Conditions: Asthma
Keywords: Asthma QAW039
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 877
Healthy volunteers: no

Brief summary:
This study aimed to determine the efficacy and safety of QAW039 and QAW039 450 mg compared to placebo, when added to GINA (Global Initiative for Asthma) steps 4 and 5 standard-of- care (SoC) asthma therapy (GINA 2016) in the following two populations:

* patient with inadequately controlled severe asthma and high eosinophil counts (eosinophil count at Visit 1 ≥250 cells/ µl) (sub-population)
* patients with inadequately controlled severe asthma (overall study population) Inadequate control is defined as partly controlled or uncontrolled asthma (GINA 2016)

Detailed description:
This study used a randomized, multicenter, double-blind, placebo-controlled parallel-group design in which QAW039 (150 mg and 450 mg) or placebo was added to GINA steps 4 and 5 asthma therapy.

The study included:

* Screening period of up to 2 weeks to assess eligibility;
* Run-in period of approximately 2 weeks and a maximum of 6 weeks on placebo to collect baseline data for efficacy variables and compliance with the Electronic Peak Flow/ eDiary device. Upon completion of the run-in period, all patients who met the eligibility criteria were randomized to one of three treatments: QAW039 150 mg or QAW039 450 mg or placebo once daily in a ratio of 1:1:1.
* Treatment period of 52 weeks (assessment period for all Primary and Secondary Outcome Measures). Clinic visits were scheduled approximately 4 weeks after randomization and then at approximately 8-week intervals during the active-treatment period. Phone calls occurred at specified time points between visits occurring at 8-week intervals. Patients who had successfully completed 52 weeks of treatment in this study were offered an optional participation in a safety study (CQAW039A2315).
* Follow-up period of 4 weeks, investigational and drug-free, following the last dose of study drug. A follow-up visit occurred approximately 4 weeks (i.e., approximately 30 days) following the last dose of study therapy to complete safety assessments and pregnancy testing (if applicable).

The follow-up period applied to all patients except those patients who had entered the optional safety study (CQAW039A2315) directly after the Week 52 study visit

Arms:
arm 1: QAW039 150 mg once daily arm 2: QAW039 450 mg once daily arm 3: Placebo once daily

Interventions: intervention 1: QAW039 intervention 2: QAW039 intervention 3: Placebo
Intervention descriptions: intervention 1: QAW039 150 mg once daily intervention 2: QAW039 450 mg once daily intervention 3: Placebo once daily

Protocol document:
Prot_000.pdf: 
Global Clinical Development - General Medicine
QAW039 / NCT03215758
Clinical Trial Protocol CQAW039A2314
A 52-week, multicenter, randomized, double-blind, placebo-
controlled study to assess the efficacy and safety of 
QAW039 when added to existing asthma therapy in 
patients with uncontrolled severe asthma
Authors:
Document type:
Amended Protocol Version 
EUDRACT number:
2015 003172 67
Version number:
v03 Clean
Development phase:
III
Release date:
10-Feb-2017
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis
Clinical Trial Protocol Template Version 2.0, November, 2013


Novartis
Confidential
Page 2
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms.................................................................................................................9
10
11
11
14
Protocol summary..............................................................................................................15
1
Introduction .......................................................................................................................21
1.1
Background............................................................................................................21
1.2
Purpose ..................................................................................................................22
2
Study objectives.................................................................................................................22
2.1
Primary objective(s)...............................................................................................22
2.2
Secondary objectives .............................................................................................22
23
3
Investigational plan ...........................................................................................................24
3.1
Study design...........................................................................................................24
3.2
Rationale of study design.......................................................................................26
3.3
Rationale of dose/regimen, route of administration and duration of treatment.....27
3.4
Rationale for choice of comparator .......................................................................28
3.5
Purpose and timing of interim analyses/design adaptations..................................28
3.6
Risks and benefits..................................................................................................28
4
Population..........................................................................................................................32
4.1
Inclusion criteria ....................................................................................................32
4.2
Exclusion criteria...................................................................................................34
5
Treatment...........................................................................................................................37
5.1
Protocol requested treatment .................................................................................37
5.1.1
Investigational treatment.......................................................................37
5.1.2
Additional study treatment....................................................................38
5.2
Treatment arms ......................................................................................................38
5.3
Treatment assignment, randomization...................................................................38
5.4
Treatment blinding.................................................................................................39
5.5
Treating the patient................................................................................................39
5.5.1
Patient numbering .................................................................................39


Novartis
Confidential
Page 3
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
5.5.2
Dispensing the investigational treatment ..............................................39
5.5.3
Handling of study treatment..................................................................40
5.5.4
Instructions for prescribing and taking study treatment........................40
5.5.5
Permitted dose adjustments and interruptions of study treatment ........41
5.5.6
Rescue medication ................................................................................41
5.5.7
Background therapy ..............................................................................42
5.5.8
Concomitant treatment..........................................................................42
5.5.9
Prohibited Treatment.............................................................................44
5.5.10
Discontinuation of study treatment .......................................................44
5.5.11
Discontinuation from study...................................................................46
5.5.12
Withdrawal of consent ..........................................................................46
5.5.13
Lost to follow-up...................................................................................46
5.5.14
Emergency breaking of assigned treatment code..................................46
5.5.15
Study completion and post-study treatment..........................................47
5.5.16
Early study termination.........................................................................47
6
Visit schedule and assessments .........................................................................................47
6.1
Information to be collected on screening failures and run-in failures...................59
6.2
Patient demographics/other baseline characteristics .............................................59
6.3
Treatment exposure and compliance .....................................................................60
6.4
Efficacy..................................................................................................................60
6.4.1
Asthma exacerbations ...........................................................................60
6.4.2
Asthma Control Questionnaire (ACQ-5) ..............................................60
6.4.3
Asthma Quality of Life Questionnaire for 12 years and older 
(AQLQ+12)...........................................................................................61
62
63
63
64
6.4.8
Spirometry (FEV1 
)................................................................65
6.4.9
Appropriateness of efficacy assessments..............................................65
6.5
Safety.....................................................................................................................65
6.5.1
Physical examination ............................................................................66
6.5.2
Vital signs..............................................................................................66
6.5.3
Height and weight .................................................................................67
6.5.4
Laboratory evaluations..........................................................................67
6.5.5
Electrocardiogram (ECG) .....................................................................68
6.5.6
Pregnancy and assessments of fertility .................................................68


Novartis
Confidential
Page 4
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
6.5.7
Appropriateness of safety measurements..............................................69
6.6
Other assessments..................................................................................................69
69
69
70
6.6.4
Airways hyper-reactivity test ................................................................70
7
Safety monitoring ..............................................................................................................70
7.1
Adverse events.......................................................................................................70
7.2
Serious adverse events...........................................................................................72
7.2.1
Definition of SAE .................................................................................72
7.2.2
SAE reporting........................................................................................73
7.3
Liver safety monitoring .........................................................................................74
7.4
Renal safety monitoring.........................................................................................75
7.5
Idiosyncratic drug reactions monitoring................................................................76
7.6
Pregnancy reporting...............................................................................................76
8
Data review and database management.............................................................................76
8.1
Site monitoring ......................................................................................................76
8.2
Database management and quality control............................................................77
8.3
Data Monitoring Committee..................................................................................78
8.4
Data collection.......................................................................................................79
8.5
Adjudication Committee........................................................................................79
9
Data analysis......................................................................................................................79
9.1
Analysis sets ..........................................................................................................79
9.2
Patient demographics and other baseline characteristics.......................................80
9.3
Treatments .............................................................................................................80
9.4
Analysis of the primary variable(s) .......................................................................80
9.4.1
Variable(s).............................................................................................80
9.4.2
Statistical model, hypothesis, and method of analysis..........................81
9.4.3
Handling of missing values/censoring/discontinuations.......................83
9.4.4
Supportive analyses...............................................................................84
9.5
Analysis of secondary variables ............................................................................85
9.5.1
Efficacy variables..................................................................................85
9.5.2
Safety variables .....................................................................................88
90
90
90
90


Novartis
Confidential
Page 5
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
9.6
Interim analyses .....................................................................................................90
9.7
Sample size calculation..........................................................................................90
10 Ethical considerations........................................................................................................93
10.1
Regulatory and ethical compliance........................................................................93
10.2
Informed consent procedures.................................................................................93
10.3
Responsibilities of the investigator and IRB/IEC..................................................94
10.4
Publication of study protocol and results...............................................................94
10.5
Quality Control and Quality ..................................................................................94
11 Protocol adherence ............................................................................................................95
11.1
Protocol Amendments ...........................................................................................95
12 References .........................................................................................................................95
13 Appendix 1: Clinically notable laboratory values and vital signs.....................................98
14 Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.....................................................................................................................99
15 Appendix 3: List of IDRs for investigators .....................................................................102
16 Appendix 4: Blood collection logs..................................................................................103
17 Appendix 5: Spirometry Guidance..................................................................................105
17.1
References for appendix ......................................................................................107
108
19 Appendix 7: Estimated Equivalence of Inhaled Corticosteroids.....................................109
20 Appendix 8: Asthma Control Questionnaire ...................................................................110
21 Appendix 9: Asthma Quality of Life Questionnaire for 12 years and older 
(AQLQ+12) .....................................................................................................................112
118
119
List of tables
Table 5-1
Medications allowed under certain conditions......................................42
Table 5-2
Medications to be withheld prior to spirometry....................................43
Table 5-3
Prohibited medications..........................................................................44
Table 6-1
Assessment schedule.............................................................................50
Table 7-1
Specific Renal Alert Criteria and Actions.............................................75
Table 9-1
Power for the primary variable .............................................................92
Table 9-2
Power of each dose for the analyses of key secondary variables..........93
Table 14-1
Liver Event and Laboratory Trigger Definitions ..................................99
Table 14-2
Follow Up Requirements for Liver Events and Laboratory Triggers ...99
Table 15-1
Definition of potential idiosyncratic drug reactions............................102


Novartis
Confidential
Page 6
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
Table 16-1
Time schedule for blood sampling for safety, Total IgE and 
RAST/ImmunoCAP test......................................................................103
 
104
List of figures
Figure 3-1
Study design..........................................................................................25
Figure 9-1
Closed testing procedure for primary and key secondary objectives....82


Novartis
Confidential
Page 7
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
List of abbreviations
Abbreviation:
Explanation:
ACQ
Asthma Control Questionnaire
AE(s)
Adverse Event(s)
AHR
Airway Hyper-reactivity Test
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
AQLQ+12 
Asthma Quality of Life Questionnaire for 12 years and above
AST
Aspartate aminotransferase
ATS/ERS
American Thoracic Society/European Respiratory Society
AUC
Area under the plasma concentration-time curve. The time interval may 
be specified e.g. AUCinf means the interval 0 to infinity. 
b.i.d.
Twice a day
BMI
Body Mass Index
CFR
United States Code of Federal Regulations 
CK
Creatine kinase
CPO
Country Pharma Organization
CRO
Contract Research Organization
CRF
Case Report/Record Form (paper or electronic)
CRTh2
Chemoattractant receptor-homologous molecule expressed on Th2
DK-PGD2
13,14-dihydro-15-ketoprostaglandin D2
DP
Prostaglandin D2 receptor
DMC
Data Monitoring Committee
DS&E
Drug Safety & Epidemiology
ECG
Electrocardiography
EDC
Electronic Data Capture
eGFR
Estimated Glomerular Filtration Rate
FCT
Film-coated tablet
FDA
Food and Drug Administration
FEV1
Forced Expiratory Volume in 1 second
GCP
Good Clinical Practice
GINA
Global Initiative for Asthma
HbA1c
Hemoglobin A1c; Glycosylated Hemoglobin
hCG
Human Chorionic Gonadotropin
ICH
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use
ICS
Inhaled Corticosteroid
IDR
Idiosyncratic Drug Reactions
IEC
Independent Ethics Committee
IgE
Immunoglobulin E
IL
Interleukin


Novartis
Confidential
Page 8
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
Abbreviation:
Explanation:
ImmunoCAPR
Specific IgE test
IN
Investigator Notification
IRB
Institutional Review Board
IRT
Interactive Response Technology
LABA
Long-acting Beta-agonist
LAMA
Long-acting muscarinic antagonist
LC-MS/MS
Liquid chromatography–mass spectrometry/mass spectrometry
LFT
Liver Function Test
LLOQ
Lower Limit of Quantification
LTRA
Leukotriene Receptor Antagonist
MedDRA
Medical Dictionary for Regulatory Activities
MDRD
Modification of Diet in Renal Disease Study
MID
Minimally Important Difference
MMRM
Mixed Model Repeated Measures
NYHA
New York Heart Association
OC/RDC
Oracle Clinical/Remote Data Capture
OCS
Oral corticosteroids
PGD2
Prostaglandin D2
PK
Pharmacokinetic
PoC
Proof of Concept
PRO
Patient Reported Outcome
p.o.
Oral(ly)
q.d.
Quaque die /once a day
QOL
Quality of life
QTcF
Fridericia QT correction formula
RAST
Radioallergosorbent Test
SABA
Short-acting Beta-agonist
SAE(s)
Serious Adverse Event(s)
SD
Standard Deviation
SoC
Standard of care
SUSAR
Suspected Unexpected Serious Adverse Reactions
TD
Treatment Discontinuation
Th2
T helper type 2 cells
UGT
Uridinediphosphate glucuronosyltransferase
ULN
Upper Limit of Normal


Novartis
Confidential
Page 9
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
Glossary of terms
Assessment
A procedure used to generate data required by the study
Cohort 
A group of newly enrolled patients treated at a specific dose and 
regimen (i.e. treatment group) at the same time
Control drug
Any drug (an active drug or an inactive drug, such as a placebo) 
which is used as a comparator to the drug being tested in the trial
Dose level
The dose of drug given to the patient (total daily or weekly etc.)
Enrollment
Point/time of patient entry into the study at which informed 
consent must be obtained (i.e. prior to starting any of the 
procedures described in the protocol)
Epoch 
A portion of the study which serves a specific purpose. Typical 
Epochs are: screening/recruitment, wash-out, treatment, and 
follow-up
Investigational drug
The drug whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is 
synonymous with “investigational new drug” or “investigational 
medicinal product.”
Investigational treatment
All investigational drug(s) whose properties are being tested in the 
study as well as their associated treatment controls. 
This includes any placebos, any active controls, as well as 
approved drugs used outside of their indication/approved dosage 
or tested in a fixed combination. 
Investigational treatment generally does not include protocol-
specified concomitant background therapies  when these are 
standard treatments in that indication
Medication number
A unique identifier on the label of each investigational/study drug 
package in studies that dispense medication using an IRT system
Protocol
A written account of all the procedures to be followed in a trial, 
which describes all the administrative, documentation, analytical 
and clinical processes used in the trial.
Premature subject/patient 
withdrawal
Point/time when the patient exits from the study prior to the 
planned completion of all study treatment administration and/or 
assessments; at this time all study treatment administration is 
discontinued and no further assessments are planned, unless the 
patient will be followed for progression and/or survival
Randomization number
A unique identifier assigned to each randomized patient, 
corresponding to a specific treatment arm assignment
Study drug/ treatment
Any single drug or combination of drugs administered to the 
patient as part of the required study procedures; includes 
investigational drug (s), active drug run-ins or background therapy 
Study/investigational 
treatment discontinuation
Point/time when patient permanently stops taking 
study/investigational treatment  for any reason; may or may not 
also be the point/time of premature patient withdrawal
Subject Number 
A number assigned to each patient who enrolls into the study 
Variable
A measured value or assessed response that is determined in 
specific assessments and used in data analysis to evaluate the 
drug being tested in the study


Novartis
Confidential
Page 10
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314


Novartis
Confidential
Page 11
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314


Novartis
Confidential
Page 12
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314


Novartis
Confidential
Page 13
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314


Novartis
Confidential
Page 14
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314


Novartis
Confidential
Page 15
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
Protocol summary
Protocol number
CQAW039A2307
Title
A 52-week, multicenter, randomized, double-blind, placebo-controlled 
study to assess the efficacy and safety of QAW039 when added to 
existing asthma therapy in patients with uncontrolled severe asthma.
Brief title
Study of efficacy and safety of QAW039 in male and female patients (≥12 
years) with severe asthma inadequately controlled with standard of care 
asthma treatment.
Sponsor and Clinical 
Phase
Novartis, Phase III.
Investigation type
Drug.
Study type
Interventional.
Purpose and rationale
The overall purpose of this study is to determine the efficacy and safety 
of QAW039 (150 mg and 450 mg once daily), compared with placebo, 
when added to GINA steps 4 and 5 standard-of-care (SoC) asthma 
therapy (GINA 2016), in patients with inadequately controlled severe 
asthma and high eosinophil counts (eosinophil count at Visit 1 
≥250 cells/µl).  Inadequate control is defined as partly controlled or 
uncontrolled asthma (GINA 2016).
The study will also determine the efficacy and safety of QAW039 (150 mg 
and 450 mg once daily), compared with placebo, in the overall study 
population.
The rationale for this approach is to determine whether QAW039 reduces 
the rate of moderate-to-severe asthma exacerbations in the subset of 
patients with severe asthma and high eosinophil counts (≥250 cells/µl) as 
well as in the overall study population regardless of eosinophil counts. 
Primary Objectives 
In patients with severe asthma and high eosinophil counts (≥250 cells/µl) 
receiving SoC asthma therapy, to demonstrate the efficacy (as measured 
by rate of moderate-to-severe asthma exacerbations) of at least one dose 
level of QAW039 (150 mg or 450 mg once daily), compared with placebo, 
at the end of the 52-week active-treatment epoch.
In patients with severe asthma receiving SoC asthma therapy, to 
demonstrate the efficacy (as measured by rate of moderate-to-severe 
asthma exacerbations) of at least one dose level of QAW039 (150 mg or 
450 mg once daily), compared with placebo, at the end of the 52-week 
active-treatment epoch.
Secondary Objectives
In patients with severe asthma and high eosinophil counts (≥250 cells/µl) 
receiving SoC asthma therapy:

To demonstrate the efficacy of at least one dose level of QAW039 
(150 mg or 450 mg once daily), compared with placebo, with respect 
to change from baseline in Asthma Quality of Life Questionnaire 
(AQLQ+12) scores at the end of the 52-week active-treatment epoch.

To demonstrate the efficacy of at least one dose level of QAW039 
(150 mg or 450 mg once daily), compared with placebo, with respect 
to change from baseline in Asthma Control Questionnaire-5 (ACQ-5) 


Novartis
Confidential
Page 16
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
score at the end of the 52-week active-treatment epoch.

To demonstrate the efficacy of at least one dose level of QAW039 
(150 mg or 450 mg once daily), compared with placebo, with respect 
to change from baseline in pre-dose FEV1 at the end of the 52-week 
active-treatment epoch.

To assess the safety of QAW039 (150 mg and 450 mg once daily), 
compared with placebo, with respect to adverse events, 
electrocardiograms (ECGs), vitals sign, laboratory tests and 
hypersensitivity reactions.
In all patients with severe asthma receiving SoC asthma therapy:

To demonstrate the efficacy of at least one dose level of QAW039 
(150 mg or 450 mg once daily), compared with placebo, with respect 
to change from baseline in Asthma Quality of Life Questionnaire 
(AQLQ+12) scores at the end of the 52-week active-treatment epoch.

To demonstrate the efficacy of at least one dose level of QAW039 
(150 mg or 450 mg once daily), compared with placebo, with respect 
to change from baseline in Asthma Control Questionnaire-5 (ACQ-5) 
score at the end of the 52-week active-treatment epoch.

To demonstrate the efficacy of at least one dose level of QAW039 
(150 mg or 450 mg once daily), compared with placebo, with respect 
to change from baseline in pre-dose FEV1 at the end of the 52-week 
active-treatment epoch.

To assess the safety of QAW039 (150 mg and 450 mg once daily), 
compared with placebo, with respect to adverse events, 
electrocardiograms (ECGs), vitals sign, laboratory tests and 
hypersensitivity reactions.
Study design
This study uses a randomized, multicenter, double-blind, placebo-
controlled parallel-group study design in which QAW039 or placebo is 
added to GINA steps 4 and 5 asthma therapy.
The study will include: 

a Screening epoch of up to 2 weeks to assess eligibility; 

a Run-in epoch of approximately 2 weeks and a maximum of 6 
weeks to collect baseline data for efficacy variables and compliance 
with the Electronic Peak Flow/ eDiary device (if a patient experiences 
an asthma exacerbation during the run-in epoch, the run-in epoch 
must be extended to 6 weeks to permit for resolution of the asthma 
exacerbation before randomization.  The run-in epoch should only be 
extended beyond 2 weeks (+/- 5 days) for an asthma exacerbation.);

a Treatment epoch of 52 weeks; 

a Follow-up epoch of 4 weeks, investigational and drug-free, 
following the last dose of study drug.
Population
The study population will include approximately 846 males and females 
aged ≥12 years with inadequately controlled severe asthma (partly 
controlled or uncontrolled asthma on treatment at GINA steps 4 and 5).
Approximately 15% of the patients will be adolescents (aged ≥12 to <18 
years).
Approximately two thirds of randomized patients will have a blood 
eosinophil count ≥ 250 cells/µl and one third a blood eosinophil count < 
250 cells/µl.
Inclusion criteria

Written informed consent and assent (if applicable) must be obtained 
within 14 days prior to or at Visit 1 before any assessment is 


Novartis
Confidential
Page 17
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
performed including any adjustment to asthma medication.

Male and female patients aged ≥12 years (or ≥ lower age limit 
allowed by health authority and/or ethics committee/institutional 
review board approvals).   

Patients must have a diagnosis of asthma (according to GINA 2016) 
for a period of at least 24 months prior to Visit 1.

Patients have been treated with:

Medium or high-dose inhaled corticosteroids (ICS) plus long-
acting beta agonist (LABA), or 

Medium or high-dose ICS plus leukotriene receptor antagonist 
(LTRA), or

Medium or high-dose ICS plus theophylline, or

Medium or high-dose ICS plus Long-acting muscarinic 
antagonist (LAMA), or

Medium or high-dose ICS plus LABA plus LAMA, or

Medium or high-dose ICS plus LABA plus LTRA, or

Medium or high-dose ICS plus LABA plus theophylline,
with or without maintenance oral corticosteroids for at least 3 months 
prior to Visit 1. The doses must have been stable for at least 4 
weeks prior to Visit 1. 

See GINA 2016 for the definition of medium and high-dose 
ICS (Appendix 7 contains the estimated equivalence of 
inhaled corticosteroids per GINA 2016).

For patients aged ≥18 years, FEV1 of ≤80% of the predicted normal 
value for the patient, after withholding bronchodilators at Visit 1 and 
Visit 101.

For patients aged 12 to <18 years, FEV1 of ≤90% of the predicted 
normal value for the patient, after withholding bronchodilators at Visit 
1 and Visit 101.

Demonstration of inadequate control of asthma based on an ACQ 
score ≥1.5 at Visit 1.

A history of 2 or more asthma exacerbations within the 12 months 
prior to Visit 1 that required either:

Treatment with systemic corticosteroids (tablets, suspension or 
injection) 
OR

Hospitalization (defined as an inpatient stay or >24-hour stay in 
an observation area in the emergency room of other equivalent 
facility.

A clinical diagnosis of asthma supported by at least one of the 
following: 

An increase of ≥12% and ≥200 ml in FEV1 approximately 10 to 
15 minutes after administration of 400 mcg of 
salbutamol/albuterol (or equivalent dose) prior to randomization.   
Spacer devices are not permitted during reversibility testing.  All 
patients must perform a reversibility test at Visit 1.  If reversibility 
is not demonstrated at Visit 1*, the following historical 
information may be used:

Documented evidence of reversibility that was performed 
according to ATS/ERS guidelines (ATS/ERS 2005) within
the 2 years prior to Visit 1.  Where a patient is assessed as 


Novartis
Confidential
Page 18
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
eligible based on historical evidence of reversibility, a copy 
of the original printed spirometry report with relevant 
spirometry tracings must be available as source 
documentation.

Documented evidence of a positive airways hyper-reactivity 
(AHR) test result within the 2 years prior to or at Visit 101, 
defined as a provoked fall in FEV1 of 20% by methacholine 
at ≤8 mg/ml (or histamine ≤10 mg/ml or acetylcholine <20 
mg/mL) when not on ICS or ≤16 mg/ml or histamine ≤20 
mg/ml or acetylcholine <40 mg/mL) on ICS therapy 
performed according to ATS/ERS guidelines.
*NOTE: If reversibility is not demonstrated at Visit 1 and 
documented evidence for one of the other criteria for a clinical 
diagnosis of asthma is not met, then the reversibility test may 
be repeated at Visit 101.
Key exclusion criteria

Use of other investigational drugs within 5 half-lives of enrollment, or 
within 30 days until the expected pharmacodynamic effect has 
returned to baseline, whichever is longer.

Patients who have participated in another trial of QAW039 (i.e. 
patient received study medication [active (QAW039), placebo or 
other].

Patients with a resting QTcF (Fridericia) ≥450 msec (male) or ≥460 
msec (female) at Visit 1 or at Visit 101.

Patients with a history of malignancy of any organ, treated or 
untreated, whether or not there is evidence of local recurrence of 
metastases, with the exception of local basal cell carcinoma of the 
skin.

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 laboratory test.

Women of child-bearing potential, defined as all women 
physiologically capable of becoming pregnant, unless they are using 
effective methods of contraception during dosing of study treatment. 

Patients who have a clinically significant laboratory abnormality at the 
Visit 1 laboratory test.

Patients with serious co-morbidities including, but not limited to, 
neurodegenerative diseases, rheumatoid arthritis and other 
autoimmune diseases.

Patients on >20 mg of simvastatin, > 40 mg of atorvastatin, >40 mg 
of pravastatin, or >2 mg of pitavastatin.  Statin doses less than or 
equal to these doses as well as other statins will be permitted during 
the study.

Patients on any statin therapy with a CK level >2 X ULN at Visit 1.

Patients with a history of conditions other than asthma that could 
result in elevated eosinophils (e.g., hypereosinophilic syndromes, 
Churg-Strauss Syndrome, eosinophilic esophagitis).  Patients with 
known parasitic infestation within 6 months prior to Visit 1 are also 
excluded.
Investigational and 
reference therapy

QAW039 150 mg once daily

QAW039 450 mg once daily

Placebo to QAW039 once daily


Novartis
Confidential
Page 19
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
Efficacy assessments

Asthma exacerbations

Asthma Quality of Life Questionnaire for 12 years and older 
(AQLQ+12)

Asthma Control Questionnaire (ACQ-5)

Spirometry (Pre-dose FEV1)
Safety assessments

History and physical examination

Vital signs

Hematology

Blood chemistry including liver function tests, metabolic panels, 
amylase, lipase and hsCRP.

CK-MB and Troponin I (in response to CK results outside of the 
normal range)

HbA1c (collected at screening only)

Urinalysis

Pregnancy test (females of childbearing potential)

ECG

Adverse events including serious adverse events
Data analysis
The primary variable for this study is the number of moderate-to-severe 
asthma exacerbations experienced by each patient per patient year of 
follow-up. The primary variable will be analyzed using a negative binomial 
regression model with the natural logarithm of the duration of follow-up as 
an offset variable, treatment group, randomization strata and region as 
fixed class effects, as well as the natural logarithm of the number of 
asthma exacerbations in the 12 months prior to screening and the 
baseline pre-dose FEV1 as continuous linear covariates. Missing data will 
be imputed assuming no further treatment effect versus placebo for 
QAW039 patients that discontinue treatment and are lost to follow-up due 
to (or following a treatment discontinuation due to) lack of efficacy, 
adverse events or death. In contrast a continued treatment effect for 
QAW039 patients being lost to follow-up for reasons likely to be unrelated 
to study treatment (e.g. lost to follow-up, withdrew consent) will be 
imputed.
The superiority of QAW039 over placebo will be considered confirmed if 
at least one of the four primary null hypotheses regarding the 
exacerbation rates is rejected in favor of the respective two-sided 
superiority alternative hypothesis. 
The familywise type I error rate will be controlled at the two -sided 5% 
level across the primary and key secondary null hypotheses using a 
closed testing procedure. In this closed testing procedure the primary null 
hypotheses about exacerbations for each dose and population act as 
gatekeepers for the key secondary null hypotheses for the same dose 
and population.
188 patients per arm in the subpopulation with blood eosinophils ≥ 250 
cells/μl and 282 patients per arm in the overall population corresponding 


Novartis
Confidential
Page 20
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
to a total sample size of 846 patients provide greater than 80% power for
demonstrating the superiority of each dose of QAW039 compared to 
placebo in the subpopulation with blood eosinophils ≥ 250 cells/μl and 
overall population. Treatment discontinuation rate of 15% by 1 year is 
assumed in the active treatment groups and the placebo group. No 
further treatment effect versus placebo has been assumed during the off-
treatment period. Additionally, the planned sample size will give 80% 
power for FEV1 for each dose in the subpopulation at the resulting local 
two-sided significance level of 1.625% and 90% power for each dose in 
the overall population at the resulting local two-sided significance level of 
0.698% once the respective primary null hypothesis has been rejected. It 
was assumed that QAW039 achieves a difference of 150 mL against 
placebo in FEV1 after 52 weeks for patients that remain on treatment. A 
SD of 380 mL was assumed for FEV1.
The key secondary variables of this trial are AQLQ+12, ACQ-5 and 
average of the two pre-dose FEV1 assessments at the end of the 52 
week treatment period. 
For each key secondary variable, QAW039 dose and population the null 
hypothesis that the difference to placebo at week 52 is zero will be tested 
versus the two-sided alternative hypothesis that the treatment difference 
at week 52 ≠0 using analysis of covariance. Prior to analysis, missing 
values for key secondary variables will be imputed in a similar manner as 
for the primary variable.
Safety summaries will be primarily based on on-treatment data for the 
safety set with selected tables also presented for the all data after the first 
intake of study drug, while all databased safety data will be listed.
Key words
Efficacy and safety of QAW039, placebo-controlled, add-on to standard 
of care, uncontrolled severe asthma, female and male patients ≥12 years


Novartis
Confidential
Page 21
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
1
Introduction
1.1
Background
Asthma presents a major global health burden. Despite existing therapies, there is still 
significant unmet medical need in asthma, with an estimated 300 million people affected 
worldwide. The World Health Organization estimates that 15 million disability–adjusted life 
years are lost annually due to asthma, representing 1% of the total global burden. Annual 
worldwide deaths have been estimated at 250,000 (Masoli, et al 2004). Uncontrolled asthma 
has a prevalence of greater than 6 million patients worldwide. 
Severe asthma is defined as asthma that requires treatment with high dose inhaled 
corticosteroids (ICS) plus a second controller and/or systemic corticosteroids to prevent it 
from becoming "uncontrolled" or that remains "uncontrolled" despite this therapy. Severe 
asthma is a heterogeneous condition consisting of phenotypes such as eosinophilic asthma 
(Chung, et al 2014). This subgroup has also been defined as "refractory" asthma (Proceedings 
of the ATS workshop on refractory asthma 2000).
Recurrent exacerbations are a major problem in some patients with severe asthma and can 
predominate in the subgroup with eosinophilic airway inflammation (Haldar, et al 2009). A 
number of therapeutic interventions impact on eosinophilic airway inflammation as measured 
by sputum eosinophilia. These include inhaled and oral corticosteroids and a number of 
biologic therapies (including anti-IL-5, anti-IL-5R, anti-IgE, and anti-IL-4Rα therapies). 
Generally, when a therapeutic agent has successfully suppressed sputum eosinophil levels, 
evidence of efficacy, as measured by a reduction in asthma exacerbations, has also been 
demonstrated (Pavord, et al 2012; Nowak, et al 2015; Wenzel, et al 2013; Takaku, et al 2013). 
In more severe asthma, inhaled and oral corticosteroids may not be as effective in reducing 
sputum eosinophilia as they are in milder disease (Wenzel, et al 2005; Nair, et al 2009). 
Consequently, there remains a need for well tolerated, easily-administered, anti-inflammatory 
therapies with the capability of suppressing sputum eosinophilia and reducing asthma 
exacerbations, particularly, for those patients appearing to be steroid resistant.
Chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2) is a receptor 
for prostaglandin D2 (PDG2) which is one of the major prostanoid inflammatory mediators 
identified in asthma.  QAW039 is a CRTh2 antagonist expected to provide benefit in asthma 
by binding to CRTh2 receptors on eosinophils, basophils, and T lymphocytes in the blood and 
tissues; thus, inhibiting migration and activation of these cells into the airway tissues and 
blocking the PGD2-driven release of Th2 cytokines (Chevalier, et al 2005). Since these are 
the major effector cells and soluble factors driving airway inflammation in asthma, treatment 
with QAW039 should result in a decrease in these parameters of airway inflammation as well 
as a clinical improvement in asthma.  In support of this premise are the results of Study 
CQAW039A2208: a randomized, placebo-controlled, 12-week sputum study of QAW039 
(225 mg BID), compared with placebo, in patients with severe eosinophilic asthma.  In this 
study, QAW039 demonstrated a fall in sputum eosinophils of 71% (geometric mean) after 12 
weeks treatment.  
Given published results with other asthma therapies in which a reduction in sputum 
eosinophils is associated with a reduction in asthma exacerbations (Haldar, et al 2009; Pavord, 


Novartis
Confidential
Page 22
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
et al 2012), and the observed reduction in sputum eosinophils in Study CQAW039A2208, it is 
postulated QAW039 will reduce the rate of asthma exacerbations.
1.2
Purpose 
The overall purpose of this study is to determine the efficacy and safety of QAW039 (150 mg 
and 450 mg once daily), compared with placebo, when added to GINA steps 4 and 5 standard-
of-care (SoC) asthma therapy (GINA 2016)†, in patients with inadequately controlled severe 
asthma and high eosinophil counts (eosinophil count at Visit 1 ≥250 cells/ µl).  Inadequate 
control is defined as partly controlled or uncontrolled asthma (GINA 2016).
The study will also determine the efficacy and safety of QAW039 (150 mg and 450 mg once 
daily), compared with placebo, in the overall study population.  
This approach will permit the determination of the effect of QAW039 in reducing asthma 
exacerbations in the subset of patients with severe asthma and high eosinophil counts as well 
as in the overall study population regardless of eosinophil counts. 
†Medium or high-dose ICS plus a second controller and/or systemic corticosteroids.
2
Study objectives
2.1
Primary objective(s)

In patients with severe asthma and high eosinophil counts (≥250 cells/µl) receiving SoC 
asthma therapy, to demonstrate the efficacy (as measured by rate of moderate-to-severe 
asthma exacerbations) of at least one dose level of QAW039 (150 mg or 450 mg once 
daily), compared with placebo, at the end of the 52-week active-treatment epoch.

In all patients with severe asthma receiving SoC asthma therapy, to demonstrate the 
efficacy (as measured by rate of moderate-to-severe asthma exacerbations) of at least one 
dose level of QAW039 (150 mg or 450 mg once daily), compared with placebo, at the end 
of the 52-week active-treatment epoch.
2.2
Secondary objectives
In patients with severe asthma and high eosinophil counts (≥250 cells/µl) receiving SoC 
asthma therapy:

To demonstrate the efficacy of at least one dose level of QAW039 (150 mg or 450 mg 
once daily), compared with placebo, with respect to change from baseline in Asthma 
Quality of Life Questionnaire (AQLQ+12) scores at the end of the 52-week active-
treatment epoch.

To demonstrate the efficacy of at least one dose level of QAW039 (150 mg or 450 mg 
once daily), compared with placebo, with respect to change from baseline in Asthma 
Control Questionnaire-5 (ACQ-5) score at the end of the 52-week active-treatment epoch.

To demonstrate the efficacy of at least one dose level of QAW039 (150 mg or 450 mg 
once daily), compared with placebo, with respect to change from baseline in pre-dose   
FEV1 at the end of the 52-week active-treatment epoch.


Novartis
Confidential
Page 23
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314

To assess the safety of QAW039 (150 mg and 450 mg once daily), compared with placebo, 
with respect to adverse events, electrocardiograms (ECGs), vitals sign, laboratory tests 
and hypersensitivity reactions.
In all patients with severe asthma receiving SoC asthma therapy:

To demonstrate the efficacy of at least one dose level of QAW039 (150 mg or 450 mg 
once daily), compared with placebo, with respect to change from baseline in Asthma 
Quality of Life Questionnaire (AQLQ+12) scores at the end of the 52-week active-
treatment epoch.

To demonstrate the efficacy of at least one dose level of QAW039 (150 mg or 450 mg 
once daily), compared with placebo, with respect to change from baseline in Asthma 
Control Questionnaire-5 (ACQ-5) score at the end of the 52-week active-treatment epoch.

To demonstrate the efficacy of at least one dose level of QAW039 (150 mg or 450 mg 
once daily), compared with placebo, with respect to change from baseline in pre-dose 
FEV1 at the end of the 52-week active-treatment epoch.

To assess the safety of QAW039 (150 mg and 450 mg once daily), compared with placebo, 
with respect to adverse events, electrocardiograms (ECGs), vitals sign, laboratory tests 
and hypersensitivity reactions.


Novartis
Confidential
Page 24
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
3
Investigational plan
3.1
Study design
This study uses a randomized, multicenter, double-blind, placebo-controlled parallel-group 
study design in which QAW039 or placebo is added to GINA steps 4 and 5 asthma therapy 
(Figure 3-1).  
Within 14 days prior to or at Visit 1, an informed consent will be obtained from patients 
before any study related assessments or procedures are performed. All patients signing 
informed consent must be registered in the Interactive Response Technology (IRT). Asthma 
and other medications and eligibility criteria will be reviewed. Patients will be instructed 
regarding medications to be withheld prior to spirometry for Visit 101 (See Section 5.5.8).
Approximately 2400 patients will be screened to randomize 846 patients into this study.
The study will include: 

a Screening epoch of up to 2 weeks to assess eligibility;

a Run-in epoch of approximately 2 weeks and a maximum of 6 weeks to collect baseline 
data for efficacy variables and compliance with the Electronic Peak Flow/ eDiary device
(if a patient experiences an asthma exacerbation during the run-in epoch, the run-in epoch 
must be extended to 6 weeks to permit for resolution of the asthma exacerbation before 
randomization.  The run-in epoch should only be extended beyond 2 weeks (+/- 5 days) 
for an asthma exacerbation.);

a Treatment epoch of 52 weeks;

a Follow-up epoch of 4 weeks, investigational and drug-free, following the last dose of 
study drug. Note: the follow-up epoch applies to all patients except those patients who 
enter the safety study directly after Visit 299.


Novartis
Confidential
Page 25
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
Figure 3-1
Study design
Upon completion of the run-in epoch, all patients who met the eligibility criteria will be 
randomized to 1 of 3 treatments (QAW039 [150 mg or 450 mg once daily] or placebo once 
daily) in a ratio of 1:1:1.  Randomized patients will stratified according to their peripheral 
blood eosinophil counts (<250 cells/l or ≥250 cells/l), patient age (<18 years or ≥18 years),
and their baseline use or non-use of oral corticosteroids as part of their SoC asthma therapy at 
Visit 1.  Clinic visits will be scheduled approximately 4 weeks after randomization and then at 
approximately 8-week intervals during the active-treatment epoch.  Phone calls will occur at 
specified time points between visits occurring at 8-week intervals (see schedule of 
assessments Table 6-1).  A follow-up visit will occur approximately 4 weeks (i.e., 
approximately 30 days) following the last dose of study therapy to complete safety 
assessments and pregnancy testing (if applicable). Please refer to the assessment schedule 
(Section 6) for a list of procedures to be conducted at each visit.
A Safety Study of QAW039 is planned.  At sites participating in the Safety Study, patients 
who successfully complete 52 weeks of treatment in this study (Study A2307) may be offered 
participation in the Safety Study; patient participation in the Safety Study will be optional. 
The study design and procedures for the Safety Study will be described in a separate protocol.
Note: 
Patients experiencing an asthma exacerbation during the run-in epoch should receive 
treatment for their exacerbation, and remain in the run-in epoch until the subject has returned 
to their baseline asthma status for at least 2 weeks (2 weeks=14 days). If patients do not return 
to their baseline status for at least 2 weeks prior to Visit 199, patients will not be eligible for 
randomization and will be designated a run-in failure.
In addition to periodic unblinded safety reviews by an independent Data Monitoring 
Committee, a single futility interim analysis is planned as described in Section 3.5.


Novartis
Confidential
Page 26
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
3.2
Rationale of study design
This randomized, double-blind, parallel-group, placebo-controlled, design supports the 
assessment of efficacy as well as safety of QAW039 as add-on treatment for patients with 
inadequately controlled severe asthma otherwise treated according to GINA 2016 (steps 4 and 
5) guidelines. According to GINA guidelines, the goals of asthma therapy are to attain asthma 
control and reduce future risk of asthma worsening while maintaining minimal side effects of 
therapy.  By maintaining good asthma control in patients with appropriate use of therapies, 
potential future risk to patients may be reduced. The endpoints included in this study measure 
symptomatic and objective parameters of asthma control (symptomatic parameters: daytime 
and nighttime asthma symptoms, SABA use, quality of life, Asthma Control Questionnaire 
[ACQ] scores; objective: lung function [FEV1, peak flow]) and future risk (moderate-to-
severe asthma exacerbations, longitudinal lung function) in patients at the end of 52 weeks of 
therapy.  
Patient population 
The overall purpose of this study is to determine the efficacy and safety of QAW039 (150 mg 
and 450 mg once daily), compared with placebo, when added to GINA steps 4 and 5 standard-
of-care (SoC) asthma therapy (GINA 2016), in patients with inadequately controlled severe 
asthma and high eosinophil counts (eosinophil count at Visit 1 ≥250 cells/µl).  The study will 
also determine the efficacy and safety of QAW039 (150 mg and 450 mg once daily), 
compared with placebo, in the overall study population.
A prior study of QAW039 (Study CQAW039A2208) demonstrated QAW039 (225 mg BID), 
compared with placebo, caused a reduction in sputum eosinophils in patients with severe 
eosinophilic asthma.  Given published results with other asthma therapies in which a 
reduction in sputum eosinophils is associated with a reduction in asthma exacerbations 
(Haldar, et al 2009; Pavord, et al 2012), and the observed reduction in sputum eosinophils in 
Study CQAW039A2208, it is postulated QAW039 will reduce the rate of asthma 
exacerbations.  Further, recent published results of the MENSA study (Ortega, et al 2014), in 
which the included patient population is similar to that proposed for the current study of 
QAW039, suggest patients with severe asthma, particularly those with severe eosinophilic 
asthma, are at risk for recurrent asthma exacerbations.  Taken together, the patient population 
for the current study is appropriate to evaluate the effect of QAW039 on reduction in rate of 
asthma exacerbations when patients stratified by eosinophil counts.
Screening epoch 
The screening epoch allows for assessment of patient entry criteria and for patients to become 
familiar with spirometry measurement and daily eDiary entry prior to the collection of 
baseline values. 
Run-in epoch 
The run-in epoch allows for patients to become familiar with administration of investigational 
treatment, to determine patient’s level of asthma control based on ACQ score (for eligibility),
and to collect baseline data for all efficacy variables.  This epoch will also assess patients’ 
compliance with an Electronic Peak Flow/ eDiary device and treatment. 


Novartis
Confidential
Page 27
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
Treatment epoch 
During this epoch oral QAW039 (150 mg and 450 mg) or placebo (1:1:1) will be 
administered once daily for 52 weeks, with the last dose given at Week 52 and final 
assessment for the treatment period at week 52. A 52-week study duration is necessary to 
minimize the impact of the seasonal variation on the primary endpoint, the rate of asthma 
exacerbations. Since one of the secondary endpoints is predose FEV1, patients will receive 
witnessed doses of study drug at clinic visits after spirometry is performed for the FEV1 
assessment.  This will allow for appropriate assessment of predose FEV1 prior to dosing.
Follow-up epoch 
The 4 week wash out epoch will monitor the safety and tolerability profile after the last dose 
of study drug. Note: the follow-up epoch applies to all patients except those patients who 
enter the safety study directly after Visit 299.
3.3
Rationale of dose/regimen, route of administration and duration 
of treatment
QAW039 will be administered at doses of 150 mg and 450 mg once daily as oral film-coated 
tablets (FCTs) in this study. 
A 450 mg once daily dose was selected for inclusion in the study based on the following:

At a dose of 450 mg once daily, >98% receptor occupancy is expected for the entire 
dosing interval in a “typical patient” at steady state allowing inhibition of eosinophil 
migration over the entire treatment interval.

A 500 mg once daily dose of QAW039 was efficacious on the endpoint of pre-dose FEV1 
in a sub-set of patients with percent predicted FEV1 <70% at baseline in Study 
CQAW039A2201 (proof-of-concept study). A 450 mg total daily dose was also 
efficacious on the endpoint of pre-dose FEV1 in study CQAW039A2206.

A total daily dose of 450 mg (225 mg twice daily) was evaluated in Study 
CQAW039A2208 in patients with severe asthma as add-on to SoC asthma therapy.  In this 
study, QAW039 caused significant reduction of sputum eosinophilia in patients with 
severe eosinophilic asthma.  The reduction in sputum eosinophils was comparable to that 
observed with the anti-IL5 antibodies, Mepolizumab (Pavord, et al 2012) and Reslizumab 
(Castro, et al 2011 and 2015).  An association between reduction of eosinophilic airway 
inflammation and frequency of exacerbations has been reported in the literature (Haldar, et 
al 2009; Pavord, et al 2012; Nowak, et al 2012; Wenzel, et al 2013; Takaku, et al 2013), 
suggesting QAW039 may also cause a reduction in the frequency of asthma exacerbations 
in patients with severe refractory eosinophilic asthma.
The dose of 150 mg once daily was selected for inclusion in the study because it was the 
lowest dose of QAW039 with “maximal efficacy” on the endpoint of FEV1 in a prior dose-
ranging study (Study CQAW039A2206) in patients with moderate-to-severe asthma (GINA 
treatment steps 4 and 5) as add-on to low-dose ICS.  This dose is ½ log lower than highest 
dose. 
Since the QAW039 dose of 150 mg was considered the optimal dose (i.e., lowest dose 
providing maximal efficacy) in a prior dose-ranging study, doses lower than 150 mg will not 
be included in this study.


Novartis
Confidential
Page 28
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
3.4
Rationale for choice of comparator
All patients in this study will continue to receive their asthma medications as background 
treatment. QAW039 or placebo will be administered as add-on therapy.
The use of placebo will permit the assessment of improvement in terms of incidence of 
moderate-to-severe asthma exacerbations for patients with uncontrolled disease who are 
treated with QAW039, in comparison to those continuing solely on existing SoC asthma 
therapy.  Additionally, the use of placebo will permit a controlled evaluation of the safety of 
QAW039 in these patients.
This study does not include an active comparator since QAW039 will be given as add -on 
therapy to standard of care asthma therapy in patients with severe asthma (GINA treatment 
steps 4 and 5).
3.5
Purpose and timing of interim analyses/design adaptations
An independent Data Monitoring Committee (see Section 8.3) will conduct periodic 
unblinded safety reviews of the accumulating data (including specific safety summaries for 
adolescent participants) from this trial and other Phase III trials of the QAW039 asthma 
development program to ensure safety of trial participants. 
In addition, a single interim analysis for futility will be conducted to assess whether the study 
should be stopped for futility or safety, or whether treatment in one or more QAW039 d ose 
groups should be discontinued for safety reasons. There will be no stopping for demonstrated 
efficacy prior to the completion of the study at either the unblinded safety reviews or the 
futility interim analysis, because a sufficiently large safety dataset is needed in addition to 
efficacy data.  Therefore, no statistical adjustment will be made to the final analysis.
This interim analysis for futility will occur when approximately 200 patient-years of follow-
up data have accumulated.  The timing of the futility interim analysis may be modified based 
on the progress of recruitment, the logistics of arranging DMC meetings, the data accrual in 
other QAW039 asthma Phase III trials and additional external data that might become 
available. 
3.6
Risks and benefits
QAW039 is a potent and highly selective oral CRTh2 receptor antagonist being developed as 
a potential therapy treatment for patients with severe asthma.  CRTh2 is a receptor for PGD2
which mediates the activation and migration of Th-2 cells and eosinophils, some of the key 
inflammatory cell types in asthma.  Recruitment of these cells into the lung is partly 
responsible for the intermittent airway obstruction which leads to wheezing and shortness of 
breath characteristic of asthma.
QAW039 is at least 300-fold selective for the CRTh2 receptor compared to other available 
prostanoid receptors and to cyclooxygenase-1 and cyclooxygenase-2, and it has been 
demonstrated to be a potent in vitro inhibitor of human whole blood eosinophil activation and 
induction of Th-2 cytokines. After oral dosing in rats, QAW039 inhibited pulmonary 
eosinophilia induced by the PGD2 metabolite DK-PGD2. 
The potential benefits of QAW039 therapy need to be balanced against its potential risks. The 
risk to patients in this study will be minimized by compliance with the inclusion/exclusion 


Novartis
Confidential
Page 29
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
criteria and close clinical monitoring. All patients will remain on the background SoC asthma 
therapy they were taking at screening throughout the study.  Furthermore, patients will be 
instructed how to react to worsening of asthma symptoms so patients can be managed 
appropriately.
The overall clinical experience with QAW039 includes 12 studies: 10 (6 in healthy volunteers 
and 4 in patients) have completed and 2 (in patients) are ongoing. The completed phase 2 
studies consist of 3 in patients with asthma and 1 in patients with allergic rhinitis. The 
ongoing phase 2 studies include one study in patients with asthma (CQAW039A2214) and 1 
study in patients with atopic dermatitis (CQAW039X2201). 
As of January 2015, over 1300 subjects have been exposed to QAW039 in the clinical 
program. In the completed studies of QAW039, 1239 subjects (175 healthy volunteers and 
1064 patients with asthma or allergic rhinitis) received QAW039, 342 subjects received 
placebo, and 359 subjects received other treatment (rosuvastatin, simvastatin or montelukast).
QAW039 has been well tolerated in populations studied to date at total daily doses up to 500 
mg given for up to 12 weeks. In the 10 completed studies, 16 patients reported 17 serious 
adverse events (SAEs), no deaths due to SAEs were reported, and 5 discontinuations due to 
SAEs were reported. Of the 16 patients reporting SAEs, 12 patients reported 13 events, 2 
patients reported 2 events and 2 patients reported 2 events in the QAW039, placebo, and 
montelukast treatment groups, respectively. There were no SAEs with a suspected causal 
relationship to QAW039. There have been no adverse events of idiopathic drug reactions. 
Overall, the safety profile of QAW039 has been favorable across studies.
Three Phase 2 studies in patients with asthma demonstrated the effect of QAW039 across the 
range of asthma severities (mild to severe). Below is a summary of efficacy data from these 3 
completed studies in asthma. For detailed information on the studies described below, please 
refer to the Investigators Brochure.
Study A2201 (proof-of-concept [PoC] study) 
Study A2201 was a PoC study in 170 corticosteroid-free, atopic, asthmatic patients 
uncontrolled on as needed β-agonist medication who were randomized (1:1) to receive 
QAW039 500 mg or matching placebo for 28 days.  The primary objective was to assess the 
efficacy of QAW039, compared with placebo, as measured by trough FEV1 after 28 days of 
treatment. Overall benefit for QAW039 treatment was not demonstrated in the entire study 
population (patients with percent predicted FEV1 of 60% to 85% at baseline) compared with 
placebo treatment. Benefit occurred only in those patients with more severe baseline airflow 
obstruction (FEV1 < 70% predicted). Results from Study A2201 demonstrated 4 weeks of 
treatment with QAW039 (500 mg q.d.) improved both lung function (FEV1: 207 ml > placebo 
group, p=0.002, 1-sided test) and control of asthma symptoms (ACQ: 0.41 points < placebo 
group, p=0.009, 1-sided test) in the subset of patients with moderate airflow obstruction at 
baseline (FEV1 < 70% predicted) who were inadequately controlled on reliever medication 
alone.
Study A2206 (dose-ranging study) 
Study A2206 was a randomized, placebo-controlled, multi-center, dose-ranging study in 
patients with moderate-to-severe allergic asthma inadequately controlled by ICS therapy.  


Novartis
Confidential
Page 30
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
Patients who satisfied selection criteria were randomized to 1 of 15 treatment arms (13 
QAW039 treatment arms, 1 montelukast positive control arm and 1 placebo arm) for 12 
weeks followed by a single-blind, placebo wash-out period for 4 weeks. The primary 
objective of the study was to assess the efficacy of QAW039, compared with placebo, as 
measured by trough FEV1 after 12 weeks of treatment.  A total 1058 patients were 
randomized to the following treatment groups: 139 patients to montelukast, 137 patients to 
placebo and 782 patients to QAW039.  The study achieved its primary endpoint by 
demonstrating a clinically and statistically significant improvement (0.112 L; p=0.0035) in 
trough FEV1 after 12 weeks therapy with QAW039, compared with placebo, in a population 
of moderate-to-severe, persistent, atopic asthmatics with a predicted baseline, pre-
bronchodilator FEV1 of 40% to 80% of the predicted value who were uncontrolled on low 
dose ICS.
Results showed the greatest differences from placebo occurred at doses of 75 mg twice daily 
and 150 mg once daily. These doses were towards the middle of the 1 mg to 450 mg dose 
range tested. There appeared to be little difference between once daily and twice daily dosing.  
There were no significant changes compared with placebo in ACQ, AQLQ or Juniper asthma 
control diary scores across the study population either for QAW039 or the positive control, 
montelukast.  Examination of sub-groups did not provide evidence of increased efficacy for 
QAW039, compared with placebo, in terms of FEV1.
Study A2208 
Study A2208 was a single site, double-blind, placebo-controlled study to determine whether, 
in patients with sputum eosinophilia (≥ 2%) and persistent, moderate-to-severe asthma, 12 
weeks of treatment with QAW039 at a dose of 225 mg twice daily, compared with placebo, 
on top of SoC asthma treatment would reduce levels of eosinophils in induced sputum.  In 
addition to measurements of changes in sputum eosinophilia (primary endpoint) and ACQ 
(secondary endpoint), a very wide range of lung function, patient reported outcome, imaging, 
histological, proteomic and transcriptional endpoints were also measured.
A total of 61 patients were randomized and 55 patients completed their assigned double-blind 
treatment period.  The primary endpoint of the study was achieved. The level of sputum 
eosinophilia decreased by 71% (geometric mean) from baseline after 12 weeks treatment with 
QAW039.  This fall was significantly different from the change observed in placebo-treated 
patients (p=0.0007).  QAW039 led to clinically and statistically relevant asthma control (as 
measured by the ACQ test) in patients uncontrolled at baseline (i.e. baseline ACQ7≥1.5), with 
the ACQ7 improving by 0.58 points (p=0.0473) in the per-protocol population. In the overall 
population, the ACQ7 score improved by 0.40 points (p=0.0843). There was a clinically (0.5 
point) and statistically significant improvement in QoL, as measured by the AQLQ overall 
score, after 12 weeks treatment with QAW039 in comparison to placebo (treatment difference 
= 0.593 point; p=0.0080). The proportion of patients experiencing a moderate or severe 
asthma exacerbation was similar across the two treatment groups (7 in the QAW039 group 
and 6 in the placebo group).  This finding was not surprising given the study was small and of 
limited duration and, therefore, was not designed to detect an effect on this endpoint.  
Numerical increases were seen in pre-bronchodilator FEV1 in QAW039-treated patients 
regardless of whether absolute volume or % change was considered. The greatest increases 
were observed in those per protocol-treated patients whose predicted FEV1 was <70% at 
baseline (190 mL and 13.409% for volume and % change, respectively). However, none of 


Novartis
Confidential
Page 31
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
these results were statistically significant.  Given the results with other therapies (a reduction 
in sputum eosinophils is associated with a reduction in asthma exacerbations), and the 
observed reduction in sputum eosinophil numbers in the prior study of QAW039, it is 
postulated QAW039 will reduce the rate of asthma exacerbations in the current study.  
Therefore, the main purpose of the current study is to definitively demonstrate the effect of 
QAW039 on reduction in the rate of moderate-to-severe asthma exacerbations. 
Cardiovascular risks:
Transient, increases in heart rate were observed in a cardiovascular safety pharmacology study 
in dogs. These changes were not associated with any significant alterations in blood pressure, 
ECG interval duration, morphology or rhythm or any structural changes in cardiac tissues.  No 
cardiac findings have been identified in the healthy volunteer and patient studies completed to 
date apart from an observed imbalance in the frequency of post-randomization cardiac adverse 
events in study CQAW039A2206 with a higher incidence in the QAW039 treatment group 
(1.7%) compared with either placebo (0.7%) or montelukast (0%) treated patients. The cardiac 
events comprised a number of different non-serious arrhythmias and one serious adverse 
event of pericarditis not suspected to be related to study drug by the investigator. Three of the 
events in the QAW039 treatment groups occurred during the washout period and 9 resolved 
on treatment. Based on the inability to identify discernable trends with QAW039 dose, 
regimen, time-of-onset, patient age and gender, concomitant medication, event type and 
following detail ECG review, it was considered that these were most probably coincidental 
events without a causal association to study drug.
A formal QTc study has not been completed for QAW039. Monitoring for changes in vital 
signs, ECGs and biochemical parameters will be conducted.
Liver toxicity:
Dose-dependent increases in liver weights with concomitant hepatocellular hypertrophy were 
the primary findings during 2- and 13-week toxicity studies in mice. These changes were 
considered to be a species-specific adaptive metabolic response with no relevance for humans.
Liver toxicity findings have not been identified in the healthy volunteer and patient studies 
completed to date.  Monitoring of liver function tests will be conducted as described in 
Appendix 2 of this protocol.
Potential risk of idiosyncratic drug reactions
CCN362 is an acylglucuronide metabolite of QAW039 and its potential to covalently bind to 
plasma proteins, such as albumin, was demonstrated in the human ADME (Absorption, 
distribution, metabolism, and excretion) study of QAW039 (CQAW039A2104). In the 
literature, in vivo binding of acyl glucuronides to proteins has been reported to be associated 
with rare idiosyncratic drug reactions (IDRs), although a causal connection of protein 
adduction to IDRs remains uncertain (Regan, et al 2010).  There have been no IDRs observed 
with QAW039 treatment in completed clinical trials.  Surveillance of adverse events for 
identification of IDRs will be conducted.


Novartis
Confidential
Page 32
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
Drug-drug interactions
QAW039 and CCN362 did not show any relevant inhibition or induction of the cytochrome 
P450 isoenzymes or inhibition of ubiquitous efflux transporters. The most potent in vitro 
inhibition by QAW039 was found for OATP1B1, but clinically only a small impact was 
observed at 450 mg/day (~2-fold increase in Cmax of simvastatin acid and rosuvastatin 
without change in AUC).  Based on these data, as well as recommendations in the simvastatin 
label, simvastatin doses of > 20 mg per day should not be co-administered with QAW039; no 
relevant impact on the disposition of other co-medications are expected with QAW039 dosed 
up to 450 mg/day.   Patients on doses of simvastatin >20 mg, doses of atorvastatin >40 mg,
doses of pravastatin >40mg, or doses of pitavastatin >2 mg per day (Elsby et al 2012, Deng et 
al 2008, Noe et al 2007, and Kalliokoski et al 2009), as well as patients on any statins with 
high CK levels (>2 X ULN) at screening (Visit 1) will be excluded from the study (see 
Section 4.2). Furthermore, patients on statin medication who are included in the study will 
have regular monitoring for relevant symptoms and be subject to discontinuation based on 
persistent myalgia and blood CK levels (Jacobson 2008) as described in Section 5.5.10.
4
Population
The study population will include approximately 846 males and females aged ≥12 years with 
inadequately controlled severe asthma (partly controlled or uncontrolled asthma on treatment 
at GINA steps 4 and 5). Approximately 15% of the patients will be adolescents (aged ≥12 to 
<18 years).
Patients will be stratified based on blood eosinophil counts at Visit 1, so that approximately
two thirds of randomized patients will have a blood eosinophil count ≥ 250 cells/µl and one 
third a blood eosinophil count < 250 cells/µl at Visit 1. It is anticipated at least 2400 patients 
will need to be screened to randomize approximately 846 patients into the study. It is 
estimated that approximately 15% of patients will discontinue their investigational treatment
during the treatment epoch; these patients will not be replaced. 
4.1
Inclusion criteria
Patients eligible for inclusion in this study have to fulfill all of the following criteria:
1. Written informed consent and assent (if applicable) must be obtained within 14 days prior 
to or at Visit 1 before any assessment is performed including any adjustment to asthma 
medication.
2. Male and female patients aged ≥12 years (or ≥ lower age limit allowed by health authority
and/or ethics committee/institutional review board approvals).   
3. Patients must have a diagnosis of asthma (according to GINA 2016) for a period of at least 
24 months prior to Visit 1.
4. Patients have been treated with:

Medium or high-dose ICS plus long-acting beta agonist (LABA), or

Medium or high-dose ICS plus leukotriene receptor antagonist (LTRA), or

Medium or high-dose ICS plus theophylline, or

Medium or high-dose ICS plus long-acting muscarinic antagonist (LAMA), or

Medium or high-dose ICS plus LABA plus LAMA, or


Novartis
Confidential
Page 33
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314

Medium or high-dose ICS plus LABA plus LTRA, or 

Medium or high-dose ICS plus LABA plus theophylline,
with or without maintenance oral corticosteroids for at least 3 months prior to Visit 1. The 
doses must have been stable for at least 4 weeks prior to Visit 1.

See GINA 2016 for the definition of medium and high-dose ICS (Appendix 7
contains the estimated equivalence of inhaled corticosteroids per GINA 2016).
5. For patients aged ≥18 years, FEV1 of ≤80% of the predicted normal value for the patient, 
after withholding bronchodilators at Visit 1 and Visit 101. For patients aged 12 to <18 
years, FEV1 of ≤90% of the predicted normal value for the patient, after withholding 
bronchodilators at Visit 1 and Visit 101.
NOTE: Withholding of bronchodilators prior to spirometry: 

SABAs ≥ 6 hours; 

LABAs given twice daily ≥ 12 hours;

LABAs given once daily ≥ 24 hours; 

Fixed dose combinations of LABA and ICS given twice daily ≥ 12 hours; 

Fixed dose combinations of LABA and ICS given once daily ≥ 24 hours;

LAMAs ≥ 24 hours. 
6. Demonstration of inadequate control of asthma based on an ACQ score ≥1.5 at Visit 1.
7. A history of 2 or more asthma exacerbations within the 12 months prior to Visit 1 that 
required either:

Treatment with systemic corticosteroids (tablets, suspension or injection).
OR

Hospitalization (defined as an inpatient stay or >24-hour stay in an observation area in 
the emergency room of other equivalent facility.
NOTES:

For subjects receiving maintenance OCS, the OCS treatment for exacerbations must 
have been at least a 2-fold or greater increase in the dose of OCS.  

The start of the second exacerbation episode must have been at least 7 days after the 
end of the first exacerbation episode.

Investigators must use appropriate means to ensure the accuracy of the patient’s 
exacerbation history  (patient history at Visit 1 documented in source notes, pharmacy 
records, hospital records, or chart records are acceptable).
8. A clinical diagnosis of asthma supported by at least one of the following: 

An increase of ≥12% and ≥200 ml in FEV1 approximately10 to 15 minutes after 
administration of 400 mcg of salbutamol/albuterol (or equivalent dose) prior to 
randomization.   Spacer devices are not permitted during reversibility testing.  All 
patients must perform a reversibility test at Visit 1.  If reversibility is not demonstrated 
at Visit 1*, the following historical information may be used:

Documented evidence of reversibility that was performed according to 
ATS/ERS guidelines (ATS/ERS 2005) within the 2 years prior to Visit 1.  
Where a patient is assessed as eligible based on historical evidence of 


Novartis
Confidential
Page 34
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
reversibility, a copy of the original printed spirometry report with relevant 
spirometry tracings must be available as source documentation.

Documented evidence of a positive airways hyper-reactivity (AHR) test result 
within the 2 years prior to or at Visit 101, defined as a provoked fall in FEV1 of 
20% by methacholine at ≤8 mg/ml (or histamine ≤10 mg/ml or acetylcholine 
<20 mg/mL) when not on ICS or ≤16 mg/ml or histamine ≤20 mg/ml or 
acetylcholine <40 mg/mL) on ICS therapy performed according to ATS/ERS 
guidelines.
*NOTE: If reversibility is not demonstrated at Visit 1 and documented evidence for 
one of the other criteria for a clinical diagnosis of asthma is not met, then the 
reversibility test may be repeated at Visit 101.
4.2
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
1. Use of other investigational drugs within 5 half-lives of enrollment, or within 30 days until 
the expected pharmacodynamic effect has returned to baseline, whichever is longer.
2. Patients who have participated in another trial of QAW039 (i.e. patient received study 
medication [active (QAW039), placebo or other].
3. History of hypersensitivity to any ingredients of the study drugs or to drugs related to 
QAW039.
4. Patients who, in the judgment of the investigator have a clinically significant ECG 
abnormality such as (but not limited to) sustained ventricular tachycardia, or clinically 
significant second or third degree AV block without a pacemaker.
5. Patients with a history of familial long QT syndrome or known family history of Torsades 
de Pointes.
6. Patients with a resting QTcF (Fridericia) ≥450 msec (male) or ≥460 msec (female) at Visit 
1 or at Visit 101.
7. Patients receiving any medications or other agents known to prolong the QT interval.
8. Patients with a history of malignancy of any organ, treated or untreated, whether or not 
there is evidence of local recurrence of metastases, with the exception of local basal cell 
carcinoma of the skin.
9. 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 
laboratory test.
10. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using effective methods of contraception during 
dosing of study treatment. Effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject) if allowed as effective method of contraception by local regulations. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception


Novartis
Confidential
Page 35
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment.  In 
case of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening). For female 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) if allowed as effective method of contraception by local 
regulations. For UK: with spermicidal foam/gel/film/cream/ vaginal suppository 

Use of oral, injected or implanted hormonal methods of contraception or other forms 
of hormonal contraception that have comparable efficacy (failure rate <1%), for 
example hormone vaginal ring or transdermal hormone contraception

Placement of an intrauterine device (IUD) or intrauterine system (IUS)
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In 
the case of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment is she considered not of child bearing 
potential. 
11. Patients who have smoked or inhaled any substance other than asthma medications within 
the 6 month period prior to Visit 1, or who have a smoking history of greater than 10 pack 
years (Note:10 pack years = 1 pack /day x 10 yrs., or ½ pack/day x 20 yrs.).
12. Patients who have had an asthma attack/exacerbation requiring systemic corticosteroids 
hospitalization or emergency room visit within 6 weeks prior to Visit 1.  If patients 
experience an asthma attack/exacerbation requiring systemic corticosteroids, 
hospitalization or emergency room visit during screening, they may be rescreened once, 6 
weeks after recovery from the exacerbation.
13. Patients who have had a respiratory tract infection or asthma worsening within 4 weeks of 
Visit 1.   Patients who experience a respiratory tract infection of asthma worsening during 
screening may be re-screened after 4 weeks after recovery from their respiratory tract 
infection or asthma worsening.
14. Patients with any chronic condition of the respiratory tract which in the opinion of the 
investigator may interfere with study evaluation or optimal participation in the study.
15. Patients with a history of chronic lung disease other than asthma, including (but not 
limited to) chronic obstructive pulmonary disease, bronchiectasis, (non-clinically 
significant bronchiectasis may be allowed provided recent [within 3 months prior to Visit 
101] CT scan proof is available), sarcoidosis, interstitial lung disease, cystic fibrosis, and 
tuberculosis.
16. Patients with uncontrolled diabetes having an HbA1c test result ≥8% at the Visit 1 
laboratory test.


Novartis
Confidential
Page 36
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
17. Patients who have a clinically significant laboratory abnormality at the Visit 1 laboratory 
test including (but not limited to):
Total white blood cell count <2500 cells/µL 
AST or ALT>2.0 X ULN or total bilirubin >1.3 X ULN 
Estimated Glomerular Filtration Rate (eGFR) by the Modification of Diet in Renal 
Disease (MDRD) equation or Bedside Schwartz equation <55 mL/minute/1.73 m2 
18. Patients who in the judgment of the investigator have a clinically significant condition 
such as (but not limited to) unstable ischemic heart disease, NYHA Class III/IV left 
ventricular failure, arrhythmia, uncontrolled hypertension, cerebrovascular disease, 
neurodegenerative diseases, or other neurological disease,  uncontrolled hypo- and 
hyperthyroidism and other autoimmune diseases, hypokalemia, hyperadrenergic state, or 
ophthalmologic disorder or patients with a medical condition that might compromise 
patient safety or compliance, interfere with evaluation, or preclude completion of the 
study.
19. Patients with a history of myocardial infarction within 12 months of Visit 1.
20. Patients with serious co-morbidities including, but not limited to, neurodegenerative 
diseases, rheumatoid arthritis and other autoimmune diseases.
21. Patients with a history of alcohol or drug abuse within 12 months prior to Visit 1.
22. Patients with a weight <30 kg.
23. Patients receiving any medications in the classes listed in Table 5-3 should be excluded 
unless they meet the criteria as specified in Table 5-3.
24. Patients receiving medications in the classes listed in Table 5-1 should be excluded unless 
the medication has been stabilized for the specified period and the stated conditions have 
been met.
25. Patients who started immunotherapy or desensitization for allergies, within 3 months prior 
to Visit 1, or where the maintenance dose is expected to change during the study. 
26. Patients with a known history of non-compliance to medication or who are unable or 
unwilling to complete an electronic patient diary or who are unable or unwilling to use 
Electronic Peak Flow with eDiary device or who are unable to demonstrate good eDiary 
compliance (defined as >75% for eDiary compliance) during the run-in epoch.
27. Inability to comply with all study requirements and demonstrate good medication 
compliance (>=80% compliance rate) during the treatment run-in epoch.
28. Patients with any medical or psychological condition that, in the investigators opinion, 
renders the patient unable to understand the nature, scope, and possible consequences of 
the study.
29. Patients with a history of being unable to swallow tablets.
30. Patients who have received methotrexate, oral gold, troleandomycin, cyclosporine 
azathioprine or any experimental anti-inflammatory therapies within 6 months of Visit 101.
31. Patients with regular use of oral or systemic corticosteroids for diseases other than asthma 
within the 12 months or any intra-articular or short-acting, intramuscular corticosteroid 
within 1 month or intramuscular, long acting depot corticosteroids within 3 months of 
Visit 101.
32. Patients who have a history of or current treatment for hepatic disease including but not 
limited to acute or chronic hepatitis, cirrhosis or hepatic failure.


Novartis
Confidential
Page 37
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
33. Patients with a history of immunodeficiency disease or hepatitis B or hepatitis C.
34. Patients on >20 mg of simvastatin, > 40 mg of atorvastatin, >40 mg of pravastatin, or >2 
mg of pitavastatin. Statin doses less than or equal to these doses as well as other statins 
will be permitted during the study.
35. Patients on any statin therapy with a CK level >2 X ULN at Visit 1.
36. Patients on rifampin, probenecid, ritonavir and valproic acid (i.e. medications blocking 
several pathways important for the elimination of QAW039 [broad range UGT inhibition 
and/or inhibition of OAT3, OATP1B3, MXR and P-gp]).
37. No person directly associated with the administration of the study is allowed to participate 
as a study subject.
38. No family member of the investigational study staff is allowed to participate in this study.
39. History of lactose or milk sensitivity.
40. Patients with a history of conditions other than asthma that could result in elevated 
eosinophils (e.g., hypereosinophilic syndromes, Churg-Strauss Syndrome, eosinophilic 
esophagitis).  Patients with known parasitic infestation within 6 months prior to Visit 1 are 
also excluded.
41. Patients aged 12 to <18 years below the 3rd percentile for weight by age (based on local 
growth charts or the United States Center for Disease Control growth charts (Center for 
Disease Control and Prevention, 2000) if local growth charts are not available).
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
5
Treatment
5.1
Protocol requested treatment
5.1.1
Investigational treatment
The following investigational treatment will be supplied by Novartis to the study sites:

Name: QAW039

Formulation: tablet

Unit dose: 2 strengths: 150 mg and 450 mg
Please refer to the Investigator’s Brochure for composition of the QAW039 tablets.

Name: QAW039 placebo

Formulation: tablet
Unit dose: matching placebo to QAW039 150 mg, matching placebo to QAW039 450 mg
Please refer to the Investigator’s Brochure for composition of the placebo tablets.
The investigational treatment (tablets) will be supplied in bottles. The matching placebos for 
QAW039 will be identical in appearance to their active counterparts and will be identically 
packaged. 


Novartis
Confidential
Page 38
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
5.1.2
Additional study treatment
No additional maintenance asthma treatment beyond investigational treatment is requested for 
this trial.
All 
patients 
will 
be 
provided 
with 
short-acting 
β2-agonists
(SABAs)
(salbutamol/albuterol/other SABA) which they will be instructed to use throughout the study 
as rescue medication on an ‘as needed basis.’
Short-acting β2-agonists will either be supplied to the investigator sites locally by Novartis or 
be provided by the study center and reimbursed by Novartis.
5.2
Treatment arms
During the run-in epoch, all patients will receive placebo to QAW039 once daily (one tablet 
blinded placebo to QAW039 150 mg and one tablet blinded placebo to QAW039 450 mg).
Patients will be assigned to one of three treatment arms as follows in a 1:1:1 ratio in the 
treatment epoch:

QAW039 150 mg once daily (one tablet of blinded QAW039 at 150 mg dosage 
strength to be given together with one tablet blinded placebo to QAW039 450 mg)

QAW039 450 mg once daily (one tablet of blinded QAW039 at 450 mg dosage 
strength to be given together with one tablet blinded placebo to QAW039 150 mg)

Placebo to QAW039 once daily (one tablet blinded placebo to QAW039 150 mg and 
one tablet blinded placebo to QAW039 450 mg)
Patients will be instructed to take their investigational treatment (QAW039 or placebo) once 
daily in the morning without regard to time of food intake.
5.3
Treatment assignment, randomization
At Visit 201, all eligible patients will be randomized via Interactive Response Technology 
(IRT) to 1 of the 3 treatment arms (QAW039 150 mg or 450 mg once daily or placebo once 
daily) in a 1:1:1 fashion within each of the randomization strata (peripheral blood eosinophil 
counts at Visit 1(<250 cells/l or ≥250 cells/l), patient age (<18 years or ≥18 years), and 
their use or non-use of oral corticosteroids as part of their SoC asthma therapy) by IRT. 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 packages of investigational treatment to be dispensed to the patient. The 
randomization number will not be communicated to the caller.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the IRT provider using a validated system that 
automates the random assignment of patient numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the 
responsibility of Novartis Drug Supply Management using a validated system that automates 
the random assignment of medication numbers to packs containing the investigational drug(s). 


Novartis
Confidential
Page 39
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
Randomization will be stratified by peripheral blood eosinophil counts at Visit 1 (<250 
cells/l or ≥250 cells/l), patient age (<18 years or ≥18 years), and patient use or non-use of 
oral corticosteroids as part of their SoC asthma therapy.
Treatment randomization will be 
stratified at the regional level.
Note: Enrollment to patient strata may be restricted by the Sponsor prior to the end of overall 
recruitment in order to achieve the desired distribution in the trial population.
The randomization scheme for patients will be reviewed and approved by a member of the 
Novartis Randomization Group.
5.4
Treatment blinding
This study consists of a single-blind run-in epoch (i.e., only patients will be blinded to the 
identity of the treatment) followed by a double-blind randomized treatment epoch. 
Patients, investigator staff, persons performing the assessments, and data analysts will remain 
blind to the identity of the treatment from the time of randomization until database lock, using 
the following methods: (1) Randomization data are kept strictly confidential until the time of 
unblinding, and will not be accessible by anyone involved in the study 
 
 
 
 
 (2) For each dose level, the identity of the 
treatments will be concealed by the use of placebos identical in packaging, labeling, schedule 
of administration, appearance, taste, and odor to QAW039. Across the doses, a double-
dummy design will be used.
Unblinding should only occur in the case of patient emergencies and at the conclusion of the 
study. In addition, the independent DMC will be unblinded for the purpose of safety reviews 
and at the time of the futility interim analysis.
5.5
Treating the patient 
5.5.1
Patient numbering 
Each patient is uniquely identified by a Subject Number which is composed by the site 
number assigned by Novartis and a sequential number assigned by the investigator. Once 
assigned to a patient, the Subject Number will not be reused.  If a patient is re-screened they 
will be assigned a new subject number.
Upon signing the informed consent form, the patient is assigned the next sequential number 
by the investigator. The investigator or his/her staff will contact the IRT and provide the 
requested identifying information for the patient to register them into the IRT. The site should 
select the CRF book with a matching Subject Number from the EDC system to enter data. 
If the patient fails to be treated for any reason, the IRT must be notified within 2 days that the 
patient was not treated. The reason for not being treated will be entered on the Screening 
Epoch Study Disposition CRF.
5.5.2
Dispensing the investigational treatment


Novartis
Confidential
Page 40
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
Each study site will be supplied by Novartis with investigational treatment in packaging of 
identical appearance.
The investigational treatment packaging has a 2-part label. 
A unique randomization medication number is printed on each part of this label which 
corresponds to the study epoch and/or treatment arm the patient is assigned to.
Investigator staff will identify the investigational treatment package(s) to dispense to the 
patient by contacting the IRT and obtaining the medication number(s). Immediately before 
dispensing the package to the patient, investigator staff will detach the outer part of the label 
from the packaging and affix it to the source document (Drug Label Form) for that patient’s 
unique subject number. 
5.5.3
Handling of study treatment 
5.5.3.1
Handling of investigational treatment
The investigational treatment must be received by a designated person at the study site, 
handled and stored safely and properly, and kept in a secured location to which only the 
investigator and designees have access. Upon receipt, all investigational treatment should be 
stored according to the instructions specified on the labels. Clinical supplies are to be 
dispensed only in accordance with the protocol. Technical complaints are to be reported to the 
respective Novartis CPO Quality Assurance.
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the investigational treatment but no 
information about the patient except for the medication number.
The investigator must maintain an accurate record of the shipment and dispensing of 
investigational treatment in a drug accountability log. Monitoring of drug accountability will 
be performed by the field monitor during site visits and at the completion of the trial. Patients 
will be asked to return all unused investigational treatment and packaging at the end of the 
study or at the time of discontinuation of investigational treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator will return all unused investigational treatment, packaging, drug labels, and a 
copy of the completed drug accountability log to the Novartis monitor or to the Novartis 
address provided in the investigator folder at each site.
5.5.3.2
Handling of other study treatment 
No applicable.
5.5.4
Instructions for prescribing and taking study treatment
Study treatment will be single-blind during the run-in and double-blind, double-dummy, and 
placebo-controlled after randomization. At clinic visits, patients will receive a witnessed dose 
of study medication.  These in-clinic witnessed doses will be given after the completion of all 
pre-dose assessments (see Section 6) and should be given at approximately the same time at 
each clinic visit.  Between clinic visits, patients will take study medication once daily in the 


Novartis
Confidential
Page 41
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
morning.  Patients will be instructed to take their study medication at approximately the same 
time each morning.
At Visit 101, all eligible patients will be given oral placebo to QAW039 for a run-in epoch of 
2 weeks and will be instructed on the intake of the investigational treatment. In order to 
maintain the blind from the patient’s point of view, investigators should not divulge 
information regarding the fact that all individuals will be assigned to placebo during the 
run-in epoch. If a patient experiences an asthma exacerbation during the run-in epoch, the 
run-in epoch must be extended up to 6 weeks to permit for resolution of the asthma 
exacerbation before randomization. The run-in epoch should only be extended beyond 2 
weeks (+/- 5 days) for an asthma exacerbation. At Visit 201, patients will be randomized and 
stratified according to their peripheral blood eosinophil counts (<250 cells/l or ≥250 cells/l), 
patient age (<18 years or ≥18 years), and their baseline use or non-use of oral corticosteroids 
as part of their SoC asthma therapy at Visit 1. Each randomized patient will then enter a 52-
week treatment epoch where they will receive one of the following 3 treatments:  (i) QAW039 
150 mg once daily or (ii) QAW039 450 mg once daily or (iii) placebo once daily given on top 
of their individual background asthma treatment. The investigational treatment will be 
dispensed in medication packs (bottles) at each site visit during the treatment epoch to cover 
the treatment period between patient visits and to allow for late visits and other unforeseen 
events. All dosages prescribed and dispensed to the patient and all dose changes during the 
study must be recorded on the Dosage Administration Record CRF
All kits of investigational treatment assigned by IRT will be recorded/databased in the IRT. 
The investigator should instruct the patient to take the investigational treatment exactly as 
prescribed in order to ensure compliance. The patient should be instructed to contact the 
investigator if he/she is unable for any reason to take the investigational treatment as 
prescribed. 
5.5.5
Permitted dose adjustments and interruptions of study treatment
QAW039 treatment dose adjustments are not permitted.
QAW039 treatment interruption is only permitted in the following situations:

A positive urine pregnancy test requires immediate interruption of study medication 
until serum β-hCG is performed and found to be negative. 

An investigator considers an interruption is necessary for the treatment of an adverse 
event. 
Interruption to treatment must be recorded on the Dosage Administration Record CRF.
5.5.6
Rescue medication
At Visit 1 all patients will be provided with a SABA (such as salbutamol [100 mcg or 
albuterol 90 mcg]) which they will be instructed to use throughout the study as rescue 
medication on an ‘as needed basis’. Patients will be advised that between visits they can take 
their rescue medication for symptoms of asthma. Rescue medication (i.e., SABAs) will either
be supplied to the investigator sites locally by the Novartis CPO or provided by the study 
center and reimbursed by Novartis.
Nebulized salbutamol/albuterol is not allowed as rescue medication and will not be supplied.


Novartis
Confidential
Page 42
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
To standardize measurements, patients will be instructed not to use their rescue medication 
upon rising in the morning on days requiring spirometric assessments indicated in Table 6-1, 
unless absolutely necessary.  If rescue medication is taken within 6 hours prior to spirometry, 
this information will be recorded by the study site staff using the equipment provided by the 
central spirometry vendor.  Additionally, if rescue medication is taken within 6 hours prior to 
spirometry at any of the scheduled visits, the visit should be rescheduled to the next possible 
day.
Daily use of rescue medication (the number of puffs taken in the previous 12 hours) will be 
recorded (once in the morning and once in the evening) by the patient using 
/ eDiary.
Unless clinically indicated, the type of rescue medication (i.e., SABA) a patient uses, the 
device used to deliver the medication (e.g. dry powder or HFA) and the way it is administered 
(e.g. with a spacer device) should not be adjusted. Any changes relating to the above must be 
recorded on the Concomitant medications CRF after the start of study drug.
5.5.7
Background therapy
All patients will remain on the incoming SoC asthma therapy they were taking at the 
screening visit (Visit 1) throughout the study. No dosage adjustments of the patient’s 
incoming SoC therapy will be permitted during the study. Short bursts of rescue systemic 
corticosteroids are allowed for treatment of asthma exacerbations, as clinically indicated (see 
Section 6.4.1).  The duration of a burst of rescue systemic corticosteroids should be 
approximately 3 to 10 days, and be of the shortest time needed to allow symptom control.
5.5.8
Concomitant treatment 
The medications in Table 5-1 are only permitted under the circumstances given.  This table is 
not considered all-inclusive. Medications should be assessed for adherence to the indication 
and other inclusion/exclusion criteria.
Table 5-1
Medications allowed under certain conditions
Class of medication
Condition
Inhaled corticosteroids (ICS)**
Medium or high-dose* daily or equivalent. Used for 
at least 3 months prior to Visit 1 and stable for at 
least 4 weeks prior to Visit 1. Must be taken with a 
LABA or an alternate therapy (LTRA or theophylline
or LAMA) or with LABA/LAMA or with LABA/LTRA
or with LABA/theophylline.
Long-acting inhaled β-2 agonists (LABAs)**
Used for at least 3 months prior to Visit 1 and 
stable for at least 4 weeks prior to Visit 1.
Must be taken with medium or high-dose* ICS.
Fixed dose combinations of ICS and LABA 
(FDC)**
Used for at least 3 months prior to Visit 1 and 
stable for at least 4 weeks prior to Visit 1.
Leukotriene receptor antagonists 
(LTRAs)**
Used for at least 3 months prior to Visit 1 and 
stable for at least 4 weeks prior to Visit 1.
Must be taken with medium or high-dose* ICS.
Theophylline**
Used for at least 3 months prior to Visit 1 and 
stable for at least 4 weeks prior to Visit 1.


Novartis
Confidential
Page 43
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
Table 5-2 indicates the wash-out periods for allowed asthma medications prior to spirometry 
assessments. See Appendix Spirometry Guidance for more details. 
Table 5-2
Medications to be withheld prior to spirometry
Class of medication
Last dose prior to spirometry
Short-acting β2-agonists
≥ 6 hours
Long-acting β2-agonists (LABAs) given twice daily
≥ 12 hours
LABAs given once daily
≥ 24 hours
Fixed dose combinations of LABA and inhaled 
corticosteroid (ICS) given twice daily
≥ 12 hours
Fixed-dose combinations of LABA and ICS given 
once daily
≥ 24 hours
Long-acting muscarinic antagonists (LAMAs)
≥ 24 hours
Must be taken with medium or high-dose* ICS.
Long-acting muscarinic antagonists
(LAMAs)**
Used for at least 3 months prior to Visit 1 and 
stable for at least 4 weeks prior to Visit 1.
Must be taken with medium or high-dose* ICS.
Maintenance oral corticosteroids for 
treatment of asthma
Used for at least 3 months prior to Visit 1 and 
stable for at least 4 weeks prior to Visit 1.
Short bursts of rescue systemic corticosteroids are 
allowed for treatment of asthma exacerbations, as 
clinically indicated.  The duration of a burst of 
rescue systemic corticosteroids should be 
approximately 3 to 10 days, and be of the shortest 
time needed to allow symptom control.
Short-acting β2-agonist (SABAs)
Rescue medication to be taken as needed.
Maintenance immunotherapy for allergies
Stable dose for at least 3 months prior to screening 
and the dose remains stable throughout the study.
Inactivated influenza vaccine, 
pneumococcal vaccination or any other 
inactivated vaccine
Not administered within 48 h prior to a study visit.
Topical corticosteroids for treatment of 
eczema
Recommended doses and dosage regimens
Antihistamines (e.g., loratadine, cetirizine)
Recommended doses and dosage regimens
Nasal anticholinergics
Treatment regimen has been stable for at least 1 
month prior to screening (Visit 1).
In the case of as needed use, providing an 
established pattern of use has been documented.
Nasal corticosteroids
Nasal or ophthalmological preparations of 
nedocromil
Nasal or ophthalmological preparations of 
antihistamines
*See GINA 2016 for definition of medium and high-dose ICS.
**See Section 4.1 (inclusion criterion 4) for permitted combinations of therapy.


Novartis
Confidential
Page 44
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) 
administered after the patient was enrolled into the study must be recorded in the eCRF.
5.5.9
Prohibited Treatment
Use of the treatments displayed in Table 5-3 is NOT allowed after the start of study (i.e., after 
Visit 101). Each concomitant drug must be individually assessed against all exclusion criteria 
and the tables below to see if it is allowed. If in doubt, the investigator should contact the 
Novartis medical monitor or designee before randomizing a patient or allowing a new 
medication to be started. 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.
Table 5-3
Prohibited medications
Class of medication
Minimum cessation prior to run-in (Visit 101)
Other investigational drugs
30 days or 5 half-lives, whichever is longer 
Live attenuated vaccine
30 days
Other CRTh2 antagonists (e.g., ramatroban)
7 days or 5 half-lives whichever is longer
Short-acting anticholinergics
8 hours
Fixed combinations of short-acting β2 agonists 
and short-acting anticholinergics
8 hours
Systemic mast cell stabilizers (e.g. 
cromoglycate, nedocromil, ketotifen)
7 days
Monoclonal antibodies, investigational or 
approved, for the treatment of asthma (e.g.,
omalizumab)
5 months
Simvastatin >20 mg, atorvastatin >40 mg, 
pravastatin >40 mg, or pitavastatin >2 mg
total daily dose
7 days
Rifampin, probenecid, ritonavir and valproic 
acid (i.e. medications blocking several 
pathways important for the elimination of 
QAW039 (broad range UGT inhibition and/or 
inhibition of OAT3, OATP1B3, MXR and P-
gp)).
7 days
Methotrexate, gold salts, cyclosporine, 
troleandomycin, azathioprine, other 
immunomodulator drugs or 
immunomodulatory monoclonal antibodies
6 months
5.5.10
Discontinuation of study treatment
Patients may voluntarily discontinue active study medication (refuse study treatment but 
continue with study participation) at any time. Patients who wish to discontinue active 
study medication will be asked to remain in the study and complete all study visits.  
Patients withdrawn from study treatment will receive SoC asthma therapy according to 
investigator judgement. 


Novartis
Confidential
Page 45
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
The investigator should discontinue study treatment for a given patient if, on balance, he/she 
believes that continuation of study treatment would be detrimental to the patient’s well-being.  
Study treatment must be discontinued under the following circumstances: 

Withdrawal of informed consent (and the investigator must prematurely withdraw the 
patient from the study);

Pregnancy;

Female subjects non-compliant with the chosen effective method of contraception during 
the study: The investigator must provide appropriate advice on the continued use of 
effective contraception for at least one week (at least 5 half-lives of QAW039) after study 
drug discontinuation and follow up with the subject as appropriate at least to the end of 
this period;

Any protocol deviation that results in a significant risk to the patient’s safety;

Liver laboratory test abnormality / event (see Appendix 2):

Abnormal liver laboratory results requiring discontinuation – refer to Table 14-2;

If the investigator considers it appropriate after the confirmation of a liver safety 
monitoring signal:

ALT or AST ≥5xULN, or

ALT or AST ≥2.5xULN and total bilirubin  ≥1.5xULN (Appendix 2);

Premature unblinding of study treatment for a patient for any reason;

Total white blood cell count <1000 cells/µL;

If patients on statin therapy complain of persistent muscle pain without any obvious cause 
for greater than 3 days accompanied by increase in CK levels >10xULN or persistent 
intolerable muscle pain regardless of the accompanying CK level;

If a patient develops a medical condition that requires consistent use of prohibited 
treatment as per Section 5.5.9 or if patient exhibits a behavior of non-compliance 
regarding prohibited medication.
The appropriate personnel from the site and Novartis will assess whether investigational 
treatment should be discontinued for any patient whose treatment code has been broken 
inadvertently for any reason. 
Patients who discontinue investigational treatment should NOT be considered withdrawn 
from the study. If premature discontinuation of investigational treatment occurs for any reason 
the patient should continue attending the remaining study visits while off investigational 
treatment. The patient should return to the clinic as soon as possible for an investigational 
treatment discontinuation visit (TD). At this visit, the assessments listed under 
UNSCHEDULED-TD in Table 6-1 should be completed and recorded in the eCRF. The 
investigator and study staff must discuss with the patient, the patient’s continued participation 
in the study and request patients to continue attending study visits according to the study visit 
schedule with all assessments (except study drug related assessments such as compliance 
checks) completed up to Visit 299. If the patient cannot or is unwilling to attend any further 
visit(s), the site staff should maintain regular phone contact with the patient, or with a person 
pre-designated by the patient. This phone contact should preferably be done according to the 
study visit schedule. Data will continue to be collected concerning the patients’ condition and 
changes in concomitant medications, surgeries and procedures, serious and non-serious 


Novartis
Confidential
Page 46
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
adverse events, and asthma exacerbations should be recorded in the appropriate eCRF if 
applicable. If necessary an unscheduled clinical visit may be arranged.
The investigator must also contact the IRT to register the patient’s discontinuation from 
investigational treatment
5.5.11
Discontinuation from study
Patients will only be discontinued from the study if they withdraw consent, die during 
the study or are lost to follow-up (see Section 5.5.13).
5.5.12
Withdrawal of consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time. 
Withdrawal of consent occurs only when a patient does not want to participate in the study 
anymore and does not want any further visits or assessments and does not want any further 
study related contacts and does not allow analysis of already obtained biologic material.
If a patient withdraws consent, the investigator must make every effort (e.g. telephone, e-mail, 
letter) to determine the primary reason for this decision and record this information. 
Investigational treatment must be discontinued and no further assessments conducted. All 
biological material that has not been analyzed at the time of withdrawal must not be used. 
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up.
The investigator must also contact the IRT to register the patient’s withdrawal from the study.
Patients who prematurely discontinue study treatment or withdraw from the study will not be 
replaced.
5.5.13
Lost to follow-up 
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw, the investigator should show "due diligence" by contacting the 
patient, family or family physician as agreed in the informed consent and by documenting in 
the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be considered lost to follow-up until his/her 
scheduled end of study visit would have occurred.
5.5.14
Emergency breaking of assigned treatment code 
Emergency treatment code breaks should only be undertaken when it is essential to treat the 
patient safely and efficaciously. Most often, study drug discontinuation and knowledge of the 
possible treatment assignments are sufficient to treat a study patient who presents with an 
emergency condition. Emergency treatment code breaks are performed using the IRT. When 
the investigator contacts the system to break a treatment code for a patient, he/she must 
provide the requested patient identifying information and confirm the necessity to break the 
treatment code for the patient. The investigator will then receive details of the investigational 
drug treatment for the specified patient and a fax or email confirming this information. The 
system will automatically inform Novartis that the code has been broken.


Novartis
Confidential
Page 47
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
It is the investigator’s responsibility to ensure that there is a dependable, redundant procedure 
in place to allow access to the IRT code break card at any time in case of emergency. The 
investigator will provide the protocol number, investigational treatment name if available, 
patient number as well as oral and written information to the patient on how to contact his/her 
backup in cases of emergency when he/she is unavailable to ensure that un-blinding can be 
performed at any time in the case of emergency. Study drug must be discontinued after 
emergency unblinding. Study drug must also be discontinued for any patient whose treat ment 
code has been inadvertently broken or for any other non-emergency reason.
5.5.15
Study completion and post-study treatment 
Study completion for a patient will occur after he/she has completed 52 weeks of treatment 
(through to Visit 299) or they have prematurely withdrawn. Completion of the study will be 
when all randomized patients have completed 52 weeks of treatment and the post-treatment 
follow-up visit.
Patients who have been screened when enrolment target has been met will be allowed to 
proceed onto study participation.
A Safety Study of QAW039 is planned. At sites participating in the Safety Study, patients 
who successfully complete 52 weeks of treatment in this study (Study A2307) may be offered 
participation in the Safety Study; patient participation in the Safety Study will be optional. 
Patients not entering the safety study will complete the follow-up epoch and will not be given 
further access to study drug because the risk/benefit ratio will not yet have been substantiated 
and there are already other marketed therapeutic alternatives available to treat these patients. 
At the time of study completion or early termination, all patients will be placed on the 
appropriate asthma treatment as prescribed by the investigator.
The investigator must provide appropriate advice on the continued use of effective 
contraception for at least one week (at least 5 half-lives of QAW039) after the study 
completion (V299) or premature study drug discontinuation and follow up with the subject as 
appropriate at least to the end of this period.
The investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care. 
5.5.16
Early study termination 
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and treated for a prematurely withdrawn patient. 
The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the patient’s interests. The 
investigator will be responsible for informing the Institutional Review Board/Independent 
Ethics Committee (IRBs/IECs) of the early termination of the trial.
6
Visit schedule and assessments
Visits must be scheduled to allow randomized study drug to be taken in the morning 
Table 6-1 lists all of the assessments and indicates with an “x” when the visits are performed. 


Novartis
Confidential
Page 48
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
Patients should be seen for all visits as close as possible to the visit date. In case a treatment 
visit cannot occur as scheduled in the protocol, visits should be scheduled according to the 
specified visit window in the schedule of assessments. 
Patients, who discontinue study treatment before completing the study and will accept to 
remain in the study, will return for study visits as described in Section 5.5.10. If they fail to 
return for these assessments for unknown reasons, every effort should be made to contact 
them as specified in Section 5.5.10.  At the very least, patients should be asked if they can be 
contacted by phone by study personnel at the date they would have been scheduled to end the 
follow up epoch (4 weeks after premature drug discontinuation) to ask about concomitant 
medication use, surgery and procedures, SAEs, AEs and asthma exacerbations.
Patients will be required to attend the clinic in the morning at approximately the same 
time, so that pre-dose FEV1 assessments can be performed between 6:00 A.M. and 10:00
A.M. (+/- 1 hour). 
 
 At certain clinic visits, measurements will be collected 
2 hours post dosing; these measurements should be accounted for when scheduling clinic 
visits.
When the following assessments are scheduled to be performed at the same time-point, 
the order of priority will be as follows: 
1) Question on medication withholding for spirometry; 
2) Patient Reported Outcome instruments to be completed in the following order: 
ACQ-5, AQLQ+12,
at certain clinic visits; 
3) Vital signs;
4) ECGs;
5) Samples for urine/hematology/blood chemistry (At Visit 1 collect samples prior to 
spirometry. At all other visits, collect samples prior to the 1st pre-dose spirometry 
[which is the -45 min pre-dose spirometry] or between the 1st and 2nd pre-dose 
spirometry measurements.);
6) Samples for RAST/ImmunoCAP test, Total IgE, at certain clinic visit(s) (At Visit 
1 collect samples prior to spirometry. At all other visits, collect samples prior to the 1st
pre-dose spirometry [which is the -45 min pre-dose spirometry] or between the 1st and 
2nd pre-dose spirometry measurements.);
 
 
9) Spirometry assessments should be timed so that the Visit 1 spirometry assessment 
and all pre-dose spirometry assessments (i.e., FEV1 measurements) during the 
run-in epoch and treatment epoch are performed between 6:00 A.M. and 10:00
A.M. (+/- 1 hour). Other tests should be performed as close as possible to those 
spirometry times. During the run-in epoch and treatment epoch, two pre-dose 
spirometry assessments should be performed as follows:


Novartis
Confidential
Page 49
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314

First pre-dose spirometry assessment: approximately 45 minutes prior to the 
dosing of study drug at the clinic visit.

Second pre-dose spirometry assessment: approximately 15 minutes prior to the 
dosing of study drug at the clinic visit.
10) Reversibility at certain visits (spirometry after administration of SABA) may be 
performed after 10:00 A.M. (+/- 1 hour);
11) In-clinic witnessed dosing of study drug;
12) ECGs (2 hour post-dose) at certain clinic visits;


Novartis
Confidential
Page 50
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
Table 6-1
Assessment schedule
Screen
Run-in
Treatment
Follow-up
Visit Number (Site visits)1
1
101
199
201
202
203
204
205
206
207
UNSCH
EDULED
-TD
299
301
Telephone Call (TC)2
Note: TC in-between site visits 
TC1
TC2
TC3
TC4
TC5
TC6
Treatment Week
-4
-23
1
1
4
8
12
16
20
24
28
32
36
40
44
48
TD
52
56
Treatment Day
Note: *V199 and 201 will occur on the 
same day if the patient is randomized.
-28
-143
1*
1*
28
56
84
112
140
168
196
224
252
280
308
336
TD
364
392
Visit Window (Days)
NA
+/-7
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
NA
+/-5
+/-5
1Scheduled clinic visits (starting at Visit101 and thereafter) are to occur in the morning at approximately the same time, so that the -45 min and -15 min pre-dose FEV1 assessments can be performed between 06:00 
A.M. and 10:00 A.M. (+/- 1 hour).
2Scheduled telephone calls (TCs) will be conducted to check the patients’ condition (Changes in concomitant medications, surgeries and procedures, serious and non-serious adverse events, and asthma exacerbations 
should be recorded in the appropriate eCRF if applicable). If necessary an unscheduled clinical visit may be arranged.
3For patients experiencing an asthma exacerbation during the run-in epoch, the run-in may be extended up to 6 weeks.
4The follow-up epoch applies to all patients except those patients who enter the safety study directly after Visit 299.
TD = investigational treatment discontinuation (permanent treatment discontinuation but continue with limited assessments; (S) = assessment to be recorded in source documents only; assessment will not be entered 
into the eCRFs; V = Visit
Informed consent and assent (if 
applicable) 
Note: ICF must be obtained within 14 
days prior to or on V1.
X
Ask question on withholding of 
medication before clinic visits (for 
details see Section 5.5.8)
Note: If the patient has not withheld 
medications as specified in the protocol 
before a particular visit, the visit must be 
rescheduled.
X
X
X
X
X
X
X
X
X
X
X
Demographics
X
Medical history
X
Medical History – Protocol solicited 
events for asthma
X
Asthma exacerbation history
X
Smoking history
X
Prior/concomitant medication 
(asthma and non-asthma 
medications) review
X
X
X
X
X
X
X
X
X
X
X
Inclusion/exclusion criteria
X
X
X


Novartis
Confidential
Page 51
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
Screen
Run-in
Treatment
Follow-up
Visit Number (Site visits)1
1
101
199
201
202
203
204
205
206
207
UNSCH
EDULED
-TD
299
301
Telephone Call (TC)2
Note: TC in-between site visits 
TC1
TC2
TC3
TC4
TC5
TC6
Treatment Week
-4
-23
1
1
4
8
12
16
20
24
28
32
36
40
44
48
TD
52
56
Treatment Day
Note: *V199 and 201 will occur on the 
same day if the patient is randomized.
-28
-143
1*
1*
28
56
84
112
140
168
196
224
252
280
308
336
TD
364
392
Visit Window (Days)
NA
+/-7
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
NA
+/-5
+/-5
1Scheduled clinic visits (starting at Visit101 and thereafter) are to occur in the morning at approximately the same time, so that the -45 min and -15 min pre-dose FEV1 assessments can be performed between 06:00 
A.M. and 10:00 A.M. (+/- 1 hour).
2Scheduled telephone calls (TCs) will be conducted to check the patients’ condition (Changes in concomitant medications, surgeries and procedures, serious and non-serious adverse events, and asthma exacerbations 
should be recorded in the appropriate eCRF if applicable). If necessary an unscheduled clinical visit may be arranged.
3For patients experiencing an asthma exacerbation during the run-in epoch, the run-in may be extended up to 6 weeks.
4The follow-up epoch applies to all patients except those patients who enter the safety study directly after Visit 299.
TD = investigational treatment discontinuation (permanent treatment discontinuation but continue with limited assessments; (S) = assessment to be recorded in source documents only; assessment will not be entered 
into the eCRFs; V = Visit
Review and record surgeries and 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination (S)
X
X
X
Abbreviated physical examination 
(heart and lung only) (S)
X
X
X
X
X
X
X
X
Height
Note: Height must be collected using a 
standard measurement device (such as 
a stadiometer)
X
X
Weight
X
X
X
X
Parasitic screening (S)
Note: Only if required by health 
authority and/or ethics 
committee/institutional review board.  
Sites should use local laboratories.
X
Vital signs
(systolic/diastolic blood pressure, radial 
pulse (sitting), and body temperature)
X
X
X
X
X
X
X
X
X
X
X
Electrocardiograms 
X
X
Electrocardiograms (Pre-dose)
X
X
X
X
X
X
X
X
X
Electrocardiograms (2h-post dose)
X
X
X
X


Novartis
Confidential
Page 52
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
Screen
Run-in
Treatment
Follow-up
Visit Number (Site visits)1
1
101
199
201
202
203
204
205
206
207
UNSCH
EDULED
-TD
299
301
Telephone Call (TC)2
Note: TC in-between site visits 
TC1
TC2
TC3
TC4
TC5
TC6
Treatment Week
-4
-23
1
1
4
8
12
16
20
24
28
32
36
40
44
48
TD
52
56
Treatment Day
Note: *V199 and 201 will occur on the 
same day if the patient is randomized.
-28
-143
1*
1*
28
56
84
112
140
168
196
224
252
280
308
336
TD
364
392
Visit Window (Days)
NA
+/-7
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
NA
+/-5
+/-5
1Scheduled clinic visits (starting at Visit101 and thereafter) are to occur in the morning at approximately the same time, so that the -45 min and -15 min pre-dose FEV1 assessments can be performed between 06:00 
A.M. and 10:00 A.M. (+/- 1 hour).
2Scheduled telephone calls (TCs) will be conducted to check the patients’ condition (Changes in concomitant medications, surgeries and procedures, serious and non-serious adverse events, and asthma exacerbations 
should be recorded in the appropriate eCRF if applicable). If necessary an unscheduled clinical visit may be arranged.
3For patients experiencing an asthma exacerbation during the run-in epoch, the run-in may be extended up to 6 weeks.
4The follow-up epoch applies to all patients except those patients who enter the safety study directly after Visit 299.
TD = investigational treatment discontinuation (permanent treatment discontinuation but continue with limited assessments; (S) = assessment to be recorded in source documents only; assessment will not be entered 
into the eCRFs; V = Visit
Pregnancy test—serum (women of 
child bearing potential)
Note: Pregnancy testing will begin at  
Visit 1 if a patient is identified as being of 
child bearing potential
X
Pregnancy test—urine (women of 
child bearing potential)
Notes:
Pregnancy testing will begin at the visit a 
patient is first identified as being of child 
bearing potential.
A positive urine pregnancy test requires 
immediate interruption of study 
medication until serum β-hCG is 
performed and found to be negative. If 
positive, the patient must be 
discontinued from study treatment.
X
X
X
X
X
X
X
X
X
X
X
In countries where monthly 
pregnancy testing is required 
for women of child-bearing 
potential by local laws or 
regulations: Home Pregnancy 
testing- urine 
Note:  at telephone visits (S)
X
X
X
X
X
X
Urinalysis and urine chemistry
(central laboratory)
X
X
X
X
X
X
X
X
X
X


Novartis
Confidential
Page 53
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
Screen
Run-in
Treatment
Follow-up
Visit Number (Site visits)1
1
101
199
201
202
203
204
205
206
207
UNSCH
EDULED
-TD
299
301
Telephone Call (TC)2
Note: TC in-between site visits 
TC1
TC2
TC3
TC4
TC5
TC6
Treatment Week
-4
-23
1
1
4
8
12
16
20
24
28
32
36
40
44
48
TD
52
56
Treatment Day
Note: *V199 and 201 will occur on the 
same day if the patient is randomized.
-28
-143
1*
1*
28
56
84
112
140
168
196
224
252
280
308
336
TD
364
392
Visit Window (Days)
NA
+/-7
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
NA
+/-5
+/-5
1Scheduled clinic visits (starting at Visit101 and thereafter) are to occur in the morning at approximately the same time, so that the -45 min and -15 min pre-dose FEV1 assessments can be performed between 06:00 
A.M. and 10:00 A.M. (+/- 1 hour).
2Scheduled telephone calls (TCs) will be conducted to check the patients’ condition (Changes in concomitant medications, surgeries and procedures, serious and non-serious adverse events, and asthma exacerbations 
should be recorded in the appropriate eCRF if applicable). If necessary an unscheduled clinical visit may be arranged.
3For patients experiencing an asthma exacerbation during the run-in epoch, the run-in may be extended up to 6 weeks.
4The follow-up epoch applies to all patients except those patients who enter the safety study directly after Visit 299.
TD = investigational treatment discontinuation (permanent treatment discontinuation but continue with limited assessments; (S) = assessment to be recorded in source documents only; assessment will not be entered 
into the eCRFs; V = Visit
Blood for hematology and 
chemistry (central laboratory)
Notes: No fasting requirement prior to 
blood sampling.
X
X
X
X
X
X
X
X
X
X
Blood for RAST/ImmunoCAP test 
(central laboratory)
X
Blood sample for IgE
X
X
X
Review Visit 1 laboratory results 
(chemistry, hematology, HbA1c, 
RAST/ImmunoCAP, IgE, urine 
chemistry and urinalysis). (S)
Note: If results for chemistry, hematology,  
HbA1c, RAST/ImmunoCAP, IgE, urine 
chemistry and urinalysis are missing, obtain 
a repeat for the missing result.
X
Telephone contact with patient (S)
X
X
X
X
X
X
Serious adverse event recording
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse event recording
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


Novartis
Confidential
Page 54
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
Screen
Run-in
Treatment
Follow-up
Visit Number (Site visits)1
1
101
199
201
202
203
204
205
206
207
UNSCH
EDULED
-TD
299
301
Telephone Call (TC)2
Note: TC in-between site visits 
TC1
TC2
TC3
TC4
TC5
TC6
Treatment Week
-4
-23
1
1
4
8
12
16
20
24
28
32
36
40
44
48
TD
52
56
Treatment Day
Note: *V199 and 201 will occur on the 
same day if the patient is randomized.
-28
-143
1*
1*
28
56
84
112
140
168
196
224
252
280
308
336
TD
364
392
Visit Window (Days)
NA
+/-7
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
NA
+/-5
+/-5
1Scheduled clinic visits (starting at Visit101 and thereafter) are to occur in the morning at approximately the same time, so that the -45 min and -15 min pre-dose FEV1 assessments can be performed between 06:00 
A.M. and 10:00 A.M. (+/- 1 hour).
2Scheduled telephone calls (TCs) will be conducted to check the patients’ condition (Changes in concomitant medications, surgeries and procedures, serious and non-serious adverse events, and asthma exacerbations 
should be recorded in the appropriate eCRF if applicable). If necessary an unscheduled clinical visit may be arranged.
3For patients experiencing an asthma exacerbation during the run-in epoch, the run-in may be extended up to 6 weeks.
4The follow-up epoch applies to all patients except those patients who enter the safety study directly after Visit 299.
TD = investigational treatment discontinuation (permanent treatment discontinuation but continue with limited assessments; (S) = assessment to be recorded in source documents only; assessment will not be entered 
into the eCRFs; V = Visit
Record deaths
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Liver events monitoring
X
X
X
X
X
X
X
X
X
X
X
X
Renal events monitoring
X
X
X
X
X
X
X
X
X
X
X
X
Asthma exacerbation recording
Note: In case of an asthma 
exacerbation, the patient should be 
encouraged by the site to contact it for 
advice. If necessary, an unscheduled 
visit to the site may be organized
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Spirometry (centralized)
£To be performed prior to reversibility 
test. 
X£
X
1st Pre-dose Spirometry 
(centralized) - 45 min pre-dose
Note: To be performed approximately. 
45 min prior to in-clinic witnessed study 
drug administration.
X
X
X
X
X
X
X
X
X
2nd pre-dose Spirometry 
(centralized) - 15 min pre-dose
Note: To be performed approximately. 
15 min prior to in-clinic witnessed study 
drug administration.
£To be performed prior to reversibility 
test. 
X£
X£
X£
X
X
X£
X
X
X£


Novartis
Confidential
Page 55
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
Screen
Run-in
Treatment
Follow-up
Visit Number (Site visits)1
1
101
199
201
202
203
204
205
206
207
UNSCH
EDULED
-TD
299
301
Telephone Call (TC)2
Note: TC in-between site visits 
TC1
TC2
TC3
TC4
TC5
TC6
Treatment Week
-4
-23
1
1
4
8
12
16
20
24
28
32
36
40
44
48
TD
52
56
Treatment Day
Note: *V199 and 201 will occur on the 
same day if the patient is randomized.
-28
-143
1*
1*
28
56
84
112
140
168
196
224
252
280
308
336
TD
364
392
Visit Window (Days)
NA
+/-7
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
NA
+/-5
+/-5
1Scheduled clinic visits (starting at Visit101 and thereafter) are to occur in the morning at approximately the same time, so that the -45 min and -15 min pre-dose FEV1 assessments can be performed between 06:00 
A.M. and 10:00 A.M. (+/- 1 hour).
2Scheduled telephone calls (TCs) will be conducted to check the patients’ condition (Changes in concomitant medications, surgeries and procedures, serious and non-serious adverse events, and asthma exacerbations 
should be recorded in the appropriate eCRF if applicable). If necessary an unscheduled clinical visit may be arranged.
3For patients experiencing an asthma exacerbation during the run-in epoch, the run-in may be extended up to 6 weeks.
4The follow-up epoch applies to all patients except those patients who enter the safety study directly after Visit 299.
TD = investigational treatment discontinuation (permanent treatment discontinuation but continue with limited assessments; (S) = assessment to be recorded in source documents only; assessment will not be entered 
into the eCRFs; V = Visit
Reversibility test / Post-
bronchodilator FEV1 (spirometry 
after administration of short-acting 
β-agonist [SABA])
Notes:
**If reversibility is not demonstrated at 
Visit 1 and documented evidence for one 
of the other criteria for a clinical 
diagnosis of asthma is not met, then the 
reversibility test may be repeated at Visit 
101.
To be performed prior to in-clinic 
witnessed study drug administration.
ßTo be performed after the second pre-
dose spirometry (may be performed after 
10:00 AM (+/- 1 hour)).
X
X**,,ß
X,ß
X,ß
X,ß
X,ß
Airway hyper-reactivity test 
***optional test if reversibility is not met
at V1.
X***


Novartis
Confidential
Page 56
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
Screen
Run-in
Treatment
Follow-up
Visit Number (Site visits)1
1
101
199
201
202
203
204
205
206
207
UNSCH
EDULED
-TD
299
301
Telephone Call (TC)2
Note: TC in-between site visits 
TC1
TC2
TC3
TC4
TC5
TC6
Treatment Week
-4
-23
1
1
4
8
12
16
20
24
28
32
36
40
44
48
TD
52
56
Treatment Day
Note: *V199 and 201 will occur on the 
same day if the patient is randomized.
-28
-143
1*
1*
28
56
84
112
140
168
196
224
252
280
308
336
TD
364
392
Visit Window (Days)
NA
+/-7
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
NA
+/-5
+/-5
1Scheduled clinic visits (starting at Visit101 and thereafter) are to occur in the morning at approximately the same time, so that the -45 min and -15 min pre-dose FEV1 assessments can be performed between 06:00 
A.M. and 10:00 A.M. (+/- 1 hour).
2Scheduled telephone calls (TCs) will be conducted to check the patients’ condition (Changes in concomitant medications, surgeries and procedures, serious and non-serious adverse events, and asthma exacerbations 
should be recorded in the appropriate eCRF if applicable). If necessary an unscheduled clinical visit may be arranged.
3For patients experiencing an asthma exacerbation during the run-in epoch, the run-in may be extended up to 6 weeks.
4The follow-up epoch applies to all patients except those patients who enter the safety study directly after Visit 299.
TD = investigational treatment discontinuation (permanent treatment discontinuation but continue with limited assessments; (S) = assessment to be recorded in source documents only; assessment will not be entered 
into the eCRFs; V = Visit
Train and assess patient’s ability to 
use eDiary/
 and dispense 
eDiary/
 (S)
X
Review eDiary/
 compliance 
prior to randomizing the patient(S)
X
X
Review eDiary/
 entries(S)
X
X
X
X
X
X
X
X
Contact IRT (S)
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomize patient through IRT (S)
X
ACQ-5 in clinic
X
X
X
X
X
X
X
X
X
X
X
AQLQ+12 in clinic
X
X
X
X
X
X
X
X
X
X
Dispense study drug (S)
Note: The patients will be instructed to 
take their investigational treatment in the 
morning
X
X
X
X
X
X
X
X


Novartis
Confidential
Page 57
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
Screen
Run-in
Treatment
Follow-up
Visit Number (Site visits)1
1
101
199
201
202
203
204
205
206
207
UNSCH
EDULED
-TD
299
301
Telephone Call (TC)2
Note: TC in-between site visits 
TC1
TC2
TC3
TC4
TC5
TC6
Treatment Week
-4
-23
1
1
4
8
12
16
20
24
28
32
36
40
44
48
TD
52
56
Treatment Day
Note: *V199 and 201 will occur on the 
same day if the patient is randomized.
-28
-143
1*
1*
28
56
84
112
140
168
196
224
252
280
308
336
TD
364
392
Visit Window (Days)
NA
+/-7
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
NA
+/-5
+/-5
1Scheduled clinic visits (starting at Visit101 and thereafter) are to occur in the morning at approximately the same time, so that the -45 min and -15 min pre-dose FEV1 assessments can be performed between 06:00 
A.M. and 10:00 A.M. (+/- 1 hour).
2Scheduled telephone calls (TCs) will be conducted to check the patients’ condition (Changes in concomitant medications, surgeries and procedures, serious and non-serious adverse events, and asthma exacerbations 
should be recorded in the appropriate eCRF if applicable). If necessary an unscheduled clinical visit may be arranged.
3For patients experiencing an asthma exacerbation during the run-in epoch, the run-in may be extended up to 6 weeks.
4The follow-up epoch applies to all patients except those patients who enter the safety study directly after Visit 299.
TD = investigational treatment discontinuation (permanent treatment discontinuation but continue with limited assessments; (S) = assessment to be recorded in source documents only; assessment will not be entered 
into the eCRFs; V = Visit
Return and assess compliance 
with study drug (count tablets in 
returned bottles) (S)
X
X
X
X
X
X
X
X
X
In-clinic witnessed study drug 
intake
Note Complete Dose administration 
record (DAR) – at site visit 
X
X
X
X
X
X
X
X
X
Complete Dose administration 
record - Summary page
X
X
X
X
X
X
X
X
X
Complete Study Disposition page 
(screening)
X
Complete Study Disposition page 
(run-in)
Note: $V101 Disposition is only present 
if patient is a run-in failure.  
X$
X
Complete Study Disposition page 
(end of treatment )
X
Complete Study Disposition page 
(follow-up )
X
Withdrawal of informed consent
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Re-screening of patient
Notes: Re-screening of patients is 
permitted once. Once a patient enters 
the run-in epoch, the patient may not be 
re-screened. If a patient is re-screened, 
a new informed consent (and assent if 
applicable) must be obtained for the 
study as outlined in the assessment 
schedule above.
X
Appointment for next clinic visit (S)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


Novartis
Confidential
Page 58
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
Screen
Run-in
Treatment
Follow-up
Visit Number (Site visits)1
1
101
199
201
202
203
204
205
206
207
UNSCH
EDULED
-TD
299
301
Telephone Call (TC)2
Note: TC in-between site visits 
TC1
TC2
TC3
TC4
TC5
TC6
Treatment Week
-4
-23
1
1
4
8
12
16
20
24
28
32
36
40
44
48
TD
52
56
Treatment Day
Note: *V199 and 201 will occur on the 
same day if the patient is randomized.
-28
-143
1*
1*
28
56
84
112
140
168
196
224
252
280
308
336
TD
364
392
Visit Window (Days)
NA
+/-7
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
+/-5
NA
+/-5
+/-5
1Scheduled clinic visits (starting at Visit101 and thereafter) are to occur in the morning at approximately the same time, so that the -45 min and -15 min pre-dose FEV1 assessments can be performed between 06:00 
A.M. and 10:00 A.M. (+/- 1 hour).
2Scheduled telephone calls (TCs) will be conducted to check the patients’ condition (Changes in concomitant medications, surgeries and procedures, serious and non-serious adverse events, and asthma exacerbations 
should be recorded in the appropriate eCRF if applicable). If necessary an unscheduled clinical visit may be arranged.
3For patients experiencing an asthma exacerbation during the run-in epoch, the run-in may be extended up to 6 weeks.
4The follow-up epoch applies to all patients except those patients who enter the safety study directly after Visit 299.
TD = investigational treatment discontinuation (permanent treatment discontinuation but continue with limited assessments; (S) = assessment to be recorded in source documents only; assessment will not be entered 
into the eCRFs; V = Visit
Dispense patient card (S)
X
Collect patient card (S)
X
For 
patients 
participat
ing in the 
safety 
study
X
For sites participating in the Safety 
Study, discuss optional patient 
participation in the Safety Study.
X


Novartis
Confidential
Page 59
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
6.1
Information to be collected on screening failures and run-in 
failures
All patients who have signed informed consent but not entered into the next epoch (run-in)
will have the study completion page for the screening epoch, demographics, 
inclusion/exclusion, blood eosinophil counts, and serious adverse event (SAE) data collected. 
Adverse events that are not SAEs will be followed by the investigator and collected only in 
the source data.
All patients who have signed informed consent and have received single-blind study 
medication, but discontinue prior to randomization (run-in failures) should have all data for 
the visits they attended, the summary pages (Adverse Event, Concomitant Medication, 
Dosage Administrative Record), and screening and run-in disposition pages completed. All 
adverse events occurring after informed consent is signed should be recorded on the 
Adverse Event CRF. 
Investigators will have the discretion to record abnormal test findings on the medical history 
CRF whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature.
6.2
Patient demographics/other baseline characteristics 
The following demographics and baseline characteristics will be collected on all patients:

Age

Gender

Race and ethnicity

Height

Weight

Body mass index (BMI)

Duration of asthma

Number of exacerbations in prior year

Atopic Y/N (RAST/ImmunoCAP)

Smoking history

Reversibility (demonstrated or historical)

FEV1

OCS use Y/N

Baseline ACQ


Blood eosinophil counts at Visit 1 and baseline

Relevant medical history/current medical condition present before signing informed 
consent. Where possible, diagnoses and not symptoms will be recorded.


Novartis
Confidential
Page 60
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
6.3
Treatment exposure and compliance 
Study drug compliance will be assessed by the investigator and/or center personnel at 
designated visits by recording tablet counts from the previously dispensed bottles. 
The total number of doses of study drug administered since the last dispensing visit will be 
recorded in the Dosage Administration Record eCRF.
All doses of study drug taken at the clinic visits should be from the newly assigned 
medication packs, except at Visit 299 when the medication returned by the patient should 
be used.
6.4
Efficacy
6.4.1
Asthma exacerbations
The following definitions of exacerbations are used in this study.

A severe asthma exacerbation is defined as 

treatment with ‘rescue’ systemic corticosteroids for greater than or equal to 3 days 
and hospitalization; or

treatment with ‘rescue’ systemic corticosteroids for greater than or equal to 3 days 
and emergency department visit (greater than 24 hours*); or

death due to asthma. 

A moderate asthma exacerbation is defined as treatment with ‘rescue’ systemic 
corticosteroids for greater than or equal to 3 days either as an outpatient or in emergency 
department visits (Emergency department visit less than or equal to 24 hours).
*An emergency room visit greater than 24 hours is considered to be a hospitalization
‘Rescue’ systemic corticosteroids are tablets, suspension, or injection, or an increase of a 
patient’s maintenance systemic corticosteroids of greater than 2 fold (i.e., greater than 
doubling the maintenance dose of systemic corticosteroids). A single depo-injectable dose of 
corticosteroid will be considered the equivalent to a 3-day course of systemic steroids (Reddel, 
et al 2009). Endotracheal intubations will be captured on the CRF.
Scheduled spirometry should not be performed during an exacerbation until it has completely 
resolved.
If patients experience an asthma attack/exacerbation requiring systemic corticosteroids, 
hospitalization, or emergency room visit during the screening epoch, they may be re-screened 
once with the re-screening of the patient occurring 6 weeks or more after recovery from the 
asthma exacerbation. 
6.4.2
Asthma Control Questionnaire (ACQ-5)
In this study, the ACQ-5 will be used to assess improvements in asthma symptom control. 
The ACQ-5 will be collected in an electronic format.
The original ACQ consists of 7 items: 5 items on symptom assessment, 1 item on rescue 
bronchodilator use, and 1 item on airway caliber (% FEV1 predicted). The rescue 
bronchodilator use and % FEV1 predicted items are not included in the ACQ-5.  The ACQ 
was originally validated in patients with asthma over aged 17 years (Juniper 1999, 2006), and 


Novartis
Confidential
Page 61
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
is one of several asthma control measures recommended by the GINA Guidelines.  The ACQ 
has been fully validated, including patients aged from 6 to 16 years (Juniper 2010) and 
including a minimal important difference (MID) or smallest change that can be considered 
clinically important (0.5).
The ACQ-5 (see Appendix 8) will be self-administered at the clinic and only takes a few 
minutes to complete. Patients will be asked to recall how their asthma has been during the 
previous week and to respond to the symptom questions on a 7-point scale (0=no impairment, 
6=maximum impairment). The questions are equally weighted and the ACQ-5 score is the 
mean of the 5 questions: therefore, between 0 (totally controlled) and 6 (severely uncontrolled) 
(Juniper, et al 1999; Juniper, et al 2005; Juniper, et al 2006).
The ACQ will be completed by patients at the visits specified in the table of assessments (See
Table 6-1). The questionnaire should be completed before the AQLQ+12 and before any other 
assessments (see Section 6). The appropriate language version(s) of the questionnaire will be 
used in each participating country. The same language version of the questionnaire should be 
used by a particular patient throughout the study.   
The study coordinator should be familiar with the instrument and the associated user guides 
and training materials provided.  Patients should complete the questionnaire in a quiet area 
and are allowed to ask questions; however the site staff should take care not to influence the 
patient’s response. In response to a question, patients should be instructed to provide the truest 
or best response for them. 
Missing data should be avoided; therefore, the study coordinator will check the questionnaire 
for completeness before the patient leaves the clinic, and if necessary, encourage the patient to 
complete any missing responses. At later visits patients are not allowed to review their 
previous responses.
Completed questionnaires will be reviewed by the investigator for responses which may 
indicate potential AEs or SAEs.  The investigator should review not only the responses to the 
questions in the questionnaire but also for any unsolicited comments written by the patient.  If 
AEs or SAEs are confirmed then the physician must record the events as per instructions 
given in Section 7.1 and Section 7.2 of the protocol. Investigators should not encourage the 
patients to change the responses reported in the completed questionnaires.
6.4.3
Asthma Quality of Life Questionnaire for 12 years and older 
(AQLQ+12)
In this study, the disease-specific AQLQ+12 will be used to measure health-related quality of 
life in patients. The measure was originally validated for use in patients with asthma aged “12 
to 80 years (Juniper, et al 2005)”. The AQLQ+12 will be collected in an electronic format.
The AQLQ+12 comprises a total of 32 individual questions that span a total of four domains: 
symptoms, activity limitation, emotional function, and environmental stimuli. Test-retest 
reliability, construct validity (cross-sectional and longitudinal), and responsiveness have been 
demonstrated (See Appendix 9).
The AQLQ+12 will be self-administered at the clinic. It takes about 4 to 5 minutes to 
complete.  Patients are asked to recall their experiences during the previous 2 weeks and to 


Novartis
Confidential
Page 62
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
score each item on a 7-point scale (7 = not at all impaired to 1 = severely impaired). The  
AQLQ+12 yields individual domain scores, which is the mean of all items in each domain, 
and an overall score, which is the mean of all 32 individual responses. Higher scores indicate 
less impairment in HRQOL.
The questionnaire will be completed by patients at the visits specified in the table of 
assessments (See Table 6-1).
The appropriate language version(s) of the questionnaire will be used in each participating 
country. The same language version of the questionnaire should be used by a particular 
patient throughout the study.  
The study coordinator should be familiar with the instrument and the associated user guides 
and training materials provided. The patient should complete the questionnaire in a quiet area 
and be allowed to ask questions; however site staff should take care not to influence the 
patient’s responses. The patient will be instructed to provide the truest and for them best 
response. 
Missing data should be avoided, therefore, the study coordinator will check the questionnaire 
for completeness before the patient leaves the clinic, and if necessary, encourage the patient to 
complete any missing responses. At later visits patients are not allowed to review their 
previous responses. 
Completed questionnaires will be reviewed by the investigator for responses which may 
indicate potential AEs or SAEs.  The investigator should review not only the responses to the 
questions in the questionnaire but also for any unsolicited comments written by the patient.  If 
AEs or SAEs are confirmed then the physician must record the events as per instructions 
given in Section 7.1 and Section 7.2 of the protocol. Investigators should not encourage the 
patients to change the responses reported in the completed questionnaires.
The PROs ACQ, AQLQ+12, 
 questionnaires should always be completed before 
any other assessments and in the above order (see Section 6).


Novartis
Confidential
Page 63
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
 


Novartis
Confidential
Page 64
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314


Novartis
Confidential
Page 65
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
6.4.8
Spirometry (FEV1 
)
All clinic visits must occur in the morning. Please refer to Section 6 and Table 6-1 for full 
details of the scheduling of spirometry measurements.
Equipment for spirometry assessments will be provided to all study sites by a Central 
Spirometry vendor, and all measurements will be reviewed by trained spirometry overreaders
at the central vendor. The final spirometry assessments will be those provided by the 
spirometry overreaders of the central spirometry vendor.
Please refer to the Spirometry Guidance, in Appendix 5, for full details on scheduling and 
performing spirometry. Reversibility testing must be conducted in the morning.
6.4.9
Appropriateness of efficacy assessments 
The measures described above are standard outcome measures in asthma trials.
6.5
Safety
The following safety assessments as delineated in Table 6-1 will be performed:

History and physical examination

Vital signs

Hematology

Blood chemistry including but not limited to 


Novartis
Confidential
Page 66
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314

Liver function tests: ALT, AST, total bilirubin

Metabolic panel: sodium, potassium, chloride, bicarbonate, BUN/urea, creatinine, 
glucose, calcium, phosphorus, magnesium, total protein, albumin, γ-GT, alkaline 
phosphatase, LDH, CK, iron, uric acid, cholesterol, triglycerides

amylase, lipase

hsCRP

CK-MB and Troponin-I (in response to CK results outside of the normal range)

HbA1c (collected at Visit 1 only)

Urinalysis and urine chemistry.

Pregnancy test (females of childbearing potential)

ECG

Adverse events including serious adverse events
Spirometry will also be used to monitor the safety of patients during the study. Patients will 
also be provided with an eDiary/
. The data captured in the eDiary/
 will be used to 
alert the patient and/or investigator to possible signs of worsening asthma 
A central laboratory will be used to analyze and report blood chemistry/hematology/urinalysis 
and urine chemistries. A central ECG vendor will be used to collect, assess and report ECGs.
A Data Monitoring Committee will be set up to overview safety. See Section 8.3 for details.
6.5.1
Physical examination 
A complete physical examination will be performed at Visits 1 and 299
(and 
UNSECHEDULED-TD if a patient discontinues investigational treatment but continues with 
study participation).  It will include the examination of general appearance, skin, neck 
(including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular and neurological. If indicated based on medical history and/or symptoms, 
rectal, external genitalia, breast, and pelvic exams will be performed.
Abbreviated physical examinations will be performed at visits 101 to 207 (except Visit 201, 
since Visit 199 and 201 should occur on the same day). It will include the examination of the 
lungs and heart.
Information for all physical examinations must be included in the source documentation at the 
study site. Significant findings that are present prior to informed consent being granted must 
be included in the Relevant Medical History/Current Medical Conditions screen on the 
patient’s eCRF. Significant findings made after informed consent is given which meet the 
definition of an Adverse Event must be recorded on the Adverse Event screen of the patient’s 
eCRF.
6.5.2
Vital signs 
Vital signs will be assessed at every visit (except Visit 201, since Visit 199 and 201 should 
occur on the same day). Measurements will include blood pressure, pulse rate, and body 
temperature. 
After the patient has been sitting for ten minutes, with back supported and both feet placed on 
the floor, systolic and diastolic blood pressure will be measured three times using an 


Novartis
Confidential
Page 67
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
automated validated device, e.g. OMRON, with an appropriately sized cuff. The repeat sitting 
measurements will be made at 1 to 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 patient's arm 
circumference, a sphygmomanometer with an appropriately sized cuff may be used.
The patient’s condition must be monitored to rule out any clinically relevant arrhythmia or 
tachycardia.
Clinically notable vital signs are defined in Appendix 1.
6.5.3
Height and weight 
Height in centimeters (cm) will be measured at the visits specified in the table of assessments 
(See Table 6-1).
Body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, but without shoes) will be 
measured at the visits specified in the table of assessments (See Table 6-1).
Body Mass Index (BMI) will be calculated as the weight in kg divided by the height in meters 
squared. 
6.5.4
Laboratory evaluations 
A central laboratory will be used for analysis of all specimens detailed in this section. Details 
on the collections, shipment of samples and reporting of results by the central laboratory are 
provided to investigators in the laboratory manual.
Details on clinically notable laboratory findings are defined in Appendix 1.
6.5.4.1
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential, and 
platelet count will be measured according to the assessment schedule in Table 6-1. Other 
reflex testing will be performed as outlined in the laboratory manual.
6.5.4.2
Clinical chemistry
BUN/urea, creatinine, creatine kinase, total bilirubin, AST, ALT, alkaline phosphatase, 
gamma-glutamyl transpeptidase, lactate dehydrogenase, sodium, potassium, chloride, calcium, 
magnesium, iron, bicarbonate, cholesterol, triglycerides, high-sensitivity C-reactive protein, 
phosphorus, total protein, albumin, glucose, uric acid, amylase, lipase, CK-MB and Troponin-
I (in response to CK results outside of the normal range), HbA1c (collected at Visit 1 only)
and immunoglobulins (IgE, RAST/ImmunoCAP test), will be measured according to the 
assessment schedule in Table 6-1. Other reflex testing will be performed as outlined in the 
laboratory manual.
If the total bilirubin concentration is increased above 1.5 times the upper limit of normal range, 
the total bilirubin will differentiated into the direct and indirect reacting bilirubin. 
All patients with laboratory tests containing clinically significant abnormalities should be 
followed until the values return to within the normal ranges or until a clinical explanation is 
identified, even after study medication has discontinued.


Novartis
Confidential
Page 68
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
6.5.4.3
Urinalysis
Urine for urinalysis and urine chemistry will be collected according to the collection schedule 
in Table 6-1.  All samples for urinalysis and urine chemistry will be sent to the central 
laboratory for analysis.  The urinalysis evaluation by the central laboratory will include a 
urine dipstick for specific gravity, protein, glucose, leukocytes and blood and, if required, a 
microscopic examination. Urine chemistry and microscopic examination of the urine will be 
performed by the central laboratory as delineated in Table 7-1 “Specific Renal Alert Criteria 
and Actions” in Section 7.4 “Renal Safety Monitoring” of this protocol”. Other reflex testing 
will be performed as outlined in the laboratory manual.
6.5.5
Electrocardiogram (ECG) 
ECGs will be measured according to the assessment schedule in Table 6-1. At Visits 1 and 
101 an ECG will be measured to test for eligibility for trial inclusion.
ECGs must be recorded after 10 minutes of rest in the supine position to ensure a stable 
baseline. The preferred sequence of cardiovascular data collection during study visits is PRO 
collection first, followed by ECG, and then other study procedures (see Section 6). The 
Fridericia QT correction formula (QTcF) should be used for clinical decisions.
Triplicate 12 lead ECGs are to be collected with ECG machines supplied by the core 
laboratory.  Full details of all procedures relating to the ECG collection and reporting will be 
contained in an investigator manual to be provided to each investigator site.
The original trace will be sent electronically for central review directly from the ECG 
machine. Two ‘identical’ duplicate print-outs will be generated and kept at the investigator 
site as source documentation and as back-up for submission to the central laboratory in case 
of problems with the electronic transmission.  Each page of the ECG tracing should be labeled 
with study number (CQAW039A2307), subject initials (where this is allowed according to 
local regulations), subject number, date and time, and filed in the study site source documents.
For any ECGs with subject safety concerns, two additional ECGs should be performed to 
confirm the safety finding and copies forwarded to the central ECG laboratory for assessment. 
The final ECG assessments will be those provided by the central cardiologist ECG 
overreaders of the central vendor. Clinically significant ECG findings prior to dosing with 
investigational treatment must be discussed with the Novartis responsible person or designee.
Clinically significant abnormalities should be recorded on the relevant section of the medical 
history/Current medical conditions/AE CRF /eCRF page as appropriate.
In the event that the central cardiologist reports that an ECG is abnormal, then the investigator 
must comment as to whether the ECG abnormality is either clinically significant or clinically 
insignificant. If necessary a cardiologist may be consulted.
6.5.6
Pregnancy and assessments of fertility 
All women of child bearing potential will have a serum pregnancy test at Visits 1 and a urine 
pregnancy test at all other site visits (except visit 201, since Visit 199 and 201 should occur on 
the same day). 
Pregnancy testing will begin at the visit a patient is first identified as being of child bearing 
potential.


Novartis
Confidential
Page 69
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
In countries where monthly pregnancy testing is required for women of child-bearing 
potential by local laws or regulations, these patients will perform home urine pregnancy 
testing on the day of all telephone visits. These female patients will report the results of their 
home urine pregnancy test as “positive” or “negative” to study site staff as part of the 
telephone visit and the results will be recorded in source documents.
A positive urine pregnancy test requires immediate interruption of study medication until 
serum β-hCG is performed and found to be negative. If positive, the patient must be 
discontinued from the study treatment.
6.5.7
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/patient population.
6.6
Other assessments 


Novartis
Confidential
Page 70
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
6.6.4
Airways hyper-reactivity test
An airways hyper-reactivity (AHR) test should be performed at Visit 101 if reversibility is not 
demonstrated at screening (Visit 1) and documented evidence for one of the other criteria for a 
clinical diagnosis of asthma is not met (see Section 4.1). A positive result is defined as a 
provoked fall in FEV1 of 20% (PC20) by methacholine  at ≤8 mg/ml (or histamine ≤10 mg/ml 
or acetylcholine <20 mg/mL) when not on ICS or ≤16 mg/ml or histamine ≤20 mg/ml or 
acetylcholine <40 mg/mL) on ICS therapy performed according to ATS/ERS guidelines.
7
Safety monitoring
7.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 


Novartis
Confidential
Page 71
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The occurrence of adverse events should be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination, laboratory test, or 
other assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms

they are considered clinically significant

they require therapy
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patient with
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying adverse events. Alert ranges for labs and other test abnormalities are 
included in Appendix 1.
Adverse events should be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them accompanied by the following information:

the severity grade: 

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities

its relationship to the study treatment:

Yes

No

its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved should be reported.

whether it constitutes a serious adverse event (SAE - See Section 7.2 for definition of 
SAE) and which seriousness criteria have been met.

action taken regarding study treatment
All adverse events should be treated appropriately. Treatment may include one or more of the 
following: 

no action taken (i.e. further observation only) 

study treatment dosage increased/reduced

study treatment interrupted/withdrawn

concomitant medication or non-drug therapy given 

non-drug therapy given 

patient hospitalized/patient’s hospitalization prolonged 


Novartis
Confidential
Page 72
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314

its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown)
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study drug, the 
interventions required to treat it, and the outcome.
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB) or will be communicated between IB updates in the 
form of Investigator Notifications. This information will be included in the patient informed 
consent and should be discussed with the patient during the study as needed.
The investigator should also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes 
might reasonably be related to study treatment. This information should be recorded in the 
investigator’s source documents, however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis.
Adverse events of special interest are being evaluated in this study population. Definitions of 
IDRs are provided in Appendix 3.
7.2
Serious adverse events
7.2.1
Definition of SAE
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s) which meets any one of the 
following criteria:

is fatal or life-threatening 

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition under study

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

is medically significant, i.e. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.


Novartis
Confidential
Page 73
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if more severe (see Annex IV, ICH-E2D Guideline).
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse (see Annex IV, ICH-E2D Guideline).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All AEs (serious and non-serious) are captured on the CRF, SAEs also require individual 
reporting to DS&E as per Section 7.2.2.
7.2.2
SAE reporting
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days after the last study visit must be reported to 
Novartis within 24 hours of learning of its occurrence. Any SAEs experienced after the 30 
days period should only be reported to Novartis if the investigator suspects a causal 
relationship to study treatment. 
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must be 
submitted within 24 hours of the investigator receiving the follow-up information. An SAE 
that is considered completely unrelated to a previously reported one should be reported 
separately as a new event.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess the relationship of each SAE to each specific 
component of study treatment, (if study treatment consists of several components) complete 
the SAE Report Form in English, and submit the completed form within 24 hours to Novartis. 
Detailed instructions regarding the submission process and requirements for signature are to 
be found in the investigator folder provided to each site. 
Follow-up information is submitted as instructed in the investigator folder. Each re-
occurrence, complication, or progression of the original event must be reported as a follow-up 
to that event regardless of when it occurs.  The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the blind was 
broken or not, and whether the patient continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the investigational treatment a Drug Safety 
and Epidemiology Department associate may urgently require further information from the 
investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same 


Novartis
Confidential
Page 74
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
investigational treatment that this SAE has been reported. Suspected Unexpected Serious 
Adverse Reactions (SUSARs) will be collected and reported to the competent authorities and 
relevant ethics committees in accordance with EU Guidance 2011/C 172/01 or as per national 
regulatory requirements in participating countries.
7.3
Liver safety monitoring
To ensure patient 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:

Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter

Liver events, which will require close observation, follow-up monitoring and completion 
of the standard base liver CRF pages
Please refer to Table 14-1 in Appendix 2 for complete definitions of liver laboratory triggers 
and liver events. 
Every liver laboratory trigger or liver event as defined in Table 14-1 of Appendix 2 should be 
followed up by the investigator or designated personal at the trial site as summarized below. 
Detailed information is outlined in Table 14-2 in Appendix 2.
For the liver laboratory trigger:

Repeating the LFT within the next week to confirm elevation.
These LFT repeats should be performed using the central laboratory if possible. If this is not 
possible, then the repeats can be performed at a local laboratory to monitor the safety of the 
patient. Repeats laboratory should then be performed at central laboratory as soon as possible. 
If a liver event is subsequently reported, any local LFTs previously conducted that are 
associated with this event should be reported on the Liver CRF pages.

If the elevation is confirmed, close observation of the patient will be initiated, including 
consideration of treatment interruption if deemed appropriate.
For the liver events:

Repeating the LFT to confirm elevation as appropriate

Discontinuation of the investigational drug if appropriate

Hospitalization of the patient if appropriate

A causality assessment of the liver event via exclusion of alternative causes (e.g., disease, 
co-medications)

An investigation of the liver event which needs to be followed until resolution. 
These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on investigator’s discretion. All follow-up information, and 
the procedures performed should be recorded on appropriate CRF pages, including the liver 
event overview CRF pages.


Novartis
Confidential
Page 75
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
7.4
Renal safety monitoring 
To ensure patient safety and enhance reliability in determining the nephrotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
renal events has to be followed. 
The following two categories of abnormal renal laboratory values have to be considered 
during the course of the study:
1. Serum event:

confirmed (after ≥ 24h) increase in serum creatinine of ≥ 25% compared to baseline 
during normal hydration status
2. Urine event:

urinary albumin-creatinine ratio (ACR) ≥1 g/g or ≥100 mg/mmol

urinary protein-creatinine ratio (PCR ) ≥1 g/g or ≥100 mg/mmol
Every renal laboratory trigger or renal event as defined in Table 7-1 should be followed up by 
the investigator or designated personnel at the trial site as summarized below. 
Table 7-1
Specific Renal Alert Criteria and Actions
Serum Event
Serum creatinine increase
25 – 49% compared to baseline
Confirm 25% increase after 24-48h 
Follow up within 2-5 days
Acute Kidney Injury: Serum creatinine 
increase  50 % compared to baseline
Follow up within 24-48h if possible
Consider drug interruption 
Consider patient hospitalization /specialized treatment
Urine Event
Albumin-creatinine ratio (ACR) ≥1g/g or 
≥100 mg/mmol;
Protein-creatinine ratio (PCR )≥1g/g or 
≥100 mg/mmol
Confirm value after 24-48h
Perform urine microscopy
Consider drug interruption / discontinuation 
For all renal events:
1. Document contributing factors in the CRF: co-medication, other co-morbid conditions, and 
additional diagnostic procedures performed 
2.
Monitor patient regularly (frequency at investigator’s discretion) until either: 

Event resolution: sCr within 10% of baseline or protein-creatinine ratio within 50% of 
baseline, 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.


Novartis
Confidential
Page 76
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
7.5
Idiosyncratic drug reactions monitoring
IDRs are adverse drug reactions that do not occur in most patients (i.e., they are rare, 
occurring 1 in 10,000 to 1 in 100,000 patients) and do not result from known pharmacological 
effects of a drug. Their onset is unpredictable and they may involve one or more organ 
systems, most notably the immune system, liver and blood cells.  
The investigator should pay special attention to any adverse events which may be a potential 
IDR reported by a patient. If such an event occurs, the investigator should report the event as 
per standard adverse event reporting procedures (i.e., serious adverse events for those meeting 
serious criteria and non-serious adverse events for those meeting non-serious adverse event 
criteria as defined in the protocol). 
The investigator may be also be contacted by Novartis regarding AEs that may resemble an 
IDR. A list of terms considered IDRs are provided in Appendix 3 
Events with potential to be IDRs will be identified thorough a prespecified search algorithm 
based on the Standardised MedDRA Queries as described in the study analysis plan. These 
events will be reviewed by the DMC on a regular basis.
7.6
Pregnancy reporting
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications.
Pregnancy should be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the investigational treatment.
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.
8
Data review and database management
8.1
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. During 
the study, Novartis employs several methods of ensuring protocol and GCP compliance and 
the quality/integrity of the sites’ data. The field monitor will visit the site to check the 
completeness of patient records, the accuracy of entries on the (e)CRFs, the adherence to the 
protocol and to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.  Continuous remote 
monitoring of each site’s data may be performed by a centralized Novartis CRA organization.   
Additionally, a central analytics organization may analyze data & identify risks & trends for 


Novartis
Confidential
Page 77
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
site operational parameters, and provide reports to Novartis Clinical Teams to assist with trial 
oversight.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by 
the patient (a signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
patients will be disclosed.
8.2
Database management and quality control 
Novartis staff, or a CRO working on behalf of Novartis, review the data entered into the CRFs 
by investigational staff for completeness and accuracy and instruct the site personnel to make 
any required corrections or additions. Queries are sent to the investigational site using an 
electronic data query. Designated investigator site staff is required to respond to the query and 
confirm or correct the data. If the electronic query system is not used, a paper Data Query 
Form will be faxed to the site. Site personnel will complete and sign the faxed copy and fax it 
back to Novartis staff that will make the correction to the database. The signed copy of the 
Data Query Form is kept at the investigator site.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Concomitant procedures, non-drug therapies and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
ECG readings will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
Centralized spirometry readings will be processed centrally and the results will be sent 
electronically to Novartis (or a designated CRO).
Diary data will be entered into an electronic diary by the patient. The system will be supplied 
by a vendor(s), who will also manage the database. The database will be sent electronically to 
Novartis (or a designated CRO).
Randomization codes and data about all study drug(s) dispensed to the patient and all dosage 
changes will be tracked using an Interactive Response Technology (IRT). The system will be 
supplied by a vendor, who will also manage the database. The database will be sent 
electronically to Novartis (or a designated CRO).


Novartis
Confidential
Page 78
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
Each occurrence of a code break via IRT will be reported to the clinical team and monitor.  
The code break functionality will remain available until study shut down or upon request of 
Novartis. 
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unblinded and made available for data analysis. Any 
changes to the database after that time can only be made after written agreement by Novartis 
Development management.
8.3
Data Monitoring Committee 
An independent, external data monitoring committee (DMC) will be set up to review safety 
data (including specific safety summaries for adolescent participants) from this trial and other 
Phase III trials in the QAW039 asthma development program, as well as to conduct the 
planned single interim analysis for futility as described in Section 3.5 and Section 9.6. The 
DMC will consist of a group of experts independent of the sponsor, analyses for the DMC 
will be prepared by individuals independent of the sponsor and sponsor personnel will remain 
fully blinded to the interim results until the final clinical database lock as described in Section 
5.4. Based on the safety implications of the data, the DMC may recommend modification or 
termination of the study. There will be no stopping for demonstrated efficacy prior to the 
completion of the study at either the unblinded safety reviews or the futility interim analysis, 
because a sufficiently large safety dataset is needed in addition to efficacy data.  Therefore, no 
statistical adjustment will be made to the final analysis. Full details on procedures, the DMC 
and futility criteria will be specified in a DMC charter.
A charter for the Data Monitoring Committee (DMC) will be developed in a separate 
document. The DMC is the autonomous data and safety advisory group for Novartis. Novartis 
will be described as the “Sponsor” in the charter, though the Sponsor of the trial in any 
particular country may in fact be an affiliate of this entity. 
The purpose of the DMC charter is to define: 
1. the membership of the DMC 
2. responsibilities of the DMC and Novartis 
3. responsibilities of independent biostatistician and programmer 
4. the relationship of the DMC with other trial components and data flow 
5. the purpose and timing of DMC meetings 
6. procedures for ensuring proper confidentiality, addressing conflict of interest, and 
ensuring proper communication 
The charter will comply with Novartis standard operating procedures and is in accordance 
with the FDA guidance (FDA 2006) and CHMP guidelines (CHMP 2006) on DMCs. If 
significant safety issues arise in between scheduled meetings, ad-hoc meetings will be 
scheduled to review the data.


Novartis
Confidential
Page 79
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
8.4
Data collection 
Designated investigator staff will enter the data required by the protocol into the OC/RDC 
system. Designated investigator site staff will not be given access to the system until they 
have been trained. 
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The Investigator must certify that 
the data entered into the electronic Case Report Forms are complete and accurate. After 
database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site. 
8.5
Adjudication Committee 
Not required.
9
Data analysis 
9.1
Analysis sets 
The screened set (SCR) will include all patients who provided informed consent.
The Randomized Set (RAN) will include all patients that were randomized. Data from these 
patients will be analyzed according to the treatment to which the patient was assigned at 
randomization.
The full analysis set (FAS) will include all randomized patients who received at least one dose 
of study drug. It was considered reasonable to limit the FAS to patients who took trial 
medication, because the decision on whether or not treatment is started will not be influenced 
by the treatment group assignment due to the effective treatment blinding procedures 
described in Section 5.4. Following the intent-to-treat principle, patients will be analyzed 
according to the treatment they were assigned to at randomization.
The per-protocol set (PPS) will include all patients in the FAS without any major protocol 
deviations such as violation of major entry criteria. Patients may also be considered censored 
for the PPS analysis at the time of major post-baseline protocol deviations. Major protocol 
deviations will be defined in the data handling plan prior to database lock and the un-blinding 
of the study. Patients will be analyzed according to the treatment they received.
The safety set (SAF) will include all patients who received at least one dose of study drug. 
Patients will be analyzed according to the treatment they received.
 
The analysis of the primary objective will be performed on the FAS. The PPS will be used for 
the supportive analysis of the primary and the key secondary variables. The FAS will be used 
for the analysis of all other efficacy variables. The SAF will be used in the analysis of all 
safety variables.


Novartis
Confidential
Page 80
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
Note that the set of patients included in the FAS and SAF are the same except that the SAF 
allows the inclusion of non-randomized patients who receive study drug in error.
9.2
Patient demographics and other baseline characteristics 
Patient demographics and baseline characteristics measured before randomization including 
age (calculated from date of birth to date of Visit 1), sex, race, ethnicity, height, weight, body 
mass index (BMI), relevant medical history,  including smoking history, asthma duration, use 
of long-acting beta-agonists, use of oral corticosteroids, pre-
 FEV1, 
percent predicted FEV1, ACQ score, blood eosinophil count, number of exacerbations in the 
previous year 
will be summarized by treatment group for the FAS. Categorizations 
of age will include at least the categories of <18, 18 to <65, 65-74, 75-84 and ≥85 years of age.
Blood eosinophil counts will also be summarized for the SCR.
9.3
Treatments 
The duration of exposure, the number of patients randomized who completed the foreseen 
course of study medication and the number of patients who discontinued from the study 
medication will be summarized.
Medications started and stopped prior to study drug, taken concomitantly, and started 
following last study drug dose (if applicable) will be summarized by treatment group in 
separate tables in the SAF. Concomitant therapies will be recorded, listed and summarized 
separately for asthma related medications / non-drug therapies and other medications.  
Concomitant asthma related medications will be summarized by pre-defined category.  
Concomitant medications not related to asthma will be summarized by pharmacological (ATC) 
class and preferred term.  More than one ATC class per medication is possible and the 
medication will be reported under all applicable classes.
Short acting β2-agonist usage (number of puffs) during the screening epoch will be 
summarized. 
Usage of asthma medication (e.g. LABA, ICS) at baseline will be summarized. Usage of oral 
corticosteroids (OCS) including dose will also be summarized. Patients taking prohibited 
concomitant medications will be noted in the summary of protocol deviations.
Compliance with study medication over the entire study will be summarized as the percentage 
of days with study medication intake during the period from first intake to last intake.
9.4
Analysis of the primary variable(s)
The primary analysis for this study will be conducted according the intention to treat principle.
9.4.1
Variable(s)
The primary variable for this study is the number of moderate-to-severe asthma exacerbations 
as defined in Section 6.4.1 experienced by each patient per patient year of follow-up. The start 
date of a moderate-to-severe asthma exacerbation recorded in the CRF is defined as the first 
day of ‘rescue’ systemic corticosteroid use, or the date of death if no rescue corticosteroids 
were taken prior to an asthma related death. Further asthma exacerbations will only be 
considered additional events, if the start date of the next episode is at least 7 days after the end 


Novartis
Confidential
Page 81
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
of the previous exacerbation episode. The end of an exacerbation is defined as the last day of 
systemic corticosteroid use.
The key secondary variables are AQLQ+12, ACQ-5 and pre-dose FEV1 at the end of the 52 
week treatment period. Their definition and analysis is described in Section 9.5.
9.4.2
Statistical model, hypothesis, and method of analysis
Primary null hypotheses
The trial will be considered positive, if one or more of the two QAW039 doses demonstrate a 
statistically significant reduction in the rate of moderate-to-severe asthma exacerbations. As 
described below, the two doses will be tested in parallel and each dose may achieve 
statistically significant results irrespective of the results achieved by the other dose. 
The primary null hypotheses are:

H0 450 eosinophil subgroup: relative risk ratio for the QAW039 450 mg QD group versus placebo 
in patients with eosinophil count ≥ 250 cells/µl = 1, 

H0 150 eosinophil subgroup: relative risk ratio for the QAW039 150 mg QD versus placebo in 
patients with eosinophil count ≥ 250 cells/µl = 1,

H0 450 overall: relative risk ratio for the QAW039 450 mg QD versus placebo in the overall 
study population = 1 and

H0 150 overall: relative risk ratio for the QAW039 150 mg QD versus placebo in the overall 
study population = 1.
The primary alternate hypotheses are:

HA 450 eosinophil subgroup: relative risk ratio for the QAW039 450 mg QD group versus placebo 
in patients with eosinophil count ≥ 250 cells/µl ≠1,

HA 150 eosinophil subgroup: relative risk ratio for the QAW039 150 mg QD group versus placebo 
in patients with eosinophil count ≥ 250 cells/µl ≠1,

HA 450 overall: relative risk ratio for the QAW039 450 mg QD group versus placebo in the 
overall study population ≠1 and

HA 150 overall: relative risk ratio for the QAW039 150 mg QD group versus placebo in the 
overall study population ≠1.
The superiority of QAW039 over placebo will be considered confirmed if at least one of the 
four primary null hypotheses is rejected in favor of the respective two-sided alternative 
hypotheses.
Familywise type I error rate control
The familywise type I error rate will be controlled at the two-sided 5% level across the 
primary and key secondary null hypotheses using the closed testing procedure specified by 
Figure 9-1 using the graphical method of  Bretz, et al 2009. In this closed testing procedure 
the primary null hypothesis about exacerbations in the subset of patients with eosinophil count 
≥ 250 cells/µl for each dose acts as a gatekeeper for the other null hypotheses for the same 
dose. 


Novartis
Confidential
Page 82
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
Figure 9-1
Closed testing procedure for primary and key secondary objectives
Vertices with associated weights denote the individual null hypotheses and their local significance 
levels (initially α is split 50%:50% across the primary null hypotheses regarding the subgroup with 
blood eosinophils ≥ 250 cells/μl for the 2 QAW039 doses). Directed edges between the vertices 
specify how the local significance levels are propagated in case of significant results. Dotted Dashed 
edges with a weight of ε indicate that the local significance level from the key secondary null 
hypotheses of a dose will only be propagated to the other population for the same dose, once all key 
secondary null hypotheses for a dose and population have been rejected. Dotted edges with a weight 
of ε2 (much smaller than ε) indicate that the local significance level from the key secondary null 
hypotheses of a dose will only be propagated to the other dose, once all key secondary null 
hypotheses for a dose have been rejected.
Initially, 50% of the alpha is assigned to each of the primary null hypotheses regarding the 
subgroup with blood eosinophils ≥ 250 cells/μl for the QAW039 450 mg QD and QAW039 
150 mg QD doses, respectively. 
Once this first primary null hypothesis for a dose has been rejected, the alpha will be 
distributed to the other primary null hypothesis regarding the overall population for the same 
dose and the key secondary null hypotheses regarding the subgroup with blood eosinophils ≥ 
250 cells/μl for that same dose. If the null hypothesis regarding the primary endpoint for the 
overall population is rejected for a dose, then alpha is reassigned to the key secondary null 
hypotheses regarding the overall population for that dose. Alpha will only be reassigned from 
the set of null hypotheses for a dose to the null hypotheses for the other dose once all null 
hypotheses for the dose to which the alpha was originally assigned have been rejected. 
Once the primary null hypothesis for a dose and population has been rejected, all key 
secondary null hypothesis for that dose and population are tested and can be rejected 
irrespective of whether the other key secondary null hypotheses for that dose and population 
can be rejected. However, FEV1 will be initially given the highest local significance level due 
to its regulatory importance.


Novartis
Confidential
Page 83
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
Statistical model for primary variable
These hypothesis tests, as well as point estimates and confidence intervals will be based on a 
negative binomial regression model  with the natural logarithm of the duration of follow-up in 
years as an offset variable (Keene, et al 2007; Keene, et al 2008), treatment group, 
randomization stratum (use or non-use of oral corticosteroids as part of SoC asthma therapy, 
patient age at Visit 1 [<18 years or ≥18 years], and when analyzing the overall population,
peripheral blood eosinophil counts at Visit 1 [<250 cells/l or ≥250 cells/l]) and region as a 
fixed class effects, the natural logarithm of the number of asthma exacerbations (requiring 
treatment with oral or systemic corticosteroids) in the 12 months prior to screening and the 
baseline pre-dose FEV1 as a continuous linear covariate. Note that the duration of follow-up 
will be the planned duration of follow-up for all patients, because any missing data will be 
imputed as described in Section 9.4.3. The inclusion of the offset is nevertheless useful to 
make regression coefficients easier to interpret. Should despite the inclusion criteria a patient 
with no exacerbations requiring treatment with oral or systemic corticosteroids in the 12 
months prior to screening be included in the trial, such a patient will be considered to have 
had 0.5 such exacerbations.
A negative binomial model will be used, because patient heterogeneity beyond that captured 
by the available patient-level covariates is expected. This can lead to over dispersed 
cumulative counts and zero inflation. A negative binomial model can better capture such 
heterogeneity than a Poisson model and can be seen as a Poisson model with the intensity 
distributed across patients according to a Gamma distribution (Keene, et al 2007).
Summary statistics for the primary variable
The primary variable will be summarized by treatment group in terms of the mean rate (events 
per patient year of follow-up) overall and for different time intervals, the distribution of 
patients by number of exacerbations and using plots of Nelson's (1995) nonparametric 
estimate of the mean cumulative function. The components of the composite primary endpoint 
will be summarized.
9.4.3
Handling of missing values/censoring/discontinuations
Despite all attempt to ensure complete follow-up for all patients, some patients may not be 
followed for exacerbations for the whole planned study duration. Missing data will be 
imputed using a multiple imputation approach similar to the “missing at random and jump to 
reference” approach described by Keene et al. (2014). 
The first step in implementing this approach is fitting a Bayesian negative multinomial model 
with non-informative priors to the data. This model will distinguish on- and off-treatment data 
for the QAW039 group and assume that the same event rate as in the placebo group applies 
after QAW039 discontinuation. The model will include the same covariates as the primary 
model, as well as a log length of follow-up offset variable. Missing data on exacerbations in 
both treatment groups will then be imputed by simulation using independent pseudorandom 
draws from the posterior for the parameters of this model in the conditional distribution of the 
missing data given the observed data as described by Keene et al. (2014). The imputation will 
use a mixture of the jump to reference and the missing at random approaches (Keene et al. 
2014) and will distinguish the following two cases:


Novartis
Confidential
Page 84
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
1. No further treatment effect versus placebo will be imputed for QAW039 patients that 
discontinue treatment and are lost to follow-up due to (or following a treatment 
discontinuation due to) lack of efficacy, adverse events or death. 
2. A continued treatment effect for QAW039 patients being lost to follow-up for reasons 
likely to be unrelated to study treatment (e.g. lost to follow-up, withdrew consent) will be 
assumed.
A large number of imputed datasets will be created, with their number chosen based on 
computational feasibility, but at least 1,000 based on the recommendation of Keene et al. 
(2014). Each dataset will be analyzed using the model described in Section 9.4.2 and the 
results will be combined on the log-scale using Rubin’s rule (Barnard and Rubin 1999). 
Regression coefficients and their confidence intervals will then be exponentiated to obtain 
rates and risk ratios.
9.4.4
Supportive analyses
The primary and the key secondary analyses will be repeated for the PPS.
The analysis results and the imputed data for different methods for imputing missing data will 
be compared.
If feasible retrieved data after the discontinuation of treatment (retrieved drop-out) will be 
used to impute missing post-treatment discontinuation data as a sensitivity analysis. While 
retrieved drop-outs may be a particularly suitable basis for imputing data for non-retrieved 
drop-outs, this analysis may not be feasible or may require simplification of the imputation 
model, because observed post-treatment discontinuation data may be sparse.
An on-treatment analysis will also be conducted. In this analysis all moderate-to-severe 
asthma exacerbations as defined in Section 6.4.1 will be counted, if the start date of the 
exacerbation is on or after the first day of treatment with double-blind study medication, but 
before or on the day after the last day of treatment with double-blind study medication. In this 
analysis a negative binomial regression model with the natural logarithm of the duration of 
on-treatment follow-up in years as an offset variable will be used. The duration of on-
treatment follow-up in years will be calculated for each patient as (treatment end date -
treatment start date + 1 day)/365.25 without taking into account treatment interruptions. Such 
a negative binomial model assumes that missing data after censoring either due to losses to 
follow-up or the end of treatment are missing at random conditional on the baseline covariates 
and the preceding data on events per follow-up time included in the analysis (Cook and 
Lawless 2007). Under this assumption the model implicitly imputes the missing data and the 
data censored at the end of treatment assuming a hypothetical situation of continued treatment 
with an unchanged on-treatment event rate for the patient (Committee for Medicinal Products 
for Human Use 2010). This analysis and missing data handling approach is in-line with the 
recently completed MENSA exacerbation trial for the monoclonal anti-interleukin-5 antibody 
mepolizumab in a similar population (Ortega, et al 2014). It is therefore the most appropriate 
analysis for a comparison of the results of the present trial to the MENSA trial.
In a tipping point analysis it will be explored by how much the event rate post-discontinuation 
would have had to increase (or continuous outcomes to worsen) in the primary and key 
secondary analyses in order to change the trial conclusions. 


Novartis
Confidential
Page 85
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
As a worst reasonable case analysis a disappearing treatment effect for all patients that are 
lost-to-follow-up will be used (jump-to-reference). This is a sensitivity analysis for the effect 
of assuming a continued treatment effect for patients withdrawing from the study for reasons 
considered to be likely unrelated to study therapy (see Section 9.4.3)
In a further rank-based sensitivity analysis for the primary endpoint withdrawal from the trial 
and death will be directly treated as negative trial outcomes for patients. Patients that 
completed the trial will be ranked as having had a more favorable outcome than patients that 
withdrew from the trial, who will in turn be ranked as having had a more favorable outcome 
than patients that died. Within each of these categories patients will be ranked according to 
(number of exacerbations + 0.5)/patient years of follow-up. Compared to solely ranking 
patients according to the number of exacerbations or solely according to the duration of 
follow-up, this ensures that patients lost to follow-up very early in the trial without 
experiencing any exacerbations will not be ranked more favorably than patients that nearly 
completed the trial and only had 1, or 2 exacerbations, while also ensuring that a patient with 
10 exacerbations that was lost to follow-up after 11 months and 1 day is not ranked as having 
a more favorable outcome than a patient with 0 exacerbations that was lost to follow-up after 
11 months. A Wilcoxon rank-sum test stratified by randomization stratum will be used to 
analyze the ranked data.
Supportive analyses will also explore whether allowing the possibility of declining or 
increasing exacerbation rates over time affects study conclusions.
Time to first asthma exacerbation and mean duration of asthma exacerbations will also be 
analyzed.
The absolute difference in the rates of moderate to severe asthma exacerbation rates per 
patient year and resulting number of patients that needs to be treated for 1 year to prevent one 
exacerbation will also be reported with confidence intervals.
For comparison to historical study results, data for the key secondary endpoints using last-
observation-carried-forward will also be provided.
Subgroups
The primary and key secondary analyses will also be conducted by subgroup including for 
key demographic (e.g. age, sex, race, BMI, geographic region) and disease related subgroups 
(e.g. number of exacerbations in the previous year, OCS use/GINA step, baseline FEV1 
tertiles, ACQ tertiles, as well as blood eosinophil counts).
Relationship of efficacy and baseline eosinophil levels
In addition to subgroup analyses with different baseline eosinophil levels, the functional 
relationship between the treatment effect and baseline blood eosinophil levels as a continuous 
covariate will be investigated for the primary and key secondary variables.
9.5
Analysis of secondary variables
9.5.1
Efficacy variables 
The key secondary variables of this trial are the mean of the two pre-dose FEV1 assessments 
at the week 52 visit, AQLQ+12 and ACQ-5 at the end of the 52 week treatment period. Data 


Novartis
Confidential
Page 86
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
from the preceding visits will be used primarily to describe the onset of action and for missing 
data imputation.
The key secondary variables of AQLQ+12, ACQ-5 and pre-dose FEV1 will be analyzed using 
an analysis of covariance (ANCOVA) model with factors for treatment group, randomization 
stratum and region, as well as the baseline AQLQ+12, baseline ACQ-5 and baseline  pre-
bronchodilator FEV1 as continuous linear covariates.
The null hypothesis will be tested for each dose group, each population (subgroup with 
peripheral blood eosinophil counts at Visit 1 ≥250 cells/l or overall population) and each key 
secondary variable using this model versus the two-sided alternative hypotheses
For each key secondary endpoint, each QAW039 dose and each population the null 
hypothesis is that the treatment difference compared to placebo at the week 52 visit = 0, while 
the alternative hypothesis is that the treatment difference to placebo at the week 52 visit ≠0.
This model will be fitted to each of multiple imputations generated using the jump-to-
reference approach described by Carpenter et al. (2013). In a similar manner to the primary 
analysis a continued treatment effect will be imputed for QAW039 patients with intermittent 
missing data and those QAW039 patients discontinuing double-blind study medication due to 
reasons likely to be unrelated to study medication (see Section 9.4.3). For all other QAW039 
patients with missing data and placebo patients with missing data imputation will be based on 
the placebo group. The average of the two FEV1 assessments will only be formed after 
multiple imputations so that if one of the two FEV1 assessments at a visit is missing, the 
average will be between the one available assessment and a second imputed assessment.
The test for the key secondary variables AQLQ+12, ACQ-5 and pre-dose FEV1 in patients 
with eosinophil count ≥ 250 cells/µl and for the overall population for each dose will be 
performed, if the primary null hypothesis has been rejected for the same dose for patients with 
eosinophil count ≥ 250 cells/µl and for the overall population, respectively. The local 
significance level for each secondary null hypothesis will be determined based on the closed 
testing procedure specified by Figure 9-1.
Sensitivity analyses for the key secondary endpoints
A range of sensitivity analyses for the key secondary endpoints similar to those described in 
Section 9.4.3 and Section 9.4.4 will be conducted. Further supportive analyses will look at the 
treatment effect separately for each visit. 
Additionally, a mixed model for repeated measures (MMRM) with an unstructured covariance 
structure will be fitted for secondary variables to evaluate the average treatment effect during 
weeks 12 to 52 of the trial. These MMRMs will include treatment group, visit, randomization 
stratum and region as fixed class effects, and the baseline AQLQ+12, baseline ACQ-5 and 
baseline pre-bronchodilator FEV1 as continuous linear covariates. Treatment group by week 4 
visit and baseline value by visit interactions will also be included in the model. This average 
effect will be both investigated using the main data imputation approach, as well as in an on-
treatment analysis. Note that the supportive on-treatment analysis for the on-treatment values 
(from start of double-blind study medication to the day after the last day of treatment) will use 
a MMRM with an unstructured covariance structure. This model implicitly imputes 
unrecorded values and the data censored at the end of treatment assuming a hypothetical 
situation of continued treatment with an unchanged on-treatment effect that is constant across 


Novartis
Confidential
Page 87
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
the week 12 to 52 visits for patients in a similar manner as the on-treatment analysis using a 
negative binomial model described in Section 9.4.4. 
An analysis of percent change from baseline in pre-dose FEV1 will also be performed. For 
this analysis pre-dose FEV1 and its baseline will be log-transformed for analysis and results 
will be back-transformed to obtain geometric means and ratios of geometric means to allow 
an interpretation as percent change from baseline. 
9.5.1.1
Asthma Quality of Life Questionnaire for 12 years and older 
(AQLQ+12)
The 32 items in the AQLQ+12 are divided into 4 domain-specific scores and a total score as 
follows: 

Symptoms = Mean of Items 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 29, 30 (12 items) 

Activity limitation  = Mean of Items 1, 2, 3, 4, 5, 11, 19, 25, 28, 31, 32 (11 items) 

Emotional function  = Mean of Items 7, 13, 15, 21, 27 (5 items) 

Environmental Stimuli = Mean of Items 9, 17, 23, 26 (4 items) 

Overall Score = Mean of Items 1 to 32 (32 items) 
Each item of the AQLQ+12 is equally weighted and scored along a 7-point scale, where 1 
indicates maximal impairment and 7 indicates no impairment. Thus, higher scores indicate 
better asthma-related HRQOL. There is a mean score calculated for each of the four domains, 
as well as an overall quality-of-life score, which is the mean score of all 32 items. The 
resultant overall scores will be between 1 and 7.
The developer suggests no more than 10% of missing data. This means no more than 3 
missing responses for the overall score and no more than 1 missing response per domain.  For 
the symptoms and activity domain scores, one missing value per domain is allowed.  For the 
emotional function and environmental stimuli domain scores, no missing values are allowed.
If these limits for missing questions are exceeded, the variable will be considered missing and 
will be imputed as described in Section 9.5.1.
The minimal important difference (MID), defined as “the smallest difference in score which 
patients perceive as beneficial and would mandate, in the absence of troublesome side effects 
and excessive cost, a change in the patient’s management,” of 0.5 has been established for this 
questionnaire as clinically significant (Juniper, et al 1994).
9.5.1.2
Pre-dose FEV1
The baseline measurement is defined as the mean of the pre-bronchodilator FEV1 values
taken at the last visit in the clinic prior to first dose of study drug. 
If the pre-dose FEV1 is taken within 6 hours of SABA use, or within 12 hours of twice-daily 
LABA (including fixed dose combinations of LABA and ICS) use, or 24 hours of once-daily 
LABA (including fixed dose combinations of LABA and ICS) use, or 24 hours of once-daily 
LAMA use, then the individual FEV1 value is set to missing. 
9.5.1.3
Asthma Control Questionnaire (ACQ-5)
The ACQ measures asthma symptom control and consists of 7 items. It includes the 5 most 
important symptoms, 1 about rescue bronchodilator use and 1 about airway calibre (FEV1 % 


Novartis
Confidential
Page 88
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
predicted pre-bronchodilator). Patients will be asked to recall their experiences during the past 
one week and to response items 1-6 (night-time waking, symptoms on waking, activity 
limitation, shortness of breath, wheeze, and rescue short-acting β2-agonist use) on a 7-point 
scale (0 – totally controlled, 6 – extremely poorly controlled). The ACQ-5 score calculated 
based on the 5 questions of the 5 most important symptoms. The5 questions of the ACQ-5 are 
equally weighted. The ACQ-5 score is the mean of the responses to the 5 questions. The 
resultant score will be between 0 and 6.
A score of 1.5 at baseline indicates patients who entered the study had inadequately controlled 
asthma (Juniper 2006). In addition, the minimal important difference (MID) or smallest 
change that can be considered clinically important is 0.5. 
9.5.2
Safety variables
All safety data will be summarized for the safety set.
Safety summaries will be primarily based on on-treatment data with selected tables also 
presented for the all data after the first intake of study drug, while all databased safety data 
will be listed. 
Unless otherwise specified, all safety summaries will be provided for patients with eosinophil 
count ≥ 250 cells/µl, for patients with eosinophil count < 250 cells/µl and for the overall study 
population.
Adverse events
Adverse events after informed consent including asthma exacerbations will be summarized 
and listed.
Adverse events starting on or after the time of the first intake of study drug and until the day 
after the last intake of study drug will be classified as a treatment emergent adverse events. 
Any adverse events that started during the study after informed consent before the time of the 
first intake of study drug will be classified as a prior adverse events and not included in 
tabulations of treatment emergent adverse events. 
The following treatment emergent adverse event summaries will be produced, overall by 
system organ class and preferred term, overall by system organ class, preferred term and 
maximum severity, suspected drug-related adverse events by system organ class and preferred 
term, serious adverse events by system organ class and preferred term, and adverse events 
leading to permanent discontinuation of study-drug by system organ class and preferred term.
Additionally, 
summaries 
including 
both 
treatment 
emergent 
and 
post-treatment 


Novartis
Confidential
Page 89
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
discontinuation events will be produced for adverse events and serious adverse events by 
system organ class and preferred term.
The number and percentage of patients with treatment emergent adverse events of special 
interest (e.g. IDRs), as well as cardiac events  will be summarized for each type of event with 
a break-down for each type of event by SMQ (when applicable) and preferred term. Time-to-
first-event analyses using Kaplan-Meier plots and Cox regression with the same model terms 
as the primary efficacy analysis model will be reported for each type of event, as well as 
incidence for recurrent events per patient-year of follow-up. The strategy for identifying these 
events will be defined in the detailed statistical analysis plan for this trial.
Vital signs
On-treatment data from the vital signs (systolic blood pressure, diastolic blood pressure, and 
pulse rate) will be summarized by treatment and scheduled visit. The maximum and minimum 
on-treatment systolic blood pressure, diastolic blood pressure, and pulse rate post-baseline 
(including values from post-baseline unscheduled and premature discontinuation visits) can 
also be summarized by treatment. Absolute on-treatment body weight will be summarized by 
scheduled visit. The on-treatment change from baseline to each scheduled post-baseline visit 
will be summarized by vital sign parameter, scheduled visit and treatment with standard 
descriptive statistics.
Notable on-treatment values and notable on-treatment changes from baseline in vital signs 
will be summarized.
Electrocardiogram (ECG) 
The on-treatment changes from baseline will be summarized by ECG parameter, schedule 
visit where baseline and post baseline values are both available. 
The following quantitative on-treatment variables will be summarized by treatment at each 
scheduled post-baseline visit: ventricular rate, QT interval, RR interval, PR interval, QRS 
duration, heart rate, and Fridericia’s QTc. The maximum on-treatment QTc (including values 
from post-baseline unscheduled and premature discontinuation visits) will also be summarized. 
Notable on-treatment values and notable on-treatment changes from baseline in quantitative 
ECG variables will be summarized.
Laboratory data
All laboratory data will be listed with abnormal values flagged. The laboratory on-treatment 
values and the on-treatment change from baseline for continuous laboratory parameters will 
be summarized at each visit. A frequency table of results for categorical on-treatment 
laboratory parameters will be produced for the whole study duration. 
Shift tables relative to the normal reference ranges will be used to summarize the on-treatment 
change from baseline to post-baseline for each laboratory parameter. For each on-treatment 
laboratory parameter, the patients will be classified into one of the four mutually exclusive 
groups (low, normal, high, and low + high).
For selected laboratory parameters, the number and percentage of patients with newly 
occurring or worsening on-treatment laboratory abnormalities meeting the clinically notable 


Novartis
Confidential
Page 90
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
criteria will be summarized by laboratory parameter at any time-point over the treatment 
period, considering all post-baseline data from scheduled, unscheduled and premature 
discontinuation visits. Patients with any newly occurring or worsening on-treatment value 
meeting the clinically notable criteria will be counted under the applicable criteria. 
9.6
Interim analyses 
As described in Section 3.5, a single futility interim analysis will be conducted in addition to 
periodic unblinded safety reviews by the DMC (see Section 8.3) using data (including specific 
safety summaries for adolescent participants) from this trial and other Phase III trials in the 
QAW039 asthma development program. No stopping for demonstrated efficacy prior to the 
completion of the study is foreseen at either the unblinded safety reviews or the futility 
interim analysis, because a sufficiently large safety dataset is needed in addition to efficacy 
data and thus, no statistical adjustment will be made to the final analysis.
9.7
Sample size calculation
To be conservative a mean placebo event rate of 1.5 events per patient year of follow-up has 
been assumed for this study; this is a slightly lower rate than the 1.75 events per patient-year 
observed in the placebo group of the MENSA trial (Ortega, et al 2014) and the same event 
rate as assumed for the DREAM trial, although the actual DREAM placebo event rate was 2.4 
events per patient year of follow-up (Pavord, et al 2012). A 40% reduction in the rate of 
asthma exacerbations per year in the QAW039 treatment compared to placebo has been 
assumed for the subgroup with high eosinophils ≥ 250 cells/μl for this study; this is 
considered to be highly clinically relevant and at the same time realistic based on the DREAM 
and MENSA trials conducted in similar patient populations. In the DREAM trial 75 mg 
mepolizumab reduced the number of asthma exacerbations per patient per year by 48%, 


Novartis
Confidential
Page 91
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
250mg mepolizumab by 39% and 750mg mepolizumab by 52% compared with placebo. In 
the MENSA trial intravenous mepolizumab reduced the number of asthma exacerbations per 
patient per year by 47% and subcutaneous mepolizumab by 53% compared with placebo. 
These relative risk reductions were taken into account, because the observed reduction in 
sputum eosinophils with QAW039 in Study CQAW039A2208 were similar to those observed 
with mepolizumab (Haldar, et al 2009; Pavord, et al 2012). On this basis it is postulated 
QAW039 may reduce the rate of asthma exacerbations to a similar extent as mepolizumab. 
For the subgroup with eosinophils < 250 cells/μl a lesser relative risk reduction of 30% was 
assumed. However, it should be noted that the trial may produce a significant result with a 
smaller reduction in exacerbations than that assumed for power calculations and that such a 
reduction could still be considered clinically relevant.
As reported in online supplementary material for the MENSA publication the negative 
binomial dispersion parameter for the exacerbation rates was estimated to be 0.8 in the 
DREAM trial. In the DREAM trial approximately 15% of patients in the mepolizumab arms 
and 20% of patients in the placebo arm were lost to follow-up by the end of the 1-year trial, 
while in the 32 week MENSA trial only 6 to 8% of patients were lost across groups. Therefore, 
a constant exponential hazard rate over time for treatment discontinuation is assumed with 
15% of patients off treatment by 1 year in the active treatment groups and the placebo group.
No further treatment effect versus placebo has been assumed during the off-treatment, i.e. a 
mean event rate of 1.5 events per patient year has been assumed for patients after treatment 
discontinuation in both the QAW039 and placebo groups.
A 1:1:1 randomization was used, even though the power to demonstrate the superiority of at 
least one arm versus placebo would likely have been higher with an increased assignment to 
the placebo group, in order to not reduce the amount of efficacy and safety information for 
each QAW039 dose group. 
Negative binomial counts were simulated based on the assumptions above and the testing 
procedure in Figure 9-1 was applied to each simulation result. For the purpose of evaluating 
the power for the primary trial objectives, it was assumed that none of the key secondary null 
hypotheses would be rejected.
For this study a two-sided significance level of 5% is used for testing. As shown in Table 9-1
188 patients per arm in the subpopulation with blood eosinophils ≥ 250 cells/μl and 282
patients per arm in the overall population corresponding to a total sample size of 846 patients 
provide greater than 80% power for demonstrating the superiority of each dose of QAW039 
compared to placebo in the subpopulation with blood eosinophils ≥ 250 cells/μl and overall 
population under the described assumptions.


Novartis
Confidential
Page 92
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
Table 9-1
Power for the primary variable
True relative risk reduction
Upper row: Subpopulation
Lower row: Other population
Power (%)
Upper row: Subpopulation
Lower row: Overall population
450 mg
150 mg
At least one
All doses
(%)
(%)
450 mg
150 mg
dose significant
Significant
40
30
40
30
89%
84%
89%
84%
96%
93%
82%
75%
40
20
40
20
89%
76%
89%
76%
96%
88%
82%
64%
40
0
40
0
89%
49%
89%
49%
96%
66%
82%
32%
Subpopulation means the subpopulation with blood eosinophils ≥ 250 cells/μl, while other 
population refers to the subpopulation with blood eosinophils < 250 cells/μl. Power results 
are based on 100,000 simulated trials per scenario. Only results for primary endpoints were 
simulated. For the purpose of evaluating the power for the primary trial objectives, it was 
assumed that none of the key secondary null hypotheses would be rejected. All simulations 
were performed in SAS 9.4.
If statistical significance is achieved in the primary test, the test for the key secondary 
variables pre-dose FEV1, AQLQ+12 and ACQ-5 will be performed. The local significance 
level for each secondary null hypothesis will be determined based on the closed testing 
procedure shown in Figure 9-1. For the power for each key secondary variable in the 
subpopulation with blood eosinophils ≥250 cells/μl and overall population, it was 
conservatively assumed that only the null hypothesis for the primary endpoint for the 
respective dose in the subpopulation and overall population would be rejected. For AQLQ+12 
and ACQ5 the power was additionally calculated conditional on both the null hypothesis for 
the primary endpoint and pre-dose FEV1 for the respective dose in the subpopulation and 
overall population having been rejected. The power for each key secondary endpoint is shown 
in Table 9-2. However, note that the power for the key secondary endpoints will be higher 
once the null hypotheses relating to other key secondary variables or other doses have been 
rejected. For the power calculation of secondary endpoints no further treatment effect versus 
placebo has been assumed for patients with treatment discontinuation.
It was assumed that QAW039 achieves a difference of 150 mL against placebo in FEV1 after 
52 weeks for patients that remain on treatment. A SD of 380 mL was assumed for the analysis 
in FEV1. Given a 15% treatment discontinuation rate by week 52, the planned sample size
will give 80% power for each dose in the subpopulation at the resulting local two-sided 
significance level of 1.625% and 90% power for each dose in the overall population at the
resulting local two-sided significance level of 0.698%.
Assuming a clinically important true improvement of at least 0.5 in AQLQ+12 after 52 weeks 
treatment for patients that remain on treatment, a standard deviation (SD) of 1 and 15% 
treatment discontinuation rate by week 52, the planned sample size per arm will provide 76% 
power for each dose in the subpopulation with blood eosinophils ≥ 250 cells/μl at the resulting 
local two sided significance level of 0.075% and 93% power for each dose in the overall 


Novartis
Confidential
Page 93
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
population at the resulting local two-sided significance level of 0.038% after the respective 
primary null hypothesis has been rejected. 
Assuming a difference of 0.5 against placebo in ACQ-5 after 52 weeks for patients without 
treatment discontinuation, a SD of 1.1, and a 15% treatment discontinuation rate by week 52, 
the planned sample size will give 59% power for each dose in the subpopulation at the
resulting local two-sided significance level of 0.05% and 78% power for each dose in the 
overall population at the resulting two-sided local significance level of 0.015% after the 
respective primary null hypothesis has been rejected.
Table 9-2
Power of each dose for the analyses of key secondary variables 
Pre-dose FEV1
AQLQ+12
ACQ-5
Difference of effect (δ) for patients 
without treatment discontinuation
150 mL
0.5
0.5
SD (σ)
380 mL
1
1.1
Treatment discontinuation rate
15%
15%
15%
Subpopulation 
Local two-sided 
significance level
1.625%
0.075%*
1.294%†
0.05%*
0.456%†
Power
80%
76%*
95%†
59%*
81%†
Overall population
Local two-sided 
significance level
0.698%
0.038%*
0.561%†
0.015%*
0.189%†
Power
90%
93%*
99%†
78%*
93%†
Subpopulation means the subpopulation with blood eosinophils ≥ 250 cells/μl.
* For local two-sided significance level and power in AQLQ+12 and ACQ5 the upper row shows the 
value when only the null hypothesis for the primary endpoint for the respective dose in the 
subpopulation and overall population have been rejected. 
† The lower row shows the value when both the null hypothesis for the primary endpoint and pre-dose 
FEV1 for the respective dose in the subpopulation and overall population have been rejected.
10
Ethical considerations 
10.1
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented and reported in accordance with 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US CFR 21, and Japanese Ministry of 
Health, Labor, and Welfare), and with the ethical principles laid down in the Declaration of 
Helsinki.
10.2
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of doing 
so, after such consent has been provided by a legally acceptable representative(s) of the 
patient. In cases where the patient’s representative gives consent, the patient should be 


Novartis
Confidential
Page 94
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
informed about the study to the extent possible given his/her understanding. If the patient is 
capable of doing so, he/she should indicate assent by personally signing and dating the written 
informed consent document or a separate assent form. Informed consent must be obtained 
before conducting any study-specific procedures (i.e. all of the procedures described in the 
protocol). The process of obtaining informed consent should be documented in the patient 
source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy 
of the approved version must be provided to the Novartis monitor after IRB/IEC approval.
Women of child bearing potential should be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.
In the event that Novartis wants to perform testing on the samples that are not described in
this protocol, additional Institutional Review Board and/or Ethics Committee approval will be 
obtained.
10.3
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution should obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment 
procedures (e.g., advertisements) and any other written information to be provided to patients. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Quality Assurance representatives, designated 
agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the 
clinical site is requested by a regulatory authority, the investigator must inform Novartis 
immediately that this request has been made.
10.4
Publication of study protocol and results 
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results.
10.5
Quality Control and Quality 
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections.


Novartis
Confidential
Page 95
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
Audits of investigator sites, vendors, and Novartis systems are performed by Novartis Pharma 
Auditing and Compliance Quality Assurance (CQA), a group 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.
11
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safety of patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances should an 
investigator collect additional data or conduct any additional procedures for any research 
related purpose involving any investigational drugs.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented. All significant protocol deviations will be recorded and reported in the CSR.
11.1
Protocol Amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate 
hazard to patients may be implemented immediately provided the Health Authorities are 
subsequently notified by protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7 Safety Monitoring should be followed.
12
References 
References are available upon request.
ATS/ERS (2005) Recommendations for Standardized Procedures for Online and Offline 
Measurement of Exhaled Lower Respiratory Nitric Oxide and Nasal Nitric Oxide. AJRCCM; 
171: 912-930.
Barnard J, Rubin D (1999) Small-sample degrees of freedom with multiple imputation. 
Biometrika; 86:948–955.
Bretz F, Maurer W, Brannath W et al. (2009) A graphical approach to sequentially rejective 
multiple test procedures. Statistics in Medicine; 28(4): 586-604.
Carpenter JR, Roger JH and Kenward MG (2013) Analysis of Longitudinal Trials with 
Protocol Deviation: A Framework for Relevant, Accessible Assumptions, and Inference via 
Multiple Imputation. Journal of Biopharmaceutical Statistics, 23:6, 1352-1371


Novartis
Confidential
Page 96
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
Castro M, Mathur S, Hargreave F et al (2011) Reslizumab for poorly controlled, eosinophilic 
asthma. Am J Resp Crit Care Med; 184: 1125-1132.
Castro M, Zangrilli J, Wechsler ME et al. (2015) Reslizumab for inadequately controlled 
asthma with blood eosinophil counts from two, multicentre, parallel, double-blind, 
randomised, placebo-controlled, phase 3 trials. Lancet Respir Med; Published Online: 23 
February 2015.
Center for Disease Control and Prevention (Cdc.gov) (2000). Growth Charts - Homepage. 
Available from: http://www.cdc.gov/growthcharts/.
Chevalier E, Stock J, Fisher T et al. (2005) Cutting edge: chemoattractant receptor-
homologous molecule expressed on Th2 cells plays a restricting role on IL-5 production and 
eosinophil recruitment. J Immunol; 175: 2056–2060.
Chung KF, Wenzel S, Brozek J et al. (2014) International ERS/ATS guidelines on definition, 
evaluation and treatment of severe asthma. Eur Respir J; 43:343.
Cook, Richard J., and Jerald F. Lawless. The statistical analysis of recurrent events. Springer, 
2007.
Deng JW, Song IS, Shin HJ et al (2008) The effect of SLC01B1*15 in the disposition of 
pravastatin and pitavastatin is substrate dependent: the contribution of transporting activity 
changes by SLC01B1*15.  Pharmacogenetics and Genomics; 18(5): 424-433.
Elsby R, Hilgendorf C, and Fenner K (2012) Understanding the critical disposition pathways 
of statins to assess drug-drug interaction risk during drug development: it’s not just about 
OATP1B1. Clin Pharmacol and Ther; 92: 585-598.
Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma 
(GINA) 2016.  Available from http://www.ginasthma.org/. 
Haldar P, Brightling CE, Hargadon B et al. (2009) Mepolizumab and exacerbations of 
refractory eosinophilic asthma. N Engl J Med.; 360(10):973-84.
Hurst H, Bolton  J.  (2004) Assessing the clinical significance of change  scores  recorded  on 
subjective outcome  measures. J Manipulative Physiol Ther; 27:26-35.
Jacobson TA (2008) Toward “pain-fee” statin prescribing: clinical algorithm for diagnosis 
and management of myalgia. Mayo Clin Proc; 83: 687-700.
Juniper EF, O'Byrne PM, Guyatt GH et al. (1999) Development and validation of the 
questionnaire to measure asthma control. Eur Resp J, 14: 902-907.
Juniper EF, Svensson K, Moerk AC, Ståhl E (2005) Modification of the Asthma Quality of 
Life Questionnaire (standardised) in patients 12 years and older. Health and Quality of Life 
Outcomes. Health Qual of Life Outcomes; 3: 58.
Juniper EF, Bousquet J, Abetz L et al., GOAL Committee (2006) Identifying ‘well-controlled’ 
and ‘not well-controlled’ asthma using the Asthma Control Questionnaire. Respir Med; 100: 
616- 621.
Juniper EF, Gruffydd-Jones K, Ward S, Svensson K (2010) Validation, measurement 
properties and interpretation of the Asthma Control Questionnaire in children. Eur Respir J;
36: 1410-1416.
Kalliokoski A and Niemi M (2009)  Impact of OATP transporters on pharmacokinetics.  B J 
P; 158: 693-705.


Novartis
Confidential
Page 97
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
Keene, O. N., Jones, M. R., Lane, P. W., & Anderson, J. (2007) Analysis of exacerbation rates 
in asthma and chronic obstructive pulmonary disease: example from the TRISTAN study. 
Pharmaceutical statistics; 6(2): 89-97.
Keene ON, Calverley PM, Jones PW, Vestbo J, Anderson JA (2008) Statistical analysis of 
exacerbation rates in COPD: TRISTAN and ISOLDE revisited. Eur Respir J; 32: 17–24.
Keene ON, Roger JH, Hartley BF and Kenward MG (2014) Missing data sensitivity analysis 
for recurrent event data using controlled imputation. Pharmaceut. Statist.; 13: 258–264
Masoli M, Fabian D, Holt S et al. (2004) The global burden of asthma: executive summary of 
the GINA Dissemination Committee Report. Allergy; 59: 469-478.
Nair P, Pizzichini MM, Kjarsgaard M et al (2009) Mepolizumab for prednisone-dependent 
asthma with sputum eosinophilia. N Engl J Med; 360(10):985-93.
Nelson, W (1995) Confidence Limits for Recurrence Data—Applied to Cost or Number of 
Product Repairs. Technometrics; 37: 147–157.
Noe J, Portmann R, Brun ME et al (2007) Substrate-dependent drug-drug interactions 
between gemfibrozil, fluvastatin, and other organic anion-transporting peptide (OATP) 
substrates on OATP1B1, OATP2B1, and OATP1B3. Drug Metab Dispos 35(8): 1308-1314.
Nowak RM, Parker JM, Silverman RA et al (2015) A randomized trial of benralizumab, an 
antiinterleukin 5 receptor α monoclonal antibody, after acute asthma. Am J Emergency Med; 
33:14-20.
Ortega H, Liu MC, Pavord ID et al. (2014) Mepolizumab treatment in patients with severe 
eosinophilic asthma. N Engl J Med; 371(13): 1198-1207.
Pavord ID, Korn S, Howarth P et al. (2012) Mepolizumab for severe eosinophilic asthma 
(DREAM): a multicenter, double-blind, placebo-controlled trial. Lancet; 380: 651-659.
Reddel HK, Taylor DR, Bateman ED et al. (2009) An official American Thoracic 
Society/European Respiratory Society statement: asthma control and exacerbations: 
standardizing endpoints for clinical asthma trials and clinical practice. Am J Respir Crit Care 
Med; 180: 59-99.
Regan SL, Maggs JL, Hammond TG et al (2010) Acyl glucuronides: the good, the bad and the 
ugly. Biopharm Drug Dispos; 31:367-95.
Santanello NC, Barber BL, Reiss TF et al (1997) Measurement characteristics of two asthma 
symptom diary scales for use in clinical trials.  Eur Resp J; 10: 646-651.
Takaku Y, Soma T, Nishihara F et al. (2013) Omalizumab attenuates airway inflammation 
and interleukin-5 production by mononuclear cells in patients with severe allergic asthma. Int 
Arch Allergy Immunol; 161 Suppl 2:107-17.
Wenzel S (2005) Severe asthma in adults. Am J Respir Crit Care Med; 172(2):149-60. Epub 
2005 Apr 22.
Wenzel S, Ford L, Pearlman D (2013) Dupilumab in persistent asthma with elevated 
eosinophil levels. N Engl J Med; 368(26): 2455-66.
Woodruff PG, Modrek B, Choy DF et al. (2009) T-helper type 2-driven inflammation defines 
major subphenotypes of asthma. Am J Respir Crit Care Med; 180(5):388-95.


Novartis
Confidential
Page 98
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
13
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 Appendix 2 for specific liver event and laboratory test trigger definitions and follow-
up requirements.
For ECGs, a notable QTc value is defined as a QTcF (Fridericia) interval of ≥450 msec for 
males or ≥460 msec for females – all such ECGs will be flagged by the Central CRO and 
require assessment for clinical relevance and continuance of the patient by the Investigator.  


Novartis
Confidential
Page 99
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
14
Appendix 2: Liver event and Laboratory trigger Definitions 
and Follow-up Requirements
Table 14-1
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 14-2
Follow Up Requirements for Liver Events and Laboratory Triggers
Criteria
Actions required
Follow-up monitoring
Potential Hy’s 
Law casea

Discontinue the study drug 
immediately

Hospitalize, if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc
(frequency at investigator 
discretion)
ALT or AST
> 8 × ULN

Discontinue the study drug 
immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc
(frequency at investigator 
discretion)
> 3 × ULN and 
INR > 1.5

Discontinue the study drug 
immediately

Hospitalize, if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc
(frequency at investigator 
discretion)
> 5 to ≤ 8 × ULN

Repeat LFT within 48 hours

If elevation persists, continue 
follow-up monitoring
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc
(frequency at investigator 


Novartis
Confidential
Page 100
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
Criteria
Actions required
Follow-up monitoring

If elevation persists for more than 2 
weeks, discontinue the study drug

Establish causality

Complete liver CRF
discretion)
> 3 × ULN 
accompanied by 
symptomsb

Discontinue the study drug 
immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT 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
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc
(frequency at investigator 
discretion)
ALP (isolated)
> 2 × ULN (in the 
absence of 
known bone 
pathology)

Repeat LFT within 48 hours

If elevation persists, establish 
causality

Complete liver CRF
Investigator discretion
Monitor LFT within 1 to 4 weeks 
or at next visit
TBL (isolated)
> 2 × ULN (in the 
absence of 
known Gilbert 
syndrome)

Repeat LFT within 48 hours

If elevation persists, discontinue 
the study drug immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT 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 drug 
immediately

Hospitalize the patient

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc
(frequency at investigator 
discretion)
Any AE 
potentially 
indicative of a 
liver toxicity*

Consider study drug interruption or 
discontinuation 

Hospitalization if clinically 
appropriate

Establish causality

Complete liver 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.


Novartis
Confidential
Page 101
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
Refer to Section 5.5.10 for additional guidance on study treatment discontinuation due to liver 
laboratory abnormality / liver event, and to Section 7.3 for guidance on liver safety 
monitoring.


Novartis
Confidential
Page 102
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
15
Appendix 3: List of IDRs for investigators
Table 15-1
Definition of potential idiosyncratic drug reactions 
Type of reaction
Possible events diagnoses and signs/symptoms
Anaphylaxis 
Anaphylactic/anaphylactoid reactions 
Angioedema: diagnosis 
and/or signs and symptoms
Angioedema, site specific angioedema  urticaria, 
anisarca/generalized edema urticaria
Severe skin reactions
Acute generalised exanthematous pustulosis, Cutaneous 
vasculitis, Drug reaction with eosinophilia and systemic 
symptoms (DRESS), Epidermal necrosis, Toxic skin eruption , 
Oculomucocutaneous syndrome, Skin necrosis, Stevens-
Johnson syndrome (SJS), Toxic epidermal necrolysis (TENS)
Agranulocytosis and other 
cytopenic events
Agranulocytosis, aplastic anemia, pancytopenia
Other hypersensitivity 
reactions
Other suspected hypersensitivity to suspected drug  
Liver reactions
Any event that qualifies as a liver laboratory trigger or event as 
defined in Appendix 2
While this list is intended as a guide to the investigator, other potential IDRs may arise. 


Novartis
Confidential
Page 103
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
16
Appendix 4: Blood collection logs
Table 16-1
Time schedule for blood sampling for safety, Total IgE and 
RAST/ImmunoCAP test
*For patients who discontinue study drug early and remain in the study (see Section 5.5.10), extra 
blood samples must be taken at the UNSCHEDULED-TD visit.


Novartis
Confidential
Page 104
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314


Novartis
Confidential
Page 105
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
17
Appendix 5: Spirometry Guidance
Equipment
Spirometers must meet the specifications and performance criteria recommended in the 
American Thoracic Society (ATS)/European Respiratory Society (ERS) Standardization of 
Spirometry1. Spirometers must have the capacity to print 
 tracings.  All spirometry values 
should be reported at BTPS by the method established by the manufacturer.
Calibration
The spirometer should be calibrated every morning before any spirometric measurements for 
the study are performed. Calibration reports should be printed and stored as source data at the 
site. 
Preparing the test subject
On study days when spirometry will be performed, patients should refrain from the following:

Coffee, tea, chocolate, cola and other caffeine-containing beverages and foods and ice-
cold beverages  for 4 hours prior to spirometry

Alcohol for 4 hours prior to spirometry

Strenuous activity for 12 hours prior to spirometry 

Exposure to environmental smoke, dust or areas with strong odors 
Every effort should be made to assure consistent testing conditions throughout the study.  A 
seated position with nose clips is recommended to reduce risks related to dizziness or syncope.  
When possible, spirometry should be conducted by the same technician using the same 
spirometer.  To minimize the effects of diurnal variation on lung function, spirometry visits 
should start at approximately the same time of day at each visit.  
Performing Spirometry
The subject’s age, height and gender will be entered into the spirometer.  It is important that 
the height is measured accurately at the study site. Spirometry, an effort-dependent test, 
requires careful instruction and cooperation of the subject.  The technician should ensure a 
good seal around the mouthpiece, and confirm that the subject’s posture is correct. The 
subject should be instructed to perform a maximal inspiration, followed by maximum forced 
expiration until no more air can be exhaled or for at least 6 seconds. Expiration must be rapid 
with exertion of maximal effort. The results of spirometry should meet the ATS/ERS criteria 
for acceptability and repeatability. Acceptability criteria should be applied before repeatability 
is determined.  
 
 


Novartis
Confidential
Page 106
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
Acceptability
An acceptable maneuver has the following characteristics: 

No hesitation or false start;

A rapid start;

No cough, especially during the first second of the maneuver;

No glottic closure or obstruction by tongue or dentures

No early termination of exhalation (minimum exhalation time of 6 seconds is 
recommended, or no volume change for at least 1 second) or the subject cannot continue 
to exhale further
Repeatability
The 2 largest 
 FEV1 values from 3 acceptable maneuvers should not vary by more 
than 0.150 L.
If patient does not meet the repeatability or acceptability criteria during the screening epoch, 
patient may be rescreened once or allow one spirometry retest.
Recording of data
The greatest FEV1
 from any of the acceptable curves are recorded. (The greatest 
FEV1
 may not necessarily result from the same acceptable curve).  
Predicted normal
For all subjects, this study will utilize the global lung function 2012 equations (GLI2012) 
published by Quanjer et al 20122 or Japanese Respiratory Society3.
Reversibility
All reversibility evaluations should follow the recommendations of the ATS/ERS Task force: 
Standardization of Lung Function Testing1. A pre-bronchodilator spirometry* assessment 
should be performed after withholding of specified medications as specified in Table 5-2
“Medications to be withheld prior to spirometry”.
Administer 400µg of salbutamol/albuterol (or equivalent) following the completion of the pre-
bronchodilator assessment*. 
 
Subjects will be considered reversible if an increase of at least 12% (and 200 ml) is
demonstrated after administration of the salbutamol/albuterol.
*NOTE: At visits with two pre-dose spirometry assessments (please see Table 6-1 for 
schedule of assessments) the FEV1 from the 2nd pre-dose spirometry assessment (performed 


Novartis
Confidential
Page 107
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
approximately 15 min prior to in-clinic witnessed study drug administration) should be used
for FEV1 (pre-bronchodilator).
17.1
References for appendix
1 Miller MR et al (2005) Standardization of Lung Function Testing. Eur Resp J; 26:153-161.
2Quanjer PH, Stanojevic S, Cole TJ, Baur X, L Hall GL, Culver B, Enright PL, Hankinson JL, 
Zheng J, Stocks J and the ERS Global Lung Function Initiative (2012) Multi ethnic reference 
values for spirometry for the 3-95 year age range: the global lung function 2012 equations. 
Report of the Global Lung Function Initiative (GLI), ERS Task Force to establish improved 
Lung Function Reference Values. Eur Resp J; 40:1324-1343.
3 Kubota, Kobayashi, Quanjer PH, et al. Reference values for spirometry, including vital 
capacity, in Japanese adults calculated with the LMS method and compared with previous 
values. Clinical Pulmonary Functions Committee of the Japanese Respiratory 
Society. Respiratory Investigations 2014, 242-250.


Novartis
Confidential
Page 108
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314


Novartis
Confidential
Page 109
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
19
Appendix 7: Estimated Equivalence of Inhaled 
Corticosteroids
From the Global Strategy for Asthma Management and Prevention 2016, © Global Initiative 
for Asthma (GINA) all rights reserved. Available from http://www.ginasthma.org.
For the purposes of calculating total daily dose for the study, if the table has the medication 
dose listed by DPI, but not by MDI, then use the DPI classification as the reference and vice 
versa (i.e., if the table has the medication dose listed by MDI, but not by DPI, then use the 
MDI classification).


Novartis
Confidential
Page 110
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
20
Appendix 8: Asthma Control Questionnaire
A SAMPLE of the Asthma Control Questionnaire – 5 is included below.  The format of the 
administered test may vary.


Novartis
Confidential
Page 111
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314


Novartis
Confidential
Page 112
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314
21
Appendix 9: Asthma Quality of Life Questionnaire for 12 
years and older (AQLQ+12)
A SAMPLE of the Asthma Quality of Life Questionnaire for 12 years and older is included 
below.  The format of the administered test may vary.


Novartis
Confidential
Page 113
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314


Novartis
Confidential
Page 114
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314


Novartis
Confidential
Page 115
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314


Novartis
Confidential
Page 116
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314


Novartis
Confidential
Page 117
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314


Novartis
Confidential
Page 118
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314


Novartis
Confidential
Page 119
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314


Novartis
Confidential
Page 120
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314


Novartis
Confidential
Page 121
Amended Protocol Version v03 – Clean
Protocol No. CQAW039A2314

SAP_001.pdf: 
Clinical Development
QAW039/Fevipiprant
CQAW039A2314 / NCT03215758
A 52-week, multicenter, randomized, double-blind, placebo 
controlled study to assess the efficacy and safety of 
QAW039 when added to existing asthma therapy in 
patients with uncontrolled severe asthma
Statistical Analysis Plan (SAP)
Author:
, Trial Statistician
Document type:
SAP Amendment 2
Document status:
Final
Release date:
26-Aug-2019
Number of pages:
61
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


Novartis
For business use only
Page 2
SAP
26-Aug-2019 (10:13)
CQAW039A2314


Novartis
For business use only
Page 3
SAP
26-Aug-2019 (10:13)
CQAW039A2314
Table of contents
Table of contents......................................................................................................... 3
1
Introduction................................................................................................................. 7
1.1
Study design.................................................................................................... 7
1.2
Study objectives and endpoints....................................................................... 8
Primary objective(s).................................................................................................... 8
Secondary objectives .................................................................................................. 8
9
2
Statistical methods.................................................................................................... 10
2.1
Data analysis general information................................................................. 10
2.1.1
Population..................................................................................... 10
2.1.2
Study day...................................................................................... 10
2.1.3
Baseline definition........................................................................ 10
2.1.4
Post-baseline measurement .......................................................... 12
2.1.5
Change from baseline................................................................... 12
2.1.6
Study completion and last contact................................................ 12
2.1.7
Visit remapping and assessment windows ................................... 12
2.2
Analysis sets.................................................................................................. 13
2.3
Patient disposition, demographics and other baseline characteristics........... 13
2.3.1
Patient disposition ........................................................................ 13
2.3.2
Background and demographic characteristics.............................. 14
2.3.3
Medical History............................................................................ 15
2.4
Subgroup of interest...................................................................................... 15
2.5
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)................................................................................................... 16
2.5.1
Study treatment / compliance....................................................... 16
2.5.2
Prior, concomitant and post therapies .......................................... 17
2.6
Analysis of the primary objective................................................................. 18
2.6.1
Primary endpoint .......................................................................... 18
2.6.2
Statistical hypothesis, model, and method of analysis ................. 21
2.6.3
Handling of missing values/censoring/discontinuations .............. 24
2.6.4
Supportive/sensitivity analyses .................................................... 25
2.7
Analysis of the key secondary objectives ..................................................... 26
2.7.1
Key secondary endpoints.............................................................. 26
2.7.2
Statistical hypothesis, model, and method of analysis ................. 27
2.7.3
Handling of missing values/censoring/discontinuations .............. 28
2.7.4
Supportive/sensitivity analysis for secondary endpoints.............. 29
29


Novartis
For business use only
Page 4
SAP
26-Aug-2019 (10:13)
CQAW039A2314
29
30
31
31
31
31
34
34
34
34
2.9
Safety analyses.............................................................................................. 35
2.9.1
Adverse events (AEs)................................................................... 35
2.9.2
Laboratory data............................................................................. 36
2.9.3
Other safety data........................................................................... 41
43
44
2.12
Interim analysis............................................................................................. 44
3
Sample size calculation............................................................................................. 44
47
48
48
50
50
51
6
Appendix................................................................................................................... 51
6.1
Imputation rules ............................................................................................ 51
6.1.1
AE date imputation....................................................................... 51
6.1.2
Prior and Concomitant medication date imputation..................... 53
6.2
Statistical models .......................................................................................... 55
6.2.1
Primary analysis ........................................................................... 55
6.2.2
Key secondary analysis ................................................................ 57
6.3
Background asthma therapy.......................................................................... 58
6.3.1
Prednisone equivalent OCS doses................................................ 58
6.4
Rule of exclusion criteria of analysis sets..................................................... 59
7
Reference .................................................................................................................. 60


Novartis
For business use only
Page 5
SAP
26-Aug-2019 (10:13)
CQAW039A2314
List of abbreviations
ACQ
Asthma Control Questionnaire
AE
Adverse event
ALP
Alkaline Phosphatase
ALT 
Alanine aminotransferase
AM
ante meridiem
ANCOVA
Analysis of covariance
AQLQ+12
Asthma Quality of Life Questionnaire for 12 years and above
AR(1)
Autoregressive model of order 1
AST
Aspartate aminotransferase
ATC
Anatomical Therapeutic Classification
AUC
Area Under the Curve
bid
bis in diem/twice a day
BMI 
Body Mass Index
CM
Concomitant Medication
CSR 
Clinical Study Report
DAR 
Drug administration record
DMC
Data Monitoring Committee
DSPP
Development Safety Profiling Plan
ECG
Electrocardiography
eCRF
Electronic Case Report Form
FAS
Full Analysis Set
FEV1
Forced Expiratory Volume in 1 second
HRQOL
Health-Related Quality of Life
ICS
Inhaled Corticosteroid
IDR
Idiosyncratic drug reaction
IgE
Immunoglobulin E
ImmunoCAPR
Specific IgE test
IRT
Interactive Response Technology
JRS
Japan Respiratory Society
LABA
Long-acting Beta-agonist
LAMA
Long-acting muscarinic antagonist
LTRA
Leukotriene Receptor Antagonist
MAR 
Missing at random
MedDRA
Medical Dictionary for Drug Regulatory Affairs
MID
Minimally Important Difference
MMRM
Mixed Model Repeated Measures
OCS
Oral corticosteroids
PK
Pharmacokinetics
PM
post meridiem
PPS 
Per-Protocol Set
PRO
Patient-reported Outcomes
QD
Qua’que di’e / once a day
PT
Preferred Term


Novartis
For business use only
Page 6
SAP
26-Aug-2019 (10:13)
CQAW039A2314
QoL
Quality of Life
QTcF
Fridericia QT correction formula
RAN
Randomized set
RAST
Radioallergosorbent test
SABA
Short acting β2-agonist
SAE
Serious adverse event
SAF
Safety set
SAP 
Statistical Analysis Plan
SCR
Screened set
SD
Standard Deviation
SGLT
Sodium glucose transporter
SGOT
Serum glutamic oxaloacetic transaminase
SMQ
Standardised MedDRA Queries
SOC
System Organ Class
SOC
Standard of care
TBL 
Total bilirubin
TFLs
Tables, Figures, Listings
Th2
Type 2 helper T
ULN
Upper Limit of Normal


Novartis
For business use only
Page 7
SAP
26-Aug-2019 (10:13)
CQAW039A2314
1
Introduction
Data will be analyzed by the sponsor according to the data analysis section 9 of the study
protocol which is available in Appendix 16.1.1 of the CSR. Important information is given in
the following sections and details will be provided, as applicable, in Appendix 16.1.9 of the
CSR.
1.1
Study design
This study uses a randomized, multicenter, double-blind, placebo-controlled parallel-group 
study design in which QAW039 or placebo is added to GINA steps 4 and 5 asthma therapy 
(Figure 1-1).  
The study will include: 

a Screening epoch of up to 2 weeks to assess eligibility; 

a Run-in epoch of approximately 2 weeks and a maximum of 6 weeks to collect baseline 
data for efficacy variables and compliance with the Electronic Peak Flow/ eDiary device 
(if a patient experiences an asthma exacerbation during the run-in epoch, the run-in epoch 
must be extended to 6 weeks to permit for resolution of the asthma exacerbation before 
randomization.  The run-in epoch should only be extended beyond 2 weeks (+/- 5 days) 
for an asthma exacerbation.);

a Treatment epoch of 52 weeks; 

a Follow-up epoch of 4 weeks, investigational and drug-free, following the last dose of 
study drug. Note: only applicable for patients not participating in the safety study 
CQAW039A2315.Popu;at
Figure 1-1
Study design
Upon completion of the run-in epoch, all patients who met the eligibility criteria will be 
randomized to 1 of 3 treatments (QAW039 [150 mg or 450 mg once daily] or placebo once 
daily) in a ratio of 1:1:1.  Randomized patients will stratified by their peripheral blood 
eosinophil counts (<250 cells/l or ≥250 cells/l), patient age (<18 years or ≥18 years), and 


Novartis
For business use only
Page 8
SAP
26-Aug-2019 (10:13)
CQAW039A2314
their baseline use or non-use of oral corticosteroids as part of their SoC asthma therapy at Visit 
1. Treatment randomization will also be stratified at the regional level.
Clinic visits will be scheduled approximately 4 weeks after randomization and then at 
approximately 8-week intervals during the active-treatment epoch.  Phone calls will occur at 
specified time points between visits occurring at 8-week intervals.  A follow-up visit will occur 
approximately 4 weeks (i.e., approximately 30 days) following the last dose of study therapy 
to complete safety assessments and pregnancy testing (if applicable). 
1.2
Study objectives and endpoints
Primary objective(s)

In patients with severe asthma and high eosinophil counts (≥250 cells/µl) receiving SoC 
asthma therapy, to demonstrate the efficacy (as measured by rate of moderate-to-severe 
asthma exacerbations) of at least one dose level of QAW039 (150 mg or 450 mg once 
daily), compared with placebo, at the end of the 52-week active-treatment epoch.

In all patients with severe asthma receiving SoC asthma therapy, to demonstrate the 
efficacy (as measured by rate of moderate-to-severe asthma exacerbations) of at least one 
dose level of QAW039 (150 mg or 450 mg once daily), compared with placebo, at the 
end of the 52-week active-treatment epoch.
Secondary objectives
In patients with severe asthma and high eosinophil counts (≥250 cells/µl) receiving SoC asthma 
therapy:

To demonstrate the efficacy of at least one dose level of QAW039 (150 mg or 450 mg 
once daily), compared with placebo, with respect to change from baseline in Asthma 
Quality of Life Questionnaire (AQLQ+12) scores at the end of the 52-week active-
treatment epoch.

To demonstrate the efficacy of at least one dose level of QAW039 (150 mg or 450 mg 
once daily), compared with placebo, with respect to change from baseline in Asthma 
Control Questionnaire-5 (ACQ-5) score at the end of the 52-week active-treatment epoch.

To demonstrate the efficacy of at least one dose level of QAW039 (150 mg or 450 mg 
once daily), compared with placebo, with respect to change from baseline in pre-dose   
FEV1 at the end of the 52-week active-treatment epoch.

To assess the safety of QAW039 (150 mg and 450 mg once daily), compared with 
placebo, with respect to adverse events, electrocardiograms (ECGs), vitals sign, 
laboratory tests and hypersensitivity reactions.
In all patients with severe asthma receiving SoC asthma therapy:

To demonstrate the efficacy of at least one dose level of QAW039 (150 mg or 450 mg 
once daily), compared with placebo, with respect to change from baseline in Asthma 
Quality of Life Questionnaire (AQLQ+12) scores at the end of the 52-week active-
treatment epoch.

To demonstrate the efficacy of at least one dose level of QAW039 (150 mg or 450 mg 
once daily), compared with placebo, with respect to change from baseline in Asthma 
Control Questionnaire-5 (ACQ-5) score at the end of the 52-week active-treatment epoch.


Novartis
For business use only
Page 9
SAP
26-Aug-2019 (10:13)
CQAW039A2314

To demonstrate the efficacy of at least one dose level of QAW039 (150 mg or 450 mg 
once daily), compared with placebo, with respect to change from baseline in pre-dose   
FEV1 at the end of the 52-week active-treatment epoch.

To assess the safety of QAW039 (150 mg and 450 mg once daily), compared with 
placebo, with respect to adverse events, electrocardiograms (ECGs), vitals sign, 
laboratory tests and hypersensitivity reactions.


Novartis
For business use only
Page 10
SAP
26-Aug-2019 (10:13)
CQAW039A2314
2
Statistical methods
2.1
Data analysis general information
The final analysis will be performed by the sponsor. The most recent version of SAS and R 
available in the statistical programming environment will be used for the analysis. The interim 
analyses will be performed by a contracted CRO and the statistical analysis for the interim 
analyses will be planned in a separate document. In this document, ‘study treatment’ or ‘study 
drug’ will be used to refer to investigational therapy assigned to a patient. Specifically, for the 
double-blind treatment phase, study treatment refers to QAW039 or placebo as assigned to a 
patient at randomization.
2.1.1
Population
Unless otherwise specified, both the efficacy and safety analysis will be performed for the 
patients with eosinophil count ≥ 250 cells/µl (high eosinophils subpopulation) and the overall 
study population.
2.1.2
Study day 
Study day is defined as the number of days since the date of first dose of study medication. The 
date of first dose of study medication is defined as Day 1 and the day before the first dose of 
study medication is defined as Day -1.
Therefore, for a particular date, study day will be calculated as follows:

for dates on or after the first date of study medication,
Study day = Assessment date – Date of first dose of study medication + 1;

for dates prior to the first date of study medication,
Study day = Assessment date – Date of first dose of study medication.
If a patient never took study medication, the randomization date will be used instead of the date 
of first dose of study medication. In that case, the randomization date is defined as Day 1 and 
the day before the randomization is defined as Day -1.
2.1.3
Baseline definition
Data from unplanned visits prior to screening are not included in analysis. 
For analysis purposes, the baseline value is defined to be the last result obtained at or prior to 
start of study medication (Day 1) for baseline demographics, medical history, lab values,vital 
signs and ECGs.  Most variables will have their baseline at Day 1, unless otherwise specified. 
For assessments not performed at Day 1, the assessment at the screening visit or most recent 
assessment prior to start of study medication will be used as baseline.

The baseline measurement of pre-dose FEV1 is defined as the mean of the two pre-
bronchodilator FEV1 values taken in the clinic at 45 minutes and 15 minutes prior to 
the first dose of study drug on Day 1. If the pre-dose FEV1 is taken within 6 hours of 


Novartis
For business use only
Page 11
SAP
26-Aug-2019 (10:13)
CQAW039A2314
SABA use, or within 12 hours of twice-daily LABA (including fixed dose 
combinations of LABA and ICS) use, or 24 hours of once-daily LABA (including 
fixed dose combinations of LABA and ICS) use, or 24 hours of once-daily LAMA 
use, then the individual FEV1 value is set to missing.
Checks will be performed to ensure both values were taken prior to the first dose of 
study drug. If one of the - 45 and - 15 min values is missing (or is not confirmed to be 
pre-dose) then the remaining non-missing value will be taken as the baseline. 
If both assessments are missing (or are not confirmed to be pre-dose) then the last 
available FEV1  measurement (scheduled or unscheduled) prior to first dose of study 
medication will be used for baseline. 

Vital signs include body temperature, pulse rate and systolic and diastolic blood pressures.
Baseline vital signs are defined as the last assessment taken pre-dose on Day 1. Checks 
will be performed to ensure the assessments were indeed taken prior to the first dose of 
study drug on Day 1.  If this assessment is missing or not confirmed to be pre-dose, the 
last value prior to the first dose will be used for baseline. Otherwise, the vital sign 
baseline will be set to missing without imputation. 

Baseline height and weight are defined to be the last result obtained at or prior to Day 1. 
Missing baseline values will not be imputed.

Three ECG measurements are collected for each assessment. There are multiple 
assessments at different timepoints for a particular visit. For each timepoint an average of 
the three values are considered. Baseline ECG is defined as the average of the three 
values taken prior to the first dose of study drug on Day 1. Checks will be performed to 
ensure the ECGs were indeed obtained prior to the first dose of study drug. If the value on 
Day 1 is missing (or not confirmed to be pre-dose) then the average of the last values
prior to the first dose will be used for baseline. Otherwise, the ECG baseline will be set to 
missing without imputation.
Baseline ECG interpretation will be the value recorded pre-dose on Day 1, if present and 
confirmed to be pre-dose, otherwise the last interpretation prior to the first dose will be 
used

Laboratory data include hematology, biochemistry and urinalysis. Baseline hematology, 
biochemistry and urinalysis are defined as the last assessment taken prior to first dose of 
study drug on Day 1. Checks will be performed to ensure baseline hematology,
biochemistry and urinalysis laboratory values were indeed assessed pre-dose. If the pre-
dose measurement on Day 1 is missing (or was not confirmed to be pre-dose), then the 
last value prior to the first dose will be used. Otherwise, the baseline laboratory data will 
be set to missing.  

Baseline oral corticosteroid (OCS) use, atopic (yes/no) will be assessed Patients will be 
considered atopic, if they test positive for at least one allergen in the baseline RAST 
and/or ImmunoCAP test.

Baseline AQLQ+12 score is defined as AQLQ+12 score obtained on Day 1. If the 
AQLQ+12 score on Day 1 is missing then the last available AQLQ+12 score prior to Day 
1 will be used. If the AQLQ+12 score is missing on Day 1 and on all visits before Day 1, 
the respective baseline value will be set to missing.

Baseline ACQ-5 score is defined as ACQ-5 scores obtained on Day 1 . If the ACQ-5
score on Day 1 is missing then the last available ACQ-5 score prior to Day 1 will be used.


Novartis
For business use only
Page 12
SAP
26-Aug-2019 (10:13)
CQAW039A2314
If the ACQ-5 score is missing on Day 1 and on all visits before Day 1, the respective 
baseline value will be set to missing.

 
 


 
 
 
 
 
For e-dairy data, the morning assessment for Day 1 counts towards the baseline and the evening 
assessment for Day 1 counts as the treatment period.
2.1.4
Post-baseline measurement
Post baseline measurements are defined as those assessments  after the start of study treatment.  
2.1.5
Change from baseline
When change from baseline is of interest the following formula will be used for each scheduled 
visit and time-point where baseline and post-baseline values are both available:
Change from baseline = post-baseline value – baseline value; and
If baseline or post-baseline values are missing, then the change from baseline will be missing.
2.1.6
Study completion and last contact
Study completion for a patient will occur after he/she has completed 52 weeks of treatment 
(through to Visit 299) or they have prematurely withdrawn. At sites participating in the Safety 
Study (CQAW039A2315), patients who successfully complete 52 weeks of treatment in this 
study (
) may be offered participation in the Safety Study (CQAW039A2315); 
patient participation in the Safety Study will be optional.
Patients not entering the safety study CQAW039A2315 will complete the follow-up epoch. 
The maximum of the date of last visit, date of last epoch completion, date of withdrawal of 
consent would be the date of last contact for the patient participating in the study.
2.1.7
Visit remapping and assessment windows
If a scheduled visit did not occur, the data from the treatment discontinuation or study 
discontinuation visit may be used as the data from the scheduled visit, if the treatment 
discontinuation or study discontinuation visit occured closer to the planned study day of the 
missing scheduled visit than to the planned study day of any other scheduled visit. In this case 
the treatment discontinuation or study discontinuation visit will be treated as the scheduled visit 
for the purpose of all analyses so that no missing data imputation will be necessary. Otherwise 
the data from any scheduled visit that did not occur will be dealt with like any other missing 
data. If the treatment discontinuation or study discontinuation visit is not re-mapped to any 


Novartis
For business use only
Page 13
SAP
26-Aug-2019 (10:13)
CQAW039A2314
scheduled visit, it will be treated as an unscheduled visit that does not appear in by visit 
summaries.
2.2
Analysis sets
Screened set (SCR): All patients who provided informed consent.
Randomized set (RAN): This set will consist of all patients who were assigned a 
randomization number, regardless of whether or not they actually received study medication. 
Patients will be analyzed according to the treatment they were assigned to at randomization.
Full analysis set (FAS): All randomized patients who received at least one dose of study drug. 
It was considered reasonable to limit the FAS to patients who took trial medication, because 
the decision on whether or not treatment is started will not be influenced by the treatment group 
assignment due to the effective treatment blinding procedures. Following the intent-to-treat 
principle, patients will be analyzed according to the treatment they were assigned to at 
randomization.
Per-protocol set (PPS): All patients in the FAS without any major protocol deviations such 
as violation of major entry criteria. Patients may also be considered censored for the PPS 
analysis at the time of major post-baseline protocol deviations. Major protocol deviations will 
be defined in the data review plan prior to database lock and the un-blinding of the study. 
Patients will be analyzed according to the treatment they received.
Safety set (SAF): All patients who received at least one dose of study drug. Patients will be 
analyzed according to the treatment they received. If the patient received more than one 
treatment they will be analyzed as randomized. 
 
The analysis of the primary objective will be performed on the FAS. The PPS may be be used 
for the supportive analysis of the primary and the key secondary variables. The FAS will be 
used for the analysis of all other efficacy variables. The SAF will be used in the analysis of all 
safety variables.
Note that the set of patients included in the FAS and SAF are the same except that the SAF 
allows the inclusion of non-randomized patients who receive study drug in error.
If an incorrect randomization stratum is inadvertently selected for a patients by the 
investigator in the IRT, patients will still be included in all analyses. The corrected stratum 
information as per the CRF data will be used in any analysis models.
2.3
Patient disposition, demographics and other baseline 
characteristics
2.3.1
Patient disposition
The number of patients screened, randomized, completed and discontinued from the study will 
be summarized for overall population and high eosinophil subpopulation. In addition, the 
number of patients randomized, completed and discontinued from the treatment period will be 
summarized for overall population, by country . Patients discontinued from the study will also 
be summarized with reasons for discontinuation. In addition, patients who discontinued study 
treatment but stay in the study will be summarized. Patients who discontinued study treatment 


Novartis
For business use only
Page 14
SAP
26-Aug-2019 (10:13)
CQAW039A2314
but stay in the study are defined as patients with the date of study discontinuation or Visit 299 
- the end date of study treatment > 0. Patient randomization numbers and whether they 
completed or discontinued from the study will be listed, with date of last dose and primary 
reason for discontinuation, including the unblinding date if applicable.  
Time to study discontinuation will be displayed graphically for each treatment group using a 
Kaplan-Meier curve for the FAS. The date of study discontinuation is defined as the maximum 
of the last known visit date for treatment period and the date of last dose of study medication. 
Patients who completed the study will be censored at the final study visit.
The number of subjects with protocol deviations will be tabulated by category and deviation
for the RAN. 
The number of subjects included in each analysis set will be tabulated. Reasons for exclusions 
from analysis sets will be tabulated for RAN. Patient exclusion from analysis sets will be listed 
for all patients with reasons for exclusion ( including protocol deviations).
2.3.2
Background and demographic characteristics
Patient demographics and baseline characteristics including
age, sex, race, ethnicity, height, weight, body mass index (BMI), relevant medical history, 
including smoking history, asthma duration, background asthma therapy, use of oral 
corticosteroids, pre-
, percent predicted FEV1, ACQ-5 score, 
AQLQ+12 score, blood eosinophil count, number of exacerbations in the previous year and 
 will be summarized by treatment group for the FAS. Categorizations of age will 
include the categories of <18 years, >=18- <65 years and >=65 years of age. 
Screening blood eosinophil counts will also be summarized as this reflects the randomization 
stratum.
Continuous variables will be summarized using descriptive statistics (mean, median, standard 
deviation, minimum and maximum, first and third quartiles) and categorical variables will be 
summarized in terms of the number and percentage of subjects in each category (a missing 
category will be included if required).
The number and percentage of patients on ICS at screening (concomitant medication start date
on or before Visit 1 and end date after Visit 1) and the number and percentage of patients in 
each of the low, medium, high categories of ICS use at screening will be presented. The 
categorization of the dose of ICS can be done based on Appendix 7 in study protocol. The 
number of patients on OCS at screening (concomitant medication start date on or before Visit 
1 and end date after Visit 1) and the average prednisone equivalent OCS dose among patients 
on OCS use at screening will be summarized. The prednisone equivalent OCS doses can be 
calculated based on Appendix 5.3. 
Background asthma therapy will be categorized into GINA steps and will be summarized at 
screening. Background asthma therapy is defined as concomitant medication start date on or 
before Visit 1 and end date after Visit 1.
Derivation of the demographics and baseline characteristics

Baseline values are as described in “Baseline measurements” section above.

BMI is calculated as: BMI (kg/m2) = Weight (kg) / [Height (m) * Height (m)]


Novartis
For business use only
Page 15
SAP
26-Aug-2019 (10:13)
CQAW039A2314

Estimated number of pack years is calculated by the total years of smoking multiplied by 
cigarette packs smoked per day. This will be summarized as recorded on the eCRF. 
Smoking history in package years will be calculated as: (1 pack year = 20 cigarettes/day x 
1 year or 10 cigarettes/day x 2 years). 

% of (pre-bronchodilator) predicted FEV1 is obtained as a percentage of FEV1 relative to 
the predicted normal value. 
 
 At visits with two pre-dose 
spirometry assessments the FEV1 from the 2nd pre-dose spirometry assessment (15 min prior 
to in-clinic witnessed study drug administration) should be considered the pre-bronchodilator 
FEV1 value. A patient is considered to have demonstrated reversibility at clinic at baseline if 
there is an increase of 12% and >=200 ml any particular visit prior to Day 1.

Duration of asthma is calculated from the date of asthma first diagnosed recorded on the 
eCRF until Visit 1. If the date is missing in day and/or month, it will be imputed as follows. 
If the year is before the first visit, the missing days will be imputed as the first of the month 
and the missing months will be imputed as July. If the year is the current year of the first 
visit, the missing days will be imputed as the first of the month and the missing months will 
be imputed as January.

QTc will be calculated, by the third party vendors, from the QT interval and RR (in seconds) 
using Fridericia’s formula (QTcF)  
2.3.3
Medical History
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) terminology using the most recent version at the time of database lock. 
History/conditions as well as protocol solicited events for asthma will be summarized for the 
FAS by primary system organ class and preferred term. Verbatim recorded history/conditions 
will be listed together with the coded terms, date of diagnosis/surgery and whether the problem 
was ongoing  at the start of the study . 
Current medical conditions are defined as those which were reported as "Ongoing" at 
baseline.
2.4
Subgroup of interest
Subgroup analyses will be performed for primary variable and key secondary variables on the 
on-study data (considering multiple imputations based on a combination of missing at random 
and jump-to-reference approaches as described in Sections 2.6.3 and 2.7.3) and for patients 
with eosinophil count ≥ 250 cells/µl and for the overall study population separately.
For subgroup analyses of primary variable or key secondary variables the same model as for 
the main analysis will performed by subgroup but with additional model terms for the subgroup
(if not already included in the model) and subgroup-by-treatment interaction terms. The 
subgroup variables are listed below: 

age at entry into study (<18 years, >=18 years)

Geographic region (The definition of geographic region will be same as the definition of 
region at the randomization e.g. North America, Latin America, Europe, China/AMAC, 
Japan)


Novartis
For business use only
Page 16
SAP
26-Aug-2019 (10:13)
CQAW039A2314

Blood Eosinophil counts at Visit 1 (< 250 cells/µl, ≥ 250 cells/µl). This subgroup is only 
considered for the analysis on overall study population.

Use or non-use of oral corticosteroids as part of their SoC asthma therapy

Gender (male, female) 

race (Caucasian, Black, Asian, other) 

number of asthma exacerbations  in year prior to screening(2, 3, 4, ≥ 5): defined as per 
inclusion criteria in protocol. The categories for the variable may be updated depending 
on the number of patients and events in each treatment group. 

 
 

Baseline IgE (≤100 IU/mL,  >100 IU/mL)

baseline %predicted FEV1 (> 70%, ≤ 70%) 

baseline FEV1 (tertiles 1, tertiles 2, tertiles 3)  

Baseline FEV1 reversibility demonstrated at the clinic (yes, no) 

Background asthma therapy (ICS plus number of controller therapies defined as 1, 2, 3+)

Atopic asthma status at entry into study status (yes, no)

GINA step 4 patients with LTRA co-treatment (i.e. GINA step 4 patients taking at least 
LTRA) vs others (i.e. GINA step 4 patients not taking LTRA)

Subgroup analyses contributing key regulatory information will be provided for each country 
or region in line with regulatory requirements.
Patients randomized to the study in the sites in Japan will be considered as the Japanese 
patients. Separate analyses on this subset of patients will be performed and the specific 
outputs will be marked by suffix ‘J’ in the study TFL shells. In case the model fails to 
converge for the analysis on the subgroup of Japanese patients, then the following variables 
will be dropped in the following sequence: patient age at Visit 1 [<18 years or ≥18 
years], use or non-use of oral corticosteroids as part of SoC asthma therapy, screening blood 
eosinophil counts (<250 cells/l or ≥250 cells/l). If then also, the model does not converge 
only treatment will be considered as a factor and the model will be rerun.
 
Formal multiplicity adjusted testing on the subgroups will not be performed.
2.5
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.5.1
Study treatment / compliance
Since the study has a double dummy design, each patient will be dispensed two bottles of study 
medication at the dispensing visits. Bottle 1 has study medication corresponding to 150 mg 
QAW039 or placebo and Bottle 2 has study medication corresponding to 450 mg QAW039 or 
placebo. Exposure and compliance will be presented on the SAF. Exposure will be presented 


Novartis
For business use only
Page 17
SAP
26-Aug-2019 (10:13)
CQAW039A2314
for each treatment while compliance will be presented by treatment arm for each of the bottles 
separately. 
2.5.1.1
Duration of exposure
Duration of exposure to a treatment will be calculated as the number of days between the first
dose date and the last dose date exposed to that treatment over the specified period (expressed 
as: Duration of exposure = Date of last known dose of study drug – Date of first dose of study 
drug + 1). In addition, the duration of exposure will be summarized as a categorical variable 
classified into <4 weeks, >=4 to <12 weeks, >=12 to <26 weeks, >=26 to <52 weeks, >=52 
weeks. Cumulative exposure will be summarized as a categorical variable classified into >=4 
weeks, >=12 weeks, >=26 weeks, >=52 weeks. 
Patients in the randomized set who received any wrong study medications will be listed. These 
patients will be identified using the information recorded on the DAR page of the eCRF. If 
there is a record with reason = dispensing error, then the pack number will be used to identify 
whether or not the patient received the wrong study drug.
2.5.1.2
Compliance
Compliance will be calculated as the percentage of days with study medication intake as per 
protocol during the period from first intake to last intake taking into account the duration of the 
drug interruptions.
Percentage of days with study medication intake = 100 x number of days with study medication 
intake as per protocol / (Day of the last known dose of study drug – Day 1 +1). 
Compliance will be categorized as <80%, 80% -100%and summarized by treatment arm for 
each of the bottles separately based on the SAF.
Time to study treatment discontinuation will be displayed graphically for each treatment group 
using a Kaplan-Meier curve for the SAF. The date of study treatment discontinuation is defined 
as the date of last dose of study medication. Patients who completed the study treatment will 
be censored at the final visit for treatment period.
2.5.2
Prior, concomitant and post therapies
Medications started and stopped prior to study drug and taken concomitantly will be 
summarized by treatment group in separate tables in the SAF. The medication will be classified 
into “prior”, “concomitant”, “post-treatment” based on the start/end dates.
Prior: Any medication with a start date before Day 1.
Concomitant: Any medication with end date on or after Day 1 or ongoing at the end of trial or 
missing end date and start date before the end of treatment. Medications can be considered both 
prior and concomitant. Post treatment medication will be defined as any medication with start 
date after the end of treatment, including medications taken in the follow-up period.
Concomitant therapies will be recorded and summarized separately for asthma related 
medications, non-asthma related medications, surgical and medical procedures. Concomitant 
asthma related medications will be summarized by pre-defined category. Concomitant 
medications not related to asthma will be summarized by pharmacological (ATC) class and 
preferred term. More than one ATC class per medication is possible and the medication will 
be reported under all applicable classes.


Novartis
For business use only
Page 18
SAP
26-Aug-2019 (10:13)
CQAW039A2314
SABA (short acting β2-agonist) usage (number of puffs) during the screening epoch will be
summarized.
The total prednisone equivalent OCS dose associated with exacerbations taken by patients over 
the 52 week treatment period will be summarized and compared between treatment groups. A 
histogram will also be presented. 
2.6
Analysis of the primary objective
The primary analysis for this study will be conducted according the intention to treat principle
and will be based on the FAS.
2.6.1
Primary endpoint
The primary variable for this study is the number of moderate-to-severe asthma exacerbations 
experienced by each patient per patient year of follow-up. The start date of a moderate-to-
severe asthma exacerbation recorded in the CRF is defined as the first day of ‘rescue’ systemic 
corticosteroid use, or the date of death if no rescue corticosteroids were taken prior to an asthma 
related death. The end of an exacerbation is defined as the last day of systemic corticosteroid 
use. The duration of follow-up in years will be calculated for each patient as (last date of 
scheduled visit in treatment epoch - treatment start date + 1 day)/365.25.
The following definitions of exacerbations are used in this study.
A severe asthma exacerbation is defined as

treatment with ‘rescue’ systemic corticosteroids for greater than or equal to 3 days
and hospitalization; or

treatment with ‘rescue’ systemic corticosteroids for greater than or equal to 3 days*
and emergency department visit (greater than 24 hours**); or

death due to asthma.
A moderate asthma exacerbation is defined as treatment with ‘rescue’ systemic
corticosteroids for greater than or equal to 3 days either as an outpatient or in emergency
department visits (Emergency department visit less than or equal to 24 hours).
*In order to identify treatment with ‘rescue’ systemic corticosteroids for greater than or equal to 3 days, 
at least one of the following options should be marked on the Asthma Exacerbation episodes CRF page: 
"Systemic corticosteroid for >=3 days","Increase maintenance systemic corticosteroid for >=3 
days","Single depot injection".
**An emergency room visit greater than 24 hours is considered to be a hospitalization.
Rules for combining multiple records to one continuous exacerbation episode 
The asthma exacerbations will be collapsed and deemed one continuous episode for patients 
with multiple records on the asthma exacerbation CRF page if the start date of the next episode 
is within 7 days after the end of the previous exacerbation episode.. The start/end date as 
reported on the CRF will be used to collapse the events using the 7-day rule described below. 
Exacerbations will be collapsed if symptoms of the following exacerbation begun within 7 days 
of the previous episodes or episodes overlap based on start and end of symptoms. 
Consider the case where a patient has two asthma exacerbations. If there are three or more 
exacerbations they are dealt with sequentially according to these rules.


Novartis
For business use only
Page 19
SAP
26-Aug-2019 (10:13)
CQAW039A2314

For asthma exacerbations without missing start and end dates, if the end of one 
exacerbation is seven or more days before the start date of the next exacerbation then 
they will be treated as two separate episodes. If the end of one exacerbation is less than 
seven days before the beginning of the next exacerbation (or they overlap) then they 
will be assumed to be one continuous episode. The earliest of the start dates and the 
latest of the end dates will be the start and end dates of the collapsed episode.  

For asthma exacerbations with missing end dates, 
o
If the one which starts earlier has a missing end date and:

Start date is within 7 days of the start date of the next exacerbation, then 
the exacerbations will be combined as one episode. In this case, the start 
date of the collapsed episode is taken from the first exacerbation and the 
end date is from the second or last exacerbation.

Start date is greater than 7 or more days of the start date of the next 
exacerbation, then the exacerbations will be considered as two separate 
episodes.
o
If the later event has a missing end date and it is the last asthma exacerbation, 
then the second event is treated as ongoing at the end of trial.  
For all efficacy analyses, collapsed exacerbations will be considered while uncollapsed
exacerbations will be considered for all safety summaries and listings. Separate summaries  
based on observed and non-imputed on-study and on-treatment data will be presented.
Severity of the collapsed episode:
The severity of the collapsed episode is defined by whether the collapsed episode fulfils the 
severity criteria of the records contributing to the collapsed episode. 
For all exacerbation efficacy parameters (described in Section 2.6 and Section 2.8) on-
treatment data are defined as data on or after the first day of treatment with double-blind 
study medication, but before or on the day after the last day of treatment with double-blind 
study medication. For all exacerbation efficacy parameters on-study data are defined as data 
on or after the first day of treatment with double-blind medication, but before or on the day 
after the last day of treatment period.
2.6.2
Estimand for primary endpoint
The definition and rationale for the estimand for the primary endpoint are given in Table 2-1. 
Novartis proposes the most informative estimand to be one that considers the maintenance 
treatment effect that could be expected in clinical practice. The statistical strategy to handle 
each intercurrent event is described in more detail in Section 2.6.3.


Novartis
For business use only
Page 20
SAP
26-Aug-2019 (10:13)
CQAW039A2314
Table 2-1
Summary of estimand for the primary endpoint
Population
Inadequately 
controlled 
severe 
asthma 
patients 
with 
high 
eosinophil 
counts 
(eosinophil count at screening ≥250 cells/μl)
Inadequately 
controlled 
severe 
asthma 
patients 
Variables
Number 
of 
moderate-to-severe 
asthma 
exacerbations experienced by each patient 
per patient year of follow-up at the end of the 
52-week active-treatment epoch
Intercurrent event
Description
Strategy to handle 
event
Justification
Discontinuation 
of 
study treatment but 
continuing in study
Patients who wish to 
discontinue 
active 
study 
medication 
will be asked to 
remain in the study 
and 
complete 
all 
study visits. 
All data (including 
after treatment 
discontinuation) 
used.
Effect regardless of 
adherence to study 
drug (Treatment 
policy) is quantified
Discontinuation 
from study due to 
reasons likely to be 
related 
to 
study 
treatment
Reasons: adverse 
event, death, 
physician decision, 
subject/guardian 
decision
Analyzed assuming 
jump-to-reference
(J2R) approach. 
Missing 
data 
imputed by MI under 
MAR for placebo 
and J2R for QAW
treatment arms
Assume similar 
outcomes as Placebo
patient
Discontinuation 
from study due to 
reasons unlikely to 
be related to study 
treatment
Reasons: pregnancy, 
study terminated by 
sponsor, 
technical 
problems, 
lost 
to 
follow-up
Analyzed assuming 
missing at random 
approach
Missing data 
imputed by MI 
under MAR for 
placebo and QAW
Assume similar 
outcomes as if they 
had continued taking 
assigned treatment 
till trial end 
Hypothetical on-
treatment value for 
reason not related to 
treatment 


Novartis
For business use only
Page 21
SAP
26-Aug-2019 (10:13)
CQAW039A2314
(Hypothetical 
Strategy)
Summary measures
Relative risk ratio versus placebo for each of the two QAW039 doses
2.6.3
Statistical hypothesis, model, and method of analysis
2.6.3.1
Primary null hypotheses
The trial will be considered positive, if one or more of the two QAW039 doses demonstrate a 
statistically significant reduction in the rate of moderate-to-severe asthma exacerbations. As 
described below, the two doses will be tested in parallel and each dose may achieve statistically 
significant results irrespective of the results achieved by the other dose. 
The primary null hypotheses are:

H0 450 eosinophil subgroup: relative risk ratio for the QAW039 450 mg QD group versus placebo 
in patients with eosinophil count ≥ 250 cells/µl = 1, 

H0 150 eosinophil subgroup: relative risk ratio for the QAW039 150 mg QD versus placebo in 
patients with eosinophil count ≥ 250 cells/µl = 1,

H0 450 overall: relative risk ratio for the QAW039 450 mg QD versus placebo in the overall 
study population = 1 and

H0 150 overall: relative risk ratio for the QAW039 150 mg QD versus placebo in the overall 
study population = 1.
The primary alternate hypotheses are:

HA 450 eosinophil subgroup: relative risk ratio for the QAW039 450 mg QD group versus placebo 
in patients with eosinophil count ≥ 250 cells/µl ≠ 1,

HA 150 eosinophil subgroup: relative risk ratio for the QAW039 150 mg QD group versus placebo 
in patients with eosinophil count ≥ 250 cells/µl ≠ 1,

HA 450 overall: relative risk ratio for the QAW039 450 mg QD group versus placebo in the 
overall study population ≠ 1 and

HA 150 overall: relative risk ratio for the QAW039 150 mg QD group versus placebo in the 
overall study population ≠ 1.
The superiority of QAW039 over placebo will be considered confirmed if at least one of the 
four primary null hypotheses is rejected in favor of the respective two-sided alternative 
hypotheses and it demonstrated positive trends in favor of QAW039.
2.6.3.2
Familywise type I error rate control
The familywise type I error rate will be controlled at the two-sided 5% level across the primary 
and key secondary null hypotheses using the closed testing procedure specified by Figure 2-1
using the graphical method of  Bretz, et al 2009. In this closed testing procedure the primary 
null hypothesis about exacerbations in the subset of patients with eosinophil count ≥ 250 
cells/µl for each dose acts as a gatekeeper for the other null hypotheses for the same dose. 


Novartis
For business use only
Page 22
SAP
26-Aug-2019 (10:13)
CQAW039A2314
Figure 2-1
Closed testing procedure for primary and key secondary objectives
Vertices with associated weights denote the individual null hypotheses and their local significance 
levels (initially α is split 50%:50% across the primary null hypotheses regarding the subgroup with 
blood eosinophils ≥ 250 cells/μl for the 2 QAW039 doses). Directed edges between the vertices 
specify how the local significance levels are propagated in case of significant results. Dotted Dashed 
edges with a weight of ε indicate that the local significance level from the key secondary null 
hypotheses of a dose will only be propagated to the other population for the same dose, once all key 
secondary null hypotheses for a dose and population have been rejected. Dotted edges with a weight 
of ε2 (much smaller than ε) indicate that the local significance level from the key secondary null 
hypotheses of a dose will only be propagated to the other dose, once all key secondary null 
hypotheses for a dose have been rejected.
Initially, 50% of the alpha is assigned to each of the primary null hypotheses regarding the 
subgroup with blood eosinophils ≥ 250 cells/μl for the QAW039 450 mg QD and QAW039 
150 mg QD doses, respectively. 
Once this first primary null hypothesis for a dose has been rejected, the alpha will be distributed 
to the other primary null hypothesis regarding the overall population for the same dose and the 
key secondary null hypotheses regarding the subgroup with blood eosinophils ≥ 250 cells/μl 
for that same dose. If the null hypothesis regarding the primary endpoint for the overall 
population is rejected for a dose, then alpha is reassigned to the key secondary null hypotheses 
regarding the overall population for that dose. Alpha will only be reassigned from the set of 
null hypotheses for a dose to the null hypotheses for the other dose once all null hypotheses for 
the dose to which the alpha was originally assigned have been rejected. 
Once the primary null hypothesis for a dose and population has been rejected, all key secondary 
null hypothesis for that dose and population are tested and can be rejected irrespective of 
whether the other key secondary null hypotheses for that dose and population can be rejected. 
However, FEV1 will be initially given the highest local significance level due to its regulatory 
importance. Both adjusted and unadjusted p-values for all the endpoints, doses, populations 
stated in Figure 2-1 will be presented. 
2.6.3.3
Summary statistics for the primary variable
The primary variable will be summarized by treatment group in terms of the mean rate (events 
per patient year of follow-up) overall, the distribution of patients by number of exacerbations 


Novartis
For business use only
Page 23
SAP
26-Aug-2019 (10:13)
CQAW039A2314
(i.e. the proportion of patients with 0, 1, 2, 3, 4, >=5… exacerbation episodes during the 52 
week period for each treatment group) and using plots of Nelson's (1995) nonparametric 
estimate of the mean cumulative function on the on-study data. The plots of Nelson’s 
nonparametric estimates will be calculated based on the independent censoring assumption. 
The components of the composite primary endpoint will be summarized for on-study and on-
treatment data. The components include the following: severe exacerbations, exacerbations 
with ‘rescue’ systemic corticosteroids for greater than or equal to 3 days and hospitalization,  
treatment with ‘rescue’ systemic corticosteroids for greater than or equal to 3 days and 
emergency department visit (greater than 24 hours), death due to asthma, moderate 
exacerbations. Separate summaries  based on observed and non-imputed on-study and on-
treatment data will be presented. Based on the summary data, the difference in the rates of 
moderate to severe asthma exacerbations per patient year and resulting number of patients that 
needs to be treated for 1 year to prevent one exacerbation will also be reported with confidence 
intervals. The confidence interval for the difference in rates of exacerbations are presented and 
obtained using the normal approximation. (Liu et. al, 2006) 
2.6.3.4
Statistical model for primary variable
These hypothesis tests, as well as point estimates and confidence intervals will be based on a 
negative binomial regression model  with the natural logarithm of the duration of follow-up in 
years as an offset variable (Keene, et al 2007; Keene, et al 2008), treatment group, 
randomization strata (use or non-use of oral corticosteroids as part of SoC asthma therapy, 
patient age at Visit 1 [<18 years or ≥18 years], and when analyzing the overall population, 
peripheral blood eosinophil counts at Visit 1 [<250 cells/l or ≥250 cells/l] and region) as a 
fixed class effects, the natural logarithm of the number of asthma exacerbations in the 12 
months prior to screening that required treatment per protocol and the baseline pre-dose FEV1 
as a continuous linear covariate. When analyzing the subpopulation with baseline blood 
eosinophil counts ≥250 cells/l, only the subpopulation data will be used for the analysis. Note 
that the duration of follow-up will be the planned duration of follow-up for all patients, because 
any missing data will be imputed as described in Section 2.6.3. The inclusion of the offset is 
nevertheless useful to make regression coefficients easier to interpret. Should despite the 
inclusion criteria a patient with no exacerbations in the 12 months prior to screening that 
required treatment per protocol be included in the trial, such a patient will be considered to 
have had 0.5 such exacerbations.
The ratios of the exacerbations  for QAW039 to Placebo, the associated 95% confidence 
intervals and the p-values (adjusted and unadjusted) will be presented.  
A negative binomial model will be used, because patient heterogeneity beyond that captured 
by the available patient-level covariates is expected. This can lead to over dispersed cumulative 
counts and zero inflation. A negative binomial model can better capture such heterogeneity 
than a Poisson model and can be seen as a Poisson model with the intensity distributed across 
patients according to a Gamma distribution (Keene, et al 2007).


Novartis
For business use only
Page 24
SAP
26-Aug-2019 (10:13)
CQAW039A2314
Use of randomization strata in the analysis model
The variables ((use or non-use of oral corticosteroids as part of SoC asthma therapy, patient 
age at Visit 1 [<18 years or ≥18 years], and when analyzing the overall population, peripheral 
blood eosinophil counts at Visit 1 [<250 cells/l or ≥250 cells/l] and region) which constitute 
the randomization strata will be included separately in the analysis model. In case the model 
fails to converge then the following variables will be dropped in the following sequence: patient 
age at Visit 1 [<18 years or ≥18 years], region, use or non-use of oral corticosteroids as part of 
SoC asthma therapy and the models will be rerun till the model converges. 
2.6.3.5
Handling of missing values/censoring/discontinuations
Despite all attempts to ensure complete follow-up for all patients, some patients may not be 
followed for asthma exacerbations for the whole planned study duration. Missing data will be 
imputed using a multiple imputation approach similar to the “missing at random and jump to 
reference” approach described by Keene et al. (2014). 
The first step in implementing this approach is fitting a Bayesian hierarchical random effects 
Poisson model with non-informative priors to the data. This model will distinguish on- and off-
treatment data for the QAW039 group and will include the same covariates as the primary 
model, as well as a log length of follow-up offset variable. Missing data on exacerbations in 
both treatment groups will then be imputed by simulation using independent pseudorandom 
draws from the posterior for the parameters of this model in the conditional distribution of the 
missing data given the observed data (including on-treatment and off-treatment data) as 
described by Keene et al. (2014). The imputation will use a mixture of the jump to reference 
and the missing at random approaches (Keene et al. 2014) and will distinguish the following 
three cases:
1. Missing data in QAW039 patients that discontinue treatment and are lost to follow-up due 
to (or following a treatment discontinuation due to) adverse event, death, physician 
decision and subject/guardian decision will be imputed assuming the same effect as the 
placebo group (Jump-to reference approch).
2. A continued treatment effect for QAW039 patients being lost to follow-up for reasons 
likely to be unrelated to study treatment (pregnancy, study terminated by sponsor, 
technical problems, lost to follow-up) will be assumed, i.e. for such patients 
postwithdrawal events will be imputed assuming MAR based on the event distribution of 
the arm patients were randomized to.
3. An unchanged event rate will be assumed for placebo patients with missing data. For the 
placebo patients events for time periods with missing data will be imputed assuming that 
missing data are missing at random
A large number of imputed datasets will be created, with their number chosen based on 
computational feasibility, but at least 1,000 based on the recommendation of Keene et al. 
(2014). Each dataset will be analyzed using the model described in Section 2.6.3 and the 
results will be combined on the log-scale using Rubin’s rule (Barnard and Rubin 1999). 


Novartis
For business use only
Page 25
SAP
26-Aug-2019 (10:13)
CQAW039A2314
2.6.3.6
Supportive/sensitivity analyses
The primary analyses may be repeated for the PPS.
As a supportive analyses, the primary analyses will be repeated using a marginal approach
(Bartlett 2018). Additionally, the differences in the rates of moderate-to-severe asthma 
exacerbations will be calculated based on the estimates obtained using the marginal approach.
An on-treatment analysis will also be conducted. In this analysis all moderate-to-severe asthma 
exacerbations will be counted, if the start date of the exacerbation is on or after the first day of 
treatment with double-blind study medication, but before or on the day after the last day of 
treatment with double-blind study medication. In this analysis a negative binomial regression 
model with the natural logarithm of the duration of on-treatment follow-up in years as an offset 
variable will be used. Two sided confidence intervals for the rate ratios will be computed based 
on the profile likelihood function. The duration of on-treatment follow-up in years will be 
calculated for each patient as (treatment end date - treatment start date + 1 day)/365.25 without 
taking into account treatment interruptions. Such a negative binomial model assumes that 
missing data after censoring either due to losses to follow-up or the end of treatment are missing 
at random conditional on the baseline covariates and the preceding data on events per follow-
up time included in the analysis (Cook and Lawless 2007). Under this assumption the model 
implicitly imputes the missing data and the data censored at the end of treatment assuming a 
hypothetical situation of continued treatment with an unchanged on-treatment event rate for 
the patient (Committee for Medicinal Products for Human Use 2010). This analysis and 
missing data handling approach is in-line with the recently completed MENSA exacerbation 
trial for the monoclonal anti-interleukin-5 antibody mepolizumab in a similar population 
(Ortega, et al 2014). It is therefore the most appropriate analysis for a comparison of the results 
of the present trial to the MENSA trial.
In a tipping point analysis it will be explored by how much the rate of exacerbations post-study 
discontinuation would have had to increase in order to change the trial conclusions. Two 
dimensional tipping point analyses, allowing assumptions about the exacerbation rate post-
study discontinuation on the two arms (active QAW treatment, placebo) to vary independently 
and including scenarios where dropouts on treatment have higher exacerbation rates than 
dropouts on control, will be perfomed. 
As a worst reasonable case analysis a disappearing treatment effect for all patients that are lost-
to-follow-up will be used (jump-to-reference). This is a sensitivity analysis for the effect of 
assuming a continued treatment effect for patients withdrawing from the study for reasons 
considered to be likely unrelated to study therapy (see Section 2.6.3.5.5)
In a further rank-based sensitivity analysis for the primary endpoint withdrawal from the trial 
and death will be directly treated as negative trial outcomes for patients. Patients that completed 
the trial will be ranked as having had a more favorable outcome than patients that withdrew 
from the trial, who will in turn be ranked as having had a more favorable outcome than patients 
that died. Within each of these categories patients will be ranked according to (number of 
exacerbations + 0.5)/patient years of follow-up. If patients in same category have same scores, 
then midranks are used. Compared to solely ranking patients according to the number of 
exacerbations or solely according to the duration of follow-up, this ensures that patients lost to 
follow-up very early in the trial without experiencing any exacerbations will not be ranked 
more favorably than patients that nearly completed the trial and only had 1, or 2 exacerbations, 
while also ensuring that a patient with 10 exacerbations that was lost to follow-up after 11 


Novartis
For business use only
Page 26
SAP
26-Aug-2019 (10:13)
CQAW039A2314
months and 1 day is not ranked as having a more favorable outcome than a patient with 0 
exacerbations that was lost to follow-up after 11 months. A Wilcoxon rank-sum test stratified 
by randomization strata (Van Elteren test) will be used to analyze the ranked data.
The primary analyses of on-study data considering a multiple imputation framework based on 
a combination of missing at random and jump-to-reference approaches as described in Section
2.6.3 will also be conducted by subgroup including key demographic and disease related 
subgroups (See Section 2.4 for the details of subgroups). The results of the subgroup analyses 
will be displayed graphically in forest plots.
Summary of total prednisone equivalent OCS use (in grams) associated with moderate-to-
severe on-treatment asthma exacerbations over 52 week treatment period by population will be 
presented. 
2.7
Analysis of the key secondary objectives
2.7.1
Key secondary endpoints
The key secondary variables of this trial are the mean of the two pre-dose FEV1 assessments 
at the week 52 visit, AQLQ+12 and ACQ-5 at the end of the 52 week treatment period. Data 
from the preceding visits will be used primarily to describe the onset of action and for missing 
data imputation. The key secondary analyses for this study will be conducted for FAS.
2.7.1.1
Asthma Quality of Life Questionnaire for 12 years of age and older 
(AQLQ+12)
The 32 items in the AQLQ+12 are divided into 4 domain-specific scores and a total score as 
follows: 

Symptoms = Mean of Items 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 29, 30 (12 items) 

Activity limitation  = Mean of Items 1, 2, 3, 4, 5, 11, 19, 25, 28, 31, 32 (11 items) 

Emotional function  = Mean of Items 7, 13, 15, 21, 27 (5 items) 

Environmental Stimuli = Mean of Items 9, 17, 23, 26 (4 items) 

Overall Score = Mean of Items 1 to 32 (32 items) 
Each item of the AQLQ+12 is equally weighted and scored along a 7-point scale, where 1 
indicates maximal impairment and 7 indicates no impairment. Thus, higher scores indicate 
better asthma-related HRQOL (Health-Related Quality of Life). There is a mean score 
calculated for each of the four domains, as well as an overall quality-of-life score, which is the 
mean score of all 32 items. The resultant overall scores will be between 1 and 7.
The developer suggests no more than 10% of missing data. This means no more than 3 missing 
responses for the overall score and no more than 1 missing response per domain.  For the 
symptoms and activity domain scores, one missing value per domain is allowed.  For the 
emotional function and environmental stimuli domain scores, no missing values are allowed. 
If these limits for missing questions are exceeded, the variable will be considered missing and 
will be imputed as described in Section 2.6.3.5.
The minimal important difference (MID), defined as “the smallest difference which patients 
perceive as beneficial and would mandate, in the absence of troublesome side effects and 


Novartis
For business use only
Page 27
SAP
26-Aug-2019 (10:13)
CQAW039A2314
excessive cost, a change in the patient’s management,” of 0.5 has been established for this 
questionnaire as clinically significant (Juniper, et al 1994).
2.7.1.2
Pre-dose FEV1
Pre-dose FEV1 is the average of two FEV1 assessments taken at approximately 45 minutes 
and approximately 15 minutes prior to the dosing of study drug at clinic visits. 
Spirometry measurements affected by prohibeted or rescue medication (as defined in the 
masterscope) will be censored (set to missing). 
2.7.1.3
Asthma Control Questionnaire (ACQ-5)
The ACQ-5 measures asthma symptom control and consists of 5 items. Patients will be asked 
to recall their experiences during the past one week and to response items 1-6 (night-time 
waking, symptoms on waking, activity limitation, shortness of breath, wheeze and rescue 
short-acting β2-agonist use) on a 7-point scale (0 – totally controlled, 6 – extremely poorly 
controlled). The ACQ-5 score calculated based on the 5 questions of the 5 most important 
symptoms. The 5 questions of the ACQ-5 are equally weighted. The ACQ-5 score is the 
mean of the responses to the 5 questions. The resultant score will be between 0 and 6.
The mean will be calculated as the sum of scores divided by the number of questions that were 
answered, as long as there were at least 4 questions answered and the missing question is not 
Question 1 ('On average, during the past week, how often were you woken by your asthma 
during the night?').  If  Question 1 is missing or if there are less than 4 questions answered then 
the ACQ-5 score will be considered as missing and the data will be imputed using the 
imputation method described in Section 2.6.3.5.
A score of 1.5 or more at baseline indicates patients who entered the study had inadequately 
controlled asthma (Juniper 2006). In addition, the minimal important difference (MID) or 
smallest change that can be considered clinically important is 0.5.
For efficacy endpoints described in this Section and in Section 2.8 on-treatment data are 
defined as data on or after the first day of treatment with double-blind medication, but before 
or on the day of the last day of treatment with double-blind study medication.
For efficacy endpoints described in this Section and in Section 2.8 on-study data are defined as 
data on or after the first day of treatment with double-blind medication, but before or on the 
day of the last day of treatment period.
2.7.2
Statistical hypothesis, model, and method of analysis
AQLQ+12, ACQ-5 and pre-dose FEV1 will be summarized by treatment for all visits. All the 
summaries will be based on observed and non-imputed on-treatment data.
The key secondary variables of AQLQ+12, ACQ-5 and pre-dose FEV1 will be analyzed using 
an analysis of covariance (ANCOVA) model with factors for treatment group, randomization 
strata, as well as the baseline AQLQ+12, baseline ACQ-5 and baseline  pre-dose FEV1 as 
continuous linear covariates. 
The null hypothesis will be tested for each dose group, each population (subgroup with 
peripheral blood eosinophil counts at Visit 1 ≥250 cells/l or overall population) and each key 
secondary variable using this model versus the two-sided alternative hypotheses. 


Novartis
For business use only
Page 28
SAP
26-Aug-2019 (10:13)
CQAW039A2314
For each key secondary endpoint, each QAW039 dose and each population the null hypothesis 
is that the treatment difference compared to placebo at the week 52 visit = 0, while the 
alternative hypothesis is that the treatment difference to placebo at the week 52 visit ≠ 0.
2.7.3
Handling of missing values/censoring/discontinuations
Missing baseline AQLQ+12, ACQ-5 and pre-dose FEV1 will be assumed to be missing at 
random as assessments are performed prior to any knowledge of treatment allocation and will 
be imputed using the mean value of all randomised patients included in the FAS. 
The FEV1 value analysed at each visit is based on the average of the two FEV1 assessments 
taken at at approximately 45 minutes and approximately 15 minutes prior to the dosing of study 
drug at clinic visits. In cases where one of the values is missing this will be imputed within 
treatment group via multiple imputation and the average will be calculated based on the one 
available assessment and a second imputed assessment.
Due translation errors some of the questions on ACQ-5, AQLQ+12 will be considered as 
missing. Questions with these errors were flagged by an external vendor and then excluded 
from the analysis datasets. These translation errors were due to some quality issues which were 
identified but did not impact patient outcomes. Such missing data are clearly missing for 
reasons unrelated to patient outcomes and will therefore be imputed under a missing at random 
assumption.
If there is intermittent missingness between two visits, then the missing values will be imputed 
under MAR assumption in all treatment arms.
Once these imputations are complete subsequent missing data will be imputed as follows: 
1. Missing data in QAW039 patients that discontinue treatment and are lost to follow-up due 
to (or following a treatment discontinuation due to) adverse event, death, physician 
decision and subject/guardian decision will be imputed assuming the same effect as the 
placebo group (Jump-to reference approach).
2. A continued treatment effect for QAW039 patients being lost to follow-up for reasons 
likely to be unrelated to study treatment (pregnancy, study terminated by sponsor, 
technical problems, lost to follow-up) will be assumed, i.e. for such patients 
postwithdrawal events will be imputed assuming MAR based on the event distribution of 
the arm patients were randomized to.
3. A continued treatment effect for placebo patients being lost to follow-up for any reason 
i.e. for the placebo patients values for visits with missing data will be imputed assuming 
that missing data are missing at random
The imputation and analysis will be implemented using the “five macros” available from 
www.missingdata.org.uk (for a full description see Carpenter et al (2013)). These fit a Bayesian 
Normal repeated measures model to estimate parameters from the observed values and then 
use these to build possible predicted profiles for the unobserved values following withdrawal 
in a separate imputation model, one for each pattern of withdrawal. These profiles represent 
what we expect would happen to subjects after they withdraw. Missing values for an individual 
are then imputed based on the profile of predicted means that matches their treatment, and their 
reason for, and time of, withdrawal. The complete datasets are then analysed using a univariate 
ANOVA at each visit with results summarized across imputations using Rubin’s rules.


Novartis
For business use only
Page 29
SAP
26-Aug-2019 (10:13)
CQAW039A2314
The test for the key secondary variables AQLQ+12, ACQ-5 and pre-dose FEV1 in patients 
with eosinophil count ≥ 250 cells/µl and for the overall population for each dose will be 
performed, if the primary null hypothesis has been rejected for the same dose for patients 
with eosinophil count ≥ 250 cells/µl and for the overall population, respectively. The local 
significance level for each secondary null hypothesis will be determined based on the closed 
testing procedure specified by Figure 2-1.
2.7.4
Supportive/sensitivity analysis for secondary endpoints
An on-treatment analysis of all visits will be conducted for the key secondary endpoints. In this 
analysis the measurements will be used, if the date of the measurement is on or after the first 
day of treatment with double-blind study medication, but before or on the day after the last day 
of treatment with double-blind study medication. The on-treatment analysis for the on-
treatment values will use a MMRM with an unstructured covariance structure. If this model 
does not converge, a heterogeneous compound symmetric covariance structure will be used. 
These MMRMs will include treatment group, visit and randomization strata as fixed class 
effects, and the baseline AQLQ+12, baseline ACQ-5 and baseline pre-dose FEV1 as 
continuous linear covariates. Treatment group by visit interactions and baseline value (of the 
variable under analysis) by visit interactions will also be included in the model. Only observed 
on-treatment data will be used in this analysis. This model implicitly imputes unrecorded 
values and the data censored at the end of treatment assuming a hypothetical situation of 
continued treatment with an unchanged on-treatment effect.
The analyses on key secondary variables on on-study data considering a considering multiple 
imputation framework based on a combination of missing at random and jump-to-reference 
approaches as described in Sections 2.7.3 will also be conducted by subgroup including key 
demographic  and disease related subgroups (See Section 2.3 for the details of subgroups). The 
results of the subgroup analyses will be displayed graphically in forest plots.


Novartis
For business use only
Page 30
SAP
26-Aug-2019 (10:13)
CQAW039A2314


Novartis
For business use only
Page 31
SAP
26-Aug-2019 (10:13)
CQAW039A2314


Novartis
For business use only
Page 32
SAP
26-Aug-2019 (10:13)
CQAW039A2314


Novartis
For business use only
Page 33
SAP
26-Aug-2019 (10:13)
CQAW039A2314


Novartis
For business use only
Page 34
SAP
26-Aug-2019 (10:13)
CQAW039A2314


Novartis
For business use only
Page 35
SAP
26-Aug-2019 (10:13)
CQAW039A2314
2.9
Safety analyses
All safety data will be summarized for the safety set.
Safety summaries will be primarily based on on-treatment data with selected tables also 
presented for all data after the first intake of study drug, while all safety data will be listed. 
Unless otherwise specified, all safety summaries will be provided for patients with eosinophil 
count ≥ 250 cells/µl, and for the overall study population.
2.9.1
Adverse events (AEs)
Adverse events after informed consent including asthma exacerbations will be summarized .
Adverse events starting on or after the day of the first intake of study drug but not later than 
the last intake of study drug + 7 days will be classified as treatment emergent adverse events.
Serious adverse events starting on or after the day of the first intake of study drug but not 
later than the last intake of study drug + 30 days will be classified as treatment emergent
serious adverse events.
Adverse events that started during the study after informed consent and before the day of the 
first intake of study drug will be classified as  prior adverse events and not included in 
tabulations of treatment emergent adverse events. 
The number and percentage of patients who reported treatment-emergent adverse events 
(TEAEs) will be summarized by primary system organ class, preferred term, and treatment for

all adverse events

all adverse events by maximum severity

adverse events suspected to be related to study drug

adverse events leading to permanent study drug discontinuation

all adverse events by standardized MedDRA query (SMQ) level

serious adverse events
Unless otherwise specified, primary system organ classes will be sorted alphabetically and, 
within each primary system organ class, the preferred terms will be sorted in descending order 
of frequency in the QAW039 150 mg once daily treatment group. If a patient reported more 
than one AE with the same preferred term, the AE will be counted only once. If a patient 
reported more than one AE within the same primary system organ class, the patient will be 
counted only once at the system organ class level.
In addition, the most frequent AEs will be presented by preferred term in descending order of 
frequency in the QAW039 150 mg once daily treatment group.
Missing AE severity will be assumed to be severe in the summary table. Relationship to study 
drug is coded as suspected for those adverse events where the study drug relationship is 
unknown.
2.9.1.1
Adverse events of special interest / grouping of AEs
Adverse events of special interest definitions are found in the compound electronic Case 
Retrieval Strategy (eCRS). The classification reflects the current version of the DSPP and 


Novartis
For business use only
Page 36
SAP
26-Aug-2019 (10:13)
CQAW039A2314
might be updated based on review of accumulating data. To identify AEs of special interest at 
the time of the final analysis the latest version of the eCRS where Core safety topic risk (SP) = 
‘Yes’ or Other Search risk (OS) = ‘Yes’ will be used. 
The number and percentage of patients with AEs of special interest will be summarized by risk 
category, SMQ (when applicable), preferred term and treatment. In addition, AEs of special 
interest that are considered serious 
 
2.9.1.2
Deaths
The number of deaths resulting from TEAEs will be summarized by SOC and PT. Death refers 
to treatment emergent adverse events with fatal outcome. All the deaths in the clinical database 
including those occurring during screening will be listed. 
2.9.1.3
Adverse events reporting for safety disclosure
For the legal recruitments of clinicaltrials.gov and EudraCT, two required tables on treatment 
emergent adverse events which are not serious adverse events with an incidence greater than 
a certain threshold based on the final database and on treatment emergent serious adverse 
events and SAE suspected to be related to study treatment will be provided by system organ 
class and preferred term on the safety set population. If for a same patient, several 
consecutive AEs (irrespective of study treatment causality, seriousness and severity) occurred 
with the same SOC and PT:
- a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE
- more than one occurrence will be counted if there is > 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if 
at least one SAE is occurring, then one occurrence is calculated for that SAE.The number of 
deaths resulting from SAEs suspected to be related to study treatment and SAEs irrespective 
of study treatment relationship will be provided by SOC and PT.
2.9.2
Laboratory data
Laboratory data consist of hematology, biochemistry and urinalysis measurements. Laboratory 
data measured after first intake of study drug and up to 7 days after last intake of study drug 
are regarded as on-treatment data. Laboratory data measured more than 7 days after last intake 
of study drug are regarded as post-treatment data and will not be summarized.All on-treatment 
data will be included in the analyses regardless of rescue medication use. All data will be listed 
with abnormal values flagged. 
2.9.2.1
Summary of absolute values
For all continuous laboratory parameters, the absolute on-treatment laboratory values, 
including the worst case post-baseline values (including values from post-baseline unscheduled 
and premature discontinuation visits), will be summarized with standard descriptive statistics 


Novartis
For business use only
Page 37
SAP
26-Aug-2019 (10:13)
CQAW039A2314
by parameter, scheduled visit and time-point, and treatment. The direction of interest for worst 
case post-baseline for selected hematology and biochemistry parameters is tabulated in Table 
2-2. For continuous urinalysis parameters the direction of interest is always High.
For categorical laboratory parameters and categorical urinalysis parameters, a frequency table 
of results will be produced by laboratory parameter, scheduled visit and time-point, and 
treatment. Worst-case post-baseline on-treatment values (including values from post-baseline 
unscheduled and premature discontinuation visits) will also be included. 
For summary tables and figures on laboratory parameters considering values, which are lower 
or greater than the limit of quantification, the following approach will be taken. For values 
which are flagged as lower than the lower limit of quantification, the values presented in 
summary tables should be multiplied by 0.5 and for values which are flagged as greater than 
upper limit of quantification as 1.5, the values presented in summary tables should be 
multiplied by 1.5.
2.9.2.2
Summary of change from baseline 
For continuous laboratory parameters, the on-treatment change from baseline at each scheduled 
visit and time-point, and the on-treatment change from baseline to the worst case post-baseline 
values (including values from post-baseline unscheduled and premature discontinuation visits) 
will be summarized by laboratory parameter, scheduled visit and time-point, and treatment with 
standard descriptive statistics.
In order to observe the tendency of treatment effect on mean values, box plots by treatment 
arm for post-baseline values and worst case post-baseline will be presented on the change 
from baseline for all   laboratory parameters. Albumin: Creatinine ratio (ACR) value will be 
considered missing if either the albumin or the creatinine values are missing. Similarly, 
Protein: Creatinine ratio (PCR) will be considered missing if either the protein or the 
creatinine values are missing.
2.9.2.3
Notable values
For selected laboratory parameters, abnormalities occurring at any time-point over the 
treatment period, considering all post-baseline on-treatment data from scheduled, unscheduled 
and premature discontinuation visits will be summarized. Patients with any newly occurring or 
worsening on-treatment value meeting the clinically notable criteria will be counted under the 
applicable criteria. 
For a patient to meet the criterion of a newly occurring clinically notable value, the patient 
needs to have a baseline value which is not clinically notable for that parameter.  For a patient 
to meet the criterion of a worsening clinically notable value, the patient needs to have a baseline 
value which is clinically notable and also have a worse post-baseline value. For patients with 
a missing baseline value, any post-baseline notable value will be considered as newly occurring.
The criteria for clinically notable values are presented in Table 2-3. 


Novartis
For business use only
Page 38
SAP
26-Aug-2019 (10:13)
CQAW039A2314
Table 2-2
Direction of interest for worst case value for laboratory parameters 
Laboratory Parameter
Direction of interest for worst case value
A. Hematology
Basophils
High
Eosinophils
High
Hematocrit
Low
Hemoglobin
Low
Lymphocytes
Low and high
Monocytes
High
Neutrophils
Low and high
Platelets
Low and high
RBC 
Low
WBC total
Low and high
B. Chemistry
Albumin
Low
Sodium
Low and High
Alkaline Phosphatase
High
ALT/SGPT
High
AST/SGOT
High
Bilirubin Total
High
Blood Urea Nitrogen (BUN)
High
CPK
High
Creatinine
High
Gamma GT
High
Glucose 
Low and high 
Potassium
Low and high
Uric acid
High
Table 2-3
Clinical notable criteria for selected laboratory tests 
Laboratory parameter (unit)
Bound for notably low
values
Bound for notably high 
values
Hematology
Hematocrit (v/v)
     Male 12-17
     Male 18-65
     Male >=66
0.34
0.37
0.34


Novartis
For business use only
Page 39
SAP
26-Aug-2019 (10:13)
CQAW039A2314
Laboratory parameter (unit)
Bound for notably low
values
Bound for notably high 
values
     Female 12-65
     Female >=66
0.32
0.31
Hemoglobin (g/L)
    Male 12-17
    Male >=18
    Female
100
110
95
Thrombocytes (x10E9/L
75 
700
WBC’s (x109/L)
2.8
16.0
Chemistry
Alkaline Phosphatase (IU/L)
-
3xULN
Total Bilirubin (µmol/L)
-
34.2
Creatinine (µmol/L)
176.8
Potassium (mmol/L)
3
6
Glucose (mmol/L)
2.78
9.99
ALT/SGPT (U/L)
-
3 x ULN
AST/SGOT (U/L)
-
3 x ULN
Urea (mmol/L)
9.99
Sodium (mmol/L)
125
160
Gamma GT (U/L)
3 x ULN
CPK (IU/L)
4 x ULN
Urinalysis
Dipstick blood
≥2+
Dipstick glucose
≥2+
Dipstick leukocytes
≥2+
Dipstick protein
≥2+
v = volume, ULN = upper limit of normal 
Laboratory test units will be converted to standard units. Based on agreement within our 
standards, if we have a multi-region study the Blood Urea Nitrogen (BUN) / Urea test would 
be represented as BUN [mg/dL] for the regions used to conventional results (US, Latin 
America) and as Urea [mmol/L] for the regions used to SI results. Therefore both BUN and 
Urea parameters will be included in the data. 
BUN is always reported as mg/dL and Urea as mmol/L. BUN and Urea are the same 
measurement in the lab and should be considered the same test. Hence for the summary 
tables, it is expressed in SI units.  Conversion to SI units includes the factor which 
incorporates a conversion from BUN to Urea as well as a conversion from mg/dL to mmol/L. 
This is necessary because BUN is Urea Nitrogen, not Urea and there are two nitrogens in 
each urea molecule. The factor of 0.357 converts BUN in mg/dL to Urea in mmol/L.
Listings of patients with notable laboratory values will be provided by laboratory parameter, 
treatment group, and patient number.


Novartis
For business use only
Page 40
SAP
26-Aug-2019 (10:13)
CQAW039A2314
Liver function tests
To evaluate potential drug-induced liver injury, newly occurring or worsening abnormalities 
in liver function tests will be evaluated (see Table 2-4 for a summary of the notable values) for 
both populations.
Table 2-4
Notable liver function test values
Criterion  
ALT  > 3 x ULN
ALT > 5 x ULN
ALT > 8 x ULN
ALT > 10 x ULN
ALT > 20 x ULN
ALT or AST > 3 x ULN
ALT or AST > 5 x ULN
ALT or AST > 8 x ULN
ALT or AST > 10 x ULN
ALT or AST > 20 x ULN
Total Bilirubin > 1 x ULN
Total Bilirubin > 1.5 x ULN
Total Bilirubin > 2 x ULN
Total Bilirubin > 3 x ULN
ALP > 1.5 x ULN
ALP > 2 x ULN
ALP > 3 x ULN
ALP > 5 x ULN
ALT or AST > 3 x ULN and Total Bilirubin > 1.5 x ULN
ALT or AST > 3 x ULN and Total Bilirubin > 2 x ULN
ALT or AST > 5 x ULN and Total Bilirubin > 2 x ULN
ALT or AST > 8 x ULN and Total Bilirubin > 2 x ULN
ALT or AST > 10 x ULN and Total Bilirubin > 2 x ULN
ALT or AST > 20 x ULN and Total Bilirubin > 2 x ULN
ALP > 3 x ULN and Total Bilirubin > 2 x ULN
ALP > 5 x ULN and Total Bilirubin > 2 x ULN
ALT or AST > 3 x ULN and Total Bilirubin > 2 x ULN and ALP ≤ 2 x ULN (Hy's law)
ALT or AST > 3 x ULN and (nausea or vomiting or fatigue or general malaise or abdominal pain or 
(rash and eosinophilia))*
ALT=alanine aminotransferase; AST=aspartate aminotransferase; ALP=alkaline phosphatase; 
ULN=upper limit of normal. *Based on the signs/symptoms information as recorded on the liver 
events eCRF, not the adverse events eCRF in the NCDS studies.
When a criterion contains multiple laboratory parameters, the criterion will only be considered 
to be met when all conditions occur at the same time (i.e., in the same sample). A case where 
all criteria are met at a post-baseline time point but not met at baseline will be considered as 


Novartis
For business use only
Page 41
SAP
26-Aug-2019 (10:13)
CQAW039A2314
newly occurring. A case will be considered as worsening if all the criteria are met at baseline 
and at least one component is worsening from baseline, irrespective of whether the other(s) are 
better. 
The number and percentage of patients with newly occurring liver enzyme abnormalities any 
time post-baseline will be summarized for both populations. Listings of patients with notable 
liver function test lab values and liver events will be provided.
To evaluate drug induced serious hepatotoxicity eDish plots will be presented by population.
The eDish plot will reflect the worst value of each of the parameters; they do not need to occur 
at the same visit.
2.9.3
Other safety data
2.9.3.1
ECG and cardiac imaging data
ECG measurements include heart rate, QT interval, RR interval, PR interval, QRS duration, 
and Fridericia’s QTc (calculated as QTcF = QT / 3√RR (in seconds), where 3√denotes the 
cube root). Furthermore, an overall interpretation of the central cardiologist will be provided 
as well as a specification of abnormal findings.
ECG data measured more than 7 days after last intake of study drug are regarded as post 
treatment data and will not be summarized, only listed. All data will be included in the analyses 
regardless of rescue medication use.
Summary of absolute values and change from baseline
Absolute values and change from baseline will be summarized by parameter, and visit. 
Clinically relevant and notable values

The number and percentage of patients with newly occurring or worsening clinical notable
QTcF values (The clinically notable ranges for QTcF are shown in Table 2-5) will be 
summarized at any time on treatment considering all post-baseline data from scheduled, 
unscheduled and premature discontinuation visits.

A summary table will also be produced for number and percentage of subjects with 
clinically relevant QT and QTcF intervals (irrespective of the timpoint) using the 
following categories:
a. any treatment emergent (new) QTcF ≥450 ms – 480 ms, > 480 ms – 500 ms or > 500 
ms
b. QTcF increase from baseline of , 30 ms -60 ms, > 60 ms
c. QTcF increase from baseline of ≥ 30 ms plus QTcF interval ≥450 ms, > 480 ms or > 
500 ms
d. QTcF increase from baseline of ≥ 60 ms plus QTcF interval ≥450 ms, > 480 ms or > 
500 ms

The number and percentage of subjects with noteworthy PR, QRS and HR interval 
changes will be reported using the below categories:
a. New PR > 200 ms to <= 220 ms; and > 220 ms 
b. New QRS > 110 ms to <= 120 ms; and > 120 ms
c. PR increase > 25% to a value > 200 ms 


Novartis
For business use only
Page 42
SAP
26-Aug-2019 (10:13)
CQAW039A2314
d. QRS increase > 25% to a value > 120 ms 
e. HR decrease > 25% to a HR < 50 bpm
f.
HR increase  > 25% to a HR > 100 bpm
Patients with notable post-baseline ECG values will be listed. Box plots of ECG by scheduled 
visit and treatment for the parameters: QTcF, summary (mean) heart rate will be presented.  
Table 2-5
Clinical notable criteria for QTcF (Fridericia's formula)
ECG parameter (unit)
Clinically notable range
Notable value considering newly occurring or worsening cases
QTc (msec)
≥450 (male)
QTc (msec)
≥460 (female)
QTc (msec)
> 500 (both) 
Notable change from baseline
QTc
1- < 30 
QTc
30 – 60
QTc
> 60
Overall ECG interpretation
Using the morphologic determinations, the number and percentage of subjects with 
qualitative ECG abnormality will be summarized for each visit. The abnormality will be 
summarized by baseline condition (NO/YES) for each type of abnormality (i.e. newly 
occurring cases, or persistent/recurrent cases). The qualitative ECG abnormality will be 
determined by abnormality of Rhythm, Ectopy, Conduction, Morphology, Myocardial 
infarction, ST segment, T wave abnormalities, abnormal U wave. If patients does not have 
abnormality in any of the ECG records at baseline, then the baseline flag is considered as 
normal. If patients had at least once ECG abnormality at baseline, the baseline flag will be 
abnormal. Similarly for post baseline visits, if there is an abnormality in at least one of the  
records at any particular visit then ECG is considered to be abnormal at that visit. Number 
and percentage of patients with newly occuring or persistent/recurrent abnormalities in 
overall ECG interpretation at any time post-baseline will also be presented.
  
2.9.3.2
Vital signs
Vital signs measurements include systolic and diastolic blood pressure (SBP and DBP), pulse 
rate, height and body weight. Vital signs data taken on or after the time of the first intake of 
study drug and up to 7 days after the last intake of study drug are regarded as on-treatment 
data. Vital signs data measured more than 7 days after last intake of study drug are regarded as 
post-treatment data and will not be summarized. All data will be included in the analyses 
regardless of rescue medication use.
The following analyses will be performed by treatment group:

absolute on-treatment values and change from baseline summarized by parameter, and visit 

the number and percentage of patients with newly occurring or worsening notable vital 
signs on-treatment values (see Table 2-6 for definition of notable values) summarized by 


Novartis
For business use only
Page 43
SAP
26-Aug-2019 (10:13)
CQAW039A2314
parameter (except height), at any time on treatment considering all post-baseline data from 
scheduled, unscheduled and premature discontinuation visits

Number and percentage of patients with clinically relevant on-treatment vital signs values 
that occur at any time post-baseline: 
1. Pulse rate:  < 40 bpm, 40 – 90 bpm, and > 90 bpm
2. Systolic blood pressure: < 90 mm Hg, 90 – 140 mm Hg, and > 140 mm Hg
3. Diastolic blood pressure: < 50 mm Hg, 50 – 90 mm Hg, and > 90 mm Hg.
for minimum and maximum post-baseline values.  
The same approach as for notable laboratory values will be used to define a newly occurring 
notable vital sign value and a worsening notable vital sign value.A listing of all patients with 
notable vital sign values and changes will be provided.
Table 2-6
Vital signs - clinical notable values
Vital sign parameter (unit)
Lower bound of clinically 
notable range
Upper bound of 
clinically notable range
Notable value considering newly occurring or worsening cases
Systolic blood pressure (mmHg)
< 75 
> 200
Diastolic blood pressure (mmHg)
< 40
> 115
Pulse rate (bpm)
< 40
> 130
Notable change from baseline
Systolic blood pressure (mmHg)
≤ 90 and decrease from 
baseline by ≥ 20 
≥ 180 and increase 
from baseline by ≥ 20
Diastolic blood pressure (mmHg)
≤ 50 and decrease from 
baseline by ≥ 15
≥ 105 and increase 
from baseline by ≥ 15
Pulse rate (bpm)
≤ 50 and decrease from 
baseline by ≥ 15
≥ 120 and increase 
from baseline by ≥ 15
Weight (kg)
Decrease ≥ 7% from 
baseline
Increase ≥ 7% from 
baseline
2.9.3.3
Renal events
Summary of treatment emergent renal event overview data by treatment and population will 
be presented. All renal event overview data will be listed. 
2.9.3.4
Liver events
Summary of treatment emergent liver event overview data by treatment and population will be 
presented. All liver event overview data will be listed.
  


Novartis
For business use only
Page 44
SAP
26-Aug-2019 (10:13)
CQAW039A2314
 
2.12
Interim analysis
An independent Data Monitoring Committee will conduct periodic unblinded safety reviews 
of the accumulating data (including specific safety summaries for adolescent participants) from 
this trial and other Phase III trials of the QAW039 asthma development program to ensure 
safety of trial participants.
In addition, a single interim analysis for futility will be conducted to assess whether the study
should be stopped for futility or safety, or whether treatment in one or more QAW039 dose
groups should be discontinued for safety reasons. There will be no stopping for demonstrated
efficacy prior to the completion of the study at either the unblinded safety reviews or the futility 
interim analysis, because a sufficiently large safety dataset is needed in addition to efficacy 
data. Therefore, no statistical adjustment will be made to the final analysis.
This interim analysis for futility will occur when approximately 200 patient-years of followup
data have accumulated. The timing of the futility interim analysis may be modified based on 
the progress of recruitment, the logistics of arranging DMC meetings, the data accrual in other 
QAW039 asthma Phase III trials and additional external data that might become available.
Statistical methods for the interim analysis
Detailed statistical methods will be specified in a separate document. In general, statistical 
approaches will follow those outlined in this analysis plan. Patients administratively censored 
due to the analysis cut-off for the interim analysis will have their missing data imputed under 
a missing at random assumption unless they have discontinued treatment. This reflects that 
such patients are expected to continue treatment.
3
Sample size calculation
To be conservative a mean placebo event rate of 1.5 events per patient year of follow-up has 
been assumed for this study; this is a slightly lower rate than the 1.75 events per patient-year 
observed in the placebo group of the MENSA trial (Ortega, et al 2014) and the same event 
rate as assumed for the DREAM trial, although the actual DREAM placebo event rate was 2.4 
events per patient year of follow-up (Pavord, et al 2012). A 40% reduction in the rate of 
asthma exacerbations per year in the QAW039 treatment compared to placebo has been 
assumed  for  the  subgroup  with  high  eosinophils  ≥  250  cells/μl for  this  study;  this  is 
considered to be highly clinically relevant and at the same time realistic based on the DREAM 
and MENSA trials conducted in similar patient populations. In the DREAM trial 75 mg 
mepolizumab reduced the number of asthma exacerbations per patient per year by 48%,
250mg mepolizumab by 39% and 750mg mepolizumab by 52% compared with placebo. In 
the MENSA trial intravenous mepolizumab reduced the number of asthma exacerbations per 
patient per year by 47% and subcutaneous mepolizumab by 53% compared with placebo. 
These relative risk reductions were taken into account, because the observed reduction in 
sputum eosinophils with QAW039 in Study CQAW039A2208 were similar to those observed 
with mepolizumab (Haldar, et al 2009; Pavord, et al 2012). On this basis it is postulated 
QAW039 may reduce the rate of asthma exacerbations to a similar extent as mepolizumab. 


Novartis
For business use only
Page 45
SAP
26-Aug-2019 (10:13)
CQAW039A2314
For the subgroup with eosinophils < 250 cells/μl a lesser relative risk reduction of 30% was 
assumed. However, it should be noted that the trial may produce a significant result with a 
smaller reduction in exacerbations than that assumed for power calculations and that such a 
reduction could still be considered clinically relevant.
As reported in online supplementary material for the MENSA publication the negative 
binomial dispersion parameter for the exacerbation rates was estimated to be 0.8 in the 
DREAM trial. In the DREAM trial approximately 15% of patients in the mepolizumab arms 
and 20% of patients in the placebo arm were lost to follow-up by the end of the 1-year trial, 
while in the 32 week MENSA trial only 6 to 8% of patients were lost across groups. Therefore, 
a constant exponential hazard rate over time for treatment discontinuation is assumed with 15% 
of patients off treatment by 1 year in the active treatment groups and the placebo group. No 
further treatment effect versus placebo has been assumed during the off-treatment, i.e. a mean 
event rate of 1.5 events per patient year has been assumed for patients after treatment 
discontinuation in both the QAW039 and placebo groups.
A 1:1:1 randomization was used, even though the power to demonstrate the superiority of at 
least one arm versus placebo would likely have been higher with an increased assignment to 
the placebo group, in order to not reduce the amount of efficacy and safety information for 
each QAW039 dose group. 
Negative binomial counts were simulated based on the assumptions above and the testing 
procedure in Figure 2-1 was applied to each simulation result. For the purpose of evaluating 
the power for the primary trial objectives, it was assumed that none of the key secondary null 
hypotheses would be rejected.
For this study a two-sided significance level of 5% is used for testing. As shown in Table 3-1
188 patients per arm in the subpopulation with blood eosinophils ≥ 250 cells/μl and 282 patients 
per arm in the overall population corresponding to a total sample size of 846 patients provide 
greater than 80% power for demonstrating the superiority of each dose of QAW039 compared 
to placebo in the subpopulation with blood eosinophils ≥ 250 cells/μl and overall population
under the described assumptions.
Table 3-1
Power for the primary variable
True relative risk reduction
Upper row: Subpopulation
Lower row: Other population
Power (%)
Upper row: Subpopulation
Lower row: Overall population
450 mg
150 mg
At least one
All doses
(%)
(%)
450 mg
150 mg
dose significant
Significant
40
30
40
30
89%
84%
89%
84%
96%
93%
82%
75%
40
20
40
20
89%
76%
89%
76%
96%
88%
82%
64%
40
0
40
0
89%
49%
89%
49%
96%
66%
82%
32%
Subpopulation means the subpopulation with blood eosinophils ≥ 250 cells/μl, while other 
population refers to the subpopulation with blood eosinophils < 250 cells/μl. Power results 
are based on 100,000 simulated trials per scenario. Only results for primary endpoints were 
simulated. For the purpose of evaluating the power for the primary trial objectives, it was 
assumed that none of the key secondary null hypotheses would be rejected. All simulations 
were performed in SAS 9.4.


Novartis
For business use only
Page 46
SAP
26-Aug-2019 (10:13)
CQAW039A2314
If statistical significance is achieved in the primary test, the test for the key secondary variables 
pre-dose FEV1, AQLQ+12 and ACQ-5 will be performed. The local significance level for each 
secondary null hypothesis will be determined based on the closed testing procedure shown in 
Figure 2-1. For the power for each key secondary variable in the subpopulation with blood 
eosinophils ≥250 cells/μl and overall population, it was conservatively assumed that only the 
null hypothesis for the primary endpoint for the respective dose in the subpopulation and 
overall population would be rejected. For AQLQ+12 and ACQ5 the power was additionally 
calculated conditional on both the null hypothesis for the primary endpoint and pre-dose FEV1 
for the respective dose in the subpopulation and overall population having been rejected. The 
power for each key secondary endpoint is shown in Table 3-2. However, note that the power 
for the key secondary endpoints will be higher once the null hypotheses relating to other key 
secondary variables or other doses have been rejected. For the power calculation of secondary 
endpoints no further treatment effect versus placebo has been assumed for patients with
treatment discontinuation.
It was assumed that QAW039 achieves a difference of 150 mL against placebo in FEV1 after 
52 weeks for patients that remain on treatment. A standard deviation (SD) of 380 mL was 
assumed for the analysis in FEV1. Given a 15% treatment discontinuation rate by week 52, the 
planned sample size will give 80% power for each dose in the subpopulation at the resulting 
local two-sided significance level of 1.625% and 90% power for each dose in the overall 
population at the resulting local two-sided significance level of 0.698%.
Assuming a clinically important true improvement of at least 0.5 in AQLQ+12 after 52 weeks 
treatment for patients that remain on treatment, a SD of 1 and 15% treatment discontinuation 
rate by week 52, the planned sample size per arm will provide 76% power for each dose in the 
subpopulation with blood eosinophils ≥ 250 cells/μl at the resulting local two sided significance 
level of 0.075% and 93% power for each dose in the overall population at the resulting local 
two-sided significance level of 0.038% after the respective primary null hypothesis has been 
rejected. 
Assuming a difference of 0.5 against placebo in ACQ-5 after 52 weeks for patients without 
treatment discontinuation, a SD of 1.1, and a 15% treatment discontinuation rate by week 52, 
the planned sample size will give 59% power for each dose in the subpopulation at the resulting 
local two-sided significance level of 0.05% and 78% power for each dose in the overall 
population at the resulting two-sided local significance level of 0.015% after the respective 
primary null hypothesis has been rejected.
Table 3-2
Power of each dose for the analyses of key secondary variables 
Pre-dose FEV1
AQLQ+12
ACQ-5
Difference of effect (δ) for patients 
without treatment discontinuation
150 mL
0.5
0.5
SD (σ)
380 mL
1
1.1
Treatment discontinuation rate
15%
15%
15%
Subpopulation
Local two-sided 
significance level 
1.625%
0.075%*
1.294%†
0.05%*
0.456%†
Power
80%
76%*
95%†
59%*
81%†
Overall population
Local two-sided 
significance level 
0.698%
0.038%*
0.561%†
0.015%*
0.189%†


Novartis
For business use only
Page 47
SAP
26-Aug-2019 (10:13)
CQAW039A2314
Pre-dose FEV1
AQLQ+12
ACQ-5
Power
90%
93%*
99%†
78%*
93%†
Subpopulation means the subpopulation with blood eosinophils ≥ 250 cells/μl.
* For local two-sided significance level and power in AQLQ+12 and ACQ5 the upper row shows the 
value when only the null hypothesis for the primary endpoint for the respective dose in the 
subpopulation and overall population have been rejected.
† The lower row shows the value when both the null hypothesis for the primary endpoint and 
pre-dose FEV1 for the respective dose in the subpopulation and overall population have been 
rejected.


Novartis
For business use only
Page 48
SAP
26-Aug-2019 (10:13)
CQAW039A2314


Novartis
For business use only
Page 49
SAP
26-Aug-2019 (10:13)
CQAW039A2314


Novartis
For business use only
Page 50
SAP
26-Aug-2019 (10:13)
CQAW039A2314


Novartis
For business use only
Page 51
SAP
26-Aug-2019 (10:13)
CQAW039A2314
5.4
Safety variables
Safety summaries for patients with eosinophil count < 250 cells/µl will be summarized outside 
of CSR. The number and percentage of patients who reported treatment-emergent adverse 
events will be summarized by primary system organ class, preferred term, and treatment for all 
6
Appendix
6.1
Imputation rules
6.1.1
AE date imputation
6.1.1.1
AE end date imputation
Rules for imputing AE end dates are stated below. Date of last contact in the study has been 
defined as in Section 2.1.1.6 . 
1. If the AE end date month is missing, the imputed end date should be set to the 
earliest of the (date of last contact, 31DECYYYY, date of death).
2. If the AE end date day is missing, the imputed end date should be set to the earliest 
of the (date of last contact, last day of the month, date of death).
3. If AE year is missing or AE is ongoing, the end date will not be imputed.
6.1.1.2
AE start date imputation
Rules for imputing the AE start date:


Novartis
For business use only
Page 52
SAP
26-Aug-2019 (10:13)
CQAW039A2314
The following table explains the notation used in the logic matrix. Please note that missing 
start dates will not be imputed.
Day
Month
Year
Partial Adverse Event Start Date
Not used
MON
YYYY
Treatment Start Date 
Not used
TRTM
TRTY
The following matrix explains the logic behind the imputation. 
MON
MISSING
MON < TRTM
MON = TRTM
MON > TRTM
YYYY
MISSING
( 1 )
No convention
( 1 )
No convention
( 1 )
No convention
( 1 )
No convention
YYYY < TRTY
( 2.a )
Before Treatment 
Start
( 2.b )
Before Treatment 
Start
( 2.b )
Before Treatment 
Start
( 2.b )
Before Treatment 
Start
YYYY = TRTY
( 4.a )
Uncertain
( 4.b )
Before Treatment 
Start
( 4.c )
Uncertain
( 4.c )
After Treatment Start
YYYY > TRTY
( 3.a )
After Treatment Start
( 3.b )
After Treatment Start
( 3.b )
After Treatment Start
( 3.b )
After Treatment Start
Before imputing AE start date, find the AE start reference date. 
1. If the imputed AE end date is complete and the imputed AE end date < treatment start date 
then AE start reference date = min(informed consent date, earliest visit date).
2. Else AE start reference date = treatment start date
Impute AE start date -
1. If the AE start date year value is missing, the date uncertainty is too high to impute a rational 
date.  Therefore, if the AE year value is missing, the imputed AE start date is set to NULL.
2. If the AE start date year value is less than the treatment start date year value, the AE started 
before treatment.  Therefore:
a.
If AE month is missing, the imputed AE start date is set to the mid-year point 
(01JulYYYY).
b. Else if AE month is not missing, the imputed AE start date is set to  the mid-month 
point (15MONYYYY).
3. If the AE start date year value is greater than the treatment start date year value, the AE 
started after treatment.  Therefore:
a.
If the AE month is missing, the imputed AE start date is set to the year start point 
(01JanYYYY).


Novartis
For business use only
Page 53
SAP
26-Aug-2019 (10:13)
CQAW039A2314
b. Else if the AE month is not missing, the imputed AE start date is set to the later of 
(month start point (01MONYYYY), AE start reference date + 1 day).
4. If the AE start date year value is equal to the treatment start date year value:
a.
And the AE month is missing the imputed AE start date is set to the AE reference 
start date + 1 day.
b. Else if the AE month is less than the treatment start month, the imputed AE start 
date is set to the mid-month point (15MONYYYY).
c.
Else if the AE month is equal to the treatment start date month or greater than the 
treatment start date month, the imputed AE start date is set to the later of (month 
start point (01MONYYYY), AE start reference date + 1 day).
If complete imputed AE end date is available and the imputed AE start date is greater than the 
imputed AE end date, then imputed AE start date should be set to the imputed AE end date.
6.1.2
Prior and Concomitant medication date imputation
6.1.2.1
Concomitant medication end date imputation
Rules for imputing the CM end date are stated below. Date of last contact in the study has been 
defined as in Section 2.1.1.6. Concomitant medication end dates will not be imputed for 
ongoing records.
1. If CM end day is missing and CM month/year are non-missing then impute CM day as 
the minimum of  date of last contact and the last day of the month.
2. If CM end day/month are missing and CM year is non-missing then impute CM day as 
the minimum of  date of last contact and the end of the year (31DECYYYY).
3. If CM day/month/year is missing then use the date of last contact + 1 day as the imputed 
CM end date. 
4. If imputed CM end date is less than the CM start date, use the CM start date as the 
imputed CM end date.
6.1.2.2
Concomitant medication start date imputation
Rules for imputing the CM start date:
The following table explains the notation used in the logic matrix. Please note that missing start dates 
will not be imputed.
Day
Month
Year
Partial CMD Start Date
Not used
MON
YYYY
Treatment Start Date
Not used
TRTM
TRTY
The following matrix explains the logic behind the imputation.


Novartis
For business use only
Page 54
SAP
26-Aug-2019 (10:13)
CQAW039A2314
MON
MISSING
MON < TRTM
MON = TRTM
MON > TRTM
YYYY
MISSING
( 1 )
Uncertain
( 1 )
Uncertain
( 1 )
Uncertain
( 1 )
Uncertain
YYYY < TRTY
( 2.a ) 
Before Treatment Start
( 2.b )
Before Treatment Start
( 2.b )
Before Treatment Start
( 2.b )
Before Treatment Start
YYYY = TRTY
( 4.a )
Uncertain
( 4.b )
Before Treatment Start
( 4.a )
Uncertain
( 4.c )
After Treatment Start
YYYY > TRTY
( 3.a )
After Treatment Start
( 3.b )
After Treatment Start
( 3.b )
After Treatment Start
( 3.b )
After Treatment Start
1. If the CM start date year value is missing, the imputed CM start date is set to one day 
prior to treatment start date. 
2. If the CM start date year value is less than the treatment start date year value, the CM 
started before treatment.  Therefore:
a.
If the CM month is missing, the imputed CM start date is set to the mid-year 
point (01JulYYYY).
b. Else if the CM month is not missing, the imputed CM start date is set to the mid-
month point (15MONYYYY).
3. If the CM start date year value is greater than the treatment start date year value, the 
CM started after treatment. Therefore:
a.
If the CM month is missing, the imputed CM start date is set to the year start 
point (01JanYYYY).
b. Else if the CM month is not missing, the imputed CM start date is set to the 
month start point (01MONYYYY).
4. If the CM start date year value is equal to the treatment start date year value:
a.
And the CM month is missing or the CM month is equal to the treatment start 
date month, then the imputed CM start date is set to one day prior treatment start 
date.
b. Else if the CM month is less than the treatment start date month, the imputed 
CM start date is set to the mid-month point (15MONYYYY).
c.
Else if the CM month is greater than the treatment start date month, the imputed 
CM start date is set to the month start point (01MONYYYY).
If complete imputed CM end date is available and the imputed CM start date is greater than the 
(imputed) CM end date, then imputed CM start date should be set to the (imputed) CM end 
date.


Novartis
For business use only
Page 55
SAP
26-Aug-2019 (10:13)
CQAW039A2314
6.2
Statistical models
6.2.1
Primary analysis
6.2.1.1
Bayesian hierarchical random effects Poisson model
To perform the specified multiple imputation, a Bayesian random effects Poisson model will 
be fitted using Markov-Chain-Monte-Carlo (MCMC) methods. This model will be fitted to 
data that will have up to two records per patient:
1. a record for the time during which the patient is receiving double-blind study 
medication and
2. a record for any observed post-treatment follow-up during the double-blind study 
period after discontinuation of study treatment.
The linear predictor for the log-mean rate of the Poisson random effects model is as follows:
!
intercept,
!
a random subject effect on the intercept,
!
treatment assigned at the time of randomization as a factor with the following levels
o
placebo or discontinued double-blind treatment,
o
QAW039 150 mg QD and
o
QAW039 450 mg QD,
!
randomization strats as  factors,
!
natural logarithm of the number of exacerbations in the previous year that required 
treatment per protocol  – using log(0.5) if there was no exacerbation – as a covariate,
!
baseline FEV1 as a covariate, and
!
the log follow-up in the time period covered by the record  as an offset variable. This 
follow-up is either the on-treatment follow-up (during which the patient received 
double-blind study medication) for the first type of record for a patient, or the post-
treatment follow-up during the double-blind study period for the second type of 
record for a patient.
If the baseline FEV1 value is missing, then mean of the non-missing baseline FEV1 values 
are considered. If the number of exacerbations in the previous year that required treatment 
per protocol is missing, then median of the non-missing values are considered.
The random subject effect on the intercept is the logarithm of a gamma distributed random 
variable with mean 1. The exponentiated random subject effects exp(Ui)|κ are independent 
identically distributed random variables that follow a gamma distribution with shape 
parameter 1/κ and rate parameter 1/κ, where κ>0 is the dispersion parameter of the model. To 
improve the convergence of the MCMC sampler and to avoid numerical issues, we specify 
the random subject effect in terms of a latent random variable vi, which satisties ui:=vi × 
exp(0.5 × log κ) + log κ subject i=1,…,n. The log-probability density for the vi is given by 
f(v1,…,vn;a)  - n×(lgamma(a) + log(a)/2) + ∑i=1,...,n(vi×√a -exp(vi/√a)),
where lgamma is the log-gamma function and a:=exp(-log κ). 
Note that, if the model terms for a single subject did not differ between the records for a 
subject, this Poisson random effects model is a negative binomial model. The only difference 


Novartis
For business use only
Page 56
SAP
26-Aug-2019 (10:13)
CQAW039A2314
is that the Poisson random effects model explicitly includes random subject effects, which 
makes it easier to predict future time periods for the same subjects. In a negative binomial 
model these random effects have been integrated out, which has computational advantages.
6.2.1.2
Generating the multiple imputations
For patients, for whom some follow-up needs to be imputed, we then generate Poisson 
distributed random variables with a rate parameter based on the posterior of the Bayesian 
hierarchical model described above. The following two changes are made:
1. The offset becomes the logarithm of the follow-up time, for which data needs to be 
imputed for a patient. 
2. The coefficient for the treatment effect will depend on the assumptions we wish to 
make in the imputation. In the primary analysis this differs from patient to patient 
depending on the reason for treatment discontinuation:

For a jump-to-reference imputation (J2R), we base it on the posterior for the 
placebo effect. In the primary analysis a J2R imputation will be used for 
patients that discontinue treatment and are lost to follow-up due to (or 
following a treatment discontinuation due to) lack of efficacy, adverse events 
or death.

For a missing-at-random (MAR) imputation, we based it on the posterior of 
the coefficient for the treatment group the patient is in. In the primary analysis 
a MAR imputation will be applied for patients being lost to follow-up for 
reasons likely to be unrelated to study treatment (e.g. lost to follow-up, 
withdrew consent).

For a tipping point analysis, we subtract a fixed value from the MCMC 
samples for the treatment group based on which we are imputing.
For each of the MCMC samples, we generate one imputation based on the sample from the 
posterior for the model parameters in that MCMC sample. The imputed datasets consist of 
these imputed number of extra events added to the observed number of events per patient. For 
all imputed datasets, the observed plus imputed follow-up is either the actual follow-up (for 
patients that completed the trial) or 1 year.
For the inferential analyses involving imputation in high eosinophil population (eosinophil 
count ≥ 250 cells/µl at screening), the imputation will be based on the subset of patients in 
the high eosinophil population only. 
6.2.1.3
Analyzing the imputed data
The primary analysis model is fitted to each of the imputed datasets. The resulting log-mean 
rates and log-rate ratios – and the associated standard errors – will be combined across the 
imputations using Rubin’s rule.


Novartis
For business use only
Page 57
SAP
26-Aug-2019 (10:13)
CQAW039A2314
6.2.2
Key secondary analysis
The key secondary variables of this study are pre-dose FEV1, AQLQ+12 and ACQ-5 at the 
end of the 52 week treatment epoch. The imputation and analysis of these key secondary 
variables will be implemented using the “five macros” available from www.missingdata.org.uk
(for a full description see Carpenter et al (2013)). The purpose and activities of each of the five 
macros  is described below.

Part1A declares the parameter estimation model and checks consistency with the 
input dataset. It builds a master dataset which holds details of the current job and also 
builds indexes for the classification variables, which may be either numeric or 
character.

Part1B fits the parameter estimation model using the MCMC procedure and draws a 
pseudo-independent sample from the joint posterior distribution for the linear 
predictor parameters and the covariance parameters.

Part2A calculates the predicted mean under MAR, and under MNAR for each subject 
based on their withdrawal pattern once for each draw of the linear predictor parameter 
estimates. The choice of MNAR is controlled by the method used, which may vary 
from subject to subject.

Part2B imputes the intermediate missing values using MAR and the trailing missing 
values using MNAR, by deriving the conditional distribution for the missing values 
conditional on the observed values and covariates, using the appropriate sampled 
covariance parameter estimates.

Part3 carries out a univariate ANOVA analysis at selected time points usually based 
on the same covariates as the parameter estimation model. It then combines the least-
squares means and their differences using the MIANALYZE procedure to provide 
final results.
This is example code to implement the analysis of ACQ-5:
%part1A(Jobname=acqs
,Data=acqtests
,Subject=subjid
,Response=aval
,Time=visit
,Treat=trt01pn
,Covbytime= baseacq baseaqlq basefev
,Catcov=stratum
);
where subjid
= subject identifier
aval
= change from baseline in ACQ-5 value at a  visit during the treatment 
epoch
visit
= treatment period visit number
trt01pn
= planned treatment
baseacq
= baseline ACQ-5 value
baseaqlq = baseline AQLQ+12 value


Novartis
For business use only
Page 58
SAP
26-Aug-2019 (10:13)
CQAW039A2314
basefev
= baseline FEV1 value
             stratum = randomization strata (peripheral blood eosinophil counts at Visit 1 for 
analyzing overall population(<250 cells/µl or ≥250 cells/µl), patient age (<18 years or 
≥18 years), use or non-use of oral corticosteroids as part of SoC asthma therapy, 
region)
%part1B(Jobname=acqs
,Ndraws=1000
,thin=750
,seed=12345
);
%part2A(Jobname=acqs_J2R
,inname=acqs
    ,methodV=Mymethod
,refV=Myreference
    );
where Mymethod
= Method used to impute missing data: J2R for QAW patients who 
discontinued treatment for an adverse event, death, physician decision or 
subject/guardian decision and MAR otherwise.
Myreference
= Placebo
%part2B(Jobname=acqs_J2R
,seed=832216);
%part3(Jobname=acqs_J2R
,ANTreat=trt01pn
       ,LsmOpt=OM
,label=Mixed MAR and J2R);
Results will be presented with Least Squares Mean (LSM) and standard errors (SE) for 
treatment effects and LSM, SE, associated two-sided 95% confidence interval, and two-sided 
p-value for all relevant treatment contrasts.
6.3
Background asthma therapy
6.3.1
Prednisone equivalent OCS doses
Prednisone 5 mg is comparable to 
Drug
Dose
Conversion factor
Deflazacort
6 mg
0.83
Triamcinolone
4 mg
1.25


Novartis
For business use only
Page 59
SAP
26-Aug-2019 (10:13)
CQAW039A2314
Dexamethasone
0.75 mg
6.67
Methylprednisolone
4 mg
1.25
Prednisolone
5 mg
1
Betamethasone
0.75 mg
6.67
Prednisone
5 mg
1
Hydrocortisone
20 mg
0.25
Fluocortolone
5 mg
1
Meprednisone
4 mg
1.25
6.4
Rule of exclusion criteria of analysis sets 
The following protocol deviations will lead to exclusion of patients from the per-protocol set, 
FAS, SCR or safety set: 
Table 6-1
Protocol deviations that cause subjects to be excluded
Devation 
ID 
Description of Deviation
Exclusion from Analyses
COMD02
Prohibited asthma related 
ConMed during run-in and 
treatment epoch 
Exclude from PPS
EXCL12
Patient received high dose
Inhaled Corticosteroids 
(ICS) prior to Visit 1 
without Long-acting 
inhaled Beta-2 agonists 
(LABA)  or alternate 
therapy.
Exclude from PPS
EXCL22
    Patient receiving 
maintenance oral 
corticosteroids 3 months 
prior to Visit 1 and stable 
for 4 weeks prior to Visit 1, 
however without LABA 
(bid.) or alternate therapy
Exclude from PPS
EXCL25
Patient has a smoking 
history of > 10 pack years
Exclude from PPS
EXCL26
Patient had an asthma 
exacerbation within 6 
weeks prior to Visit 1
Exclude from PPS
EXCL27
Respiratory Tract Infection 
or asthma worsening 
within 4 weeks prior to V1.
Exclude from PPS
EXCL29
Other investigational drug 
used within 30 days or 5 
half-lives prior to 
Screening
Exclude from PPS
EXCL45
Prohibited Asthma 
Conmed taken during 
Run-In or treatment 
period.
Exclude from PPS


Novartis
For business use only
Page 60
SAP
26-Aug-2019 (10:13)
CQAW039A2314
INCL04
Reversibility test is 
negative or missing or not 
performed as per protocol 
OR Hyperreactivity test is 
negative or missing or not 
performed as per protocol
Exclude from PPS
INCL05
Did not sign informed 
consent
Exclude from all analyses 
sets
INCL08
ACQ-5 score < 1.5 or 
missing
Exclude from PPS
INCL15
Patient did not have at 
least 2 asthma 
exacerbation(s) within 12 
months prior to Visit 1 that 
required treatment with 
systemic corticosteroids or 
ER or hospitalization
Exclude from PPS
COMD06
Patient used prohibited 
asthma related ConMed
during run-in and 
treatment epoch according 
to Protocol Version 2
Exclude from PPS
INCL23
Patient received medium 
or high dose ICS prior to 
Visit 1 which was not 
taken in combination with 
LABA or LAMA or LTRA or 
Theophylline or their 
combinations  as required 
per Protocol v03.
Exclude from PPS
INCL24
Patient was not receiving 
medium or high dose 
Inhaled corticosteroids 
(ICS) prior to Visit 1 and 
throughout the study as 
required under protocol 
version 03.
Exclude from PPS
7
Reference
Akacha, Mouna, and Emmanuel O. Ogundimu. "Sensitivity analyses for partially observed 
recurrent event data." Pharmaceutical statistics 15.1 (2016): 4-14.
Barnard J, Rubin D (1999) Small-sample degrees of freedom with multiple imputation. 
Biometrika; 86:948–955.
Bartlett J W (2018) Covariate adjustment and estimation of mean response in randomised trials. 
Pharmaceutical statistics; 17(5): 648–666.
Bretz F, Maurer W, Brannath W et al. (2009) A graphical approach to sequentially rejective 
multiple test procedures. Statistics in Medicine; 28(4): 586-604.


Novartis
For business use only
Page 61
SAP
26-Aug-2019 (10:13)
CQAW039A2314
Carpenter JR, Roger JH and Kenward MG (2013) Analysis of Longitudinal Trials with 
Protocol Deviation: A Framework for Relevant, Accessible Assumptions, and Inference via 
Multiple Imputation. Journal of Biopharmaceutical Statistics, 23:6, 1352-1371
Committee for Medicinal Products for Human Use (2010) Guideline on Missing Data in 
Confirmatory Clinical Trials
Cook, Richard J., and Jerald F. Lawless. The statistical analysis of recurrent events. Springer, 
2007.
Efron, B. (1977), “The Efficiency of Cox’s Likelihood Function for Censored Data,” Journal of the 
American Statistical Association, 72, 557–565.
Haldar P, Brightling CE, Hargadon B et al. (2009) Mepolizumab and exacerbations of 
refractory eosinophilic asthma. N Engl J Med.; 360(10):973-84.
Juniper EF, Guyatt GH, Willan A, Griffith LE. Determining a minimal important change in a 
disease-specific quality of life instrument. J Clin Epidemiol 1994; 47: 81-87.
Juniper EF, Bousquet J, Abetz L et al., GOAL Committee (2006) Identifying ‘well-controlled’ 
and ‘not well-controlled’ asthma using the Asthma Control Questionnaire. Respir Med; 100: 
616- 621.
Keene, O. N., Jones, M. R., Lane, P. W., & Anderson, J. (2007) Analysis of exacerbation 
rates in asthma and chronic obstructive pulmonary disease: example from the TRISTAN 
study. Pharmaceutical statistics; 6(2): 89-97.
Keene ON, Calverley PM, Jones PW, Vestbo J, Anderson JA (2008) Statistical analysis of 
exacerbation rates in COPD: TRISTAN and ISOLDE revisited. Eur Respir J; 32: 17–24.
Keene ON, Roger JH, Hartley BF and Kenward MG (2014) Missing data sensitivity analysis 
for recurrent event data using controlled imputation. Pharmaceut. Statist.; 13: 258–264.
Liu et al (2006) Confidence intervals for an exposure adjusted incidence rate difference with 
applications to clinical trials. Stat Med. 2006 Apr 30;25(8):1275-86.
Nelson, W (1995) Confidence Limits for Recurrence Data—Applied to Cost or Number of 
Product Repairs. Technometrics; 37: 147–157.
Ortega H, Liu MC, Pavord ID et al. (2014) Mepolizumab treatment in patients with severe 
eosinophilic asthma. N Engl J Med; 371(13): 1198-1207.
Pavord ID, Korn S, Howarth P et al. (2012) Mepolizumab for severe eosinophilic asthma 
(DREAM): a multicenter, double-blind, placebo-controlled trial. Lancet; 380: 651-659.
Ratitch, B., O'Kelly, M., & Tosiello, R. (2013) Missing data in clinical trials: from clinical 
assumptions to statistical analysis using pattern mixture models. Pharmaceutical statistics, 
12(6), 337-347.
Woodruff  PG, Modrek B, Choy DF et al. (2009) T-helper type 2-driven inflammation 
defines major subphenotypes of asthma. Am J Respir Crit Care Med; 180(5):388-95.