBW251 vs. placebo at week 12 is of primary interest. 
Based on the fitted Bayesian model for repeated measures, the posterior 
probability of QBW251 effect over placebo for log10CFU will be 
calculated. Statistical evidence will be concluded if there is 90% 
probability that the true effect over placebo for log10CFU is >0.
Key words

Bronchiectasis, QBW251, colony forming units


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1
Introduction
1.1
Background
Bronchiectasis (BE) is defined as the irreversible dilatation of bronchi with destruction of elastic 
and muscular components of their walls. The gold standard method for diagnosis is via high 
resolution computerized tomography (HRCT) scan. Bronchiectasis is frequently idiopathic in 
origin, or may be a result of a number of post-infectious causes, congenital diseases 
(e.g., immunodeficiency, primary ciliary dyskinesia, cystic fibrosis), inflammatory diseases 
(e.g., rheumatoid arthritis, inflammatory bowel disease) or anatomic obstruction, all of which 
predispose to a cycle of chronic infection and inflammation, and airways damage. While 
the cause of bronchiectasis is highly diverse, impaired mucociliary clearance is a shared 
mechanism across all phenotypes of the disease.
Bronchiectasis is often associated with bacterial infections that may be linked to higher 
morbidity and mortality. Pseudomonas aeruginosa infection in particular is associated with 
a 3 folds increased risk of death and a higher risk of hospitalization and exacerbation in 
bronchiectasis. The pathogens most frequently associated with bronchiectasis in addition to 
P. aeruginosa
which accounts for 12-31% are: Haemophilus influenzae (30-47%), 
Streptococcus pneumoniae (7-11%), Staphylococcus aureus (4-7%), and Moraxella catarrhalis 
(2-20%) (O’Donnell 2008). Chronic infection with pathogenic microorganisms is associated 
with 
worse 
clinical 
outcomes 
including 
increased 
frequency 
of 
exacerbations 
(Chalmers et al 2014).
A high morbidity due to frequent exacerbations impair quality of life, facilitate resistance to 
antibiotics, and lead to reduced lung function in BE patients. Most frequent symptoms include 
cough, coughing up large amounts of thick mucus every day, hemoptysis, dyspnea, chest pain, 
fatigue, weight loss, frequent respiratory infections and exacerbations (~1.3 to 3 per patient per 
year). There is also a high socioeconomic impact through frequent use of primary and secondary 
healthcare with an economic burden estimated to be similar to COPD (Polverino et al 2017). 
It is estimated that there is an approximately 2-fold higher age-adjusted mortality compared to 
the general population (Quint et al 2016).
There is an increasing awareness of bronchiectasis and its impact on morbidity, mortality and 
health care costs. Bronchiectasis is likely underdiagnosed or misdiagnosed, the first 
international treatment guidelines were published in September 2017.
As Bronchiectasis is a progressive respiratory debilitating disease that evokes significant 
symptoms and poor quality of life for patients, there is a high unmet need for new therapeutic 
options beyond antibiotics and off-label use of bronchodilators.
The ERS 2017 guidelines for the management of adult bronchiectasis highlighted the lack of 
evidence for many treatments for bronchiectasis (Polverino et al 2017). Treatments to prevent 
exacerbations are also limited to antibiotics (inhaled or macrolides), airway clearance 
techniques and some mucoactive drugs such as isotonic or hypertonic saline for which there is 
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Chronic bronchitis, asthma and non-CF bronchiectasis (NCFBE) share many clinical and 
pathologic features with cystic fibrosis (CF), a lung disease potentially caused by gene 
mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR, a cAMP 
regulated chloride channel is resident on the surface of epithelial cells in several body organs 
such as the airways, intestine, pancreas, bile ducts and kidney (Boucher 2007; 
O’Sullivan, Freedman 2009). Loss of CFTR function in the lung is associated with reduced 
mucociliary clearance (MCC), chronic bacterial infection and increased inflammation 
(Amaral, Kunzelmann 2007).
There is evidence that bronchiectasis may represent a spectrum of CFTR-related disorders as 
there are increased frequencies of CFTR mutations in patients in various studies 
(Bergougnoux et al 2015). In addition to the associations of CFTR mutant alleles in 
bronchiectasis, CFTR functional defects have been discovered in patients harboring no-CFTR 
mutant alleles using sweat chloride and nasal potential difference measurements 
(Bienvenu et al 2010). Thus, while the mechanisms of CFTR dysfunction in bronchiectasis and 
asthma are not well understood, there is evidence that certain subsets of patients demonstrate 
CFTR dysfunction. The association of CFTR dysfunction with complications of these diseases, 
however, is unknown (Solomon et al 2017).
The resulting mucus stasis is associated with excess mortality and a more rapid decline in 
pulmonary function (Hogg et al 2004; Fahy, Dickey 2010). While cystic fibrosis is caused by 
genetic dysfunction of CFTR, there is evidence that in bronchiectasis, COPD and other airways 
diseases, both genetic and acquired CFTR dysfunction in the airways are through mechanisms 
including chronic inflammation and cigarette smoking.
CFTR dysfunction may be a central disease mechanism and provides a potential joint 
therapeutic target. The discovery of CFTR potentiators, that can also potentiate even wild type 
of forms of CFTR, may therefore represent a new therapeutic strategy (Solomon et al 2017). 
The CFTR potentiator QBW251 represents a novel mechanism-of-action. QBW251 is a low 
molecular weight CFTR potentiator of both wild-type and mutated CFTR protein. 
The modulation of CFTR function may improve airway hydration, decrease mucus viscosity 
and thus enhance mucociliary clearance. CFTR also regulates airway surface liquid pH by 
bicarbonate secretion that is important in the fight against pathogens (Pezzulo et al 2012). 
Hence, CFTR potentiation may be effective in patients with bronchiectasis in reducing airway 
inflammation/infection and obstruction.
QBW251 is safe and well tolerated in healthy volunteers at doses up to 750 mg bid and in 
patients with CF at the 150 mg bid and 450 mg bid doses over 14 days. QBW251 demonstrated 
efficacy by promoting significant pharmacodynamic activity (decrease in sweat chloride and/or 
improvement in lung function) in heterozygous CF patients with a gating or residual function. 
Clinical data from patients homozygous for F508del mutation did not demonstrate clinical 
evidence of pharmacodynamic effect after treatment with QBW251.
In a 28-day randomized, placebo-controlled PoC study, QBW251 demonstrated in GOLD 2-3 
COPD patients with chronic bronchitis and with various background inhaled therapies an 
improvement 
in 
lung 
function 
(FEV1) 
and 
sweat 
chloride 
over 
placebo. 
Furthermore, exploratory sputum analyses have suggested a trend for decreased bacterial 
colonization with QBW251. In addition, there was a significant reduction of fibrinogen, 


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a systemic inflammation marker, which is considered to be a prognostic biomarker for patients 
at increased risk for all-cause mortality or COPD exacerbation and approved as such by FDA 
(Mannino et al 2015).
This PoC in BE is proposed given similar pathophysiology to CF and COPD based on 
dysfunctional mucociliary clearance. CFTR potentiation may improve airway hydration, 
enhance mucociliary clearance, and reduce airway bacterial colonization in patients with BE; 
additionally, it may improve lung function in those patients with an obstructive ventilation 
defect. These benefits are thought to translate into a reduction of exacerbations and 
improvement of symptoms in BE patients with persistent mucus-related symptoms.
The study has been developed and will be executed as part of the iABC (inhaled Antibiotics in 
Bronchiectasis and Cystic Fibrosis) project. iABC, as an IMI (Innovative Medicines Initiative) 
project, is a collaboration between EFPIA partners (including Novartis) and academic partners, 
with the managing entity being Queen’s University Belfast. Novartis retains the role of 
the sponsor and as such is responsible for the regulatory and pharmacovigilance activities, and 
the conduct of this clinical trial.
1.2
Purpose
The purpose of this study is to determine whether potentiating the cystic fibrosis transmembrane 
conductance regulator (CFTR) with QBW251 in subjects with bronchiectasis will demonstrate 
clinical safety and efficacy related to improved mucociliary clearance with reduced bacterial 
colonization as potential drivers of airway obstruction, reduced airway inflammation, 
exacerbations and mucus load, improved lung function, clinical symptoms and quality of life to 
support further development in bronchiectasis.
2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

To assess the change on sputum bacterial 
colonization

Change from baseline in bacterial load of 
colony forming units (CFU/mL, 
1 CFU/mL = 1 CFU/g) of potentially 
pathogenic microorganisms in 
spontaneous sputum with QBW251 
compared to placebo at week 12
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To assess the change of QBW251 
compared to placebo on sputum bacterial 
clearance

Proportion of subjects with absence of 
any CFU of potentially pathogenic 
bacteria in sputum culture after 12 weeks 
of treatment


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Objective(s)
Endpoint(s)

To assess the change on patient reported 
outcomes on bronchiectasis symptom 
assessment

Changes from baseline in
Quality of Life Questionnaire for 
Bronchiectasis (QOL-B) (Respiratory 
symptoms domain) after 12 weeks of 
treatment.

To assess the change of fibrinogen 
plasma concentration

Change from baseline in fibrinogen 
plasma concentration after 12 weeks of 
treatment

To assess the change in rescue 
medication use

Change from baseline in rescue 
medication use (salbutamol/albuterol) 
after 12 weeks of treatment.

To assess the change on lung function.

Changes from baseline in pre-
bronchodilator FEV1, FVC after 
12 weeks treatment, measured by 
spirometry

To assess the change in airway structure 
and function

Change from baseline in airway wall and 
lumen parameters along with extent of 
global and regional air trapping after 
12 weeks of treatment, as measured by 
HRCT.

To assess the pharmacokinetics of 
QBW251 in patients with bronchiectasis

Assessment of drug exposure (Cmax, 
AUC) and other PK parameters when 
feasible on Days 1 and 28 (for a subset 
of patients at selected sites).
Pre- and post- dose concentration 
(Ctrough and around Cmax) on Days 1, 
28, 56 and 84 (for all patients).

To assess the safety and tolerability of 
QBW251 in patients with bronchiectasis

All safety endpoints (including adverse 
events, vital signs, ECG, and safety 
laboratory changes) during the study
Exploratory objective(s)
Endpoint(s) for exploratory objective(s)

To examine the change from baseline on 
sputum bacterial colonization after 12 
weeks of treatment with QBW251 
compared to placebo and at times of 
potential exacerbation for assessments of 
pathogens and bacterial load.

Change from baseline in sputum 
bacterial colonization after 12 weeks of 
treatment measured by 16S rRNA PCR


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Objective(s)
Endpoint(s)

To assess the change on patient reported 
outcome

Changes from baseline in the following 
PRO after 12 weeks of treatment

St. George's Respiratory 
Questionnaire (SGRQ)

Euro Quality of Life-5 Dimensions-
3 level (EQ-5D-3L)

To explore the effect of QBW251 on 
additional HRCT outcome measures

Change from baseline in 
HRCT endpoints for distribution of 
mucus (whole lung and regional) after 
12 weeks of treatment

IMI collaboration: HRCT scores and 
change from baseline in airway-artery 
ratios

To assess the effect of QBW251 on 
bronchiectasis exacerbation

Time to first event,

Annualized rate of exacerbations as 
defined by EXACT-PRO 
questionnaire

To assess the change on biomarkers of 
inflammation

Changes from baseline in blood and 
sputum after 12 weeks of treatment in 
markers that may include, but are not 
limited to:

Serum hsCRP

Blood inflammatory cells 
e.g. neutrophils, eosinophils

Sputum inflammatory proteins 
e.g. IL-6, IL-8

Serum protein levels  measured by 
SomaScan

To perform assessment of bacterial 
species profile in sputum

Sputum samples will be biobanked for
potential exploration of  sputum bacterial 
profile measured by 16s rRNA gene 
sequencing

To perform DNA assessments to 
examine whether individual genetic 
variation in genes relating to drug 
metabolism and transportation or 
individual genetic variations in CFTR 
genes or other disease-relevant genetic 
pathways confer differential response to 
QBW251 treatment or correlate with 
disease severity

Genomic analysis in correlation with 
exposure to QBW251 or response to 
QBW251 or disease severity.
DNA will be biobanked for potential 
future analysis of CFTR mutations and 
for genomic analysis


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3
Study design
This is a randomized, subject- and investigator-blinded, placebo-controlled, parallel-group 
study investigating the preliminary efficacy and safety of QBW251 administered orally for 
12 weeks in subjects with bronchiectasis. Approximately 72 subjects will be randomized in 
a 1:1 ratio to receive either QBW251 or placebo in order to achieve 60 subjects who complete 
the treatment period based on the assumption of a 16% drop-out rate. The sample size 
assumptions will be reviewed in an interim analysis in a blinded manner when approximately 
14 subjects complete the treatment period.
The study consists of the following periods: Screening, baseline/Day 1, treatment period, and 
end of study assessments (EOS) visit followed by an additional post-treatment safety follow up 
via phone call. The total duration for each patient in the study is up to approximately 19 weeks.
The study design is described in Figure 3-1 below.
Figure 3-1
Study Flowchart
3.1
Study visits
The study employs the following visits:
Screening visit (Day -42 to Day -1):
Screening assessments can be performed over a 6-week period maximum (up to 42 days).
Informed consent must be obtained prior to implementing any study specific procedure.
Inclusion and exclusion criteria will be checked to confirm patient's eligibility.
This check includes medical history, maintenance therapy of LABA/ICS or LABA/LAMA or 
LABA/LAMA/ICS and/ or macrolides, physical examination, ECG, vital signs, oxygen 
saturation, and clinical laboratory evaluations (hematology, blood chemistry, coagulation,
urinalysis). Sputum will be collected once within the screening window to confirm bacterial 


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load with at least one strain of potentially pathogenic bacteria (refer to Section 5.1). The sputum 
microbiology results at screening will need to be available prior to randomization. Retesting is
allowed once.
At screening, all subjects will be provided with an electronic diary (eDiary) and be trained on 
its use on how to record information about their rescue medication (salbutamol/albuterol), 
other concomitant medication use, how to complete questionnaires, how to record 
study medication intake (from Day 1 onwards) as well as symptoms.
A HRCT assessment will be performed during screening period except at selected sites where 
HRCT is optional with Sponsor approval. The screening HRCT can also be used to confirm 
the diagnosis of BE if no historical HRCT is available. At selected sites, where HRCT is 
optional, diagnosis of BE must be available from a historical scan.
Baseline/Randomization Day 1:
Subjects who meet the eligibility criteria will be admitted to baseline/Day1 safety and efficacy 
evaluations before randomization.
During baseline, sputum samples will be collected at the same time of the day 
(sputum collection procedure and timing will be detailed in the SOM and laboratory manual) 
for biomarker assessments (bacterial load and colonization as well as inflammatory markers). 
Subjects will be also asked to complete various scales and questionnaires (refer to
the Assessment Schedule for the type of questionnaires and time points).
There is no antibiotic intervention or change of mucous clearance regimen allowed for 
pulmonary exacerbation between screening and baseline except for the use of macrolides for 
subjects who are on this medication before enrolment. In this case, macrolides are to be 
continued at the same dose and regimen during the study. Baseline mucous regimen should 
remain unchanged between screening and baseline.
Once all baseline assessments have been completed and subjects are again confirmed as being 
eligible for the study, they can be randomized on the same day (baseline/randomization Day 1). 
In the case that sputum sample cannot be collected or other assessments can't be completed at 
baseline visit for various reasons, the site must not randomize the subject on the same day. 
An unscheduled visit needs to be planned for sputum collection prior to randomization and 
treatment allocation. Once sputum is collected and required assessments are completed, 
the subject can be randomized on the same day of the unscheduled visit.
Treatment Period (Day 1 to Day 84):
The treatment period will be 84 days (Day 1 to Day 84), with dosing occurring on Days 1 
through 84, and will include a Day 1 Visit, a Day 14 visit (via telephone check), a Day 28 Visit, 
a Day 56 Visit, and a Day 84 Visit.
On Day 1, after completion of all pre-dose assessments (including the Concomitant medication 
therapy as per Table 6-2 and Table 6-6) , eligible subjects will be randomized in a 1:1 ratio to 
receive QBW251 300 mg b.i.d. or matching placebo for 84 consecutive days.
At randomization, stratification will be done according to the status of macrolides use and 
geographic region (sites from China/sites outside China) in order to balance patient distribution 


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in treatment and placebo group. The first study medication for this treatment period should be 
administered in the clinic in the morning of Day 1, following the pre-dose pharmacokinetic 
blood sample collection as indicated in the Assessment Schedule (NOTE: all PK sampling times 
are relative to the first dose of the treatment day).
During treatment period, subjects will return to the site for scheduled visits for biomarker 
blood/sputum sample collections, PK, safety and efficacy assessments including completion of 
the questionnaires. On visit days, subjects will take their morning dose in the clinic after 
completion of pre-dose assessments.
On scheduled sputum collection visits, sputum specimens are recommended to be collected in 
the morning at pre-dose time point and if possible before breakfast. In case subjects can’t 
produce enough sputum on the individual scheduled visits, they can come back to site up to 
3 days after the scheduled visit to try to produce a sputum sample. If spontaneous sputum 
collection attempts are still not satisfactory, investigator may take decision to collect sputum 
sample after induction by the inhalation of saline.
At Day 14, site will call the subject to evaluate the compliance and to check patient well-being.
Pharmacokinetic blood sampling (pre-dose and 3hr post dose) will be done at Day 1, Day 28, 
Day 56 and Day 84 visits. Additionally, although serial PK sampling is optional, efforts will be 
made to have a subset of approximately 30-40 subjects undergo serial PK sampling at pre- and 
up to 8 hours post-dose on Day 1 and Day 28.
As the completed thorough QT study (CQBW251A2105) indicated that QBW251 at 300 mg 
b.i.d. did not have clinically relevant effects on studied ECG parameters, single ECGs 
pre- and post-dose at Tmax will be performed at visits on Day 1, Day 28, Day 56 and Day 84 
(end of treatment). These assessments will be complemented by PK sampling (trough and 
Cmax) on the matching timepoints, at visits on Day 1, Day 28, Day 56 and Day 84.
The morning dose on Day 84 will be the final dose administration for this treatment period. End 
of treatment assessment, e.g. safety assessment, lung function assessments and PROs will be 
performed on Day 84.
If spontaneous sputum collection is not possible at Day 84, site needs to reschedule the visit 
within 3 days after Day 84 and subject must continue to take study medication. If spontaneous 
sputum collection attempts are still not satisfactory, investigator may take decision to collect 
sputum sample after induction by the inhalation of saline. Other assessments that have been 
completed on Day 84 do not need to be repeated.
A second HRCT will be performed at Day 84 after the morning dose of study medication at site. 
If the HRCT can't be performed at Day 84 for any reason, the assessment needs to be planned 
within approximately the 3 coming days and patient must continue to take study medication.
In case of symptom deterioration (via e-diary alert), subjects must visit their study center to 
determine whether exacerbation criteria have been met and an immediate antibiotic treatment 
may be necessary. In addition, other markers of inflammation such as fibrinogen in blood will 
be taken to gain more information on systemic inflammation and sputum sample collection to 
determine 
if 
there 
are 
changes 
in 
pathogen 
or 
bacterial 
load 
that may 
have resulted in the exacerbation. Subjects experiencing an exacerbation during the treatment 


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period will continue with the study treatment along with the standard of care (SOC) therapy for 
an exacerbation (i.e. antibiotics).
End of Study (EoS) visit (Day 91):
Approximately one week upon completion of the treatment period, subjects will be invited to 
the center for study visit completion (EOS) assessments.
Safety follow-up call (Day 114)
A follow-up phone call for safety will occur 30 days after the last dose administration. 
The safety follow-up includes adverse events safety monitoring.
For a complete list of assessments, refer to the Assessment Schedule in Table 8-1.
4
Rationale
4.1
Rationale for study design
This is a non-confirmatory, multi-center, randomized, placebo-controlled, subject- and 
investigator-blinded, parallel-group trial with a 12-week treatment period. Key efficacy 
endpoints will be evaluated over the time during the study period.
The design of this study addresses the primary objective to assess the effect of QBW251 
compared to placebo administered for 84 days on sputum bacterial colonization. A reduction 
from baseline in colony forming units of potentially pathogenic microorganisms in spontaneous 
sputum by one log unit was associated with a significant reduction in risk of exacerbation by 
approximately 20% in patients with bronchiectasis, which is considered to be clinically relevant 
(Chalmers et al 2012).
In order to optimize the rigor and integrity of the study and minimize bias, a randomized, 
subject- and investigator-blinded parallel group is used. The design is well-established in 
respiratory clinical trials and enables the study treatment to be given for an appropriate and 
practical length of time to assess the efficacy and safety of the treatment. A parallel study design 
was chosen because a crossover design assumes patients will return to their own baseline levels 
of CFU in each period and this may not be the case in the study. It is more versatile in that 
a stable disease state is not a pre-requisite which is beneficial as also newly diagnosed patients 
with bronchiectasis may be included.
QBW251, an effective Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) 
potentiator, is hypothesized to be efficacious in patients with bronchiectasis based on improved 
mucociliary clearance (MCC), resulting in decreased bacterial colonization, decreased small 
airway inflammation, improved FEV1 and ultimately fewer exacerbations. Recent evidence 
suggests the molecular mechanism for reduced mucociliary clearance in bronchiectasis may 
relate to dysfunction of wild-type and mutated CFTR. Bronchiectasis patients may also have 
a component of ion channel dysfunction, including CFTR. COPD data suggests that QBW251 
may decrease bacterial colonization and small airway inflammation (reduced fibrinogen). 
In addition, QBW251 demonstrated statistically important improvement in lung function 


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(FEV1) in cystic fibrosis (CF) following 2 weeks of treatment and in COPD following 4 weeks 
of treatment.
Therefore, in addition to the primary endpoint, several complementary endpoints will be used 
in this study to assess efficacy, including spirometry and patient reported outcomes (PROs) as 
well as pharmacokinetic parameters. These evaluations provide a comprehensive view of 
airway structure and function as well as an assessment of patients' well-being in addition to 
the safety and tolerability evaluation.
The study will also include the measurement of soluble biomarkers to provide additional 
information relevant to the endpoints.
4.1.1
Rationale for choice of background therapy
Not Applicable
4.2
Rationale for dose/regimen and duration of treatment
The selection of QBW251 300 mg b.i.d. oral dose as the relevant clinical dose in this study is 
based on the data previously collected in the QBW251 program.
Clinical activity was observed in CF and COPD patients in studies CQBW251X2101 (150 and 
450 mg b.i.d.) and CQBW251X2201 (300 mg b.i.d. for 4 weeks), respectively. The COPD PoC 
study (CQBW251X2201) provided evidence of efficacy (FEV1 improvement) with a 300 mg 
b.i.d. regimen. Safety results from the COPD PoC study also demonstrated that 300 mg b.i.d. 
of QBW251 over 4 weeks was safe and well tolerated in COPD patients.
At completion of the dose range finding (DRF) study in COPD (CQBW251B2201) 300 mg 
b.i.d. was the highest dose administered to patients. Initially, five dose levels (25, 75, 150, 300, 
and 450 mg b.i.d.) were being tested in the DRF study. Following the DMC meeting in 
April 2020, the 450 mg b.i.d. dose was discontinued based on the statistical stopping rule pre-
specified in the protocols. There were no safety findings in any of the treatment arms that 
contributed to this decision. Accordingly, Novartis has made the decision to use the 300 mg 
b.i.d. dose as the highest dose in the QBW251 program.
An independent DMC was established with the primary goal of performing periodic reviews of 
the accumulating PK and safety data from the DRF study in COPD (CQBW251B2201), Mode 
of Action study in COPD (CQBW251B2202) and bronchiectasis study (QBW251C12201) at 
pre-specified time intervals. Study data coming from these three studies was submitted to 
the DMC for consideration as to whether a proportion of patients have exceeded the NOAEL 
threshold (AUC0-24h=91,700 ng*h/ml) or more than one patient has exhibited a projected 
AUC0-24h above the upper range of the individual monkey exposures (AUC0-24h=159,000 
ng×h/mL).
In May 2022, the DMC reviewed the data available from all clinical studies of QBW251 and 
concluded the following:
1. There were no substantial differences in the adverse event profiles of patients with 
exposure exceeding the previously specified NOAEL threshold values and those who did 
not. However, the comparison groups were of very different size and mean exposure data 


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for the 300 mg and 450 mg b.i.d. doses were not available. No AEs or SAEs occurred in 
the patients who exceeded the pre-specified threshold values.
2. There was a trend for elevations of the gamma glutamyl transpeptidase to occur more 
often in patients with higher plasma levels of QBW251 but the interpretation of these 
findings was limited by the small numbers of patients in each subgroup.
3. It was reasonable to dispense with PK monitoring in the ongoing studies and future phase 
3 trials of the 300 mg b.i.d. dose as this would not provide more insight into 
the acceptability of treatment.
Accordingly, Novartis decided to stop further PK threshold monitoring in the present study, 
though planned PK measurements will continue. The selection of 300 mg b.i.d. as the maximum 
clinical dose is supported by both the animal chronic toxicology and the clinical study data 
currently available. The NOAEL dose in the 26-week rat and 39-week monkey chronic 
toxicology studies was 30 mg/kg/day and 150 mg/kg/day, respectively. Mean systemic 
exposure (AUC0-24h) at the NOAEL dose was 163,500 ng*h/mL for the rat at Week 26. For 
the monkey, the mean exposure (AUC0-24h) at the NOAEL dose (150 mg/kg/day) at Week 39 
was 91,700 (range from 52,000 to 159,000) ng*h/mL. Based on the population PK modeling 
from COPD DRF study (CQBW251B2201), the mean steady-state daily exposure (AUC0-24h) 
of QBW251 following 300 mg b.i.d. dose in the COPD patients was 16,460 ng*h/mL, 
approximately 5-fold lower than the mean preclinical exposure threshold of 91,700 ng*h/mL.
The twice-daily dosing regimen was chosen based on the half-life of QBW251 (10-16 hours) 
and the intent to have a sustained effect on the ion channel. Additionally, a twice daily regimen 
is expected to provide a reduced Cmax/Ctrough fluctuation compared to once daily dosing. 
In comparison with a single dosing regimen designed to achieve the same trough concentrations, 
the proposed twice daily regimen is expected to yield higher average concentrations during 
the dosing interval. A twice daily regimen was therefore selected to maximize the opportunity 
of observing efficacy of QBW251 in bronchiectasis patients.
A study duration of 12 weeks is expected to provide clinically significant changes in 
mucociliary clearance allowing the assessment of safety and tolerability. Moreover, an adequate 
study duration of at least 3 months is especially important for patient reported outcomes such 
as quality of life to obtain significant treatment effects.
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
There is currently no approved CTFR potentiator for treatment of bronchiectasis that could 
serve as a comparator. Therefore, QBW251 is tested against placebo, 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.


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4.4
Purpose and timing of interim analyses/design adaptations
A blinded interim analysis is planned for this study when approximately 14 patients have 
completed Day 84 post treatment assessment. The purpose of this IA is to confirm sample size 
assumptions while assessing the variability in bacterial colonization of PPMs in this population.
One or more interim analyses for efficacy and safety may be conducted to support decision 
making in relation to the current clinical study, or the future of the sponsor’s clinical 
development plan or in case of any exposure threshold criteria exceeded or safety concerns from 
this study or ongoing clinical studies.
4.5
Risks and benefits
Risks
The risk to subjects in this trial will be minimized by compliance with the eligibility criteria 
and study procedures, safety evaluations, PK data as well as close clinical monitoring.
Potential risks of QBW251
Potential risks of QBW251 are the adverse events observed with increased exposure of 
QBW251 as noted in previous studies, comprising of (refer to Investigator Brochure):

Gastrointestinal events (nausea, diarrhea, vomiting)

Nervous system disorders (headache, fatigue and dizziness)

Hypersensitivity reactions to QBW251 cannot be excluded, however have not been 
observed in the previous studies with QBW251.
Risks associated with maintenance treatment (double or triple inhaled therapy) or 
macrolides
Adverse events associated with maintenance inhaled therapy include:

Nasopharyngitis, hypertension, back pain and oropharyngeal pain, dyspepsia, 
gastroenteritis, chest pain, fatigue, peripheral edema, rash/pruritus, insomnia, dizziness, 
bladder obstruction/urinary retention, atrial fibrillation, palpitations, tachycardia, upper 
and lower respiratory tract infection, pneumonia, diarrhea, headache, gastroesophageal 
reflux disease, hyperglycemia, rhinitis, dysgeusia, cough, arthralgia, oral 
candidiasis (approved labels for Trelegy Ellipta, Breo Ellipta (EU name Relvar Ellipta), 
Incruse Ellipta and Utibron Neohaler US label)

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).

The following additional adverse reaction of angioedema has been identified during 
worldwide post-approval use of indacaterol/glycopyrrolate at higher than the 
recommended dose (Utibron Neohaler US label)


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Adverse events associated with macrolides include:

The most common adverse effects associated with macrolide antibiotics (e.g. 
erythromycin products) are gastrointestinal. They include nausea, vomiting, abdominal 
pain, diarrhea and anorexia.

Reversible hearing loss associated with doses of erythromycin usually greater than 4g per 
day has been reported.

Treatment with macrolides may also result in cardiac arrhythmias such as QT 
prolongation
Other risks related to study procedures:
Procedural risks may include:

Local reactions to venipuncture, including pain, hematomas, fainting, swelling, infections, 
and erythema due to blood sample collection from patients.

Spirometry may be associated with cough, shortness of breath and headache.

HRCT involves exposure to radiation. The total amount of radiation for acquisition at 
baseline and Week 12 of HRCT scans will be optimized to be within the annual limits of 
exposure defined in both EU and China guidelines.

Hypertonic saline solution might cause bronchospasm.
Risk mitigations:
Based on the above risk considerations, clinical monitoring will include the use of an electronic 
diary with the EXACT-PRO questionnaire to enable daily symptoms assessment, as well as 
safety assessments during visit days at the investigational site. These safety assessments include 
a careful assessment of adverse events, ECGs, hematologic and blood biochemistry laboratory 
assessments, urinalysis and vital signs measurements.
As the completed thorough QT study (CQBW251A2105) indicated that QBW251 at 300 mg 
b.i.d. did not have clinically relevant effects on studied ECG parameters, ECGs pre- and post-
dose (at Tmax) will be performed at Day 1 and Day 28 (when steady state exposure is achieved), 
and at Day 56 and Day 84 (end of treatment). These assessments will be complemented by 
the corresponding PK sampling (Ctrough and Cmax).
In addition to the sampling described above, additional PK samples are requested to be taken 
in case of treatment-emergent serious adverse events.
Finally, although serial PK sampling is optional, efforts will be made to have a sub-group of 
approximately 30 - 40 patients undergo serial PK assessments to further characterize the PK 
profile of QBW251 in BE patients, which will provide important understanding of the 300 mg 
b.i.d. dose in BE patients. Women of childbearing potential and sexually active males must be 
informed that taking the study treatment may involve unknown risks to the fetus if pregnancy 
were to occur during the study. In order to participate in the study, participants must agree to 
adhere to the contraception requirements outlined in the exclusion criteria throughout the study 
and for at least one week following the last administration of investigational medicinal product. 
If there is any question that the subject will not reliably comply, they should not be entered or 
continue in the study. Based on the reproductive toxicity studies results, women of childbearing 


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potential are allowed to enter the study as long as they are using the effective method of 
contraception (see specific guidance in Section 5.2 Exclusion Criteria). This group of patients 
is relevant for the targeted disease and their inclusion is aligned with the ICHM3 (R2) guidance. 
In a hormonal contraception study (CQBW251X2102), it was demonstrated that QBW251 may 
enhance cytochrome P450 mediated degradation of contraceptive hormones; thus, hormonal 
contraception methods are not acceptable methods of contraception in the study. Based on 
clinical DDI study CQBW251A2107, at maximal QBW251 plasma concentrations achieved 
following oral administration of doses ≤ 300 mg b.i.d., QBW251 moderately inhibits 
the metabolic clearance of co-medications metabolized by CYP1A2 and CYP2C19. In addition,
QBW251 was also found to weakly induce both CYP3A4 and CYP2C8. Based on in vitro data, 
QBW251 and its metabolites may also increase the exposure of drugs which are substrates for 
CYP2B6, BCRP, OCT1, OAT3 and MRP2.
Reflecting the current characterization of QBW251 potential for clinical drug-drug interactions, 
the protocol uses cautionary language for drugs that may potentially interact with QBW251, 
such drugs are sensitive substrates of CYP1A2, CYP2B6, CYP2C19, CYP3A4, CYP2C8, 
OAT3, BCRP, OCT1 and MRP2. These drugs are not prohibited but their substitution with 
alternative agents is advised; when not possible, closer monitoring is recommended.
Additionally, use of co-medication which are sensitive substrates of CYP1A2 or CYP2C19 and 
have narrow therapeutic range are 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. As UGT mediated 
glucuronidation is likely a significant elimination pathway, use of certain UGT inhibitors and 
potential inducers is prohibited (see Table 6-5).
QBW251 may also impact the systemic exposure of the individual components of maintenance 
therapy.
However, efficacy of the inhaled
therapies (such as LABA/LAMA, LABA/ICS, 
LABA/LAMA/ICS) is not expected to be impacted due to the delivery directly to the lungs. 
In addition to the inhaled therapies, as a perpetrator, QBW251 is not expected to have 
significant impact on the PK exposure of the macrolides (such as erythromycin and 
clarithromycin) as they are not sensitive substrates of metabolite enzymes of CYP1A2, 3A4, 
2B6, 2C8, 2C19 or UGTs.
Please refer to the respective labels of the maintenance therapy for additional information on 
drug interactions. Any concomitant medications should be noted in the CRF. When additional 
clinical drug interaction information becomes available during the QBW251 development, 
this information will be further updated and reflected in the QBW251 Investigator Brochure.
No SARs are considered expected by the sponsor for the purpose of expedited reporting of 
suspected unexpected serious adverse reactions (SUSARs). Refer to the Investigator's Brochure 
for further details.
Benefits
A transient benefit may be observed if QBW251 provides efficacy. A positive outcome from 
this study may lead to further development of QBW251 for eligible patients with bronchiectasis.


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4.5.1
Blood sample volume
A volume smaller than a typical blood donation is planned to be collected from each subject 
during Screening, Baseline, during the 12 weeks of the treatment period and at the end of 
the study.
For the subset of patients who will undergo serial PK sampling at pre- and up to 8 hours post-
dose on Day 1 and Day 28, the additional blood samples will be collected.
Additional samples may be required for safety monitoring.
Timings of blood sample collection are outlined in the Assessment schedule (Table 8-1).
A summary blood log is provided in the SOM. Instructions for all sample collection, processing, 
storage and shipment information is also available in the SOM and central laboratory manual.
See the Section 8.5.3.3 on the potential use of residual samples.
5
Population
The study population will consist of approximately 72 male and female patients with 
bronchiectasis.
5.1
Inclusion criteria
Subjects eligible for inclusion in this study must meet all the following criteria:
1. Written informed consent must be obtained before any assessment is performed.
2. Male or female patients aged ≥18 years at screening.
3. Proven diagnosis of bronchiectasis by chest CT at screening as determined by 
the investigator. The screening HRCT can be used to confirm the diagnosis if no historical 
chest CT is available.
4. Evidence of sputum bacterial load of ≥106 CFU/mL with at least one potentially 
pathogenic microorganism at screening (H. Influenzae, M catarrhalis, S aureus, 
S pneumoniae, Enterobacteriaceae, P aeruginosa, Stenotrophomonous maltophilia, or any 
potential pathogenic non-fermenting Gram-negative bacteria measured by 
dilution/outgrowth.) NOTE: H. parainfluenzae is not considered pathogenic in this study 
and therefore growth of this organism alone does not satisfy this criterion.
5. Documented history of at least one bronchiectasis exacerbation between January 2019 to 
study screening.
6. Patients with bronchial hypersecretion, defined as productive cough that occurs on most 
days (defined as >50% days) for at least three consecutive months within 12 months prior 
to screening, as assessed by documentation of patient recollection (anamnesis) or 
documented in patients' record.
7. Patients are allowed to stay on fixed or free combinations of LABA/LAMA or LABA/ICS 
or LABA/LAMA/ICS as maintenance therapy if they are treated with them at a stable 
dose for the last 3 months prior to screening. Patients are also allowed to stay on 
macrolides as maintenance therapy if they are treated with them at a stable dose 3 months 
before screening. Patients will be allowed to use mucolytics or hyperosmolar agents if 
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If prescribed, patients are included in the study with unchanged chest physiotherapy for at 
least 4 weeks prior to screening.
8. Clinically stable pulmonary status in the opinion of the investigator and unlikely to require 
any change in the standard regimen of care during the course of the study.
9. Able to perform reliable, reproducible pulmonary function test maneuvers per American 
Thoracic Society/European Respiratory Society (ATS/ERS) guidelines at screening. 
At screening, patients who have failed to meet ATS/ERS requirements for acceptability 
and reproducibility for spirometry will be allowed one additional repeat testing session 
during the screening period.
10. Able to communicate well with the investigator, to understand and comply with 
the requirements of the study. Patients should be able to understand and sign the written 
informed consent.
5.2
Exclusion criteria
Subjects meeting any of the following criteria are not eligible for inclusion in this study.
1. Use of other investigational drugs at the time of enrollment, or within 5 half-lives of 
enrollment, or within 30 days, whichever is longer; or longer if required by local 
regulations. Current or planned participation in another clinical trial during this study.
2. History of hypersensitivity to the study drugs or to drugs of similar chemical classes or 
excipients.
3. Patients with a history of long-QT syndrome or the QTcF interval at screening or baseline 
is prolonged (QTcF >450 ms in males, >460 ms in females).
4. Patients who have a clinically significant ECG abnormality before randomization, as 
determined by the investigator.
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).
5. Patients with a history or current treatment for hepatic disease including but not limited to 
acute or chronic hepatitis, cirrhosis or hepatic failure. A history of resolved Hepatitis A is 
not exclusionary. Patients with prothrombin time international normalized ratio (PT/INR) 
of more than 1.5xULN at screening. Patients excluded for the PT/INR of more than 
1.5xULN can be re-screened when the values have returned to normal.
6. History of lung transplant or malignancy of any organ system (other than localized basal 
cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of 
whether there is evidence of local recurrence or metastases, with the exception of 
localized basal cell carcinoma of the skin. Patients with segmentectomy for other reasons 
than cancer are allowed to be included in the study. 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.
7. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
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8. Women of child-bearing 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, 
postovulation methods) and withdrawal are not acceptable methods of contraception.

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six 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.
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 child-bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least 
6 weeks ago. In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment is she considered 
not of child-bearing potential.
9. Use of prescription drugs prohibited as stated in the Section 6.2.2 within 1 week prior to 
Day 1.
10. Clinically significant laboratory values abnormalities (including GGT, AST, ALT, total 
bilirubin or creatinine) in the opinion of the investigator at screening. For additional 
guidance on hepatic parameters refer to exclusion criterion #5.
11. Patients requiring long-term oxygen therapy for chronic hypoxemia. This is typically 
patients requiring oxygen therapy >12 h per day delivered by home oxygen cylinder or 
concentrator. Note: Nocturnal oxygen therapy for transient oxygen desaturations 
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12. Patients with bronchiectasis who have had a pulmonary exacerbation with a deterioration 
in three or more of the following key symptoms for at least 48 h:

cough;

sputum volume and/or consistency;

sputum purulence;

breathlessness and/or exercise tolerance;

fatigue and/or malaise;

haemoptysis
AND
A clinician determines that a change in bronchiectasis treatment is required (e.g. requiring 
systemic glucocorticosteroid treatment and/or systemic, inhaled antibiotics or change in 
mucous clearance regimen) within 4 weeks prior to screening.
In the event of an exacerbation occurring 4 weeks before screening, or between 
the screening and baseline (please see definition above), the patient must NOT be 
enrolled. The patient may be rescreened once, 4 weeks after the resolution of 
exacerbation.
13. Hemoptysis, requiring medical intervention at any time within 4 weeks prior to screening.
14. Bronchiectasis predominantly characterized by isolated cavitary lung lesions.
15. Patients with bronchiectasis requiring therapy that may interfere with the assessment of 
QBW251 efficiency or that are unlikely to respond to QBW251 as follows:

Patients with suspected active pulmonary tuberculosis or currently being treated for 
active pulmonary tuberculosis are not allowed. 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 baseline visit suggesting low probability of recurrent active
tuberculosis

Patients with active allergic bronchopulmonary aspergillosis and/or asthma as primary 
diagnosis

Patients with cystic fibrosis
16. Current or ex-smokers with severe emphysema as determined by the investigator.
Bidi or other similar non-filtered cigarette may be considered applicable to smoking 
history. They should be counted in the same way as standard cigarettes. 
Occasional smoking of cigars, pipes, e-cigarettes, or inhaled nicotine products are not 
relevant to smoking history (Dinakar, O’Connor 2016).
Note: An ex-smoker may be defined as a subject who has not smoked for ≥ 6 months at 
screening or at the time of assessment.
17. Patients with another concomitant pulmonary disease according to the definition of 
the International ERS/ATS guidelines, including but not limited to interstitial pulmonary 
fibrosis (IPF), sarcoidosis or other granulomatous or infectious process. Concomitant 
COPD and asthma with characteristics of airway hyperresponsiveness as well as COPD-
Asthma overlap syndrome are allowed as long as it is not the main, primary diagnosis as 


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determined by the investigator. Patients with a diagnosis of primary ciliary dyskinesia 
(PCD) may be allowed to participate with approval of the Sponsor.
18. Patients currently receiving treatment for nontuberculous mycobacterial (NTM) 
pulmonary disease. If performed, patients with one or more positive cultures in the last 
12 months for M. avium complex, M. abscessus complex, M. kansasii, M. malmoense, 
M. enopi, M. simiae or M. chelonae, unless all subsequent NTM cultures (at least two) are 
negative and in the opinion of the investigator the patient does not meet ATS criteria for 
NTM-pulmonary disease.
19. Patients with a known history of non-compliance to medication or who are unable or 
unwilling to complete an electronic patient diary or patient reported outcome 
questionnaire.
20. Recent (within three years of screening) or recurrent history of clinically significant 
autonomic dysfunction (e.g., recurrent episodes of fainting, palpitations, etc...) as 
determined by the investigator.
21. Patients with a major vascular surgery in the 6 months prior to the screening visit.
22. Patients who have clinically significant renal, cardiovascular (such as but not limited to 
unstable ischemic heart disease, 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 uncontrolled 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.
23. Known or suspected history of ongoing, chronic or recurrent infectious disease of HIV, 
Hepatitis B/C.
24. Patients receiving any medication that may influence the response to treatment within 
4 weeks prior to Day 1 including systemic or inhaled steroids (ICS alone), other systemic 
immunomodulators, recombinant human DNAse, any systemic or inhaled antibiotics other 
than chronic macrolides.
25. Patients with a body mass index (BMI) of more than 40 kg/m2 at screening.
6
Treatment
6.1
Study treatment
The study treatment includes:

Investigational drug QBW251 dose of 300 mg

Matching placebo
Details on the requirements for storage and management of study treatment, and instructions to 
be followed for subject numbering, prescribing/dispensing, and taking study treatment are 
outlined in the SOM.


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Refer to the Section 6.2.4.1 for details of dosing and food intake.
6.1.1
Investigational and control drugs
Table 6-1 presents the details of the investigational drug and its control.
Table 6-1
Investigational and control drug
Investigational/ 
Control Drug
(Name and 
Strength)
Pharmaceutical 
Dosage Form
Route of 
Administration
Supply Type
Sponsor (global or 
local)
QBW251 
300mg b.i.d.
Capsule1
Oral use
Double-blind 
supply; bottles
Novartis Pharma AG 
(global)
QBW251 
placebo b.i.d.
Capsule
Oral use
Double Blind 
supply; bottles
Novartis Pharma 
AG (global)
All capsules are of identical appearance to ensure blinding
1 QBW251 is a film coated tablet over-encapsulated as final pharmaceutical dosage form to maintain 
double-blind
6.1.2
Additional study treatments
Rescue medication
Rescue medication for pulmonary exacerbations (including systemic antibiotics) are allowed.
All subjects will also be provided with a short-acting beta2 agonist, (salbutamol 100 μg/puff or 
albuterol 90 μg/puff or equivalent dose). Patients will be instructed to use it throughout 
the study on an "as needed” basis. (No other rescue medication is permitted during the study). 
Rescue medication will be sourced locally (see Section 6.2.3 for rescue medication further 
information).
Sites will be instructed to record the short-acting beta agonist rescue medications dispensation 
in the eDiary. Use of rescue medications must be recorded on the Concomitant 
medications/Significant non-drug therapies CRF.
6.1.3
Treatment arms/group
On Day 1, subjects will be randomized to one of the following 2 treatment groups in a ratio 
of 1:1

QBW251 300 mg b.i.d.

Matching placebo to QBW251 b.i.d.
6.2
Other treatment(s)
6.2.1
Concomitant therapy
All medications, procedures, and significant non-drug therapies administered after the subject 
was enrolled into the study must be recorded on the concomitant medications / significant 
non-drug therapies or procedures eCRF page.


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Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. 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 and an overview regarding actions to be taken for 
antibiotics.
Table 6-2
Medications permitted under certain conditions
Rationale/Group
Medication
Prohibition Period
Action Taken
Maintenance therapy
Free or fixed 
combination of 
LABA/LAMA, 
LABA/ ICS or 
LABA/LAMA/ICS
Washout period before 
spirometry assessments: 
12 hours for twice-daily 
and 24h for once-daily
Reschedule spirometry 
assessment 
accordingly. Trough 
spirometry should be 
done after the washout 
period is complete. 
Otherwise, postpone 
visit to the next day 
where washout criteria 
can be fulfilled.
Rescue medication 
only
Short-Acting Beta-2 
Agonists (SABA)
Hold treatment at least 6 
hours prior to each 
Spirometry measurement
If possible, postpone 
spirometry 
measurement on 
the same day until 
the washout criterion is 
fulfilled. Trough 
spirometry should not 
be done within 6 hours 
after last rescue 
medication intake
Antibiotics for 
treatment of 
exacerbations and 
macrolides as 
maintenance 
medication
Antibiotics, e.g. 
amoxicillin; 
Macrolides, e.g. 
erythromycin
Systemic and/or inhaled 
antibiotics are allowed for 
treatment of acute 
infections, or are allowed 
for the treatment of acute 
exacerbations (but not as 
permanent prophylactic 
treatment, with the 
exception of macrolides at 
stable doses as 
maintenance therapy per 
inclusion #7).
Topical treatment (e.g. 
use of intraocular, 
intraconjunctival antibiotic 
treatments, topical use of 
creams, etc.) is permitted.
No action required


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Patients are allowed to have macrolides at stable doses as maintenance therapy throughout 
the study.
If a patient experiences a pulmonary exacerbation and/or worsening of the disease condition, 
he/she will be treated as deemed appropriate by the investigator. Antibiotics (systemic or 
inhaled) are allowed for the treatment of pulmonary exacerbations as dictated by the patient's 
condition.
QBW251 moderately inhibits the metabolic clearance of co-medications mainly metabolized 
by CYP1A2 or CYP2C19. Thus, drugs that are sensitive substrates of CYP1A2 or CYP2C19 
are expected to have an increased exposure upon co-administration of 300 mg b.i.d QBW251. 
In addition, QBW251 was observed to weakly induce both CYP3A4 and CYP2C8 based on 
results from a clinical drug interaction study. QBW251 is a time-dependent inhibitor and 
inducer of CYP3A4/5. The net effect of QBW251 on CYP3A4/5 is anticipated to be induction 
based on results of a perpetrator drug-drug interaction study of QBW251 (450 mg b.i.d.) with 
an oral contraceptive that resulted in a decrease in exposure of the substrate.
Weak in vitro inhibition of CYP2B6, BCRP, OCT1, OAT3 and MRP2 was also observed. 
QBW251 may increase the exposure of drugs which are substrates of the transporters or 
enzymes.
The above-mentioned drugs are listed in Table 6-3 and can be used when indicated and no 
alternative treatment is available. Safety and efficacy of drug should be monitored accordingly.
The following lists are not considered exhaustive and labels for individual drugs should be 
referred to.
Table 6-3
Medications which may be co-administered with QBW251 (if no 
alternative treatment is available)
Medications that may have decreased exposure due to co-administration with QBW251
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.
Narrow therapeutic index
substrates of CYP2C8
dabrafenib, erlotinib, paclitaxel
Sensitive substrates of 
CYP2C8
daprodustat, dasabuvir, paclitaxel, repaglinide


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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
Sensitive Substrates of 
CYP2B6
bupropion, efavirenz, nevirapine, sibutramine
Sensitive Substrates of 
CYP2C19
clobazam, diazepam, gliclazide, (R)-(-)-hexobarbital, (R)-
lansoprazole (dexlansoprazole), (S)-lansoprazole, (S)-
mephenytoin, (R)-mephobarbital, (R)-omeprazole, omeprazole, 
pantoprazole, proguanil, rabeprazole, tilidine, voriconazole
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.
OCT1 substrates
amantadine, cephalexin, ipratropium, lamivudine, oxyplatin, 
oxybutynin, phenformin, picoplatin, sorafenib, procainamide, 
ranitidine, thiamine, tropisetron, trospium, varenicline, 
umeclidinium
MRP2 substrates
irinotecan, mycophenolic acid, lopinavir, methotrexate, 
pravastatin, cabozantinib
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). 
Furthermore, patients should be instructed not to take grapefruit, Seville oranges or their juice for 
14 days prior to dosing, during the 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 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.


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Table 6-4
Examples of contraceptives not recommended for systemic use as
acceptable means of contraception as efficacy may be compromised 
by QBW251 administration
Medication
Period during which 
contraceptive effect may be 
compromised
Action taken
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.
Pause study treatment and 
perform a urine pregnancy test.
In order to resume study 
treatment, patient must have a 
negative urine pregnancy test 
and must use an approved 
contraception method 
(Section 5.2 – Exclusion #8).
If urine pregnancy test is 
positive, refer to Section 9.1.1.
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.
Table 6-5
Prohibited medication
Rationale/Group
Medication1
Prohibition period
Medication with a narrow 
therapeutic range and potential 
for increased exposure with 
QBW251 due to inhibition of 
CYP1A2
Theophyline
Tizanidine
1 week prior to Day 1 until End 
of Study visit
Medication with a narrow 
therapeutic range and potential 
for increased exposure with 
QBW251 due to inhibition of 
CYP2C19
Amitriptyline Clomipramine
Imipramine
1 week prior to Day 1 until End 
of Study visit
Medications lacking information 
on metabolizing enzymes
Pirbuterol
1 week prior to Day 1 until End 
of Study visit
Strong uridine diphosphate 
glucuronosyl transferase (UGT) 
inhibitors, which will potentially 
increase systemic 
concentrations of QBW251
Mefenamic acid
Probenecid
Valproic acid
1 week prior to Day 1 until End 
of Study visit


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Rationale/Group
Medication1
Prohibition period
Strong inducers mediating 
enzymes levels via PXR, which 
will potentially decrease
systemic concentrations 
of QBW251
Valproic acid
Apalutamide Avasimibe, 
Carbamazepine Enzalutamide 
Ivosidenib
Lumacaftor
Mitotane
Phenytoin
Rifampicin
Rifapentine
St. John’s wort (Hypericum 
perforatum)
1 week prior to Day 1 until End 
of Study visit
Any medication that may 
influence the response to 
treatment
Systemic or inhaled steroids 
(ICS alone), other systemic 
immunomodulators, 
recombinant human DNAse, 
any systemic or inhaled 
antibiotics, with the exception 
of oral macrolides mucolytics or 
hyperosmolar agents as noted 
in Table 6-2.
4 weeks prior to Day 1 until 
End of Study visit
Table 6-6
Respiratory related medications and required washout periods
Prohibited respiratory-related medications and washout period prior to Day 1
Class of medication1
Minimum washout period prior to Day 1
Long-acting muscarinic antagonists (LAMA) 
(other than as ingredient of study maintenance 
therapy)
12 hours for twice-daily LAMAs
24 hours for once-daily LAMAs
Short-acting muscarinic antagonists (SAMA)
6 hours
Long-acting β2 agonists (LABA)(other than as 
ingredient of study maintenance 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 maintenance therapy)
28 days
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.


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6.2.3
Treatment for exacerbations and for bronchospasm
Pulmonary exacerbations:
Treatment for pulmonary exacerbation (including systemic corticosteroids, antibiotics) is 
allowed. Use of treatment for pulmonary exacerbations must be recorded on the Concomitant 
medications/Significant non-drug therapies CRF.
Bronchospasm:
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. The rescue medication will be supplied to the investigator sites 
locally by Novartis or provided by the study center and reimbursed by Novartis. No other rescue 
medication for bronchospasm 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 prior concomitant medication page of the eCRF.
6.2.4
Restriction for study subjects
For the duration of the study, subjects should be informed and reminded of the restrictions 
outlined in this section.
6.2.4.1
Dietary restrictions and smoking
Dietary restrictions
The following are the instructions for the investigational drug (QBW251/placebo):

It is recommended not to take the investigational drug in together with high-fat meals 
(refer to SOM for details). The definition of high-fat meals follow the definition suggested 
by 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 for a total nutritional energy value of 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 as inhibitors of CYP3A.


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Smoking
Smoking is not prohibited during the study.
6.2.4.2
Other restrictions
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 beverage for 4 hours prior to spirometry

Alcohol for 4 hours prior to spirometry

Strenuous activity for 12 hours prior to spirometry

Exposure to environmental smoke, dust or areas with strong odors
6.3
Subject numbering, treatment assignment, randomization
6.3.1
Subject numbering
The subject number assigned to a subject at screening remains the unique identifier for 
the subject throughout the study. For information on subject numbering, please see ‘Subject 
numbering’ section in the SOM.
6.3.2
Treatment assignment, randomization
Upon signing the informed consent form, the subject will be assigned the next sequential 
number by the investigator. The investigator or his/her staff will contact the IRT and provide 
the requested identifying information for the subject to register them into the IRT.
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 but will be used by the IRT 
system. The patient will retain the Subject Number throughout the study as the unique identifier. 
If the subject fails to be treated for any reason, the IRT should be notified within 2 days that 
the subject was not treated, and the reason will be entered into the CRF.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. A subject 
randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of subject 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 (GCS) using a validated system that automates the random assignment 
of medication numbers to packs containing the study treatment.
The randomization scheme for subjects will be reviewed and approved by a member of 
the Randomization Office.


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Follow the details outlined in the SOM regarding the process and timing of treatment 
assignment and randomization of subjects.
Randomization will be stratified by macrolides use status and geographic region 
(from China/not from China).
6.4
Treatment blinding
Subjects, investigator staff, persons performing the assessments, will remain blinded 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, statistician and programmer supporting the CQBW251C12201 study.
(2) The identity of the treatments will be concealed by the use of identical packaging, 
labeling, schedule of administration, appearance, taste and odor for both QBW251 and 
placebo.
The sponsor will remain blinded until study completion except Trial Statistician and Trial 
Programmer who will be responsible for any interim analyses conducted at any time for efficacy 
and safety. Unblinding this study to the sponsor will happen in the case of subject emergencies 
that will be deemed necessary to evaluate the safety outcome to safeguard all subjects. 
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 a single subject at site for safety reasons (necessary for subject management) will 
occur via an emergency system in place at the site.
Table 6-7
Blinding levels
Time or Event
Role
Randomization 
list generated
Treatment 
allocation & 
dosing
Safety event 
(single subject 
unblinded)
Subjects
B
B
UI
Site staff
B
B
UI
Unblinded site staff 
e.g. pharmacy staff 
(see text for details)
B
UI
UI
Global Clinical 
Supply and 
Randomization 
Office
UI
UI
UI
Unblinded sponsor 
staff e.g. for study 
treatment re-supply, 
unblinded 
monitor(s), sample 
analyst(s) (see text 
for details),
B
UI
UI


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Time or Event
Role
Randomization 
list generated
Treatment 
allocation & 
dosing
Safety event 
(single subject 
unblinded)
Statistician/statistical 
programmer/ data 
analysts (e.g. 
biomarker, PK)
B
B
UI
All other sponsor 
staff not identified 
above
B
B
UI
B remains blinded
B* Remains blinded unless safety and/or exposure concerns
UI allowed to be unblinded on individual subject level
6.5
Dose escalation and dose modification
Investigational treatment dose adjustments are permitted under specific circumstances 
described in Section 6.5.1 and Section 6.5.2.
Temporary dose interruptions are permitted under specific circumstances described in 
Section 6.5.1.
6.5.1
Dose Interruptions
Study drug 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, 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.
6.5.2
Dose Adjustments for QTcF Prolongation
In case of QTcF > 500 msec, (or QTcF prolongation >60 msec from Baseline/Day 1)

Assess the quality of the ECG recording and the QT value and repeat, if needed

Interrupt study 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 
per Table 8-1) and record time and date of last study treatment intake
If QTcF interval > 500 msec is confirmed:

Permanently discontinue the study treatment.

Take a blood sample for PK analysis. Timepoint should be as close as possible to the ECG 
recording in question


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
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
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 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
Recommended treatment of adverse events
At present there is insufficient information to provide specific recommendations regarding 
treatment of adverse events (AEs).
Treatment of adverse events should be symptomatic. In case of questions regarding treatment 
of AEs caused by investigational product the investigator may contact the sponsor. Study drug 
discontinuation criteria as provided in Section 9.1.1 must be followed.
In case of exacerbations of bronchiectasis, adequate treatment of exacerbation as per national 
or international recommendations or current clinical practice should be instituted. These include 
administration of antibiotics and supervision until the patient is considered stable.
Medication used to treat adverse events (AEs) must be recorded on the appropriate CRF.


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6.6.3
Emergency breaking of assigned treatment code
Emergency code breaks must only be undertaken when it is required 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.
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.
After 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 study drug in packaging as described under 
the investigational and control drugs section.
6.7.1
Instruction of prescribing and taking study medication
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.)

Refer to Section 6.2.4.1 Dietary restrictions relevant to QBW251 intake.

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.
Instructions for the maintenance treatment and rescue medication should be according to 
the respective product label.


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On study visit days, patients should be reminded not to take either the investigational drug 
(QBW251/placebo) or the maintenance 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 for b.i.d. 
drugs, and

22-26 hours after the last inhalation of daily maintenance medication on the morning 
before o.d. drugs (see also Section 8.3.2).
7
Informed consent procedures
Eligible subjects may only be included in the study after providing IRB/IEC-approved informed 
consent (witnessed, where required by law or regulation).
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 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 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 child bearing 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.
The study includes optional sub studies/ DNA component/serial PK sampling component which 
requires a separate signature if the subject agrees to participate. It is required as part of this 
protocol that the Investigator presents this option 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.


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Declining to participate in these optional assessments (DNA, serial PK 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.
Refer to the SOM for a complete list of ICFs included in this study.


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8
Visit schedule and assessments
Assessment schedule (Table 8-1) lists all of the assessments when they are performed. All data obtained from these assessments must be 
supported in the subject’s source documentation.
Subjects should be seen for all visits/assessments as outlined in the assessment schedule (Table 8-1) 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 CRF.
Table 8-1
Assessment Schedule
EPOCH
Screening
Treatment
End of Study Unscheduled
Visit Name Screening Baseline2
Treatment
End 
of 
Study
Safety 
Follow 
Up
Unscheduled
Visit Numbers1
1
20
100
1103
120
130
140
1999
150
Days
-42 to -1
1
-3 +1
1
14
28
±3
56
±3
84
±3
91
±3
114
±3
-
Weeks
1
2
4
8
12
13
17
-
Time (post-dose)
-
-
0h4 1h
2h 3h 4h 6h
8h
-
0h4 1h 2h 3h 4h 6h
8h
0h4
3h
0h4
3h
-
-
-
Informed consent
X
Inclusion / Exclusion 
criteria
X
X
Demography
X
Medical history/current 
medical conditions
X
Bronchiectasis 
exacerbation history
X
Smoking history
X


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EPOCH
Screening
Treatment
End of Study Unscheduled
Visit Name Screening Baseline2
Treatment
End 
of 
Study
Safety 
Follow 
Up
Unscheduled
Visit Numbers1
1
20
100
1103
120
130
140
1999
150
Days
-42 to -1
1
-3 +1
1
14
28
±3
56
±3
84
±3
91
±3
114
±3
-
Weeks
1
2
4
8
12
13
17
-
Time (post-dose)
-
-
0h4 1h
2h 3h 4h 6h
8h
-
0h4 1h 2h 3h 4h 6h
8h
0h4
3h
0h4
3h
-
-
-
Randomization
X
Study drug 
administration5
b.i.d. dosing
In-clinic study drug 
administration
X
X
X
X
Rescue medication 
dispensation6
S
Drug accountability 
S
Concomitant 
medications
X
Physical Examination7
S
S
S
S
S
S
S
Body Height
X
Body Weight
X
X
Body Temperature
X
X
X
X
X
X
X
X
Blood Pressure
X
X
X
X
X
X
X
X
Pulse rate
X
X
X
X
X
X
X
X
Clinical Chemistry8
X
X
X
X
X
X
Coagulation8
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
Pregnancy and 
assessments of fertility9
X
X
X
X
X
X
X


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EPOCH
Screening
Treatment
End of Study Unscheduled
Visit Name Screening Baseline2
Treatment
End 
of 
Study
Safety 
Follow 
Up
Unscheduled
Visit Numbers1
1
20
100
1103
120
130
140
1999
150
Days
-42 to -1
1
-3 +1
1
14
28
±3
56
±3
84
±3
91
±3
114
±3
-
Weeks
1
2
4
8
12
13
17
-
Time (post-dose)
-
-
0h4 1h
2h 3h 4h 6h
8h
-
0h4 1h 2h 3h 4h 6h
8h
0h4
3h
0h4
3h
-
-
-
Electrocardiogram 
(ECG)10
X
X
X
X
X
X
X
X
X
X
X
St. George's 
Respiratory 
Questionnaire (SGRQ)
X
X
EQ-5D-3L
X
X
Quality of Life 
Questionnaire for 
Bronchiectasis (QOL-B)
X
X
X
X
eDiary
X
X
EXACT-PRO11
X12
X
X
HRCT13
X14
X15
Spirometry
X
X
X
X
X
X
Spirometry reversibility 
test
X
Oxygen Saturation
X
Sputum bacterial load15
X
X
X
X
X
X
Sputum 16S rRNA PCR
X
X
X
X
Exploratory Biomarkers 
in Sputum
X
X
X
X
Exploratory sputum 
bacterial profile
X
X


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EPOCH
Screening
Treatment
End of Study Unscheduled
Visit Name Screening Baseline2
Treatment
End 
of 
Study
Safety 
Follow 
Up
Unscheduled
Visit Numbers1
1
20
100
1103
120
130
140
1999
150
Days
-42 to -1
1
-3 +1
1
14
28
±3
56
±3
84
±3
91
±3
114
±3
-
Weeks
1
2
4
8
12
13
17
-
Time (post-dose)
-
-
0h4 1h
2h 3h 4h 6h
8h
-
0h4 1h 2h 3h 4h 6h
8h
0h4
3h
0h4
3h
-
-
-
Exploratory Biomarkers 
in Blood
X
X
X
Sparse PK samples 
collection
X
X17
X
X17
X
X17
X
X17
Serial PK samples 
collection (optional at 
selected sites)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Exploratory DNA 
consent (optional)
X
Exploratory DNA 
Sampling (optional)18
X
Telephone follow-up
S
Adverse Events
X
X
X
Comments
S
Safety Follow up Call
S
Study completion 
information
X
X Assessment to be recorded in the clinical database or received electronically from a vendor
S Assessment to be recorded in the source documentation only
1 Visit structure given for internal programming purpose only


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2 When Baseline and Day 1 visits occur on the same day, assessments assigned to both visits should be done only once.
3 Day 14 visit will be conducted via telephone 
4 Unless otherwise specified, assessments at 0h must be done pre-dose
5 On visit days, subjects will take their morning dose in the clinic after completion of all pre-dose assessments. All the other doses will be taken at home.
6 SABA will be provided to patients as rescue medication
7 A complete physical examination will be conducted at screening and end of treatment on Day 84. For the rest of visits with assessment scheduled, a short physical 
examination will be conducted
8 hsCRP assessment is included in the chemistry panel and fibrinogen is included in the coagulation panel
9 Serum assessment is required at screening, both serum and urine assessments are acceptable for all other visits. A positive urine test requires immediate interruption 
of study treatment until a serum test is found to be negative.
10 Single ECG measurement
11 It is to be completed by the patient at the end of every day at bedtime until the day before the last dose (Day 84)
12 In order to set up the eCOA handheld device, patients need to complete the EXACT-PRO on at least 4 out of the past 7 days before patients begin the Baseline visit to 
calculate the EXACT-PRO baseline score. If less than 4 out of the past 7 days are completed, the baseline visit will need to be postponed until that requirement is met.
13 Optional at selected sites with pre-approval of Sponsor.
14 If patients have no historical CT assessment report, the investigator can make the diagnosis of bronchiectasis based on the screening HRCT scan for eligibility check. 
When the screening HRCT is performed, it is recommended the assessment to be performed after patient has passed all the other screening criteria, prior to 
randomization. 
15 The HRCT at Day 84 must be performed after the morning dose. If screening HRCT was not performed, no Day 84 HRCT should be performed.
16 In the case that patient cannot produce enough volume of sputum on the scheduled visit, it is allowed that they can return to site within 3 days after the scheduled visit 
for sputum sample collection. Induced sputum process may be considered provided that the spontaneous attempts are not satisfactory
17 3h post-dose PK sample should be taken after the 3h post-dose ECG is performed.
18 Genetic informed consent (optional) must be signed before a genetic sample is collected. Sample may be taken at assigned visit or any visit thereafter


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8.1
Screening
It is permissible to re-screen a subject once if he/she fails the initial screening; however, each 
case must be discussed and agreed with the Sponsor on a case-by-case basis.
In the case where a safety laboratory or spirometry assessment at screening and/or baseline is 
outside of the range specified in the eligibility criteria, the assessment may be repeated once 
prior to randomization. In the case where sputum bacterial load at screening is lower than the 
threshold specified in the eligibility criteria, the assessment may be repeated twice prior to 
randomization. If the repeat value remains outside of the specified ranges, the subject must be 
screen failed. The subject can be rescreened as detailed below. If the subject has already taken 
the required baseline HRCT during the previous screening period within the past 12 months, 
the subject does not need to take the baseline HRCT again during the rescreening period.
If a subject re-screens for the study, then the subject must sign a new ICF and be issued a new 
subject number prior to any screening assessment being conducted. The investigator/qualified 
site staff will record if the subject was re-screened on the re-screening CRF along with 
the screening number the subject was issued prior to the current screening number.
The date of the new informed consent signature must be entered on the informed consent eCRF 
corresponding to the new screening subject number. For re-screening, all screening assessments 
must be performed per protocol.
Information on what data must be collected for screening failures and further information on 
re-screening is outlined in the SOM.
8.1.1
Information to be collected on screening failures
Patients who sign an informed consent but fail to be started on treatment for any reason will be 
considered a screen failure.
The reason for the screening failure will be entered on the screening disposition page. 
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.
Information on what data must collected for screening failures and further information on 
re-screening is outlined in the SOM.
8.2
Subject demographics/other baseline characteristics
Subject demographic and baseline characteristic data will be collected on all subjects. 
Relevant medical history/current medical conditions data will also be collected until signature 
of informed consent.
Smoking history information will be collected. Investigators have the discretion to record 
abnormal test findings on the medical history CRF, if in their judgment, the test abnormality 
occurred prior to informed consent signature.
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with CRF.
Details are outlined in the SOM.


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8.3
Efficacy
The efficacy assessments selected are standard for this indication/subject population. Blood and 
sputum samples will be collected and evaluated in all patients at the time points defined in 
the Assessment Schedule (Table 8-1). Follow instructions outlined in the SOM regarding 
sample collection, numbering, processing, and shipment. Number of samples/blood draws and 
total blood volume collected will not exceed those stated in the protocol. For all completed 
scales/questionnaire described below, the Investigator will be required to review and examine 
responses which may indicate potential AEs or SAEs. The investigator should review not only 
the responses to the scale but also for any unsolicited comments written by the patient. 
If the occurrence of AEs or SAEs is confirmed, the investigator/physician should record 
the events as per instructions given in Section 9.
Pharmacodynamic (PD) samples will be obtained and evaluated in all subjects at all dose levels, 
including the placebo group.
8.3.1
Microbiological assessment
Spontaneous or induced sputum will be collected for analysis of pathogenic bacterial 
colonization (CFU/mL) (e.g. H influenzae, M catarrhalis, S aureus, S pneumoniae, 
Enterobacteriaceae, P aeruginosa, Stenotrophomonous Maltophilia, or any potential 
pathogenic non-fermenting Gram negative bacteria).
On scheduled sputum collection visits, at least one sputum specimen is recommended to be 
collected in the morning at pre-dose timepoint and before breakfast (including drinks) if 
possible. If spontaneous sputum collection attempts are not satisfactory, an investigator may 
take the decision to collect sputum sample after induction by the inhalation of saline. If patients 
can’t produce enough sputum on the individual scheduled visits, they can come back within 
3 days after the scheduled visits to try to produce sputum sample. Retesting is allowed once 
during the screening period.
Treatment emerging pathogens will be determined at all visits.
Microbiological analyses, including bacterial colonization and bacterial load profiling, will be 
performed at qualified microbiology laboratory(ies). Depending on different laboratories, 
the unit of bacterial load CFU/mL is considered equal to CFU/g.
Furthermore, all patients with signs of an exacerbation will have to come to the study center 
where additional sputum sample will be collected. The analysis of this sample would help to 
determine whether the bacteria load and/ or bacterial colonization may change with 
an exacerbation.
Finally, all sputum samples must be of good quality. If the sample is determined to be a sub-
optimal, the site's staff should be contacted and immediately a request should be made for a new 
sample. Details on the collection and shipment of samples, generation of data and reporting of 
results by the microbiology laboratory are provided in a separate laboratory manual.


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8.3.2
Spirometry
Spirometry testing will be performed with the MasterScope system (manufactured by eResearch 
Technology 
GmbH) 
according 
to 
the 
ATS/ERS 
guidelines 
(Miller et al 2005a; 
Miller et al 2005b) at screening to assess patients’ lung function at the visits detailed in 
the assessment schedule in Table 8-1.
The spirometry evaluation should be performed at the site prior to the morning investigational 
drug intake and the daily maintenance therapy, such as LABA, LAMA, LABA/LAMA, as pre-
bronchodilator. Refer to instructions for medication washouts in Table 6-2. In particular, 
spirometry on visit days shall be conducted 10-14 hours after the last intake of investigational 
drug on the evening before for b.i.d drugs, and 22-26 hours for once daily drugs after the last 
inhalation of daily maintenance medication on the prior morning.
The spirometry equipment used during the trial will be provided to all study sites by a Central 
Spirometry vendor. The equipment must meet or exceed the minimal ATS/ERS 
recommendations for diagnostic spirometry equipment as defined in the guideline provided by 
the vendor. Calibration of the spirometry equipment is mandatory on all visit days and must be 
performed before the first patient spirometry test is assessed. All calibration reports and subject 
spirometry reports should be stored as source data.
The same spirometry equipment should be used for all assessments performed by a subject. 
A limited number of qualified staff, as designated by the investigator, will evaluate all patients 
at all visits throughout the entire trial. Where possible the same technician should perform all 
maneuvers for an individual subject. All staff conducting the spirometry tests must have 
received appropriate training which must be documented.
All spirometry assessments will be undergoing review by a central overreader. Acceptability of 
a spirometry assessment attempt depends on the overreader's judgement for compliance with 
and acceptability according to the ATS/ERS criteria.
A Spirometry Manual will be provided to all sites as separate document.
8.3.3
Fibrinogen
Fibrinogen is a glycoprotein, which is the most abundant clotting factor in plasma. It is 
associated with severity of disease and quality of life in bronchiectasis (Saleh et al 2017). 
For details on the collection, handling and storage/shipment of samples, refer to the Laboratory 
Manual. Samples will be collected at the time points defined in the Assessment Schedule 
(Table 8-1).
8.3.4
High Resolution Computed Tomography (HRCT)
High Resolution Computed Tomography (HRCT) will be performed at screening period and at 
Day 84 (12 weeks). At the time points specified in the schedule, a HRCT scan of the lung, 
without contrast agent, will be acquired. The acquisition will include inspiratory and expiratory 
image sets at both assessment time points. In all subjects, the baseline and follow-up HRCT 
scan should be performed where possible on the same scanner.


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HRCT assessment is optional at selected sites only with pre-approval from the Sponsor. Patients 
who opt out of the HRCT assessment must have a historical chest CT to confirm the diagnosis 
of bronchiectasis.
Protocol-specific requirements of the HRCT and machine settings are provided to all sites as 
part of a separate Imaging Manual. Additionally, the imaging vendor will provide centralized 
review of the HRCT scans.
In summary, HRCT scans will be analyzed to determine both at baseline and week 12, along 
with the associate change from baseline:

As secondary objectives: airway structure (airway wall and lumen parameters) and 
function (global and regional air trapping)

As exploratory endpoints: mucus load (whole lung and regional)
As additional endpoints, airway-artery ratios (airway lumen area and airway outer area to 
the area of the accompanying vessel) and HRCT scores (based on the presence and extent of 
BE, airway wall thickening, trapped air, parenchymal abnormalities and nodules) will be 
determined in the context of the IMI collaboration
Note: The coded medical images will be used primarily for analysis as described in this protocol; 
however, the images may also be used for the development and evaluation of new analysis 
methods directly related to the area of research that this study covers.
8.3.5
High-sensitivity C-reactive protein (hsCRP)
Serum biomarkers (e.g. hsCRP) will be analyzed to determine the effect of QBW251 treatment 
on inflammation in peripheral blood. C-reactive protein (CRP) is substance produced by 
the liver in response to inflammation.
hsCRP levels are assessed as part of the clinical chemistry panel for patient safety but will also 
be assessed as a biomarker for bronchiectasis.
8.3.6
Appropriateness of efficacy assessments
The sputum bacterial colonization and the lung function assessment such as FEV1 and FVC in 
pre-bronchodilator are standard outcome measurement in bronchiectasis disease trials.
8.4
Safety
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed.
For details on AE collection and reporting, refer to AE section.


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Table 8-2
Assessments and Specifications
Assessment
Specification
Physical examination
A complete physical examination will include the examination of 
general appearance, skin, neck (including thyroid), eyes, ears, nose, 
throat, lungs, heart, abdomen, back, lymph nodes, extremities, 
vascular, and neurological. If indicated based on medical history 
and/or symptoms, rectal, external genitalia, breast, and pelvic exams 
will be performed.
A short physical exam will include the examination of general 
appearance and vital signs (blood pressure [SBP and DBP] and 
pulse). A short physical exam will be at all visits starting from Day 1 
visit except where a complete physical examination is required (see 
footnote 6 of Assessment Schedule).
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 recorded 
on the appropriate CRF that captures medical history. Significant 
findings made after signing informed consent which meet the 
definition of an Adverse Event must be recorded as an adverse 
event.
Vital signs
Vital signs include BP and pulse measurements. After the subject has 
been sitting for five minutes, with back supported and both feet 
placed on the floor, systolic and diastolic blood pressure will be 
measured three 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 three 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 Appendix 1.
Height and weight
Height in centimeters (cm) and body weight (to the nearest 
0.1 kilogram (kg) in indoor clothing, but without shoes) will be 
measured, mass index (BMI) will be calculated as (Body weight (kg) / 
[Height M)]2) (Screening only).
The methods for each assessment and data recording details are specified in the SOM.
8.4.1
Laboratory evaluations
Central or local laboratories 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.
All abnormal lab results must be evaluated for criteria defining an adverse event and reported 
as such if the criteria are met. For those lab adverse events, repeated evaluations are mandatory 
until normalization of the result(s) or until the result is no longer considered to be clinically 
significant. Clinically significant abnormalities must be recorded on the relevant section of 
the medical history/Current medical conditions/AE CRF /eCRF page as appropriate.
Clinically notable laboratory findings are defined in Section 16.1.


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Table 8-3
Laboratory evaluations
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, Platelets, Red blood cells, White blood cells, 
Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, 
(absolute value preferred , %s are acceptable)
Chemistry
hsCRP
Albumin, Alkaline phosphatase, ALT, AST, Gamma-glutamyl-transferase (GGT), 
Lactate dehydrogenase (LDH), Bicarbonate, Calcium, Magnesium, Phosphorus, 
Chloride, Sodium, Potassium, Creatinine, Creatine kinase, Direct Bilirubin, 
Indirect Bilirubin, Total Bilirubin, Total Cholesterol, LDL, HDL, Total Protein, 
Triglycerides, Blood Urea Nitrogen (BUN) or Urea, Uric Acid, Amylase, Lipase, 
Glucose (fasting)
Urinalysis
Microscopic Panel (Red Blood Cells, White Blood Cells, Casts, Crystals) only if 
abnormalities on the macroscopic panel are detected)
Macroscopic Panel (Color, Bilirubin, Blood, Glucose, Ketones, Leukocytes 
esterase, Nitrite, pH, Protein, Specific Gravity, Urobilinogen)
Coagulation
Fibrinogen
Prothrombin time (PT), International normalized ratio [INR]), Activated partial 
thromboplastin time (APTT)
Pregnancy Test
Serum / Urine pregnancy test (refer to Section 8.4.3 'Pregnancy and 
assessments of fertility')
8.4.2
Electrocardiogram (ECG)
Full details of all procedures relating to the ECG collection and reporting are contained in 
the SOM.
PR interval, QRS duration, heart rate, RR interval, QT interval, QTcF will be assessed.
The Fridericia QT correction formula (QTcF) must be used for clinical decisions.
Unless auto-calculated by the ECG machine, the investigator must calculate QTcF at 
the Screening to assess eligibility. See the SOM for additional details.
Clinically significant abnormalities must be reported as adverse events.
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 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 might be performed if requested by local requirements.
8.4.4
Bronchiectasis exacerbation
Bronchiectasis exacerbations are defined as a deterioration in three or more of the following 
key symptoms for at least 48 hours:

cough

sputum volume and/or consistency;


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
sputum purulence;

breathlessness and/or exercise tolerance;

fatigue and/or malaise;

haemoptysis
AND
A clinician determines that a change in bronchiectasis treatment is required (e.g. requiring 
systemic glucocorticosteroid treatment and/or systemic or inhaled antibiotics).
A worsening of symptoms that either does not meet the above symptom definition but is treated 
by the investigator with antibiotics or steroids or both, or that meets the symptom definition but 
is not treated with antibiotics or steroids or both, is not considered a pulmonary exacerbation 
for the study.
For the above reported signs and symptoms, additional information will be collected to 
document if the reported signs and symptoms last for more than 48 hours.
Patients should contact the site when experiencing a pulmonary exacerbation. An unscheduled 
visit should occur within 2 working days of the event to confirm the diagnosis, unless the patient 
is hospitalized and thus unable to attend the site. AEs/SAEs, concomitant medications, and 
safety laboratory exams should be captured, as appropriate.
The start date for a pulmonary exacerbation recorded in the CRF should be the first day of 
treatment with antibiotics or steroids or both, as defined above. The end of a pulmonary 
exacerbation episode is marked by the end of treatment with antibiotics or steroids or both.
An exacerbation might result in missed or rescheduled visit(s) and missing associated CRF data 
in some circumstances.
Patients who develop a pulmonary exacerbation between screening and prior to treatment will 
be screen failed but will be permitted to be re-screened once the inclusion/exclusion criteria 
have been met (see Section 5.2 Exclusion criteria).
8.4.5
Appropriateness of safety measurements
The safety assessments selected are standard for this indication/subject population.
8.5
Additional assessments
8.5.1
Clinical Outcome Assessments (COAs)
Patient reported outcomes (PRO)
The impact of bronchiectasis on a subject’s health status will be assessed by the following 
patient-reported questionnaires (PROs) completed on the handheld electronic device which also 
contains the eDiary (see below):

The St. George Respiratory Questionnaire (SGRQ) providing the health status 
measurements

The Quality of Life Questionnaire for Bronchiectasis(QOL-B) (Respiratory Symptoms 
domain) assessing symptoms for patients with bronchiectasis


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
The European Quality of Life-5 Dimensions- 3 level (EQ-5D-3L) measuring global health 
status

EXAcerbations of COPD Tool - Patient Reported Outcome (EXACT-PRO) evaluating 
frequency, severity, and duration of exacerbations.
The appropriate language version of the questionnaires will be used in each participating 
country. Subject questionnaires will be completed in the language most familiar to the subject. 
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 associated user guides and training materials provided. The patient should complete 
the questionnaires in a quiet area and be allowed to ask questions; however, site personnel 
should take care not to influence the patient's responses. The patient will be instructed to provide 
the truest and best response for them.
A subject’s refusal to complete all or any part of a PRO measure should be documented in 
the study EDC system and will not be considered a protocol deviation.
The site personnel should check PRO measures for completeness and ask the subject to
complete any missing responses. The responses stored electronically will be considered 
the source file.
Completed measures and any unsolicited comments written by the subject should be reviewed 
and assessed by the investigator for responses which may indicate potential AEs or SAEs before 
any clinical study examinations. This assessment should be documented in the patient's source 
records. If AEs or SAEs are confirmed, the study investigator should not encourage the subject 
to change responses reported in the completed questionnaires. Study investigators must follow 
reporting instructions outlined in Section 10 (e.g. reference Section 10.1.1 Adverse Events) of 
the study protocol.
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 the Assessment Schedule 
(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 SOM.
Instrument scoring and handling of missing item data will be conducted in accordance with 
the user guide for the SGRQ.
The SGRQ contains 50 items divided into two parts covering three aspects of health related to 
Bronchiectasis: 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 three subscales and a "Total" score 


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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.
Quality of Life Questionnaire for Bronchiectasis (QOL-B) (Respiratory Symptoms)
The Quality of Life Questionnaire for Bronchiectasis (QOL-B) (Respiratory Symptoms scale)
will be used to assess respiratory symptoms for patients in this study (Quittner et al 2015). It is 
a self-administered patient-reported outcome (PRO) measure. 
QOL-B will be electronically completed by the patient at the investigator's site at the visits 
indicated in the Assessment schedule (Table 8-1).
A detailed guide relating to the administrative procedures of the questionnaire are given in SOM.
Instrument scoring and handling of missing item data will be conducted in accordance with 
the user guide for the QOL-B. The Respiratory Symptoms scale contains 9 items.
European Quality of Life-5 Dimension-3 Level (EQ-5D-3L)
The European Quality of Life–5 Dimensions–3 Level (EQ-5D-3L) developed by the EuroQol 
Group provides a standardized self-reported measure of global health status. It is a simple, 
generic measure of health for clinical and economic appraisal (EuroQol Group 1990). 
The EQ-5D-3L consists of two pages – the descriptive system and the EQ visual analogue scale 
(EQ VAS). The descriptive system comprises five dimensions (mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression), each with three levels: no problems, some 
problems, and extreme problems. The patient is asked to indicate his/her present health state 
according to the most appropriate statement for each of the five dimensions. The EQ VAS 
records the patients’ self-rated health on a 20 cm vertical, visual analogue scale with endpoints 
labeled ‘the best health you can imagine’ and ‘the worst health you can imagine’. There is no 
recall period and patient responds to the present health status.
EXACT Questionnaire
The EXACT-PRO is a validated 14-item electronic questionnaire designed to detect 
the frequency, severity, and duration of exacerbations. It is to be completed by the patient at 
the end of every day at bedtime in order to measure the underlying day to day variability of 
disease and detect worsening indicative of an exacerbation.
Within the 14-item EXACT-PRO tool, the Evaluating Respiratory Symptoms (E-RS™) scale 
is based on the 11 respiratory symptom items. These 11 items generate a total score, quantifying 
respiratory symptom severity overall, and 3 subscale scores assessing breathlessness, cough and 
sputum, and chest symptoms.
The single questionnaire will be used for two functions: quantification of respiratory symptoms 
in using E-RS total and subscale scores, and the assessment of acute exacerbations using 
the entire EXACT-PRO instrument.


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Electronic Diary (eDiary)
At screening, all patients will be provided with an electronic diary (eDiary).
The eDiary will record rescue medication, medication intake (dose) after randomization, as well 
as the study questionnaires at prespecified timepoints.
The patients will be instructed to routinely complete the rescue medication information in 
the eDiary twice daily at the same time in the morning and evening (before taking the study 
drug), approximately 12 hours apart. The eDiary is to be reviewed at each clinic visit until study 
completion.
Sites and patients will receive appropriate training and guidance on the use of the eDiary device.
A list of eDiary questions is provided in the SOM.
8.5.2
Pharmacokinetics
PK samples will be collected as per visits and time points indicated in the Assessment Schedule 
(Table 8-1). Instructions outlined in the laboratory manual regarding sample collection, 
numbering, processing and shipment shall be followed.
PK sampling (pre-dose and 3 hour post-dose) will be conducted and evaluated in all subjects 
on Days 1, 28, 56 and 84 (end of treatment).
Additionally, although serial PK sampling is optional, efforts will be made to have 
approximately 30-40 patients from selected sites undergo serial PK sampling up to 8 hours post-
dose at Day 1 and Day 28 visits as per Table 8-1 to further characterize the PK profile of 
QBW251 in BE patients, which will provide important understanding of the 300 mg b.i.d. dose 
in BE patients.
Furthermore, in case a patient prematurely discontinued treatment but continue participation in 
the study, the first visit after the discontinuation should have a PK trough assessment and 
thereafter subsequent PK sampling should be suspended.
Plasma PK samples will be evaluated only in subjects who have been administered QBW251. 
QBW251 concentration will be determined by a validated LC-MS/MS method with 
an anticipated lower limit of quantification (LLOQ) of 1 ng/mL of QBW251.
Concentrations below the LLOQ will be reported as zero and missing data will be labeled as 
such in the bioanalytical report.
The following pharmacokinetic parameters will be determined using the actual recorded 
sampling times and non-compartmental method(s) with Phoenix WinNonlin (Version 8 or 
higher): Cmax, Tmax, AUClast, AUC0-12h, T1/2,eff when feasible. 
Residual plasma samples remaining after the determination of QBW251 may be used for 
exploratory assessment of metabolites or other bioanalytical purposes (e.g. cross check between 
different sites, stability assessment).


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8.5.3
Biomarkers
Sample(s) will be collected at the time point(s) defined in the Assessment Schedule 
(Table 8-1).
Follow instructions for sample collection, numbering, processing, and shipment provided in 
the laboratory manual.
DNA sampling / Pharmacogenetics
The study includes an optional genetic research component which requires a separate informed 
consent signature if the subject agrees to participate. As permitted by local governing 
regulations and by IRB/EC, it is required as part of this protocol that the Investigator presents 
these options to the subject.
The purpose of genetic research may be to better understand the safety and efficacy of QBW251, 
or to learn more about human diseases, or to help develop ways to detect, monitor and treat 
diseases.
As technology changes over time, the most appropriate technology will be used at the time 
the exploratory genetic research is performed. This may include the study of the entire genome.
Laboratory manuals will be provided with detailed information on sample collection, handling, 
and shipment.
DNA samples
The use of DNA to search for biomarkers of disease and drug action is exploratory. Any results 
from this DNA study will not be placed in the subject’s medical records.
To maximize confidentiality, all samples and the information associated with the samples will 
be double-coded to prevent the exposure of the subject’s information and identity. 
This double-coding process allows Novartis to go back and destroy the sample at the subject’s 
request. In addition, sample information is stored in one secured database while genetic data is 
stored in an independent secured database.
8.5.3.1
Sputum biomarkers
The examination of QBW251 effect on inflammatory markers, which may include but are not 
limited to IL-6 and IL-8 will be done in sputum.
16S rRNA PCR may be performed to measure the bacterial load. If feasible, the analysis will 
be performed using remaining sputum samples collected for microbiology assessment.
Sputum samples will be biobanked for potential exploratory sputum bacterial profile measured 
by 16s rRNA gene sequencing.
Both 16S rRNA PCR and 16s rRNA gene sequencing are optional to China.


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8.5.3.2
Serum protein levels
Protein profiling applying highly multiplexed exploratory analytical platform and hypothesis 
free data analysis (SomaScan) may be applied to identify biomarker signatures, related to 
disease and/or QBW251 mode of action. Given the exploratory nature of the work, 
the analytical method used for this assessment is not validated and the results from 
this exploratory analysis will not be included in the clinical study report. This assessment is 
optional to China.
8.5.3.3
Use of residual biological samples
Any residual samples remaining after the protocol-defined analysis has been performed may be 
used for additional exploratory analysis related to the purpose of this study. This may include 
but is not limited to using residual samples for protein binding, metabolite profiling, biomarkers 
of transporters or other bioanalytical purposes (e.g., cross check between different sites and/or 
stability assessment). Residual PK plasma samples remaining after the determination of 
QBW251 may be used for exploratory assessment of metabolites or other bioanalytical 
purposes (e.g., cross check between different sites, stability assessment).
Given the exploratory nature of the work, the analytical method used for those assessments will 
not be validated. As such, the results from this exploratory analysis will not be included in 
the clinical study report.
9
Study discontinuation and completion
9.1
Discontinuation
9.1.1
Discontinuation of study treatment
Discontinuation of study treatment for a subject occurs when study treatment is stopped earlier 
than the protocol planned duration and can be initiated by either the subject or the investigator.
Subjects may voluntarily discontinue study treatment for any reason at any time.
The investigator must discontinue study treatment for a given subject if he/she believes that 
continuation would negatively impact the subject's well-being.
Study treatment must be discontinued under the following circumstances:

Subject/guardian decision

Pregnancy: a positive urine pregnancy test after start study drug requires immediate 
interruption of study drug until serum hCG is performed and found to be negative. If 
positive, the subject must discontinue study medication.

Use of prohibited treatment outlined in Section 6.2.2.

Any situation in which study participation might result in a safety risk to the subject.

Following emergency unblinding

Emergence of an AE reported as severe and suspected to be related to investigational drug 
or an SAE reported and suspected to be related to the investigational drug.


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
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

Individual serum creatinine increase ≥ 50% compared to baseline (must be confirmed).
Please refer to Section 16.3 for discontinuation criteria due to emerging renal 
abnormalities.

Study drug can be temporarily interrupted as a response to the occurrence of adverse 
events that do not fulfill the requirements above described for permanent discontinuation 
(refer to Section 6.5.1).
Discontinuation of study treatment will be at the discretion of the Investigator under 
the following circumstances:

Any other protocol deviation that results in a significant risk to the subject's safety.

Emergence of adverse event(s) or laboratory abnormalities that in the judgement of 
the Investigator, taking into account the subjects' overall status, prevent the subject from 
continuing participation in the study.
The appropriate personnel from the site and Novartis will assess whether study treatment should 
be discontinued for any subject whose treatment code has been broken inadvertently. 
Unblinding for emergency reasons requires study drug discontinuation.
If a female subject of childbearing potential withdraws from the study prematurely, 
the investigator should recommend her to maintain contraceptive measures for at least 7 days 
after the last dose of the study drug.
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the subject’s premature discontinuation of study treatment 
and record this information.
Subjects who discontinue study treatment or who decide they do not wish to participate in 
the study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see Section 9.1.2 'Withdrawal of Informed Consent'). Where possible, 
they should return for the assessments indicated for EOS (V1999) in the Assessment Schedule 
(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 (Section 9.1.3). 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 the study visit schedule.
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact:

New / concomitant treatments

Adverse Events / Serious Adverse Events


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The investigator must also contact the IRT to register the subject’s discontinuation from study 
treatment.
If discontinuation occurs because treatment code has been broken, please refer to Emergency 
breaking of treatment code Section 6.6.3.
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 (Table 8-1).
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 EU and 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 or until the end of the study.
9.1.4
Study stopping rules
The study may be put on hold pending a full safety data review, if one of the following criteria is 
met:
1. Three or more study medication-related serious adverse events (SAE) reported
2. The Sponsor considers that the number and/or severity of AEs, abnormal 
safety monitoring tests or abnormal laboratory findings justify putting the study on hold.


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The study may resume following the safety review if Lead Investigator(s) and sponsor agree it 
is safe to proceed.
Any restart following a temporary hold due to stopping rules being met will require 
the Competent Authorities and Ethic Committees approve the study to proceed, as required per 
country regulations.
9.1.5
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. 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 and treated as a prematurely withdrawn 
subject and undergo all assessments of the premature withdrawal visit. 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. 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.
9.2
Study completion and post-study treatment
Study completion is defined as when the last subject finishes their 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 
of that decision (e.g. Each subject will be required to complete the study in its entirety and 
thereafter no further study treatment will be made available to them).
All randomized and/or treated subjects should have a safety follow-up call conducted 30 days 
after last administration of study treatment. The information collected is kept as source 
documentation. All SAEs reported during this time period must be reported as described in 
Section 10.1.3 and SOM. Documentation of attempts to contact the subject should be recorded 
in the source documentation.


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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.
Adverse events must be recorded 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:

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

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 study treatment. All adverse events must be treated appropriately.
Treatment may include one or more of the following:

Dose not changed

Dose Reduced/increased

Drug interrupted/withdrawn


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6. Its outcome

not recovered/not resolved

recovered/resolved

recovering/resolving

recovered/resolved with sequelae

fatal

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 study), 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.
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 
Appendix 1.
Follow the instructions found in the SOM for data capture methodology regarding AE collection 
for subjects that fail screening.
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


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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-E2E Guidelines 2004).

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 emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to 
the ICH-E2E Guidelines 2004).
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.
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 must be reported to Novartis safety immediately, without undue delay, but under no 
circumstances later than within 24 hours of obtaining knowledge of the events (Note: If more 
stringent, local regulations regarding reporting timelines prevail). Detailed instructions 
regarding the submission process and requirements are to be found in the investigator folder 
provided to each site.


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
Screen Failures (e.g. a subject who is screened but is not treated or randomized): SAEs 
occurring after the subject has provided informed consent until the time the subject is 
deemed a Screen Failure must be reported to Novartis

Baseline Failures (e.g. A subject who is screened but not randomized/treated after 
the baseline visit ): SAEs collected between time subject signs ICF until time that subject 
is determined to be a baseline failure.

Randomized OR Treated Subjects: SAEs collected between time subject signs ICF until 
30 days after the subject has discontinued or stopped study treatment.
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 
immediately, without undue delay, and under no circumstances later than 24 hours of 
the investigator receiving the follow-up information (Note: If more stringent, local regulations 
regarding reporting timelines prevail). 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 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 (following the last administration of study 
treatment) should only be reported to Novartis Safety if the investigator suspects a causal 
relationship to study treatment.
10.1.4
Pregnancy reporting
Pregnancies
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 Novartis Chief Medical 
Office and Patient Safety (CMO&PS). 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.


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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 recorded on 
the appropriate CRF 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 Dosing 
CRF (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
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 Section 10.1
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 two 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 contributing 
factors are recorded on the appropriate CRFs
Please refer to Table 16-1 in Section 16.2 for complete definitions of liver laboratory triggers 
and liver events.


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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 (i.e. ALT, AST, TBL, 
PT/INR, ALP and G-GT) 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 recorded on the appropriate CRF

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 Section 9.1.1 Discontinuation of 
study treatment), if appropriate

Hospitalization of the subject if appropriate

Causality assessment of the liver event

Thorough follow-up of the liver event should include 

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.

All follow-up information and procedures performed must be recorded as appropriate 
in the CRF.
Refer to the SOM for additional details.
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 8-3.
Abnormal renal event findings must be confirmed after ≥24 hours but ≤ 5 days after first 
assessment.
Every renal laboratory trigger or renal event as defined in Table 16-3 and Table 16-4 should be 
followed up by the investigator or designated personnel at the trial site as summarized in 
Section 16.3, Appendix 3.
Refer to the SOM for additional details.
10.2.3
Data Monitoring Committee
Following the data review in May 2022, it was concluded that the Data Monitoring Committee 
is no longer required.


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10.2.4
Steering Committee
The Steering Committee (SC) will be established comprising investigators participating in 
the trial, i.e. not being Novartis/sponsor representatives from the Clinical Trial Team.
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the clinical trial team, the SC will also 
develop recommendations for publications of study results including authorship rules. 
The details of the role of the steering committee will be defined in the steering committee 
charter.
11
Data Collection and Database management
11.1
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, investigator site staff will not 
be given access to the 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 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 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 data will 
be sent electronically to Novartis (or a designated CRO) at specific timelines.


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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/delegated CRO representative will review the protocol and data capture 
requirements (i.e. eSource 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/delegated CRO/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 CRFs 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 CRFs are performed according to 
the study-specific monitoring plan. No information in source documents about the identity of 
the subjects will be disclosed.


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12
Data analysis and statistical methods
The analysis will be conducted on all subject data at the time the trial ends. Any data analysis 
carried out independently by the investigator should be submitted to Novartis before publication 
or presentation.
No multiplicity adjustments will be considered due to the non-confirmatory nature of this study.
12.1
Analysis sets
For all analysis sets, subjects will be analyzed according to the study treatment(s) received.
The Safety Set includes all subjects who received at least one dose of study treatment whether 
or not being randomized. The safety set will be used in the analysis of all safety variables.
The PD analysis set will include all subjects with available PD data at both baseline and at least 
one post-baseline assessment which are not affected by any protocol deviations.
The PK analysis set will include all subjects with at least one available valid (i.e. not flagged 
for exclusion) PK concentration measurement, who received any study drug and with no 
protocol deviations that affect PK data.
12.2
Subject demographics and other baseline characteristics
Demographic and other baseline data, including disease characteristics, will be listed and 
summarized descriptively by treatment group for the full analysis set.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented.
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term, by treatment group.
12.3
Treatments
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented.
The duration of exposure in days to each treatment group (QBW251 dose or placebo) will be 
summarized by means of descriptive statistics using the safety set.
Concomitant medications and significant non-drug therapies prior to and after the start of 
the study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system, by treatment group.
12.4
Analysis of the primary endpoint(s)
The primary objective of the study is to assess the change from baseline of QBW251 compared 
to placebo on the total number of bacteria over all strains after 12 weeks of treatment. The PD
Analysis Set will be used for analysis of the primary variable, unless otherwise specified.


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12.4.1
Definition of primary endpoint(s)
The primary estimand targets the hypothetical effect as if all patients had stayed on treatment 
for 12 weeks and as if antibiotics other than macrolide had not been available.

Population: patients are defined by the study inclusion and exclusion criteria. 
The protocol defines the use of allowed maintenance therapy for this target 
population, as well as medications that are prohibited.

Variable: change from baseline in bacterial load as measured by the number of 
colony forming units (CFU/ml) of potentially pathogenic microorganisms in sputum 
at week 12. A log10 transformation is applied to the CFU counts before forming 
the change from baseline computing therefore the log ratio to baseline of the bacterial 
load.

Intervention effect of interest: 

Intake of antibiotics other than macrolide and intake of rescue medication

Treatment discontinuation or study participation: hypothetical on treatment CFU counts

Summary measure: difference in variable means (QBW251 compared with placebo)
12.4.2
Statistical model, hypothesis, and method of analysis
The primary analysis will include all available data from subjects in the PD analysis set. 
The CFU counts assessed within 2 weeks after pulmonary exacerbations or during or after last 
dose of antibiotics other than macrolide would be set to missing if a valid unscheduled 
assessment did not happen at that time point for the primary analysis. 
The primary endpoint will be analyzed using a Bayesian repeated measures model with change 
from baseline in CFU counts (on log10-transformed scale) as response, including the fixed 
factors and covariates but are not limited to: treatment group, visit, effect of treatment*visit 
interaction, status of macrolides use at screening, and baseline CFU counts
(on log10-transformed scale) by time interaction. In absence of informative data, non-
informative priors for the model parameters will be used. The prior for placebo may be updated 
as a weakly informative prior and will be specified in the statistical analysis plan, should new 
relevant data become available before the database lock of this study.
A comparison of QBW251 vs. placebo is of primary interest. Based on the fitted Bayesian 
model for repeated measures, the posterior probability of QBW251 effect over placebo for 
log10CFU will be calculated. Statistical evidence will be concluded if there is 90% probability 
that the true effect over placebo for log10CFU is >0.
The posterior probabilities of efficacy will be assessed according to the following criteria:
1. Go / success criteria at final: Better than placebo with high confidence (at least 90% 
probability that the change from baseline in log10CFU for QBW251 is better than placebo, 
i.e. Posterior Prob (delta > 0) > 0.90)
Due to the nonconfirmatory nature of this study, no multiplicity adjustment will be applied.
In addition, the mean and corresponding two-sided 80% credible interval for the QBW251 
difference to placebo from the posterior distribution will be presented.


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12.4.3
Handling of missing values/censoring/discontinuations
Since the primary estimand is related to an effect outside of antibiotics intake, the CFU counts 
assessed within 2 weeks after pulmonary exacerbations or during or after last dose of antibiotics,
other than macrolide, would not be included in the primary estimand. They will be excluded 
from the primary estimand, if a valid unscheduled assessment did not happen at the time point 
for the primary analysis. This is because of the potential confounding effect were expected from 
the use of antibiotics.
If a valid unscheduled assessment happened at the time point for the primary analysis, then 
the CFU data collected during the unscheduled visit will be included in the primary estimand. 
Details about the definition of unscheduled visit is provided in the site manual.
However, the CFU counts at the following visits (if there is no antibiotics use and no pulmonary 
exacerbation) are assumed not to be confounded and will be included in the primary estimand 
of interest.
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 related to primary endpoint will not be explicitly 
imputed. If endpoint measurements are missing at random, an analysis of the available data 
provides consistent estimates of model parameters.
12.4.4
Sensitivity and Supportive analyses
The primary estimand described in Section 12.4.1 is complemented by two supplementary 
estimands. This would allow to assess the robustness of the QBW251 treatment effect on 
bacterial load drop with and without antibiotics use / pulmonary exacerbations that would be 
deemed to affect the outcome of interest.

To estimate the effect of study drug versus placebo without potential confounding due to 
the antibiotics use for exacerbation. All visits after receiving antibiotics other than 
macrolide will not be included in the CFU analysis (they will be set as missing). Note that 
this approach will lead to less data being used than the primary estimand.

To estimate the effect regardless of antibiotic use. This estimand follows the treatment 
policy strategy where antibiotics are used as needed basis on top of study treatment as in 
clinical practice. Thus, the CFU measurements collected during the intake of antibiotics will 
be included in the analysis. The estimate of treatment actually means (treatment + any 
antibiotics) in this context.


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12.5
Analysis of secondary endpoints
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)
12.5.1.1 Proportion of patients with absence of any CFU or CFU counts below 
the limit of quantification
The proportion of patients with absence of any CFU or CFU counts below the limit of 
quantification at week 12 will be analyzed using a logistic regression. The model will include 
treatment, baseline macrolide use as fixed class effects and the number of bronchiectasis 
exacerbations in the 12 months prior to screening as a categorical variable. The estimated odds 
ratios will be displayed along with the associated 80% confidence intervals.
12.5.1.2 Change from baseline in fibrinogen plasma concentration
The change from baseline in fibrinogen is assumed normally distributed. An MMRM will be 
fitted to the changes from baseline in fibrinogen for all time points until Day 84 visit including 
the following fixed factors: treatment group, visit, treatment group by visit interaction, baseline 
macrolide use, and baseline fibrinogen value by time interaction.
12.5.1.3 Change from baseline in rescue medication use (salbutamol/albuterol)
The mean night-time/day-time number of puffs of rescue medication will be calculated for each 
subject for each visit interval.
The total number of puffs of rescue medication will be divided by the total number of (full or 
half) days with non-missing rescue data to derive the mean daily number of puffs of rescue 
medication taken for the patient for each given visit interval. If the number of puffs is missing 
for part of the day (either morning or evening) then a half day will be used in the denominator.
No imputation will be used for missing rescue therapy.
The change from baseline in the mean monthly daily number of puffs of rescue medication will 
be analyzed using a similar MMRM as described in Section 12.5.1.2, with the appropriate 
baseline mean daily number of puffs replacing the baseline fibrinogen value. The total count of 
rescue medication use over the 12 week treatment period may be analyzed using a generalized 
linear model assuming a negative-binomial distribution. Details will be provided in the SAP.
Mean daily number of puffs will be summarized descriptively by monthly interval.
12.5.1.4 Changes from Baseline in pre-bronchodilator FEV1, FVC, measured by 
spirometry
The descriptive statistics for each variable will be provided by treatment.
Change from baseline in FEV1 and FVC will be analyzed using the similar statistical method 
with the same factors of interest described for the secondary efficacy endpoint 
(Section 12.5.1.2). A MMRM will be handled in the statistical model accordingly.


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12.5.1.5 Change from baseline in airway wall and lumen parameters along with 
extent of global and region air trapping as measured by HRCT
Change from baseline in airway wall and lumen parameters will be analyzed using the same 
model as for the efficacy endpoint in Section 12.5.1.2. Global and region air trapping changes 
will be summarized. Contrasts for treatment differences will be provided together with two-
sided 80% confidence intervals.
Any correlations between changes in air trapping and the lung function parameters measured 
by spirometry would be explored.
12.5.2
Safety endpoints
All safety endpoints will be analyzed based on safety set and will be summarized by actually 
received treatment group.
Safety summaries (tables, figures) 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). In addition, a separate summary for death including on treatment 
and post treatment (30 days after the last actual administration of study treatment) deaths will 
be provided. In particular, summary tables for adverse events (AEs) will summarize only on-
treatment events, with a start date during the on-treatment period (treatment-emergent AEs).
The on-treatment period lasts from the date of first administration of study treatment to one 
week after the date of the last actual administration of any study treatment.
Adverse events
All information obtained on adverse events will be displayed by treatment group and subject.
The number (and percentage) of subjects with treatment emergent adverse events (events started 
after the first dose of study medication or events present prior to start of double-blind treatment 
but increased in severity based on preferred term) 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.

by treatment, Standardized MedDRA Query (SMQ) and preferred term.
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation, and adverse events 
leading to dose adjustment or discontinuation
A subject with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class.
Vital signs
All vital signs data will be summarized with standard descriptive statistics by treatment and 
visit/time. The number of patients with vital signs meeting the definition of notably abnormal 
will be presented by parameter.


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12-lead ECG
All ECG data will be listed by treatment group, subject and visit/time, abnormalities will be 
flagged. Summary statistics will be provided by treatment and visit/time.
Clinical laboratory evaluations
All laboratory data will be listed by treatment group, subject, and visit/time and if normal ranges 
are available abnormalities will be flagged. Summary statistics will be provided by treatment 
and visit/time.
Shift tables using the low/normal/high/ (low and high) classification will be used to compare 
baseline to the worst on-treatment value.
12.5.3
Pharmacokinetics
PK analysis set will be used for the analysis of all pharmacokinetic parameters.
Descriptive statistics of QBW251 plasma concentration data will be provided by treatment and 
visit/sampling time point, including the frequency (n, %) of concentrations below the lower 
limit of quantification (LLOQ). Summary statistics of QBW251 plasma concentration data and 
PK parameters will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum, and maximum. An exception to this is Tmax, where median, 
minimum, and maximum will be presented. Concentrations below LLOQ will be treated as zero 
in summary statistics and for PK parameter calculations.
The PK parameters which will be determined from the plasma concentration time data include 
(but not limited to), where possible: Cmax, Cmin, Tmax, AUClast, AUC0-12h, and T1/2,eff 
when feasible. Pharmacokinetic parameters will be determined using WinNonlin Phoenix 
(version 8 or higher).
12.5.4
PK/PD relationships
An exploratory analysis of the relationship between pharmacokinetic and pharmacodynamic 
measures may be performed using a model-based approach, if the data measures permit.
12.5.5
Patient reported outcomes
Quality of Life Questionnaire for Bronchiectasis (Respiratory symptoms) will be summarized 
by treatment groups and visit.
12.6
Analysis of exploratory endpoints
Statistical analysis for exploratory variables will be described in the statistical analysis plan.
12.6.1
Changes from baseline in SGRQ, and EQ-5D-3L
Change from baseline will be provided by treatment group and visit.


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12.6.2
Bronchiectasis exacerbation
The following analyses will be performed to explore any differences in the exacerbation events 
that occur in QBW251 vs placebo:
12.6.2.1 Time to first bronchiectasis exacerbations
The time-to-event analyses will be carried out only upon sufficient number of exacerbation 
events occur during the study to estimate the median in either of the treatment groups.
The time to the first on-treatment bronchiectasis exacerbation (event) is defined as the earliest 
start date of a bronchiectasis exacerbation minus the date of randomization +1. Patients who do 
not experience an exacerbation or discontinued earlier without an exacerbation will be 
considered as censored for analyses purpose at the end of the treatment period. Events which 
occur after randomization and during the treatment period will be included in the analysis.
The hazard ratios for QBW251 compared with placebo and their corresponding 80% confidence 
intervals will be computed using Kaplan-Meier method. The stratification factor may include 
number of exacerbations in the last 12 months as =1 and >1.
The Kaplan-Meier estimates of the survival functions for each treatment will be plotted.
12.6.2.2 Annualized rate of bronchiectasis exacerbations
Using data from EXACT questionnaire, the number of bronchiectasis exacerbations will be 
analyzed using a generalized linear model assuming a negative binomial distribution. The time 
at risk for a patient is defined as the length of time the patient is on treatment and the log (length 
of time) will be used as the offset variable in the model. The model will include 
treatment, baseline macrolides use, and the number of bronchiectasis exacerbations in 
the 12 months prior to screening as categorical variables. An estimate of the rate ratio together 
with 80% confidence intervals and corresponding p-value will be presented.
12.6.3
Biomarkers
Exploratory biomarkers such as change from baseline in inflammatory markers in sputum, 
bacterial load of sputum as well as their association with primary and secondary efficacy 
endpoints will be analyzed. Summary statistics for biomarkers of interest will be provided by 
treatment and visit.
12.6.4
DNA
Exploratory DNA studies are designed to investigate the association between genetic factors 
(genotypes) and clinical assessments (phenotypes) which are collected during the clinical trial. 
Without prior evidence of a strong association, a number of possible associations are evaluated 
with exploratory analyses. A range of statistical tests are used for the analyses. Additional data, 
from other clinical trials, are often needed to confirm associations. Alternatively, if the number 
of subjects enrolled in the study is too small to complete proper statistical analyses, the data 
may be combined, as appropriate, with those from other studies to enlarge the dataset for 
analysis.
Data generated on hypothesis-free platforms will be reported separately (e.g. CSR addendum).


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12.7
Interim analyses
A blinded interim analysis will take place when approximately 14 patients complete Day 84 
assessments to review the sample size assumptions related to bacterial load. The variability of 
primary endpoint (change from baseline in CFU counts) will also be assessed at that time.
Additional interim analyses may be conducted to support decision making concerning 
the current clinical study, or the future of the sponsor's clinical development plan.
All enrolled subjects and the participating investigators will remain blinded during the entire 
study. Only the sponsor may be unblinded at the interim as necessary.
12.8
Sample size calculation
12.8.1
Primary endpoint(s)
This study will enroll approximately 72 patients who will be randomized in a 1:1 ratio to receive 
either QBW251 300 mg or placebo in order to achieve 60 patients who complete the treatment 
period based on the assumption of a 16% drop-out rate. There will be approximately 79% power 
to show that QBW251 is superior to placebo in reducing bacterial load with 10% level of 
significance, assuming a true difference of 1.5 log10 CFU count and a standard deviation of 2.8 
for the change from baseline to Day 84 on log10 scale. Regarding the assumption on the standard 
deviation of the change from baseline in bacterial load (log10 scale), this is derived from two 
historical trials in bronchiectasis and COPD patients with a conservative view. There will be 
about 10% chance to erroneously declare positive PoC (Type 1 error).
The sample size assumptions will be reviewed in a blinded manner when approximately 
14 patients complete the treatment period.
If deemed appropriate, in the case of a higher dropout rate than assumed or a higher variability 
of the primary endpoint in either region, or if there is foreseen a significant imbalance between 
sites in Europe and China, up to 108 subjects may be randomized in order to achieve an adequate 
number of completers.
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 International Conference on Harmonisation (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.


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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.).
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.


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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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References
References are available upon request
Amaral MD, Kunzelmann K (2007) Molecular targeting of CFTR as a therapeutic approach to 
cystic fibrosis. TRENDS in Pharmacological Sciences; 28(7):334-341
Bergougnoux A, Viart V, Miro J, et al (2015) Should diffuse bronchiectasis still be considered 
a CFTR-related disorder. J Cyst Fibros; 14(5):646-653
Bienvenu T, Sermet-Gaudelus I, Burgel PR, et al (2010) Cystic fibrosis transmembrane 
conductance regulator channel dysfunction in non-cystic fibrosis bronchiectasis. Am J Respir 
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Boucher RC (2007) Cystic fibrosis: a disease of vulnerability to airway surface dehydration. 
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Chalmers JD, Smith MP, McHugh BJ, et al (2012) Short- and Long-Term Antibiotic 
Treatment Reduces Airway and Systemic Inflammation in Non–Cystic Fibrosis 
Bronchiectasis. Am J Respir Crit Care Med; 186(7):657-665
Chalmers JD, Goeminne P, Aliberti S, et al (2014) Derivation and validation of the 
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Miller M.R, Hankinson J. et al (2005)a Standardisation of spirometry. Eur Respir J.  
26(2):319-38
Miller M.R, Crapo R.J. et al (2005)b General considerations for lung function testing. Eur 
Respir J. 26:153–161
O'Donnell AE (2008) Bronchiectasis. Chest; 134(4):815–823
O’Sullivan BP, Freedman, SD (2009) Cystic fibrosis. Lancet; 373(9673), 1891-904.


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Pezzulo AA, Tang XX, Hoegger MJ et al (2012) Reduced airway surface pH impairs bacterial 
killing in the porcine cystic fibrosis lung. Nature; 487(7405):109-13.
Polverino E, Goeminne PC, McDonnell MJ et al (2017) European Respiratory Society 
guidelines for the management of adult bronchiectasis. Eur Resp J; 50:1700629;
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Bronchiectasis: final psychometric analyses and determination of minimal important 
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modulators for COPD and other airway diseases. Curr Opin Pharmacol; 34:132-139


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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 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 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

Record the AE and contributing 
factors (e.g. conmeds, med hx, 
lab) in the appropriate CRF
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

Record the AE and contributing 
factors (e.g. conmeds, med hx, 
lab) in the appropriate CRF
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
> 3 × ULN and INR > 1.5

Discontinue the study treatment 
immediately

Hospitalize, if clinically 
appropriate

Establish causality

Record the AE and contributing 
factors (e.g. conmeds, med hx, 
lab) in the appropriate CRF
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

Record the AE and contributing 
factors (e.g. conmeds, med hx, 
lab) in the appropriate CRF
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

Record the AE and contributing 
factors (e.g. conmeds, med hx, 
lab) in the appropriate CRF
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

Record the AE and contributing 
factors (e.g. conmeds, med hx, 
lab) in the appropriate CRF
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit


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Criteria
Actions required
Follow-up monitoring
TBL (isolated)
> 2 × ULN (in the absence 
of known Gilbert syndrome)

Repeat LFT within 48 hours

If elevation persists, discontinue 
the study drug immediately

Hospitalize if clinically 
appropriate

Establish causality

Record the AE and contributing 
factors (e.g. conmeds, med hx, 
lab) in the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until 
resolutionc (frequency at 
investigator discretion)
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

Record the AE and contributing 
factors (e.g. conmeds, med hx, 
lab) in the appropriate CRF
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

Record the AE and contributing 
factors (e.g. conmeds, med hx, 
lab) in the appropriate CRF
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 three 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.
Based on investigator’s discretion investigation(s) for contributing factors for the liver event 
can include: 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.


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16.3
Appendix 3: Specific Renal Alert Criteria and Actions and Event 
Follow-up
Table 16-3
Specific Renal Alert Criteria and Actions
Renal Event
Actions
Confirmed serum creatinine increase 25 – 49%

Consider causes and possible interventions

Follow up within 2-5 days
Serum creatinine increase 50 % +
OR if <18 years old, eGFR < 35 mL/min/1.73 
m2

Consider causes and possible interventions

Repeat assessment within 24-48h if possible

Consider drug interruption or discontinuation 
unless other causes are diagnosed and 
corrected

Consider patient hospitalization and 
specialized treatment
New onset dipstick proteinuria ≥ 3+
OR
Protein-creatinine ratio (PCR) ≥ 1g/g Cr (or 
mg/mmol equivalent as converted by the 
measuring laboratory)

Consider causes and possible interventions

Assess serum albumin & serum total protein

Repeat assessment to confirm

Consider drug interruption or discontinuation 
unless other causes are diagnosed and 
corrected
New onset hematuria ≥ 3+ on urine dipstick
Assess & document

Repeat assessment to confirm

Distinguish hemoglobinuria from hematuria

Urine sediment microscopy

Assess sCr

Exclude infection, trauma, bleeding from 
the distal urinary tract/bladder, menstruation

Consider bleeding disorder
+ Corresponds to KDIGO criteria for Acute Kidney Injury
Additional specialized assessments are available to assess renal function or renal pathology.
(Note: In exceptional cases, when a nephrologist considers a renal biopsy, it is recommended 
to make slide specimen available for evaluation by the RSG to potentially identify project-wide 
patterns of nephrotoxicity.)
Whenever a renal event is identified, a detailed patient history and examination are indicated to 
identify and potentially eliminate risk factors that may have initiated or contributed to the event:

Blood pressure assessment (after 5-minute rest, with an appropriate cuff size)

Signs and symptoms like fever, headache, shortness of breath, back or abdominal pain, 
dysuria or hematuria, dependent or periorbital edema

Changes in blood pressure, body weight, fluid intake, voiding pattern, or urine output

Concomitant events or procedures such as trauma, surgical procedures, cardiac or hepatic 
failure, contrast media or other known nephrotoxin administration, or other diseases or 
causes, e.g., dehydration due to delirium, tumor lysis


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Table 16-4
Renal Event Follow Up
FOLLOW-UP OF RENAL EVENTS
Assess, document and record in CRF

Urine dipstick and sediment microscopy evidence of DIN: crystals, red blood cells 
(dysmorphic/glomerular vs. non-dysmorphic/non-glomerular), white blood cells, tubular epithelial 
cells

Blood pressure and body weight

Serum creatinine, BUN, electrolytes (sodium, potassium, phosphate, calcium), bicarbonate and 
uric acid

Urine output
Review and record possible contributing factors to the renal event (co-medications, other co-morbid 
conditions) and additional diagnostic procedures (MRI etc.) in the CRF
Monitor patient regularly (frequency at investigator’s discretion) until -
-
Event resolution: (sCr within 10% of baseline or PCR < 1 g/g Cr, or ACR <300 mg/g Cr) or
-
Event stabilization: sCr level with ±10% variability over last 6 months or protein-creatinine ratio 
stabilization at a new level with ±50% variability over last 6 months.
-
Analysis of urine markers in samples collected over the course of the DIN event

SAP_001.pdf: 
Biostatistics & Statistical Programming / 
Novartis Institutes for BioMedical Research
QBW251
CQBW251C12201
ClinicalTrials.gov Identifier: NCT04396366
A randomized, patient- and investigator-blinded, placebo-
controlled, parallel group study to assess the safety, 
tolerability, pharmacokinetics and pharmacodynamics of 
QBW251 in patients with bronchiectasis
Statistical Analysis Plan (SAP)
Author(s):
Document type:
SAP Documentation – NIBR
Document status:
Final
Release date:
14-Jul-2023
Number of pages:
18
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Personal Protected Data


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.
Date
Time point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
04-
Feb-
2021
Prior to DB 
lock
Creation of 
initial
version
N/A - First version
NA
14-
Jul-
2023
SAP 
Amendment
Amend for 
protocol 
amendment 
03
and
study 
termination
on 15-JUN-
2022
Section 
1,2,4,5,6,7


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Table of contents
Table of contents .................................................................................................................3
List of tables ........................................................................................................................4
1
Introduction .........................................................................................................................5
1.1
Scope of document ..................................................................................................5
1.2
Study reference documentation ...............................................................................5
1.3
Study objectives.......................................................................................................5
1.4
Study design and treatment......................................................................................7
2
First interpretable results (FIR) ...........................................................................................8
3
Interim analyses...................................................................................................................8
4
Analysis sets ........................................................................................................................8
5
Statistical methods for Pharmacokinetic (PK) parameters..................................................9
5.1
Variables..................................................................................................................9
5.2
Descriptive analyses ................................................................................................9
5.3
Statistical model, assumptions and hypotheses .....................................................10
6
Statistical methods for Pharmacodynamic (PD) parameters.............................................10
6.1
Primary objective...................................................................................................10
6.1.1
Variables ...............................................................................................10
6.1.2
Descriptive analysis ..............................................................................10
6.1.3
Statistical model, assumptions and hypotheses,....................................10
6.1.4
Supportive analysis ...............................................................................11
6.2
Secondary objectives .............................................................................................11
6.2.1
Variables ...............................................................................................11
6.2.2
Descriptive analyses..............................................................................12
6.2.1
Statistical model, assumptions and hypotheses.....................................12
6.2.2
PK/PD relationships..............................................................................14
6.3
Exploratory objectives...........................................................................................15
6.3.1
Variables ...............................................................................................15
6.3.2
Descriptive analyses..............................................................................15
7
Statistical methods for safety and tolerability data............................................................15
7.1
Variables................................................................................................................15
7.2
Descriptive analyses ..............................................................................................15


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List of tables
Table 1-1
Objectives and related endpoints ............................................................5
Table 4-1
Protocol deviation codes and analysis sets..............................................9
Table 6-1
Scoring algorithm for QOL-B Questionnaire (Respiratory 
symptoms domain)................................................................................12


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1
Introduction
1.1
Scope of document
The reporting and analysis process (RAP) documents contain detailed information to aid the 
production of Statistics & Programming input into the Clinical Study Report (CSR) for trial 
“CQBW251C12201”.
The statistical analysis plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol.
1.2
Study reference documentation
The SAP is developed based on the study protocol v03 dated of 02-Dec-2022.
1.3
Study objectives
Table 1-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

To assess the change on sputum bacterial 
colonization

Change from baseline in bacterial load of 
colony forming units (CFU/mL, 1 
CFU/mL = 1 CFU/g) of potentially 
pathogenic microorganisms in 
spontaneous sputum with QBW251 
compared to placebo at week 12
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To assess the change of QBW251 
compared to placebo on sputum bacterial 
clearance

Proportion of subjects with absence of 
any CFU of potentially pathogenic 
bacteria in sputum culture after 12 weeks 
of treatment

To assess the change on patient reported
outcomes on bronchiectasis symptom 
assessment

Changes from baseline in 
Quality of Life Questionnaire for 
Bronchiectasis (QOL-B) (Respiratory 
symptoms domain) after 12 weeks of 
treatment.

To assess the change of fibrinogen 
plasma concentration 

Change from baseline in fibrinogen 
plasma concentration after 12 weeks of 
treatment

To assess the change in rescue 
medication use 

Change from baseline in rescue 
medication use (salbutamol/albuterol) 
after 12 weeks of treatment. 

To assess the change on lung function.

Changes from baseline in pre-
bronchodilator FEV1, FVC after 12 


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Objective(s)
Endpoint(s)
weeks treatment, measured by 
spirometry

To assess the change in airway structure 
and function

Change from baseline in airway wall and 
lumen parameters along with extent of 
global and regional air trapping after 12 
weeks of treatment, as measured by 
HRCT.

To assess the pharmacokinetics of 
QBW251 in patients with bronchiectasis

Assessment of drug exposure (Cmax, 
AUC) and other PK parameters when 
feasible on Days 1 and 28 (for a subset 
of patients at selected sites).
Pre- and post- dose concentration 
(Ctrough and Cmax) on Days 1, 28, 56 
and 84 (for all patients).

To assess the safety and tolerability of 
QBW251 in patients with bronchiectasis

All safety endpoints (including adverse 
events, vital signs, ECG, and safety 
laboratory changes) during the study
Exploratory objective(s)
Endpoint(s) for exploratory objective(s)

To examine the change from baseline on 
sputum bacterial colonization after 12 
weeks of treatment with QBW251 
compared to placebo and at times of 
potential exacerbation for assessments of 
pathogens and bacterial load.

Change from baseline in sputum 
bacterial colonization after 12 weeks of 
treatment measured by 16S rRNA PCR

To assess the change on patient reported 
outcome 

Changes from baseline in the following 
PRO after 12 weeks of treatment

St. George's Respiratory 
Questionnaire (SGRQ)

Euro Quality of Life-5 Dimensions-
3 level (EQ-5D-3L)

To explore the effect of QBW251 on 
additional HRCT outcome measures 

Change from baseline in 
HRCT endpoints for distribution of 
mucus (whole lung and regional),

airway-artery assessments, and scoring 
after 12 weeks of treatment

To assess the effect of QBW251 on 
bronchiectasis exacerbation

Time to first event,

Annualized rate of exacerbations as 
defined by EXACT-PRO 
questionnaire


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Objective(s)
Endpoint(s)

To assess the change on biomarkers of 
inflammation 

Changes from baseline in blood and 
sputum after 12 weeks of treatment in 
markers that may include, but are not 
limited to:

Serum hsCRP

Blood inflammatory cells e.g. 
neutrophils, eosinophils

Sputum inflammatory proteins e.g. 
IL-6, IL-8

Serum protein signatures measured 
by SomaScan (only measured if 
primary endpoint is positive)

To perform assessment of bacterial 
species profile in sputum

Sputum samples will be biobanked for
potential exploration of sputum bacterial 
profile measured by 16s rRNA gene
sequencing

To perform DNA assessments to 
examine whether individual genetic 
variation in genes relating to drug 
metabolism and transportation or 
individual genetic variations in CFTR 
genes or other disease-relevant genetic 
pathways confer differential response to 
QBW251 treatment or correlate with 
disease severity

Genomic analysis in correlation with
exposure to QBW251 or response to
QBW251 or disease severity. DNA will 
be biobanked for potential future
analysis of CFTR mutations and for 
genomic analysis
1.4
Study design and treatment
This is a randomized, patient- and investigator-blinded, placebo-controlled, parallel-group 
study investigating the preliminary efficacy and safety of QBW251 administered orally for 12 
weeks in participants with bronchiectasis. Approximately 72 participants will be randomized in 
a 1:1 ratio to receive either QBW251 300 mg b.i.d. or placebo in order to achieve 60 participants
who complete the treatment period based on the assumption of a 16% dropout rate. The sample 
size assumptions will be reviewed in an interim analysis in a blinded manner when 
approximately 14 participants complete the treatment period.
The study consists of the following periods: Screening, baseline/Day 1, treatment period, and 
end of study assessments (EOS) visit followed by an additional post-treatment safety follow up 
via phone call. The total duration for each patient in the study is up to approximately 19 weeks.
The study design is described in Figure 3-1 below.


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2
First interpretable results (FIR)
First interpretable results (FIR) will not be provided for this trial due to study termination.
3
Interim analyses
A blinded interim analysis is planned for this study when approximately 14 participants will
complete Day 84 post treatment assessment. The purpose of this IA is to confirm sample size 
assumptions while assessing the variability in bacterial colonization of PPMs in this population.
If the variability is larger than the variability assumed originally, a re-estimation/adjustment of 
the sample size may be applied for the rest of the study. 
There will be no pause in enrollment at the time of interim analysis, and subjects may continue 
to be enrolled until the interim analysis is complete.
All enrolled subjects and the participating investigators will remain blinded during the entire 
study. Only the sponsor may be unblinded at the interim as necessary.
4
Analysis sets
For all analysis sets, subjects will be analyzed according to the study treatment(s) received.
No screen failure data will be presented.
The Safety Set includes all subjects who received at least one dose of study treatment. The 
safety set will be used in the analysis of all safety variables.
The PK analysis set will include all subjects with at least one available valid (i.e. not flagged 
for exclusion) PK concentration measurement, who received any study drug and with no 
protocol deviations that affect PK data. The PK serial sub-group set will include all subjects 


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with at least one evaluable drug concentration data sample and who consented to participate in 
the PK serial sub-group.
The PD analysis set will include all subjects with available PD data at both baseline and at least 
one post-baseline assessment that are not affected by any protocol deviations.
The analysis sets and protocol deviation codes are related as follows:
Table 4-1
Protocol deviation codes and analysis sets
Category
Deviation code
Text description of deviation
Data exclusion
Subjects are excluded from Safety analysis in case of these PDs: 
Exclude 
subject 
from 
Safety analysis set 
INCL01
Informed consent was not obtained before 
any assessment
Y
Subjects are excluded from PK analysis in case of these PDs:
Exclude subject from PK 
analysis set
INCL01
Informed consent was not obtained before 
any assessment
Y
OTH07
Patient received incorrect dose
Y
Subjects are excluded from PD analysis in case of these PDs:
Exclude subject from PD 
analysis sets
INCL01
Informed consent was not obtained before 
any assessment
Y
5
Statistical methods for Pharmacokinetic (PK) parameters
5.1
Variables
Summary of PK parameters of all participants in the PK set will include pre-dose concentration 
Ctrough and Cmax on Day 1, Day 28, Day 56 and Day 84. Summary of PK parameters for 
participants in the PK serial sub-group will include Cmax, Cmin, Tmax, AUClast, AUC0-12h, 
and T1/2, eff if feasible on Day 1 and Day 28.
5.2
Descriptive analyses
Plasma concentration data for QBW251 will be listed by treatment, subject and sampling time 
point. Both scheduled and actual times will be included.
Descriptive statistics of QBW251 plasma concentration data will be provided by treatment and 
visit/sampling time point, including the number and frequency (n, %) of concentrations below 
the lower limit of quantification (LLOQ), which will be summarized as zero and reported as 
BLQ in the listing.
Summary statistics of QBW251 plasma concentration data will include mean (arithmetic and 
geometric), SD, CV (arithmetic and geometric), median, minimum, and maximum. If zero 
values occur for the values being summarized due to concentrations below the LLOQ, no 
geometric mean will be calculated.


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All PK parameters of QBW251 will be listed by treatment and subject. Summary statistics will 
be displayed by treatment, using the same summary statistics as for the PK concentrations. An 
exception to this is Tmax, where only median, minimum and maximum will be presented.
All summaries will be based on the PK analysis set. For all listings displaying individual data, 
all subjects will be shown, but subjects not in the PK population and values marked as unreliable 
by the PK Scientist will be flagged.
In addition, the data from this study may be combined with data from other studies and analyzed 
by means of population modeling and reported separately.
5.3
Statistical model, assumptions and hypotheses
No model-based statistical analysis will be performed for PK.
6
Statistical methods for Pharmacodynamic (PD) parameters
6.1
Primary objective
The primary objective of the study is to assess the change from baseline of QBW251 compared 
to placebo on the total number of bacteria over all strains at week 12. The PD Analysis Set will 
be used for analysis of the primary variable.
6.1.1
Variables
The primary variable of the study is the change from baseline in bacterial load as measured by 
the number of colony forming units (CFU) of potentially pathogenic microorganisms in sputum
at week 12. As bacterial load has been found to follow a log-normal distribution, the analysis 
will be based on log10-transformed scale.
6.1.2
Descriptive analysis
The baseline CFU (on log10-transformed scale) of potentially pathogenic microorganisms in 
spontaneous sputum is defined as the bacterial load collected at baseline (on log10-transfromed 
scale). “No growth” means there is no growth from the sputum specimen for that visit. The 
maximum measurable CFU from lab culture will be set as 600,000,000. Thus, any CFU data 
that is higher than 600,000,000 will be considered as 600,000,000 in reporting.
In order to be included in the sputum analysis, a subject must provide a sufficient sputum sample 
at screening, and/or at baseline and at least one post-baseline visit. 
Summary statistics will be provided by treatment group and visit for the primary variable and 
will include mean, standard deviation (SD), coefficient of variation (CV), median, minimum 
and maximum.
6.1.3
Statistical model, assumptions and hypotheses, 
The planned Bayesian repeated measures model will not be performed due to study termination 
and in absence of informative data, the original PoC criteria will not be evaluated as well.
The primary analysis will include all available data from subjects in the PD analysis set.


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Differences between treatment groups (QBW251 versus placebo) for change from baseline in 
CFU counts (on log10-transformed scale) will be analyzed using a mixed model for repeated 
measurements (MMRM). The analysis will be carried out using SAS proc mixed procedure 
with Unstructured covariance structure, with treatment group and visit as fixed effects, baseline 
log (CFU count), status of macrolides use at screening as covariates, adjusting for effect of 
treatment*visit, baseline value*visit. Contrasts for treatment differences will be provided 
together with two-sided 80% confidence intervals.
6.1.3.1
Handling of missing values/censoring/discontinuations
The CFU counts assessed within 2 weeks after bronchiectasis exacerbations or during or after 
last dose of antibiotics will not be included in the primary analysis. This is because of the 
potential confounding effect were expected from the use of antibiotics.
However, the CFU counts at the following visits (if there is no antibiotics use and no 
bronchiectasis exacerbation) are assumed not to be confounded and will be included in the 
primary analysis.
Efficacy data collected during intake of rescue medication will be used for analysis, since no 
confounding effect is expected from the use of rescue medication. Of note, on days of rescue 
medication intake participants are instructed to fill in the e-diary for that day prior to intake of 
rescue medication.
Missing on-treatment data related to the primary endpoint will not be explicitly imputed. The 
repeated measures analysis includes all available information in terms of measurements at all 
times. If endpoint measurements are missing at random, an analysis of the available data 
provides consistent estimates of model parameters.
6.1.3.2
Graphical presentation of results
The individual participant total bacterial load of CFU of potentially pathogenic microorganisms
in sputum will be presented.
6.1.4
Supportive analysis
The planned supportive/supplementary analysis will not be performed due to study termination.
6.2
Secondary objectives
6.2.1
Variables
The secondary pharmacodynamics and efficacy endpoints are as follows:

Proportion of subjects with absence of any CFU of potentially pathogenic bacteria in sputum 
culture.

Changes from baseline in the Quality of life Questionnaire for Bronchiectasis (QOL-B) 
(Respiratory symptoms domain).

Change from baseline in fibrinogen plasma concentration.

Change from baseline in rescue medication use (salbutamol/albuterol)

Change from baseline in pre- bronchodilator FEV1, FVC measured by spirometry.

Change from baseline in airway wall and lumen parameters along with extent of global and 


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regional air trapping, as measured by HRCT.
6.2.2
Descriptive analyses
Summary statistics of change from baseline for each secondary efficacy endpoint will be 
provided by treatment group and visit for all secondary endpoints, if data allows.
6.2.1
Statistical model, assumptions and hypotheses
The modeling for secondary pharmacodynamics objectives planned as per protocol will not be
performed due to the study termination.
The secondary objective analysis will include all available data from subjects in the PD analysis 
set.
Baseline secondary efficacy parameters (QOL-B, fibrinogen, FEV1, FVC) is defined as the 
measurement taken prior to the first dose of study drug (Day 1). If this assessment is missing 
(or is not confirmed to be pre-dose), then the screening assessment will be considered as 
baseline. 
For spirometry data, only “acceptable” spirometry data will be included for analysis.  In case 2 
pre-dose spirometry assessments at -45min and -15min are performed, the first attempt (-45min)
will be used for analysis if it’s acceptable; if the first attempt is not acceptable, then the second 
attempt (-15min) will be used; if the second attempt is also not acceptable, then there would be 
no data available for that timepoint.
Changes from baseline in the Quality of life Questionnaire for Bronchiectasis 
(QOL-B) (Respiratory symptoms domain)
For Quality of Life Questionnaire for Bronchiectasis (QOL-B), the summary statistics for
change from baseline in Respiratory Symptoms scale will be reported by treatment group and 
visit. The Respiratory Symptoms scale scores, with higher scores representing fewer symptoms 
or better functioning. Refer to Table 6-1 for details of response value and the corresponding 
scores for QOL-B Questionnaire (Respiratory symptoms domain) during reporting.
Table 6-1
Scoring algorithm for QOL-B Questionnaire (Respiratory symptoms 
domain)
QUESTION 
NUMBER
QUESTION 
SHORT
QUESTION 
NAME
OPTIONS(CHAR)
OPTIONS(NUMERIC)
NAME
29
BQOL129
Congestion in 
Chest
A lot
1
A moderate amount
2
A little
3
None at all
4
30
BQOL130
Coughing During 
Day Time
A lot
1
A moderate amount
2
A little
3
None at all
4


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31
BQOL131
Cough Up 
Sputum
A lot
1
A moderate amount
2
A little
3
None at all
4
32
BQOL132
Sputum 
Observation
Clear
5
Clear to yellow
4
Yellowish-green
3
Brownish-dark
2
Green with traces of 
blood
1
Don't know
0
33
BQOL133
Shortness Breath 
When Active
Always
1
Often
2
Sometimes
3
Never
4
34
BQOL134
Have You Had 
Wheezing
Always
1
Often
2
Sometimes
3
Never
4
35
BQOL135
Have You Had 
Chest Pain?
Always
1
Often
2
Sometimes
3
Never
4
36
BQOL136
Shortness of 
Breath When 
Walking
Always
1
Often
2
Sometimes
3
Never
4
37
BQOL137
Woken Up Due 
to Coughing
Always
1
Often
2
Sometimes
3
Never
4
37
BQOL137
Woken Up Due 
to Coughing
Always
1
Often
2
Sometimes
3
Never
4
Proportion of subjects with absence of any CFU of potentially pathogenic 
bacteria in sputum culture.


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The number and percentage for participants with no CFU in sputum will be tabulated by 
treatment arm and visit. Percentages will be based on the number of participants for whom 
microbiology results exist per visit.
Change from baseline in rescue medication use (salbutamol/albuterol)
Baseline rescue medication use is defined as the average number of puffs per day in the 
screening period and the morning record at Day 1. All days with data will be used for calculating 
the baseline value.
The total number of puffs of rescue medication will be divided by the total number of (full or 
half) days with non-missing rescue data to derive the mean daily number of puffs of rescue
medication taken for the patient for each given visit interval. If the number of puffs is missing 
for part of the day (either morning or evening) then a half day will be used in the 
denominator. No imputation will be used for missing rescue therapy. Any values >48 for the 
number of puffs of rescue medication in a 12 hour period will be set to missing. These high 
numbers are not realistic and could impact the analysis.
If a participant has only 0 to 6 days of data recorded, the baseline will be set to missing. 
Participants must have at least 7 days of rescue medication data recorded to have a baseline 
level calculated 
The post-baseline treatment period is defined as the period from the evening record of Day 1 
up to the morning assessment following the day of the last dose of double-blind treatment. 
Missing diary data will not be imputed. For the derivations of on-treatment mean weekly and 
mean monthly number of puffs, only values from Day 1 up to the date of last dose of double-
blind treatment will be considered.
The daily number of puffs will be averaged for each week (Week1, Week2, 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 to be calculated. Mean daily number 
of puffs will be summarized descriptively by monthly interval.
Changes from Baseline in airway wall and lumen parameters along with extent 
of global and regional air trapping, as measured by HRCT
The baseline is defined as the HRCT performed after participants have passed all the other 
screening criteria and prior to randomization. Summary statistics of change from baseline in 
airway wall and lumen parameters will be provided. Global and region air trapping changes will 
also be summarized.
Listings for participants’ air trapping measured by HRCT will also be provided.
6.2.2
PK/PD relationships
The exploratory analysis of the relationship between pharmacokinetic and pharmacodynamic 
measures will not be performed because of low sample size resulting from study termination.


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6.3
  Exploratory objectives
The planned analyses for bronchiectasis exacerbation will not be performed due to study
termination.
6.3.1
Variables 
The exploratory endpoints are:

Change from baseline in sputum bacterial colonization measured by 16S rRNA PCR.

Changes from baseline in SGRQ, and EQ-5D-3L

Change from baseline in HRCT endpoints for distribution of mucus (whole lung and 
regional)

Change from baseline of markers in blood and sputum including:

serum hsCRP

blood inflammatory cells (e.g. neutrophils, eosinophils)

sputum inflammatory proteins (e.g. IL-6, IL-8) 
6.3.2
Descriptive analyses
Summary statistics will be provided by treatment group and visit for all exploratory endpoints, 
if data allows.
7
  Statistical methods for safety and tolerability data
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group.
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). 
In addition, a separate summary for death including on treatment and post treatment deaths will 
be provided. In particular, summary tables for adverse events (AEs) will summarize only on-
treatment events, with a start date during the on-treatment period (treatment-emergent AEs).
7.1
Variables
Adverse events, vital signs (blood pressure, pulse rate, body temperature), ECG intervals, 
laboratory measurements, as well as subject demographics, baseline characteristics, and 
treatment information.
7.2
Descriptive analyses
Categorical data will be presented as frequencies and percentages. For continuous data, mean,
standard deviation, median, minimum, and maximum will be presented. Day 1 is defined as 
the date of first study drug administration. Study day is calculated relative to Day 1.
Subject demographics and other baseline characteristics
Demographic, including age, sex, race, ethnicity, and other baseline data including, baseline 
height, baseline weight, baseline BMI, past medical history including smoking history, history 
of bronchiectasis exacerbations and current medical conditions including allergies present 


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before signing the informed consent will be summarized descriptively by treatment group for 
the Safety set, if data allows.
BMI (kg/m^2) = Weight (kg) / [Height (m) * Height (m)]
All data for background and demographic variables will be listed by treatment group and subject. 
Summary statistics will be provided by treatment group. Continuous variables will be 
summarized using descriptive statistics (mean, SD, median, minimum and maximum) and 
categorical variables will be summarized in terms of the number and percentage of subjects in 
each category.
Medical history was coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. History/conditions will be summarized for the safety analysis set, by primary 
system organ class and preferred term, and overall. Verbatim recorded history/conditions will 
be listed together with the coded terms, date of diagnosis/surgery and whether the problem was 
active at the time of first study drug dose.
Subject disposition
A disposition summary will be presented for all subjects in the safety analysis set. This table 
will present the number and percentage of subjects who randomized, completed and 
discontinued early, along with the reasons for early discontinuation.
The number and percentage of subjects in each analysis set will be summarized by treatment 
group. All analysis set results will be presented in listings by subject. A separate listing of all 
subjects excluded from any analysis set and the reasons for their exclusion will be provided.
All study completion data will be listed by subject.
Treatment
Data for study drug administration, rescue medication and concomitant therapies will be listed 
by treatment group and subject.
Summary statistics will be provided for the duration of exposure to study treatment using the 
safety analysis set.
Concomitant medications and significant non-drug therapies prior to and after the start of the
study treatment will be listed and summarized according to the Anatomical Therapeutic
Chemical (ATC) classification system, by treatment group.
Vital signs
Records taken at baseline visit will be considered as baseline value. Otherwise, records take at 
Day 1 will be considered as baseline value. Vital sign data for all subjects will be listed by 
treatment group, subject and visit/time, and abnormalities will be flagged. The normal range 
of vital signs are:

Oral body temperature: 36.5-37.5 °C

Systolic blood pressure: 90-140 mm Hg

Diastolic blood pressure: 50-90 mm Hg

Pulse rate: 50 - 100 bpmD


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ECG evaluations
ECG data will be collected at scheduled visits in single ECG or triplicate ECGs. If triplicate 
ECGs are performed, then average of the non-missing values of the 3 measurements will be 
used in the analysis. ECG data will be listed by treatment, subject and visit/time.
For ECGs, a notable QTc value is defined as a QTcF (Fridericia) interval of ≥450 msec for 
males or ≥460 msec for females.
Clinical laboratory evaluations
All laboratory data will be listed by treatment, subject, and visit/time, if normal ranges are 
available, abnormalities will be flagged. Summary statistics will be provided by treatment and 
visit/time.
Adverse events
All information obtained on adverse events will be displayed by treatment group and subject.
Summary tables for adverse events (AEs) will summarize only on-treatment events, with a 
start date during the on-treatment period (treatment-emergent AEs).
The on-treatment period lasts from the date of first administration of study treatment to 1
week after the last actual administration of any study treatment.
The number (and percentage) of subjects with treatment emergent adverse events (events started 
after the first dose of study medication or events present prior to start of double-blind treatment 
but increased in severity based on preferred term) will be summarized by treatment, primary 
system organ class, preferred term and maximum severity.
Separate summaries will be provided for study medication related adverse events, death
including on treatment and post treatment (30 days after the last actual administration of study 
treatment), serious adverse events, other significant adverse events leading to discontinuation.
A subject with multiple adverse events within a primary system organ class is only counted
once towards the total of the primary system organ class. Listings will be provided for all AEs, 
SAEs and fatal AEs. 
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 
5% 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


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
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.
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.