Conditions: Asthma
Keywords: Asthma QAW039 allergic asthma allergy triggered asthma reactive asthma asthma attack difficulty breathing
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2538
Healthy volunteers: no

Brief summary:
This study was a 2-treatment period, randomized, multicenter parallel-group study. The overall purpose of this study was to provide long- term safety data for fevipiprant (QAW039) (Dose 1 and Dose 2), compared with placebo, when added to the Global Initiative for Asthma (GINA) steps 3, 4, and 5 standard-of-care (SoC) asthma therapy (GINA 2016), in patients with moderate-to- severe asthma.

The purpose of this study was to provide long-term safety data for QAW039 150 mg once daily and 450 mg once daily, compared with placebo, when added to GINA steps 3, 4, and 5 standard-of-care asthma therapy (GINA 2020) in adult and adolescent (≥12 years) patients with moderate-to-severe asthma. The study included 2 cohorts of patients:

1. Rollover patients who had completed any of the four Phase 3 pivotal efficacy studies with QAW039 (QAW039A2307, QAW039A2314, QAW039A2316, or QAW039A2317, hereafter referred to as Studies A2307, A2314, A2316, and A2317), thus providing data for a longer duration of exposure, and
2. New patients who had not previously participated in a study of QAW039, permitting an increase in the number of patients with long-term exposure to QAW039.

By including these 2 categories of patients, the total number of patients treated with QAW039 as well as the duration of exposure to QAW039 treatment was substantially increased, supporting evaluation of the safety profile of QAW039.

Detailed description:
The study comprised 2-treatment period. Treatment Period 1 was a 52-week, double-blind treatment period in which QAW039 450 mg or 150 mg or placebo was added to standard-of-care asthma therapy according to GINA guidelines. Treatment Period 2 was an optional 104-week, single-blind treatment period in which patients received QAW039 450 mg or 150 mg or placebo added to standard-of-care asthma therapy according to GINA guidelines.

Arms:
arm 1: QAW039 Dose 1 once daily arm 2: QAW039 Dose 2 once daily arm 3: Placebo once daily

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

Protocol document:
Prot_001.pdf: 
Global Clinical Development - General Medicine 
QAW039/Fevipiprant
Clinical Trial Protocol CQAW039A2315 / NCT03052517 
A 2-treatment period, randomized, placebo-controlled, 
multicenter parallel-group study to assess the safety of 
QAW039 when added to existing asthma therapy in GINA 
steps 3, 4 and 5 patients with uncontrolled asthma
Document type:
Clinical Trial Protocol
EUDRACT number:
2016-001560-11
Version number:
v01 Clean
Clinical trial phase:
III
Release date:
17-Jan-2018
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 3.3 (February 2017)


Novartis
Confidential
Page 2
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................10
Amendment 1 ...........................................................................................................................12
Protocol summary..............................................................................................................15
1
Introduction .......................................................................................................................20
1.1
Background............................................................................................................20
1.2
Purpose ..................................................................................................................21
2
Study objectives and endpoints .........................................................................................21
2.1
Primary objective(s)...............................................................................................21
2.2
Secondary objective(s)...........................................................................................22
22
3
Investigational plan ...........................................................................................................23
3.1
Study design...........................................................................................................23
3.2
Rationale for study design .....................................................................................25
3.3
Rationale for 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..........................................................................................................................29
4.1
Inclusion criteria ....................................................................................................30
4.2
Exclusion criteria...................................................................................................31
5
Treatment...........................................................................................................................36
5.1
Study treatment......................................................................................................36
5.1.1
Investigational and control drugs..........................................................36
5.1.2
Additional treatment..............................................................................36
5.2
Treatment arms......................................................................................................36
5.3
Treatment assignment and randomization.............................................................37
5.4
Treatment blinding.................................................................................................39
5.5
Treating the patient................................................................................................40
5.5.1
Patient numbering, ................................................................................40
5.5.2
Dispensing the study drug.....................................................................40
5.5.3
Handling of study and additional treatment..........................................41


Novartis
Confidential
Page 3
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
5.5.4
Instructions for prescribing and taking study treatment........................41
5.5.5
Permitted dose adjustments and interruptions of study treatment ........43
5.5.6
Rescue medication ................................................................................43
5.5.7
Background therapy ..............................................................................44
5.5.8
Concomitant medication .......................................................................44
5.5.9
Prohibited medication ...........................................................................46
5.5.10
Emergency breaking of assigned treatment code..................................46
5.6
Study Completion and Discontinuation.................................................................47
5.6.1
Study completion and post-study treatment..........................................47
5.6.2
Discontinuation of Study Treatment.....................................................48
5.6.3
Withdrawal of informed consent...........................................................49
5.6.4
Lost to follow-up...................................................................................49
5.6.5
Early study termination by the sponsor.................................................50
6
Visit schedule and assessments .........................................................................................50
6.1
Information to be collected on screening failures..................................................74
6.2
Patient demographics/other baseline characteristics .............................................74
6.3
Treatment exposure and compliance .....................................................................74
6.4
Efficacy..................................................................................................................75
6.4.1
Spirometry (FEV1)................................................................................75
6.4.2
Asthma exacerbations ...........................................................................75
6.4.3
Appropriateness of efficacy assessments..............................................76
6.5
Safety.....................................................................................................................76
6.5.1
Physical examination ............................................................................76
6.5.2
Vital signs..............................................................................................77
6.5.3
Height and weight .................................................................................77
6.5.4
Laboratory evaluations..........................................................................77
6.5.5
Electrocardiogram (ECG) .....................................................................78
6.5.6
Pregnancy and assessments of fertility .................................................79
6.5.7
Appropriateness of safety measurements..............................................79
6.6
Other assessments..................................................................................................79
6.6.1
Clinical Outcome Assessments (COAs) ...............................................79
80
80
80
81
7
Safety monitoring..............................................................................................................81


Novartis
Confidential
Page 4
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
7.1
Adverse events.......................................................................................................81
7.2
Serious adverse events...........................................................................................82
7.2.1
Definition of SAE .................................................................................82
7.2.2
SAE reporting........................................................................................83
7.3
Liver safety monitoring .........................................................................................84
7.4
Renal safety monitoring.........................................................................................85
7.5
Idiosyncratic drug reactions monitoring................................................................85
7.6
Reporting of study treatment errors including misuse/abuse ................................86
7.7
Pregnancy reporting...............................................................................................86
8
Data review and database management.............................................................................87
8.1
Site monitoring ......................................................................................................87
8.2
Data collection.......................................................................................................87
8.3
Database management and quality control............................................................88
8.4
Data Monitoring Committee..................................................................................88
8.5
Adjudication Committee........................................................................................89
9
Data analysis......................................................................................................................89
9.1
Analysis sets ..........................................................................................................89
9.2
Patient demographics and other baseline characteristics.......................................90
9.3
Treatments .............................................................................................................90
9.4
Analysis of the primary variable(s) .......................................................................90
9.4.1
Variables ...............................................................................................91
9.4.2
Statistical model, hypothesis, and method of analysis..........................91
9.4.3
Handling of missing values/censoring/discontinuations.......................92
92
9.5
Analysis of secondary variables ............................................................................93
9.5.1
Efficacy variables..................................................................................93
9.5.2
Safety variables .....................................................................................93
95
.95
95
96
96
96
9.7
Interim analyses.....................................................................................................97
9.8
Sample size calculation..........................................................................................98
10 Ethical considerations......................................................................................................101


Novartis
Confidential
Page 5
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
10.1
Regulatory and ethical compliance......................................................................101
10.2
Informed consent procedures...............................................................................101
10.3
Responsibilities of the investigator and IRB/IEC................................................101
10.4
Publication of study protocol and results.............................................................102
10.5
Quality Control and Quality Assurance...............................................................102
11 Protocol adherence ..........................................................................................................102
11.1
Protocol Amendments .........................................................................................102
12 References .......................................................................................................................103
13 Appendix 1: Clinically notable laboratory values and vital signs...................................106
14 Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements...................................................................................................................107
15 Appendix 3: List of IDRs for investigators .....................................................................109
16 Appendix 4: Spirometry Guidance..................................................................................110
16.1
References for appendix ......................................................................................112
17 Appendix 5: Specific Renal Alert Criteria and Actions..................................................113
18 Appendix 6: Asthma Control Questionnaire ...................................................................114
List of tables
Table 5-1
Randomized Allocation of Patients into Treatment groups..................39
Table 5-2
Medications allowed under certain conditions......................................44
Table 5-3
Medications to be withheld prior to spirometry....................................45
Table 5-4
Prohibited medications..........................................................................46
Table 6-1
Assessment schedule.............................................................................53
Table 9-1 
Assumed placebo event rates for power calculations ...........................99
Table 9-2
Power (%) for a non-multiplicity adjusted confidence interval to 
exclude no-difference versus placebo for the primary safety 
variables ..............................................................................................100
Table 9-3
power (%) for a non-multiplicity adjusted confidence interval to 
exclude no-difference versus placebo for the primary safety 
variables based on different sample size scenarios.............................100
Table 14-1
Liver Event and Laboratory Trigger Definitions ................................107
Table 14-2
Follow Up Requirements for Liver Events and Laboratory Triggers.107
Table 15-1
Definition of potential idiosyncratic drug reactions............................109
Table 17-1
Specific Renal Alert Criteria and Actions...........................................113


Novartis
Confidential
Page 6
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
List of figures
Figure 3-1
Study design..........................................................................................24


Novartis
Confidential
Page 7
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
List of abbreviations
ACQ-5
Asthma Control Questionnaire 5
ADME
Absorption, distribution, metabolism, and excretion 
AE
Adverse Event
AHR
Airway hyper-responsiveness
ALT
Alanine Aminotransferase
AQLQ
Asthma Quality of Life Questionnaire 
AST
Aspartate Aminotransferase
ATC
Anatomical therapeutic chemical
AUC
Area under the curve
AV block
Atrioventricular block
ATS/ERS
American Thoracic Society/European Respiratory Society
BMI
Body Mass Index
BUN
Blood urea nitrogen
CFR
Code of Federal Regulations 
CHMP
Committee for Medicinal Products for Human Use
CK
Creatine Kinase
CK-MB
Test measuring the amount of an isoenzyme of creatine kinase (CK) in your blood
Cmax
Maximum concentration 
COA
Clinical Outcome Assessments
CPO
Country Pharma Organization
CQA
Compliance Quality Assurance
CRA
Clinical Research Associate
CRF
Case Report/Record Form (paper or electronic)
CRTh2
Chemoattractant receptor-homologous molecule expressed on Th2
CRO
Contract Research Organization
CT scan
Computed tomography scan
DAR
Dose administration record
DK-PGD2
13, 14-Dihydro-15-keto-prostaglandin D2
DMC
Data Monitoring Committee
DS&E
Drug Safety & Epidemiology
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic Data Capture
eGFR
Estimated glomerular filtration rate
EMA
European Medicines Agency
EU
European Union
FAS
Full analysis set
FCT
Film-coated Tablets
FDA
Food and Drug Administration 
FEV1
Forced Expiratory Volume in 1 second


Novartis
Confidential
Page 8
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
GCP
Good Clinical Practice
GINA
Global Initiative for Asthma
GOLD
Global Initiative for Chronic Obstructive Lung Disease
HbA1C
Glycated hemoglobin
hCG
Human chorionic gonadotropin 
HFA
Hydrofluoralkane 
hsCRP
High reactive C-reactive protein
IB
Investigator Brochure
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ICS
Inhaled corticosteroids
IDR
Idiosyncratic drug reactions
IEC
Independent Ethics Committee
IgE
Immunoglobulin
IL-5
Interleukin 5
IN
Investigator Notification
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
Intrauterine device
IUS
Intrauterine system
LABA
Long-acting beta-agonists
LAMA
Long-acting Muscarinic Antagonist
LDH
Lactate dehydrogenase 
LFT
Liver function test 
LTRA
Leukotriene Receptor Antagonist
MAA
Marketing Authorization Application
MDRD
Modification of Diet in Renal Disease 
MedDRA
Medical dictionary for regulatory activities 
MID
Minimal important difference
MMRM
Mixed Model for Repeated Measures
MXR
Multixenobiotic resistance
NDA
New Drug Application
NP
New Patients not previously participating in a phase 3 study of QAW039
NYHA
New York Heart Association
OAT3
Organic Anion Transporters
OC/RDC
Oracle Clinical/Remote Data Capture 
OCS
Oral corticosteroids
PGD2
Prostaglandin D2
P-gp
P-glycoprotein 
POC
Proof of Concept
PP
Patients previously participating in a phase 3 study of QAW039
PRO
Patient Reported Outcome
QM
Quality management 


Novartis
Confidential
Page 9
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
QoL
Quality of Life
QTc
Corrected QT Interval
QTcF
QT interval corrected using Fridericia’s formula 
RAST
Radioallergosorbant Test
SABA
Short-acting beta-agonists
SAE
Serious Adverse Event
SAF
Safety Set
SCR
Screened set
SMQ
Standardized medical query
SoC
Standard of Care
SUSAR
Suspected Unexpected Serious Adverse Reactions
TD
Study Treatment Discontinuation
Th2
T helper type 2 
UGT
UDP-glucuronosyltransferase
UK
United Kingdom
ULN
Upper limit normal
UNS
Unscheduled 
WHO
World Health Organization 
WoC
Withdrawal of Consent
y-GT
Gamma-glutamyl transpeptidase


Novartis
Confidential
Page 10
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
Glossary of terms
Cohort 
A specific group of patients/subjects fulfilling certain criteria
Control drug
Drugs(s) used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or 
evaluate comparative effects of the investigational drug
Dosage
Dose of the study treatment given to the patient in a time unit (e.g. 100 
mg once a day, 75 mg twice a day)
Electrocardiography
Electrocardiography is the process of recording the electrical activity of 
the heart over a period of time using electrodes placed on the skin.
Enrollment
Point/time of patient entry into the study at which informed consent must 
be obtained (e.g. prior to starting any of the procedures described in the 
protocol)
Electronic Data Capture 
(EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical 
study data using data collection systems, such as Web-based 
applications, interactive voice response systems and clinical laboratory 
interfaces.
EDC includes the use of Electronic Case Report Forms (eCRFs) which 
are used to capture data transcribed from paper source forms used at 
the point of care.
Epoch (Period)
A portion of the study which serves a specific purpose. Typical epochs
and/or periods 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.”
Medication pack number
A unique identifier on the label of each investigational drug package
Part 
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: a 
single dose part and a multiple dose part, or a part in patients/subjects 
with established disease and in those with newly-diagnosed disease.
Patient/subject ID 
A unique number assigned to each patient upon signing the informed 
consent 
QAW039A
Fevipiprant
Fridericia’s Correction 
Formula
A formula which takes into account the physiologic shortening of the QT 
interval which occurs as the heart rate increases, permitting comparison 
of the QT interval across a range of rates.
Randomization number
A unique identifier assigned to each randomized patient, corresponding 
to a specific treatment arm assignment
Source Data/Document
Source data refers to the initial record, document, or primary location 
from where data comes. The data source can be a database, a dataset, 
a spreadsheet or even hard-coded data, such as paper or eSource.
Study drug/ treatment
Any single drug or combination of drugs administered to the patient as 
part of the required study procedures; includes investigational drug (s), 
placebo/comparator active drug run-ins or background therapy
Study Treatment 
Discontinuation (TD)
When the patient permanently stops taking study treatment prior to the 
defined study treatment completion date 


Novartis
Confidential
Page 11
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being 
tested in the study
Withdrawal of consent 
(WoC)
Withdrawal of consent from the study is defined as when a patient does 
not want to participate in the study any longer, and does not want any 
further visits or assessments, and does not want any further study 
related contact, and does not allow analysis of already obtained biologic 
material


Novartis
Confidential
Page 12
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
Amendment 1
Amendment rationale 
This protocol is being amended to remove references and discussions related to the Oral 
Corticosteroid Tapering Study (QAW039A2319), a Phase 3 study, which was cancelled due 
to business reasons before being initiated. The removal of references and analyses pertaining 
to QAW039A2319 required the following changes:
 

Updated Section 3.1 Study Design to remove the Oral Corticosteroid Tapering Study 
from the discussion involving the dose-response relationship;

Updated Section 3.3 Rationale for dose/regimen, route of administration and duration 
of treatment to remove the Oral Corticosteroid Tapering Study from the discussion 
involving the dose-response relationship;

Updated Section 5.3 Treatment assignment and randomization to remove the Oral 
Corticosteroid Tapering Study from the randomization scheme ;

Updated Table 5-1 titled Randomization Allocation of Patients into Treatment Groups 
to remove the Oral Corticosteroid Tapering Study from the randomization ratio

Updated Table 5-2 titled Medications allowed under certain conditions to remove
references medication requirements for patients entering the trial from the Oral 
Corticosteroid Tapering Study;

Updated Section 9.4.2 Statistical model, hypothesis, and method of analysis to remove 
the Oral Corticosteroid Tapering Study from the randomization stratum for the 
primary variables;

Updated Section 9.5.2 Safety variables to remove the Oral Corticosteroid Tapering 
Study from the randomization stratum for the secondary safety endpoints;
 
 

Updated sample size in the Protocol Summary and Section 9.8 Sample size 
calculations as the removal of the Oral Corticosteroid Tapering Study requires the 
addition of more patients

Updated Table 9-1 titled Assumed placebo event rates for power calculations and 
Table 9-2 titled Power (%) for non-multiplicity adjusted confidence interval to exclude 
no-difference versus placebo for the primary safety variables as the removal the Oral 
Corticosteroid Tapering Study changed power calculations.

Added Table 9-3 titled Power (%) for a non-multiplicity adjusted confidence interval 
to exclude no-difference versus placebo for the primary safety variables based on 
different sample size scenarios.


Novartis
Confidential
Page 13
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
Changes to the protocol
The described changes in the aforementioned amendment rationale are implemented 
throughout the protocol in the sections noted.
The opportunity was also taken to:

Within the Protocol Summary and Section 2.1, one of the primary objectives was 
modified to state “study treatment discontinuations due to treatment emergent AEs”. A 
patient may continue in the study after discontinuing study treatment. Therefore, the 
evaluation of treatment emergent AEs leading to study treatment discontinuations are 
more clinically relevant to the evaluation of drug safety.

In inclusion criterion 6b, FEV1 has been aligned with the core Phase 3 studies in 
which the lower limit of the percent predicted FEV1 was removed from the protocols  
(Protocol summary, Section 4.1 [inclusion criteria]).

Within the Protocol Summary, added a clarification HbA1c is a key safety assessment
for new patients since prior patients would have already met this inclusion criterion in 
the previous study.

Removal of the exclusion criteria within the Protocol Summary and Section 4.2 which 
stated “Patients who developed a condition during the prior phase 3 study of QAW039 
that would exclude them from participating in the study” as this was already addressed 
by inclusion criteria 3a which states “Patient is able to safely continue into the study as 
judged by the investigator”.

Clarified exclusion 4b which is listed within the Protocol Summary and Section 4.2 as 
the intent was to exclude randomized patients in order to prevent duplicate patients. 
The new text states “Patients who have participated in another study of QAW039 (i.e. 
- the patient was randomized into another study of QAW039”). 

Updated Section 3.6 Risks and Benefits in order to update the clinical experience and 
exposure provided in the latest Investigator’s Brochure.

Updated exclusion 17b in Section 4.2 to include allergic rhinitis as this could result in 
elevated eosinophils and is considered to be a common co-morbidity in patients with 
asthma. 

In Section 5.5.7 and Table 5-2, removal of text pertaining to the duration of a burst of 
rescue systemic corticosteroids as based on the investigator’s clinical judgement.

Added atopic dermatitis to Table 5-2 as this is another name for eczema. 

Within Table 5-4, corrected the minimum cessation of prohibited medications to start 
prior to Visit 1 which is consistent with the exclusion criteria in Section 4.2.

Allow for as needed use of antihistamines within Table 5-2 Medications allowed under 
certain conditions as this class of medications is commonly used to treat allergic 
rhinitis, a common co-morbidity in patients with asthma. 

Shorten minimum cessation prior to Visit 1 for monoclonal antibodies, investigational 
or approved, for the treatment of asthma (e.g., omalizumab) from 6 months to 5 
months within Table 5-2 Medications allowed under certain conditions. Cessation time 
for monoclonal antibodies used for the treatment of asthma was revised based on a 
review of the half-lives of all the monoclonal antibodies for the treatment of asthma 


Novartis
Confidential
Page 14
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
that became recently available.  Approximately 5 half-lives (i.e., 5 months) is the 
required cessation time for monoclonal antibodies to treat asthma.

Added Visit 401 clarification in Section 5.6.1 Study completion and post study 
treatment. Visit 401 can be conducted as a telephone visit only for males and females 
of non-child bearing potential.  Females of child-bearing potential must come to the 
clinic for a pregnancy test.

Reconciled discontinuation criterion in Section 5.6.2 with exclusion 7b by adding to 
the discontinuation criteria the following: “Patients with QTcF (Fridericia) ≥450 msec 
(male) or ≥460 msec (female) at Visit 201 on the ECG Analysis Report provided by 
the ECG core laboratory”.

Adjust the timing of the spirometry assessments so that assessments may be performed 
between 6:00 A.M. and 10:00 A.M. (± 1 hour) in Section 6 Visit schedule and 
assessments and Section 6.4.1. Based on investigator input, for practical reasons with 
visit scheduling and workflow, the time window to complete spirometry assessments 
was increased +/- 1 hour.

Allowing a single rescreening of new patients in Section 6 Visit schedule and 
assessments and Section 6.4.2. 

Clarified in Section 6 Visit schedule and assessments that the RAST/ImmunoCap Test 
is only required for patients who have not previously participated in a study of 
QAW039

Clarify in Section 6.4.1 [spirometry (FEV1 and FVC)] that the final spirometry 
assessments will be those provided by the spirometry overreaders of the central 
spirometry vendor.

Clarify in Section 6.5.5 [electrocardiogram (ECG)] that the final ECG assessments 
will be those provided by the central cardiologist ECG overreaders of the central 
vendor.

In Section 10.2 Informed consent procedures, added new Novartis template language

In Section 10.5 Quality Control and Quality Assurance, added new Novartis template 
language
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in the 
protocol amendment.


Novartis
Confidential
Page 15
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
Protocol summary
Protocol number
CQAW039A2315
Title
A 2-treatment period, randomized, placebo-controlled, multicenter parallel-
group study to assess the safety of QAW039 when added to existing 
asthma therapy in GINA steps 3, 4 and 5 patients with uncontrolled 
asthma.
Brief title
Study of safety of QAW039 in male and female patients (≥12 years) with 
asthma inadequately controlled with standard-of-care asthma therapy.
Sponsor and Clinical 
Phase
Novartis, Phase 3
Investigation type
Drug
Study type
Interventional
Purpose and rationale
The overall purpose of this study is to provide long-term safety data for 
fevipiprant (QAW039) (150 mg once daily and 450 mg once daily), 
compared with placebo, when added to the Global Initiative for Asthma 
(GINA) steps 3, 4, and 5 standard-of-care (SoC) asthma therapy (GINA 
2016), in adult and adolescent (≥12 years) patients with moderate-to-
severe asthma.
This study is a 2-treatment period, randomized, multicenter parallel-group 
study. Treatment Period 1 is a 52-week, double-blind treatment period in 
which QAW039 or placebo is added to GINA steps 3, 4 and 5 (SoC)
asthma therapy. Treatment Period 2 is an optional 104-week, single-blind 
treatment period in which patients will receive QAW039 or placebo added 
to GINA steps 3, 4 and 5 SoC asthma therapy.
The study will include patients who completed a prior Phase 3 study of 
QAW039, as well as patients who have not previously participated in a 
study of QAW039. The inclusion of patients who received QAW039 in a 
prior Phase 3 study into Study A2315 will lengthen the duration of exposure 
to QAW039. The inclusion of patients who have not previously participated 
in a study of QAW039, along with patients who received placebo in a prior 
Phase 3 study, will allow for an increase in the number of patients with 
long-term exposure to QAW039. Therefore, by including these 2 categories 
of patients, the total number of patients treated with QAW039, as well as 
the duration of exposure to QAW039 treatment, will be substantially 
increased, supporting evaluation of the safety profile of QAW039.
Primary Objective(s) 
Treatment Period 1 (double-blind, 52-week treatment period):
In patients with moderate-to-severe asthma receiving SoC asthma therapy, 
to evaluate the long-term safety of QAW039 (150 mg once daily and 450 
mg once daily), compared with placebo, as assessed by:

treatment emergent adverse events (AEs);

treatment emergent serious adverse events (SAEs); and

study treatment discontinuations due to treatment emergent AEs.
Treatment Period 1 and Treatment Period 2 combined:
In patients with moderate-to-severe-asthma receiving SoC asthma therapy, 
to evaluate the long-term safety of QAW039 (150 mg once daily and 450 
mg once daily), compared with placebo, as assessed by:

treatment emergent AEs


Novartis
Confidential
Page 16
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315

treatment emergent SAEs; and

study treatment discontinuations due to treatment emergent AEs.
Secondary Objectives
Treatment Period 1 (double-blind, 52-week treatment period):
In patients with moderate-to-severe asthma receiving SoC asthma therapy, 
to evaluate the long-term safety of QAW039 (150 mg once daily and 450 
mg once daily), compared with placebo, as assessed by:

the rate of patients with at least 1 treatment emergent AE by primary 
system organ class; and.

the rate of treatment emergent patient deaths and patient 
hospitalizations (any visit to the hospital requiring an overnight stay or 
an emergency room visit greater than 24 hours) due to an asthma 
exacerbation.
Treatment Period 1 and Treatment Period 2 combined:
In patients with moderate-to-severe-asthma receiving SoC asthma therapy, 
to evaluate the long-term safety of QAW039 (150 mg once daily and 450 
mg once daily), compared with placebo, as assessed by:
•
the rate of patients with at least 1 treatment emergent AE by primary 
system organ class; and
•
the rate of treatment emergent patient deaths and patient 
hospitalizations (any visit to the hospital requiring an overnight stay or 
an emergency room visit greater than 24 hours) due to an asthma 
exacerbation.
Study design
This study is a 2-treatment period, randomized, multicenter parallel-group 
safety study (Figure 3-1). Treatment Period 1 is a 52-week, double-blind 
treatment period in which QAW039 or placebo is added to GINA steps 3, 4 
and 5 SoC asthma therapy. Treatment Period 2 is an optional 104-week, 
single-blind treatment period in which patients will receive QAW039 or 
placebo added to GINA steps 3, 4 and 5 SoC asthma therapy.
The study will include the following: 

Screening Period of up to 2 weeks to assess eligibility of new patients; 

Treatment Period 1—double-blind period of 52 weeks

Treatment Period 2—single-blind period of 104 weeks; 

Follow-up Period of 4 weeks, investigational and drug-free, following 
the last dose of study drug.
Population
The study population will include males and females aged ≥12 years with 
inadequately controlled asthma on treatment at GINA steps 3, 4 and 5). 
Two categories of patients will be enrolled:

Patients who completed a prior Phase 3 study of QAW039 on active 
study treatment, and 

Patients with inadequately controlled asthma who have not previously 
participated in a study of QAW039.
Key Inclusion criteria
Patients completing a prior Phase 3 study of QAW039:

Informed consent and assent (if applicable). 

Completion of the Treatment Period (on blinded study drug) of a prior 
Phase 3 study of QAW039.

Patient is able to safely continue into the study as judged by the 
investigator.
Patients who have not previously participated in a study of QAW039:

Informed consent and assent (if applicable). 


Novartis
Confidential
Page 17
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315

Male and female patients at a minimum age of 12 years (or higher 
minimum age limit as allowed by health authority and/or ethics 
committee/institutional review board (IRB) approvals)

A diagnosis of asthma (according to GINA 2016) for a period of at least 
24 months prior to Screening visit (Visit 1).

Patients have been treated with GINA steps 4 or 5 standard-of-care 
(SoC) asthma therapy for at least 3 months prior to Visit 1. The doses 
must have been stable for at least 4 weeks prior to Visit 1.

Demonstration of inadequate control of asthma based on an Asthma 
Control Questionnaire (ACQ) score ≥1.5 at Visit 1.

For patients aged ≥18 years, forced expiratory volume in the first 
second (FEV1) of ≤85% of the predicted normal value for the patient, 
after withholding bronchodilators at Visit 1. 

For patients aged 12 to <18 years, FEV1 of ≤90% of the predicted 
normal value for the patient, after withholding bronchodilators at Visit 1.

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 performed according to 
American Thoracic Society/European Respiratory Society 
(ATS/ERS) (ATS/ERS 2005) or country-specific guidelines within 
the 2 years prior to Visit 1.

Documented evidence of a positive airways hyper-responsiveness
(AHR) test result within the 2 years prior to Visit 1, 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.
Key Exclusion criteria
Patients completing a prior phase 3 study of QAW039:

Pregnant or nursing (lactating) women.  

Women of child-bearing potential, defined as all women physiologically 
capable of becoming pregnant, unless they are using basic methods of 
contraception during dosing of study drug. 

Patients who did not complete the Treatment Period on blinded study 
drug of the prior phase 3 study of QAW039 they participated in.

Inability to comply with all study requirements.

Patients who experienced a serious and drug-related AE in the prior
phase 3 study of QAW039 they participated in.
Patients who have not previously participated in a study of QAW039:

Use of other investigational drugs within 5 half-lives of enrollment, or 
within 30 days, whichever is longer.

Patients who have participated in another trial of QAW039 (i.e., the 
patient was randomized into another study of QAW039).


Novartis
Confidential
Page 18
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315

Patients with a resting QTcF (Fridericia) ≥450 msec (male) or ≥460 
msec (female) at Visit 1 or Visit 201 on the ECG Analysis Report 
provided by the ECG core laboratory. 

Use of agents known to prolong the QT interval unless it can be 
permanently discontinued for the duration of the study. 

History of malignancy of any organ system (other than localized basal 
cell carcinoma of the skin or in situ cervical cancer), treated or 
untreated, within the past 5 years, regardless of whether there is 
evidence of local recurrence or metastases.

Pregnant or nursing (lactating) women.

Women of child-bearing potential, defined as all women physiologically 
capable of becoming pregnant, unless they are using basic methods of 
contraception during dosing of study drug. 

Patients who have a clinically significant laboratory abnormality at the 
Visit 1 laboratory test.

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 rifampin, probenecid, ritonavir and valproic acid (i.e.,
medications blocking several pathways important for the elimination of 
QAW039 [broad range UDP-glucuronosyltransferase (UGT) inhibition 
and/or inhibition of organic anion transporters (OAT3), OATP1B3, 
multixenobiotic resistance (MXR) and p glycoprotein (P-gp)].
Study treatment

QAW039 150 mg once daily

QAW039 450 mg once daily

Placebo to QAW039 150 mg once daily

Placebo to QAW039 450 mg once daily
Efficacy assessments 
None for primary or secondary objectives
Key safety assessments

AEs including SAEs

History and physical examinations

Vital signs

Hematology

Blood chemistry including but not limited to liver function tests (LFTs), 
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 for new patients)

Urinalysis and urine chemistry

Pregnancy tests (females of childbearing potential)

Electrocardiogram (ECGs)
Other assessments
, ACQ 
Data analysis
The primary variables for the study are the time-to-first treatment emergent 
AE, time-to-first treatment emergent SAE and the time-to-first treatment 
emergent AE leading to discontinuation from study treatment.
The primary variables will be analyzed on the safety set (SAF) by a 
stratified Cox regression model stratified by randomization stratum.

patients on QAW039 150 mg once daily treatment in Studies 
QAW039A2307 and QAW039A2314,


Novartis
Confidential
Page 19
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315

patients on QAW039 450 mg once daily treatment in Studies 
QAW039A2307 and QAW039A2314, 

patients on placebo in Studies QAW039A2307and QAW039A2314, 

patients on QAW039 150 mg once daily treatment in Studies 
QAW039A2316 and QAW039A2317,

patients on placebo in Studies QAW039A2316 and QAW039A2317, 

patients who have not previously participated in a study of QAW039, 
and treatment group, severity of asthma (GINA treatment steps 3, 4 and 5), 
and region as fixed class effects. 
Hazard ratios comparing QAW039 450 mg once daily, QAW039 150 mg 
once daily, placebo treatments with regard to time to first treatment 
emergent AEs and their corresponding 95% profile likelihood confidence 
intervals will be presented.
Safety summaries will be primarily based on on-treatment data for the 
safety set with selected tables also presented for all the data after the first 
intake of study drug, while all databased safety data will be listed.
Approximately 1000 patients are expected to complete prior QAW039 
Phase 3 studies and join the current Study A2315, based on the following 
assumptions.

In the prior QAW039 Phase 3 studies, 85% of randomized patients 
are expected to complete the prior study and eligible for 
participation in the current study.

It is estimated that 50% of those eligible patients from Studies 
A2307 and A2314 will enter in the current study

It is estimated that 25% of those eligible patients from Studies 
A2316 and A2317 will enter in the current study
In addition, new patients (i.e., patients who have not previously participated 
in a study of QAW039) will also be recruited according to local regulatory 
requirements in certain countries. It is currently anticipated that 
approximately 570 newly recruited patients will be enrolled in the current 
study. Thus, the anticipated total sample size of this study is approximately 
1,570 patients. This number of patients participating in the safety study will 
ensure 6-month exposure for each QAW039 dose clearly across the whole 
Phase 3 program in excess of the 300 to 600 patients (as well as in excess 
of 100 patients exposed for at least 1 year) suggested by ICH E1 at the 
time of the first regulatory submission for QAW039. The number of new 
patients and total patients may be subject to change depending on the 
actual participation of patients from prior QAW039 Phase 3 studies, the 
actual dropout rate in the current study and the local regulatory 
requirements.
Key words
Safety of QAW039, placebo-controlled, add-on to standard of care, 
uncontrolled severe asthma, female and male patients ≥12 years.


Novartis
Confidential
Page 20
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
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 (WHO) 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). 
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 may be 
more common 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 (OCS) and a number 
of biologic therapies (including anti-interlukin-5 (IL-5), anti-IL-5R, anti-immunoglobulin 
(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 2005; Nair, et al 2009).  
Consequently, there remains a need for well tolerated, easily-administered, anti-inflammatory 
therapies with the capability of supressing 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 (PGD2) which is one of the major prostanoid inflammatory mediators 
identified in asthma. Fevipiprant (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 T helper type 2 (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 Phase 2 studies of QAW039 (CQAWA2201, CQAWA2206, and CQAWA2208) in 
which QAW039 demonstrated an improvement in lung function (i.e., forced expiratory 
volume in 1 second [FEV1]) in patients across a range of asthma severities, an improvement 


Novartis
Confidential
Page 21
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
in asthma control in patients with more severe asthma, and a fall in sputum eosinophils of 
71% (geometric mean) in patients with severe asthma and sputum eosinophilia over 12 weeks 
of treatment. 
1.2
Purpose 
Study CQAWA2315 (also referred to as Study A2315 in this document) is a 2-treatment 
period, randomized, multicenter, parallel-group study. Treatment Period 1 is a 52-week, 
double-blind treatment period in which QAW039 or placebo is added to GINA steps 3, 4 and 
5 standard-of-care (SoC) asthma therapy. Treatment Period 2 is an optional 104-week, 
single-blind treatment period in which patients may elect to continue to receive QAW039 or 
placebo added to GINA steps 3, 4 and 5 SoC asthma therapy.
The purpose of this study is to provide long-term safety data for QAW039 (150 mg once daily 
and 450 mg once daily), compared with placebo, when added to GINA steps 3, 4, and 5 SoC 
asthma therapy (GINA 2016), in adult and adolescent (≥12 years) patients with moderate-to-
severe asthma. The study will include patients completing a prior Phase 3 study of QAW039, 
as well as patients who have not previously participated in a study of QAW039. The inclusion 
of patients who received QAW039 in a prior Phase 3 study into Study A2315 will lengthen 
the duration of exposure to QAW039. The inclusion of patients who have not previously 
participated in a study of QAW039, along with patients who received placebo in a prior Phase 
3 study, will allow for an increase in the number of patients with long-term exposure to 
QAW039. Therefore, by including these 2 categories of patients, the total number of patients 
treated with QAW039, as well as the duration of exposure to QAW039 treatment, will be 
substantially increased, supporting evaluation of the safety profile of QAW039.
2
Study objectives and endpoints
2.1
Primary objective(s)
Treatment Period 1 (double-blind, 52-week treatment period):
In patients with moderate-to-severe asthma receiving SoC asthma therapy, to evaluate the 
long-term safety of QAW039 (150 mg once daily and 450 mg once daily), compared with 
placebo, as assessed by:

treatment emergent adverse events (AEs);

treatment emergent serious adverse events (SAEs); and

study treatment discontinuations due to treatment emergent AEs.
Treatment Period 1 and Treatment Period 2 combined:
In patients with moderate-to-severe-asthma receiving SoC asthma therapy, to evaluate the 
long-term safety of QAW039 (150 mg once daily and 450 mg once daily), compared with 
placebo, as assessed by:

treatment emergent AEs

treatment emergent SAEs; and

study treatment discontinuations due to treatment emergent AEs.


Novartis
Confidential
Page 22
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
2.2
Secondary objective(s)
Treatment Period 1 (double-blind, 52-week treatment period):
In patients with moderate-to-severe asthma receiving SoC asthma therapy, to evaluate the 
long-term safety of QAW039 (150 mg once daily and 450 mg once daily), compared with 
placebo, as assessed by:

the rate of patients with at least 1 treatment emergent AE by primary system organ class; 
and

the rate of treatment emergent patient deaths and patient hospitalizations (any visit to the 
hospital requiring an overnight stay or an emergency room visit greater than 24 hours) due 
to an asthma exacerbation.
Treatment Period 1 and Treatment Period 2 combined:
In patients with moderate-to-severe-asthma receiving SoC asthma therapy, to evaluate the 
long-term safety of QAW039 (150 mg once daily and 450 mg once daily), compared with 
placebo, as assessed by:

the rate of patients with at least 1 treatment emergent AE by primary system organ class; 
and

the rate of treatment emergent patient deaths and patient hospitalizations (any visit to the 
hospital requiring an overnight stay or an emergency room visit greater than 24 hours) due 
to an asthma exacerbation.


Novartis
Confidential
Page 23
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
3
Investigational plan
3.1
Study design
This study is a 2-treatment period, randomized, multicenter parallel-group safety study 
(Figure 3-1). Treatment Period 1 is a 52-week, double-blind treatment period in which 
QAW039 or placebo is added to GINA steps 3, 4 and 5 SoC asthma therapy. Treatment 
Period 2 is an optional 104-week, single-blind treatment period in which patients will receive 
QAW039 or placebo added to GINA steps 3, 4 and 5 SoC asthma therapy. Note: For the 
purpose of this study, single-blind will mean investigators and patients will remain blinded 
while all Novartis personnel will be unblinded.
Eligible patients will include patients completing a prior Phase 3 study of QAW039, as well 
as patients who have not previously participated in a study of QAW039. 
Patients who successfully complete the treatment period of a prior Phase 3 study of QAW039 
will be permitted to enter Study A2315 directly upon the completion of the treatment period
of the prior study without completing an off drug follow-up period in the prior study. For 
these patients completing a prior Phase 3 study of QAW039, the last visit of the treatment 
period in the prior study and Visit 1 of Study 2315 will occur on the same day (i.e., on the last 
day of study drug treatment in the prior study). Additionally, for patients completing a prior 
Phase 3 study of QAW039, Visit 201 of Study 2315 will occur the following day (1 day after 
completion of the last visit of the treatment period of the prior study and Visit 1 of this study 
[Study A2315]) so there is not any interruption in study drug treatment. 
For patients who have not previously participated in a study of QAW039, Visit 1 and Visit 
201 of Study 2315 will occur approximately two weeks apart (i.e., Visit 201 should occur 
approximately two weeks after Visit 1 in Study 2315). This will allow for review of 
inclusion/exclusion criteria and laboratory values.
For Treatment Period 1 in Study A2315, an informed consent (and assent, if applicable) may 
be obtained within 14 days prior to or at Visit 1 and before any study-related assessments or 
procedures are performed. For patients who participated in a prior Phase 3 study, the consent 
(and assent, if appropriate) for Treatment Period 1 of Study A2315 may be obtained on the
last day of the treatment period of the prior Phase 3 study. 
For Treatment Period 2, an informed consent (and assent if applicable) will be obtained at 
Visit 301 for those patients agreeing to participate in this treatment period.
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 visits with spirometry 
(which includes Visit 1) (See Section 5.5.8).
The study will include the following:
Screening Period of up to 2 weeks to assess eligibility of new patients; 
Treatment Period 1—double-blind period of 52 weeks;
Treatment Period 2—single-blind period of 104 weeks; 
Follow-up Period of 4 weeks, investigational and drug-free, following last dose of study drug.


Novartis
Confidential
Page 24
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
Figure 3-1
Study design 
Note: As information becomes available from ongoing studies, a decision to proceed with one or both 
doses of QAW039 in either a controlled or an open label fashion may take place during the conduct of 
this study.
In Treatment Period 1, patients meeting eligibility criteria will be randomized to 1 of 3 
treatments (QAW039 150 mg once daily, QAW039 450 mg once daily, or placebo once daily) 
in an approximate ratio of 3:3:1. During Treatment Period 2, patients will continue receiving 
the same treatment they received in Treatment Period 1.
During Treatment Period 1, investigators, patients, and Novartis personnel monitoring the 
study will be blinded to study treatment. During Treatment Period 2, investigators and 
patients will continue to remain blinded to study treatment while Novartis personnel 
monitoring the study will not be blinded to treatment.
To support worldwide registration of QAW039 and to address health authority requests, there 
may be interim analyses of the study. Should an interim analysis occur during Treatment 
Period 1, Novartis personnel monitoring the study will be unblinded to study treatment; 
however, investigators and patients will continue to remain blinded to study treatment.
During Treatment Period 1 and Treatment Period 2, all patients will continue to receive SoC 
asthma therapy according to the investigator’s judgment. During Treatment Period 1 and 
Treatment Period 2 of this study, investigators may adjust a patient’s SoC asthma therapy 
according to their clinical judgment.
Clinic visits will be scheduled approximately 4 weeks after randomization, approximately 13 
weeks after randomization, and then at approximately 13-week intervals during the active-
treatment periods. A follow-up visit will occur approximately 4 weeks (i.e., approximately 30 


Novartis
Confidential
Page 25
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
days) following the last dose of study therapy to complete safety assessments and pregnancy 
testing (if applicable). Please refer to the assessment schedule (Table 6-1) for a list of 
procedures to be conducted at each visit.
Two doses of QAW039 (150 mg once daily and 450 mg once daily) have been included in 
this study (see Section 3.3 for a rationale supporting inclusion of these doses). The 2 doses of 
QAW039 included in this study are also being evaluated in other Phase 3 studies of QAW039 
in patients of various asthma severities. Two studies (CQAW039A2307 and QAW039A2314) 
will evaluate the dose-response relationship of QAW039 (dosed at 150 mg once daily and 450 
mg once daily) in patients with severe asthma. 
 
 
 
 
Periodic unblinded safety reviews by an independent Data Monitoring Committee (DMC) will 
be conducted during the course of the study.
3.2
Rationale for study design
Asthma is a chronic condition with medications used in patients over long periods of time; 
therefore, it is important to assess the safety profile of new therapies (such as QAW039) in 
this setting (i.e., during long-term treatment) to determine whether the safety profile of the 
respective therapy is maintained with long-term treatment. The purpose of this study is to 
provide long-term safety data for QAW039 (150 mg once daily and 450 mg once daily), 
compared with placebo, when added to GINA steps 3, 4, and 5 SoC asthma therapy (GINA 
2016), in adult and adolescent (≥12 years) patients with moderate-to-severe asthma.
The 2-treatment period, randomized, multicenter parallel-group, study design supports the 
assessment of the long-term safety profile of QAW039 as add-on treatment for patients with 
asthma otherwise treated according to GINA 2016 (steps 3, 4, and 5) guidelines. The study is 
randomized with a control arm (placebo plus standard of care), because a controlled study 
provides a better assessment of AE data than an open, uncontrolled study in which there is no 
ability to compare the AEs on treatment with a known control. Additionally, a control arm 
helps to reduce any potential bias in reporting of adverse events that would result from an 
open-label study design. The study duration of 3 years (156 weeks) will provide sufficient 
time for the assessment of the long-term safety profile of QAW039. 
Treatment Period 1 is a 52-week, double-blind treatment period. This treatment period will 
permit a blinded, controlled evaluation of 52-week safety data. Treatment Period 2 is an 
optional 104-week, single-blind treatment period which will provide longer-term safety data 
in a controlled, single-blind fashion. Given the long duration of the study and the inclusion of 
placebo (in addition to SoC asthma therapy) in Treatment Period 1 and Treatment Period 2, 
investigators will be permitted to adjust a patient’s SoC therapy according to their medical 
judgment during the study. 


Novartis
Confidential
Page 26
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
The study will include patients who completed a prior Phase 3 study of QAW039, as well as 
patients who have not previously participated in a study of QAW039. The inclusion of 
patients who received QAW039 in a prior Phase 3 study into Study A2315 will lengthen the 
duration of exposure to QAW039. The inclusion of patients who have not previously 
participated in a study of QAW039, along with patients who received placebo in a prior Phase 
3 study, will allow for an increase in the number of patients with long-term exposure to 
QAW039. Therefore, by including these 2 categories of patients, the total number of patients 
treated with QAW039, as well as the duration of exposure to QAW039 treatment, will be 
substantially increased, supporting evaluation of the safety profile of QAW039. 
The endpoints included in this study will assess parameters of the safety profile (treatment 
emergent AEs, discontinuations due to AEs, laboratory values, and ECGs) of QAW039 over 3 
years (156 weeks) of treatment. 
Screening Period
The screening period allows for assessment of patient entry criteria, for patients to become 
familiar with study measurements, and to collect baseline values. 
Treatment Period
During Treatment Period 1, patients will receive QAW039 150 mg once daily plus SoC 
asthma therapy, QAW039 450 mg once daily plus SoC asthma therapy, or placebo plus SoC 
asthma therapy, respectively, over a 52-week treatment duration in a double-blind fashion. 
QAW039 at both doses and placebo will be given as oral tablets.
Overall, the ratio of patients in this study receiving QAW039 150 mg once daily, QAW039 
450 mg daily, and placebo will be approximately 3:3:1.  The overall 3:3:1 randomization ratio 
allows for a larger number of patients to receive QAW039 (at either the 150 mg or 450 mg 
dose) plus SoC asthma therapy compared with those who will receive placebo plus SoC 
asthma therapy. 
During Treatment Period 2, patients will receive the same medication they received during 
Treatment Period 1 (QAW039 150 mg once daily plus SoC asthma therapy, QAW039 450 mg 
once daily plus SoC asthma therapy, or placebo plus SoC asthma therapy) over a 104-week 
treatment duration in a single-blind fashion. 
The last dose of study drug will be given at Week 156 and the final assessment for the 
treatment period will be at Week 160. 
Follow-up period
This period will monitor the safety and tolerability profile for 4 weeks after the last dose of 
study drug.
The investigator must provide appropriate advice on the continued use of basic 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.


Novartis
Confidential
Page 27
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
QAW039 will be administered at doses of 150 mg once daily and 450 mg once daily as oral 
film-coated tablets (FCTs) in this study. The rationale supporting the inclusion of these 2 
doses is below.
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 predose FEV1 
in a sub-set of patients with % predicted FEV1 <70% at Baseline in Study 
CQAW039A2201 proof-of-concept study (PoC).

In study CQAW039A2206, a 450 mg total daily dose of QAW039 was also efficacious on 
the endpoint of predose FEV1.

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 Castro, et al 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 2015; 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 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 predose 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 0.5 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.
The 2 doses of QAW039 included in this study are also being evaluated in other Phase 3 
studies of QAW039 in patients of various asthma severities:
patients with severe asthma at GINA steps 4 and/or 5: QAW039 at 150 mg once daily 
and 450 mg once daily are being evaluated in CQAW039A2307
and  
CQAW039A2314; and 
patients with moderate-to-severe asthma at GINA steps 3 and 4:  QAW039 at 150 mg 
once daily is being evaluated in CQAW039A2316 and CQAW039A2317.
Note: Two studies (CQAW039A2307 and QAW039A2314) will evaluate the dose-response 
relationship of QAW039 (dosed at 150 mg once daily and 450 mg once daily) in patients with 


Novartis
Confidential
Page 28
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
severe asthma. 
 
 
 
 
 
3.4
Rationale for choice of comparator
In both Treatment Period 1 and Treatment Period 2, patients will receive QAW039 or placebo 
administered as add-on therapy to SoC asthma therapy. 
The inclusion of placebo will permit a controlled assessment of safety parameters in patients 
who are treated with QAW039, in comparison to those continuing solely on existing SoC 
asthma therapy, and reduce any potential bias in reporting of adverse events that would be 
introduced if the study was conducted in an open-label fashion.
This study does not include an active comparator since QAW039 will be given as add-on 
therapy to SoC asthma therapy in patients with moderate-to-severe asthma (GINA steps 3, 4 
and 5).
3.5
Purpose and timing of interim analyses/design adaptations
An independent Data Monitoring Committee (see Section 8.4) will conduct periodic 
unblinded safety reviews of the accumulating data from this study and other Phase 3 studies 
of the QAW039 asthma development program to ensure safety of study participants.
To support worldwide registration of QAW039 and to address health authority requests, 
interim analyses of Study A2315 may be conducted with results being submitted to health 
authorities. Once all patients have completed or discontinued Treatment Period 1, a report 
based on Treatment Period 1 data will be produced and results may be published.
3.6
Risks and benefits 
QAW039 is a potent and highly selective oral CRTh2 receptor antagonist being developed as 
a potential therapy 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.
The overall clinical experience with fevipiprant includes 16 studies: 13 (seven in healthy 
volunteers and six in patients) have completed and three (two in patients and one in healthy 
volunteers) are ongoing. The completed Phase II studies consist of four in patients with 
asthma, one in patients with allergic rhinitis and one in patients with atopic dermatitis (AD). 
Two Phase III studies (CQAW039A2307 and CQAW039A2314) in asthma and one Phase I 
study in healthy volunteers (CQAW039A2116) are ongoing. As of January 2017 over 1730 
subjects have been exposed to QAW039.
Four Phase 2 studies examined the effect of fevipiprant in patients with asthma across the 
range of asthma severities (mild to severe). In these studies, QAW039 demonstrated an effect 


Novartis
Confidential
Page 29
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
on lung function (FEV1) in patients with moderate-to-severe asthma, and an improvement in 
quality-of-life scores and asthma control questionnaire scores in severe patients uncontrolled 
at baseline. In one study, QAW039 also demonstrated a reduction in sputum eosinophils in 
patients with severe asthma.
The potential benefits of QAW039 therapy need to be balanced against its potential risks. 
Potential side effects of QAW039 include: increased heart rate, non-serious arrhythmia such 
as palpitations, headache, diarrhea, nausea, vomiting, nasopharyngitis, somnolescence and 
dizziness. In humans, one major metabolite of QAW039 has been identified which is formed 
by glucuronidation (acyl glucuronide) and partially binds to plasma proteins. 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 as of 31-Jan-2017. Taking QAW039 at the 
doses used in this study with the cholesterol-lowering drug simvastatin has been shown to 
cause a small increase in the peak blood level of simvastatin
The risk to subjects in this trial will be minimized by compliance with the eligibility criteria 
and study procedures and close clinical monitoring. Patients on doses of simvastatin > 20 mg, 
doses of atorvastatin >40 mg, doses of pravastatin >40 mg, 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 will be excluded from 
the study. 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/or blood CK levels (Jacobson 2008). Cardiovascular risks will be monitored 
based on changes in vital signs, ECGs and biochemical parameters. Monitoring of liver 
function tests and renal function will be conducted as described in Appendix 2 and Appendix 
3, respectively, of this protocol. Surveillance of adverse events for identification of 
idiosyncratic drugs will be conducted.
Refer to the QAW039 Investigator’s Brochure for further information about benefits 
and risks.
4
Population
The study population will include males and females aged ≥12 years with moderate-to-severe 
asthma on SoC asthma therapy at GINA steps 3, 4, and 5. Two categories of patients will be 
enrolled:

Patients completing a prior phase 3 study of QAW039: Patients who completed a prior 
Phase 3 study of QAW039 on active study treatment (i.e., did not discontinue blinded 
study treatment prematurely); and

Patients with inadequately controlled asthma who have not previously participated in a 
study of QAW039. 


Novartis
Confidential
Page 30
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
4.1
Inclusion criteria
Patients completing A PRIOR PHASE 3 STUDY OF QAW039:
Patients eligible for inclusion in this study must fulfill all of the following criteria:
1a. Informed consent and assent (if applicable) may be obtained at Visit 1 or within 14 days 
of Visit 1. Informed consent and assent (if applicable) must be obtained before any study 
assessment is performed. 
2a. Completion of the treatment period (on blinded study drug) of a prior Phase 3 study of 
QAW039 (i.e., did not discontinue blinded study treatment prematurely). 
3a. Patient is able to safely continue into the study as judged by the investigator.
Patients who HAVE NOT PREVIOUSLY PARTICIPATED IN A STUDY OF 
QAW039:
Patients eligible for inclusion in this study must fulfill all of the following criteria:
1b. Informed consent and assent (if applicable) may be obtained at Visit 1 or within 14 days 
of Visit 1. Informed consent and assent (if applicable) must be obtained before any study 
assessment is performed. 
2b. Male and female patients at a minimum age of 12 years (or higher minimum age limit as
allowed by health authority and/or ethics committee/institutional review board (IRB) 
approvals).
3b. Patients must have a diagnosis of asthma (according to GINA 2016) for a period of at least 
24 months prior to screening visit (Visit 1). 
4b. Patients have been treated with GINA steps 4 or 5 standard-of-care (SoC) asthma therapy 
for at least 3 months prior to Visit 1. The doses must have been stable for at least 4 weeks 
prior to Visit 1.
5b. Demonstration of inadequate control of asthma based on an ACQ score ≥1.5 at Visit 1.
6b. For patients aged ≥18 years, FEV1 of ≤85% of the predicted normal value for the patient, 
after withholding bronchodilators at Visit 1. For patients aged 12 to <18 years, FEV1 of 
≤90% of the predicted normal value for the patient, after withholding bronchodilators at 
Visit 1.
NOTE: Withholding of bronchodilators prior to spirometry: 

Short-acting β2-agonists (SABAs) ≥ 6 hours; 

Long-acting β2-agonists (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; and 

Long-acting muscarinic antagonists (LAMAs) ≥ 24 hours. 
7b. 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 the Visit 1.


Novartis
Confidential
Page 31
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
If reversibility is not demonstrated at Visit 1, the following historical information may be 
used:

Documented evidence of reversibility performed according to American Thoracic 
Society/European Respiratory Society (ATS/ERS) (ATS/ERS 2005) or country-
specific guidelines within the 2 years prior to Visit 1. Where a patient is assessed as 
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-responsiveness (AHR) test result 
within the 2 years prior to Visit 1, 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.
4.2
Exclusion criteria
Patients completing A PRIOR PHASE 3 STUDY OF QAW039:
Patients/subjects 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/subjects.
1a. 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.
2a. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using basic methods of contraception during dosing of 
study drug. Basic contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject) if allowed as basic method of contraception by local regulations. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception.

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least 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 must be the sole partner for that subject.

Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) if allowed as basic method of contraception by local regulations. 
For United Kingdom (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).


Novartis
Confidential
Page 32
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
*Not approved in Japan.
In case of use of oral contraception women must have been stable on the same pill for a 
minimum of 3 months before taking study drug.
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.
In case local regulations deviate from the contraception methods listed above, local 
regulations apply and will be described in the ICF.
3a. Patients who did not complete the treatment period on blinded study drug of the prior 
Phase 3 study of QAW039 they participated in.
4a. Inability to comply with all study requirements.
5a. Patients who experienced a serious and drug-related AE in the prior Phase 3 study of 
QAW039 they participated in.
Patients who HAVE NOT PREVIOUSLY PARTICIPATED IN A STUDY OF 
QAW039:
Patients/subjects 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/subjects.
1b. Use of other investigational drugs within 5 half-lives of enrollment, or within 30 days, 
whichever is longer.
2b. History of hypersensitivity to any of the study drugs or its excipients or to drugs of 
similar chemical classes to QAW039.
3b. History of lactose or milk sensitivity.
4b. Patients who have participated in another study of QAW039 (i.e., the patient was 
randomized into another study of QAW039).
5b. Patients with a history or current diagnosis of ECG abnormalities indicating 
significant risk of safety for patients/subjects participating in the study such as: 
clinically significant cardiac arrhythmias, e.g., sustained ventricular tachycardia, and 
clinically significant second or third degree atrioventricular (AV) block without a 
pacemaker. 
6b. History of familial long QT syndrome or known family history of Torsades de Pointes.
7b. Patients with a resting QTcF (Fridericia) ≥450 msec (male) or ≥460 msec (female) at 
Visit 1 or Visit 201. 
8b. Use of agents known to prolong the QT interval unless it can be permanently 
discontinued for the duration of the study. 


Novartis
Confidential
Page 33
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
9b. History of malignancy of any organ system (other than localized basal cell carcinoma 
of the skin or in situ cervical cancer), treated or untreated, within the past 5 years, 
regardless of whether there is evidence of local recurrence or metastases.
10b.
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.
11b.
Women of child-bearing potential, defined as all women physiologically 
capable of becoming pregnant, unless they are using basic methods of contraception 
during dosing of study drug. Basic contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject) if allowed as basic method of contraception by local regulations. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception.

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least 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 must be the sole partner for that subject.

Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) if allowed as basic 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*. *Not 
approved in Japan

Placement of an intrauterine device (IUD) or intrauterine system (IUS).
In case of use of oral contraception women must have been stable on the same pill for 
a minimum of 3 months before taking study drug.
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. 
12b.
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.).


Novartis
Confidential
Page 34
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
13b.
Patients who have had an asthma exacerbation requiring systemic corticosteroids, 
hospitalization, or emergency room visit within 6 weeks prior to Visit 1. If patients 
experience 
an 
asthma 
exacerbation 
requiring 
systemic 
corticosteroids, 
hospitalization or emergency room visit during screening, they may be rescreened 
once, ≥6 weeks after recovery from the exacerbation. 
14b.
Patients who have had a respiratory tract infection or asthma worsening within 4 
weeks of Visit 1. Patients who experience a respiratory tract infection or asthma 
worsening during screening may be re-screened after 4 weeks after recovery from 
their respiratory tract infection or asthma worsening.
15b.
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.
16b.
Patients with a history of chronic lung disease other than asthma, including (but 
not limited to) chronic obstructive pulmonary disease (as defined by Global 
Initiative 
for 
Chronic 
Obstructive 
Lung 
Disease 
(GOLD) 
standards), 
bronchiectasis, (non-clinically significant bronchiectasis may be allowed provided 
recent [within 3 months prior to Visit 1] CT scan proof is available), sarcoidosis 
interstitial lung disease, cystic fibrosis, and tuberculosis.
17b.
Patients with a history of conditions other than asthma, allergic rhinitis or sinusitis
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.
18b.
Patients with uncontrolled diabetes having an HbA1c test result ≥8% at the Visit 1 
laboratory test.
19b.
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 
20b.
Patients who in the judgment of the investigator have a clinically significant 
condition such as (but not limited to) unstable ischemic heart disease, New York 
Heart Association (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.
21b.
Patients with a history of myocardial infarction 12 months of Visit 1.


Novartis
Confidential
Page 35
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
22b.
Patients 
with 
serious 
co-morbidities 
including, 
but 
not 
limited 
to, 
neurodegenerative diseases, rheumatoid arthritis and other autoimmune diseases.
23b.
Patients with a history of alcohol or drug abuse within 12 months prior to Visit 1.
24b.
Patients with a weight <30 kg.
25b.
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, 
if local growth charts are not available) (Center for Disease Control and Prevention 
2000).
26b.
Patients receiving any medications in the classes listed in Table 5-4 must be 
excluded unless they meet the criteria as specified in Table 5-4.
27b.
Patients receiving medications in the classes listed in Table 5-2 must be excluded 
unless the medication has been stabilized for the specified period and the stated 
conditions have been met.
28b.
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. 
29b.
Inability to comply with all study requirements.
30b.
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.
31b.
Patients with a history of being unable to swallow tablets.
32b.
Patients who have received methotrexate, oral gold, troleandomycin, cyclosporine 
azathioprine or any experimental anti-inflammatory therapies within 6 months of 
Visit 1.
33b.
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 1.
34b.
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.
35b.
Patients with a history of immunodeficiency disease or hepatitis B or hepatitis C.
36b.
Patients on any statin therapy with a CK level >2 X ULN at Visit 1.
37b.
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.
38b.
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]).


Novartis
Confidential
Page 36
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
39b.
Patients who have received biologic therapy for the treatment of asthma within 5
months of Visit 1.
40b.
No person directly associated with the administration of the study is allowed to 
participate as a study subject.
41b.
No family member of the investigational study staff is allowed to participate in    
this study.
5
Treatment
5.1
Study treatment
5.1.1
Investigational and control drugs
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

Name: placebos to QAW039 150 mg and QAW039 450 mg 

Formulation: tablet

Unit dose: matching placebo to QAW039 150 mg, matching placebo to QAW039 
450mg
Please refer to the Investigator Brochure (IB) for composition of the QAW039 and 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. 
5.1.2
Additional treatment
No additional maintenance asthma treatment beyond investigational treatment will be 
provided for this trial.
All patients will be provided with SABAs (salbutamol/albuterol/other SABA) which they will 
be instructed to use throughout the study as rescue medication on an ‘as needed basis’.
SABAs 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
Treatment Period 1
Overall, the ratio of patients in this study receiving QAW039 150 mg once daily, QAW039 
450 mg daily, and placebo will be approximately 3:3:1. At Visit 201, patients will be assigned 
to receive: 


Novartis
Confidential
Page 37
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315

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); or

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 study medication (QAW039 or placebo) once daily at 
approximately the same time each morning without regard to time of food intake. 
SoC asthma therapy will be taken as directed by the investigator.
Treatment Period 2
Patients will be assigned at Visit 301 to the same treatment they received in Treatment Period
1. Patients will receive either:

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); or

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 study medication (QAW039 or placebo) once daily at 
approximately the same time each morning without regard to time of food intake. 
SoC asthma therapy will be taken as directed by the investigator.
5.3
Treatment assignment and randomization 
At Visit 201, all eligible patients/subjects will be randomized via Interactive Response 
Technology (IRT) to one of the treatment arms. The investigator or his/her delegate will 
contact the IRT after confirming that the patient fulfills all the inclusion/exclusion criteria. 
The IRT will assign a randomization number to the patient, which will be used to link the 
patient to a treatment arm and will specify a unique medication number for the first package 
of study drug 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/subjects 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 38
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
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/subjects will be reviewed and approved by a member 
of the Randomization Group.
Details of randomization scheme 
Overall, there is an approximately 85% chance patients will receive QAW039 in Study 
A2315. For patients who participated in a prior Phase 3 study, there is at least 57% 
chance a patient will remain on the same QAW039 dose they received in the prior study in 
Study A2315. 
Patients completing A PRIOR PHASE 3 STUDY OF QAW039 with 3 treatment arms 
(QAW039A2307 and QAW039A2314) will be randomized to treatment in Study A2315 as 
delineated below.

Patients who received QAW039 450 mg once daily in a prior study will be assigned to 
QAW039 450 mg once daily, QAW039 150 mg once daily, or placebo in a 5:1:1 ratio. 

Patients who received QAW039 150 mg once daily in a prior study will be assigned to 
QAW039 450 mg once daily, QAW039 150 mg once daily, or placebo in 1:5:1 ratio. 

Patients on placebo in a prior study will be assigned to QAW039 450 mg once daily, 
QAW039 150 mg once daily, or placebo in 3:3:1 ratio.
Patients completing A PRIOR PHASE 3 STUDY OF QAW039 with 2 treatment arms
(QAW039A2316, QAW039A2317) will be randomized to treatment in Study A2315 as 
delineated below.

Patients who received QAW039 150 mg once daily in a prior study will be assigned to 
QAW039 450 mg once daily, QAW039 150 mg once daily, or placebo in 2:4:1 ratio. 

Patients who received placebo in prior study will be assigned to QAW039 450 mg once 
daily, QAW039 150 mg once daily, or placebo in 4:2:1 ratio.
Patients who HAVE NOT PREVIOUSLY PARTICIPATED IN A STUDY OF QAW039 
will be randomized to treatment in Study A2315 as follows: QAW039 450 mg once daily, 
QAW039 150 mg once daily, or placebo in a 3:3:1 ratio.
Treatment randomization will be stratified at the regional level.
Table 5-1 shows the randomized allocation of patients into treatment groups in Study A2315.


Novartis
Confidential
Page 39
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
Table 5-1
Randomized Allocation of Patients into Treatment groups
Patients completing A PRIOR PHASE 3 STUDY OF QAW039: treatment allocation in Study 
A2315
Prior study
Treatment group in prior 
study
Randomization ratio in 
Study A2315
Treatment group in Study 
A2315
CQAW039A2307
CQAW039A2314
450 mg once daily
5
QAW039 450 mg once daily
1
QAW039 150 mg once daily
1
Placebo
150 mg once daily
1
QAW039 450 mg once daily
5
QAW039 150 mg once daily
1
Placebo
Placebo
3
QAW039 450 mg once daily
3
QAW039 150 mg once daily
1
Placebo
CQAW039A2316
CQAW039A2317
150 mg once daily
2
QAW039 450 mg once daily
4
QAW039 150 mg once daily
1
Placebo
Placebo
4
QAW039 450 mg once daily
2
QAW039 150 mg once daily
1
Placebo
Patients who HAVE NOT PREVIOUSLY PARTICIPATED IN A STUDY OF QAW039: treatment 
allocation in Study A2315
Prior study
Treatment group in prior 
study
Randomization ratio in 
Study A2315
Treatment group in Study 
A2315
Not applicable
Not applicable
3
QAW039 450 mg once daily
3
QAW039 150 mg once daily
1
Placebo
5.4
Treatment blinding 
Patients, investigator staff, persons performing the assessments, and data analysts will remain 
blinded to the identity of the treatment from the time of randomization until interim analyses 
are conducted to support regulatory submissions, 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 with the following exceptions: the external DMC, 
independent of the QAW039 study team, will have access to unblinded data for the purpose of 
safety reviews and at the time of the interim analyses. (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 dose levels, a 
double-dummy design is used because the identity of the study drug cannot be disguised, as 
the drug products are visibly different.


Novartis
Confidential
Page 40
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
All data up to the first interim analysis of Study A2315 will be collected with the Novartis 
study team being blinded to study treatment. At the time of the first interim analysis, Novartis 
personnel will be unblinded to treatment in order to facilitate worldwide Marketing 
Authorization Application/New Drug Application (MAA/NDA) filings while investigators 
and patients will remain blinded to treatment through the remainder of the study. Additional, 
interim analyses, as regarded appropriate, may be conducted (e.g., to provide additional data 
for regulatory submissions). Study modifications are not planned based on any interim 
analysis.
Unblinding will only occur in the case of patient emergencies (see Section 5.5.10), at the time 
of interim analyses (see Section 9.7), and at the conclusion of the study. In addition, the 
independent DMC will be unblinded for the purpose of safety reviews.
5.5
Treating the patient 
Sponsor qualified medical personnel will be readily available to advise on trial related 
medical questions or problems.
5.5.1
Patient numbering,
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 must 
select the CRF book with a matching Subject Number from the electronic data capture (EDC)
system to enter data. 
If the patient fails to be treated for any reason, the IRT must be notified within 2 days that the 
patient was not treated. The reason for not being treated will be entered on the Screening 
Period Study Disposition case report form (CRF).
Each patient is uniquely identified in the study by a combination of his/her center number and 
patient number. The center number is assigned by Novartis to the investigative site. Upon 
signing the informed consent form, the patient is assigned a patient number by the investigator. 
At each site, the first patient is assigned patient number 1, and subsequent patients/subjects 
are assigned consecutive numbers (e.g. the second patient is assigned patient number 2, the 
third patient is assigned patient number 3). 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. For studies using eCRFs, only the assigned patient number must be entered in the field 
labeled “Patient ID” on the EDC data entry screen (e.g. enter ‘1’, ‘2’, etc.). Once assigned to a 
patient, the patient number will not be reused. If the patient fails to be randomized for any 
reason, the IRT must be notified within 2 days that the patient was not randomized. The 
reason for not being randomized will be entered on the Screening Log, and the Demography 
CRF/eCRF) should also be completed. In addition, it is crucial that the investigator 
indicates the trial, center and patient identifiers that uniquely identify the patient in any 
preceding Phase 3 studies.
5.5.2
Dispensing the study drug 
Each study site will be supplied with study drug in packaging of identical appearance.


Novartis
Confidential
Page 41
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
The study drug packaging has a 2-part label. A unique medication number is printed on each 
part of this label which corresponds to one of the “three” treatment arms and a specific visit. 
Investigator staff will identify the study drug 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 and additional treatment 
5.5.3.1
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and 
designees have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels. Clinical supplies are to be dispensed only in accordance 
with the protocol. Technical complaints are to be reported to the respective Novartis Country 
Pharmaceutical Office (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 study 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 study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Patients/subjects will 
be asked to return all unused study treatment and packaging at the end of the study or at the 
time of discontinuation of study treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator will return all unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site.
5.5.3.2
Handling of additional treatment 
Not applicable.
5.5.4
Instructions for prescribing and taking study treatment
Treatment Period 1
Study treatment will be double-blind, double-dummy, and placebo-controlled during 
Treatment Period 1. QAW039 and placebo will be supplied as tablets. Since the tablets for 
QAW039 450 mg and QAW039 150 mg are not identical, treatment will be double-dummy 
and patients will take 2 tablets of study medication (1 tablet of QAW039 450 mg or matching 
placebo and 1 tablet of QAW150 mg or matching placebo) once daily as described below.
At Visit 201, eligible patients will be randomized into Treatment Period 1 (52-week double-
blind treatment period) where they will receive 1 of the following 3 oral treatments:(i) 


Novartis
Confidential
Page 42
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
QAW039 150 mg once daily or (ii) QAW039 450 mg once daily or (iii) placebo once daily 
given on top of their individual background SoC asthma therapy. The investigational 
treatment (tablets) will be dispensed in medication kits at each site visit during the treatment 
period 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.
At designated clinic visits (see Table 6-1 Assessment Schedule), patients will receive a 
witnessed dose of study medication (QAW039 or placebo). These in-clinic witnessed doses 
should be given at approximately the same time at each clinic visit. Between clinic visits, 
patients will be instructed to take study medication (QAW039 or placebo) once daily at 
approximately the same time each morning without regard to time of food intake. 
All kits of study treatment assigned by the IRT will be recorded/databased in the IRT.
The investigator must promote compliance by instructing the patient to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the patient’s 
safety and the validity of the study. The patient must also be instructed to contact the 
investigator if he/she is unable for any reason to take the study treatment as prescribed.
SoC asthma therapy will be taken as directed by the investigator.
Treatment Period 2
Study treatment will be single-blind, double-dummy, and placebo-controlled during 
Treatment Period 2. QAW039 will be supplied as tablets. Since the tablets for QAW039 450 
mg and QAW039 150 mg are not identical, treatment will be double-dummy and patients will 
take 2 tablets of study medication (1 tablet of QAW039 450 mg or matching placebo and 1 
tablet of QAW150 mg or matching placebo) once daily as described below.
Patients entering Treatment Period 2 (104-week single-blind treatment period) will continue 
to receive the same study treatment they received during Treatment Period 1. Patients will 
receive (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 SoC asthma therapy. The
investigational treatment (tablets) will be dispensed in medication packs at each site visit 
during the treatment period 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.
At designated clinic visits (see Table 6-1 Assessment Schedule), patients will receive a 
witnessed dose of study medication (QAW039 or placebo). These in-clinic witnessed doses 
should be given at approximately the same time at each clinic visit. Between clinic visits, 
patients will be instructed to take study medication (QAW039 or placebo) once daily at 
approximately the same time each morning without regard to time of food intake.
All kits of study treatment assigned by the IRT will be recorded/databased in the IRT.
The investigator must promote compliance by instructing the patient to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the patient’s 


Novartis
Confidential
Page 43
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
safety and the validity of the study. The patient must also be instructed to contact the 
investigator if he/she is unable for any reason to take the study treatment as prescribed.
SoC asthma therapy will be taken as directed by the investigator.
5.5.5
Permitted dose adjustments and interruptions of study treatment 
For patients/subjects who are unable to tolerate the protocol-specified dosing scheme, dose 
interruptions of investigational drug are permitted in order to keep the patient on study drug. 
The following guidelines must be followed: 
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 AE. 
Interruption to treatment must be recorded on the Dosage Administration Record CRF.
5.5.6
Rescue medication
At the start of screening (Visit 1), all patients will be provided with a SABA (such as 
salbutamol/albuterol/other SABA) which they will be instructed to use throughout the study 
as rescue medication on an ‘as needed’ basis. Nebulized salbutamol or albuterol or other 
SABA is not allowed as rescue medication and will not be supplied. During the active 
treatment periods, salbutamol or albuterol or other SABA should be taken for rescue purposes 
only when absolutely required for symptoms of asthma.  
Unless clinically indicated, the type of SABA a patient uses, the device used to deliver the 
medication (e.g., dry powder or hydrofluoralkane (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 (e)CRF/ significant non-drug therapies eCRF. In 
order to standardize measurements, patients should be instructed to abstain from taking SABA 
rescue medication (e.g., salbutamol/albuterol) within 6 hours of the start of each visit where 
spirometry is being performed unless absolutely necessary. If rescue medication is taken 
within 6 hours prior to a spirometry visit, the visit should be rescheduled, preferably to 
the next day. The investigator must use their judgment when deciding how many times a visit 
for an individual patient should be rescheduled. In the event that a patient uses a dose of 
rescue medication (i.e., SABA) after taking study medication at any visit, the visit should 
continue as planned. In this case, the rescue medication intake will be captured through the 
central spirometer. 
Rescue medication (i.e., SABA) will either be supplied to the investigator sites locally by 
Novartis or provided by the study center and reimbursed by Novartis.
Patients should be instructed to return any expired and used or unused rescue medication to 
the site where it should be disposed of appropriately.


Novartis
Confidential
Page 44
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
5.5.7
Background therapy
All patients will continue to receive SoC asthma medication throughout the study. During the 
active treatment periods (Treatment Period 1 and Treatment Period 2) of this study, 
investigators may adjust a patient’s SoC asthma therapy according to their clinical judgment. 
Any changes relating to SoC asthma therapy must be recorded on the Concomitant 
medications (e)CRF / significant non-drug therapies eCRF.
Short bursts of rescue systemic corticosteroids are allowed for treatment of asthma 
exacerbations, as clinically indicated (see Section 6.4.2). 
5.5.8
Concomitant medication 
The investigator must instruct the patient to notify the study site about any new medications 
he/she takes after the patient is enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) 
administered after the patient is enrolled into the study must be recorded in the concomitant 
medications / significant non-drug therapies eCRF.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis medical monitor before 
randomizing a patient or allowing a new medication to be started.
The medications in Table 5-2 are permitted under the circumstances given. Patients 
completing a prior phase 3 study of QAW039 will enter this study on the same SoC 
asthma therapy they were taking in the prior study (which may include low, medium, or 
high dose ICS) and at the doses they were taking at the last treatment visit of their 
respective Phase 3 studies.
Table 5-2
Medications allowed under certain conditions
Class of medication
Condition
Inhaled corticosteroids (ICS) 
Medium-dose or High-dose ICS*. 
Used for at least 3 months prior to Visit 1 and 
stable for at least 4 weeks prior to Visit 1.
Long-acting inhaled β-2 agonists (LABAs)
Recommended doses and dosage regimens. 
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 an ICS.
Fixed dose combinations of ICS and LABA 
(FDC)
Recommended doses and dosage regimens. 
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) 
Recommended doses and dosage regimens. 
Used for at least 3 months prior to Visit 1 and 
stable for at least 4 weeks prior to Visit 1.
Theophylline
Recommended doses and dosage regimens 
Used for at least 3 months prior to Visit 1 and 
stable for at least 4 weeks prior to Visit 1.
Long-acting muscarinic antagonists
Recommended doses and dosage regimens 


Novartis
Confidential
Page 45
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
Table 5-3 indicates the wash-out periods for allowed asthma medications prior to spirometry 
assessments. 
Table 5-3
Medications to be withheld prior to spirometry
Class of medication
Last dose 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 
≥ 24 hours
(LAMAs)
Used for at least 3 months prior to Visit 1 and 
stable for at least 4 weeks prior to Visit 1.
Mast cell stabilizers (e.g., cromoglycate, 
nedocromil, ketotifen)
Recommended doses and dosage regimens 
Used for at least 3 months prior to Visit 1 and 
stable for at least 4 weeks prior to Visit 1.
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.
Note: Short bursts of rescue systemic 
corticosteroids are allowed for treatment of asthma 
exacerbations, as clinically indicated.  
Monoclonal antibodies for the treatment of 
asthma
Recommended doses and dosage regimens 
May be added as SoC asthma therapy during 
study. 
Must not have been administered less than 5 
months prior to Visit 1.
SABAs
Rescue medication to be taken as needed.
Maintenance immunotherapy for allergies
Stable dose for at least 3 months prior to Visit 1 
and the dose remains stable throughout the study.
Inactivated influenza vaccine, 
pneumococcal vaccination or any other 
inactivated vaccine
Not administered within 48 hours prior to a study 
visit.
Topical corticosteroids for treatment of 
eczema/ atopic dermatitis 
Recommended doses and dosage regimens.
Antihistamines (e.g., loratadine, cetirzine)
Recommended doses and dosage regimens 
Nasal anticholinergics
Treatment regimen has been stable for at least 1 
month prior to 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,ophthalmological, or oral  
preparations of antihistamines
* Not applicable for patients entering this study from a prior Phase 3 study in which they were 
receiving low-dose ICS.


Novartis
Confidential
Page 46
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
Class of medication
Last dose prior to spirometry
once daily
LAMAs
≥ 24 hours
5.5.9
Prohibited medication
Use of the treatments displayed in Table 5-4 is NOT allowed after the start of investigational 
drug at Visit 1. Table 5-4 is not considered all-inclusive. Medications should be assessed for 
adherence to the indication and other inclusion/exclusion crtieria.
These medications are also prohibited if administered for other indications.
Table 5-4
Prohibited medications
Class of medication
Minimum cessation prior to Visit 1
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 SABAs and short-
acting anticholinergics
8 hours
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 for 
the treatment of conditions other than asthma
6 months
5.5.10
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to in order to treat the 
patient safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study patient who presents with an emergency 
condition. 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 the Novartis monitor for the site and the Study Team that the code 
has been broken.


Novartis
Confidential
Page 47
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The investigator 
will provide:

protocol number

study drug name (if available)

patient number
In addition, oral and written information to the subject must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-
blinding can be performed at any time.
Of note, the patient may continue in the study after discontinuing study drug.
5.6
Study Completion and Discontinuation 
5.6.1
Study completion and post-study treatment
A patient will be considered to have completed the study when the patient has completed the 
last visit planned in the protocol.
Study completion for a patient can occur after he/she has completed 52 weeks of treatment in 
Treatment Period 1, or after the additional 104 weeks of treatment in optional Treatment 
Period 2 (total of 156 weeks of treatment) or if they have prematurely withdrawn. Completion 
of the study will be when all randomized patients have met the definition of study completion 
described above and have completed the post-treatment follow-up visit.
Patients who have been screened when the enrollment target has been met will be allowed to 
proceed onto study participation.
Patients completing the study after Treatment Period 1 or Treatment Period 2 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.
For all patients/subjects a safety follow-up visit (visit 401) should be conducted (e.g. by 
telephone for males and females of non-child bearing potential; women of childbearing 
potential must come in to the clinic for pregnancy testing at Visit 401) 30 days after last visit 
(299, Week 52 for patients not continuing into Treatment Period 2 and visit 399, week 156 for 
patients completing Treatment Period 2). The information to be collected at this follow up 
visit includes concomitant medications, adverse events, pregnancy testing and survival status.
The investigator must provide appropriate advice on the continued use of basic contraception 
for at least one week (at least 5 half-lives of QAW039) after study completion (Visit 299 or 
Visit 399, as appropriate) 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. 


Novartis
Confidential
Page 48
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
5.6.2
Discontinuation of Study Treatment 
Discontinuation of study treatment for a patient occurs when study drug is stopped earlier than 
the protocol planned duration, and can be initiated by either the patient or the investigator. 
The investigator must discontinue study treatment for a given patient if, on balance, he/she 
believes that continuation would negatively impact the risk/benefit of trial participation.
Study treatment must be discontinued under the following circumstances: 

Patient wish; 

Pregnancy (see Section 6.5.6 and Section 7.7);

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 medications.

Any situation in which study participation might result in a safety risk to the patient;

Female subjects non-compliant with the chosen basic method of contraception during the 
study.
The investigator must provide appropriate advice on the continued use of basic 
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;

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;

Premature unblinding of study treatment for a patient for any reason;

Total white blood cell count <1000 cells/µL;

Patients with QTcF (Fridericia) ≥450 msec (male) or ≥460 msec (female) at Visit 201 on 
the ECG Analysis Report provided by the ECG core laboratory.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 discontinuation of study treatment occurs, the patient should NOT be considered withdrawn 
from the study. The patient should return to the clinic as soon as possible, after 
discontinuation of study drug, for a study treatment discontinuation visit. Treatment 
discontinuation visit assessments detailed in the “unscheduled treatment discontinuation visit” 
(TD) in Table 6-1 should be completed and recorded in the eCRF. The investigator must 
determine the primary reason for the patient’s premature discontinuation of study treatment 
and record this information on the Dosage Administration eCRF. 
Patients who discontinue study treatment 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 judgment. 


Novartis
Confidential
Page 49
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
If the patient cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the patient, or with a person pre-designated by the patient. This 
telephone 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 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 study 
treatment.
If study drug discontinuation occurs because treatment code has been broken, please refer to 
Section 5.5.10
5.6.3
Withdrawal of informed consent
Patients/subjects may voluntarily withdraw consent to participate in the study for any reason 
at any time. Withdrawal of consent from the study is defined as 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 
In this situation, the investigator must make every effort (e.g., telephone, e-mail, letter) to 
determine the primary reason for the patient’s decision to withdraw his/her consent and record 
this information. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final
evaluation at the time of the patient’s study withdrawal should be made as detailed in 
Table 6-1.
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.
5.6.4
Lost to follow-up 
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should show "due diligence" by 


Novartis
Confidential
Page 50
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
documenting in the source documents steps taken to contact the subject, e.g., dates of 
telephone calls, registered letters, etc. A patient cannot be considered as lost to follow-up until 
the time point of his/her scheduled end of study visit has passed.
5.6.5
Early study termination by the sponsor 
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit risk assessment of participating in the study, practical reasons, or for 
regulatory or medical reasons (including slow enrolment). Should this be necessary, the 
patient must be seen as soon as possible and treated as 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
Patients/subjects must be seen for all visits on the designated day, or as close to it as possible. 
Missed or rescheduled visits should not lead to automatic discontinuation. Patients who 
discontinue study treatment before completing the study and accept to remain in the study will 
return for study visits as described in Section 5.6.2. Patients who prematurely discontinue the 
study for any reason should be scheduled for a visit as soon as possible, at which time all of 
the assessments listed for the final visit will be performed. At this final visit, all dispensed 
investigational product should be reconciled and the adverse event and concomitant 
medications reconciled on the CRF.
Table 6-1 lists all of the assessments and indicates with an “x” when the visits are performed.
Note that the visit schedule for the screening and randomization visits (Visit 1 and Visit 201) 
for patients completing a prior Phase 3 study of QAW039 will be different from the visit 
schedule for the screening and randomization visits for patients who have not previously 
participated in a study of QAW039.

For patients completing a prior Phase 3 study of QAW039: the last visit in the 
treatment period of the prior study (e.g., Visit 299) will occur on the same day as the 
screening visit (Visit 1) for Study A2315. The randomization visit (Visit 201) will occur 
on the following day (i.e., 1 day after Visit 1) so there is no interruption of study treatment 
and to allow for pre-dose assessments for Study A2315.

For patients who have not previously participated in a study of QAW039: the 
screening visit (Visit 1) will occur approximately 2 weeks before the randomization visit 
(Visit 201).
The table below summarizes the screening visit (Visit 1) and randomization visit (Visit 201) 
timing for patients completing a prior Phase 3 study of QAW039 and for patients who have 
not previously participated in a study of QAW039. 


Novartis
Confidential
Page 51
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
Screening (Visit 1)
Randomization (Visit 201)
Patients completing a prior
Phase 3 Study of QAW039
Last day of treatment period of 
prior Phase 3 study (e.g., Visit 
299)
Day 1: Visit 1 + 1 day
Patients who have not 
previously participated in a 
study of QAW039
Day -14
Day 1: Visit 1 + 14 days
Patients must be seen for all visits on the designated day, or as close to it as possible. Missed 
or rescheduled visits should not lead to automatic discontinuation. Patients who prematurely 
discontinue the study for any reason should be scheduled for a visit as soon as possible, at 
which time all of the assessments listed for the final visit will be performed. At this final visit, 
all dispensed investigational product should be reconciled and the adverse event and 
concomitant medications reconciled on the CRF.
Patients will be required to attend the clinic in the morning at approximately the same 
time for each visit,
 
 Patients/subjects will be contacted for safety evaluations 
during the 30 days following the last administration of study treatment. 
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: ACQ-5 at Visit 1 (new patients);
3) Vital signs; 
4) ECGs;
5) Samples for urine/hematology/blood chemistry (At Visit 1, collect samples prior to 
spirometry.
 
6) Samples for Radioallergosorbant (RAST)/ImmunoCAP test, Total IgE, at certain 
clinic visit(s) (At Visit 1, collect samples prior to spirometry.
 
7) Spirometry. Spirometry assessments should be timed so that the Visit 1 spirometry 
assessment 
 
Other tests should be 
performed as close as possible to those spirometry times. 
 
 


Novartis
Confidential
Page 52
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
8)
Reversibility at certain visits (spirometry after administration of SABA) may be 
performed after 10 A.M.
9) In-clinic witnessed dosing of study drug.


Novartis
Confidential
Page 53
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
Table 6-1
Assessment schedule
Screening 
Treatment
Foll
ow-
up
Treatment Epoch 1 
Treatment Epoch 2 
Visit Number (Site visits)1
12, 3
2
201
202
203
204
205
TD
2994,5
301
302
303
304
305
306
307
308
TD
399
4016
NP
PP
Treatment Week
-2
1
1
4
13
26
39
TD
52
52
65
78
91
104
117
130
143
TD
156
160
Treatment Day 
Note: *Visit 2 and 201 will 
occur on the same day if the 
patient is randomized
-14
-1
1*
1*
28
91
182
273
TD
364
364
455
546
637
728
819
910
1001
TD
1092
1120
1Scheduled clinic visits (starting at Visit1 and thereafter) are to occur in the morning at approximately the same time, so that the specified FEV1 assessments can be performed between 06:00 A.M. and 10:00 A.M (±1 
hour).
2For patients who have not previously participated in a study of QAW039: patients experiencing an asthma exacerbation during the Screening Epoch may be re-screened ≥6 weeks after recovery from the exacerbation.
3 For patients completing a prior Phase 3 study of QAW039, Visit 1 will occur on the same day as the last day of treatment in the prior study.
4 For patients continuing into Treatment Epoch 2, Visit 299 and Visit 301 will occur on the same day.
5For the witnessed dose at Visit 299, patients will take a tablet from the study drug dispensed at Visit 205.
6Visit 401 will occur after Visit 299 for patients not continuing into Treatment Epoch 2 or after Visit 399 for patients completing Treatment Epoch 2.
†For patients completing a prior Phase 3 study of QAW039; consult the CRF Completion Guidelines for patient data to be moved from the prior Phase 3 study eCRFs to the Study A2315 eCRFs.
‡For patients completing a prior Phase 3 study of QAW039, the assessment from the last visit of the Treatment Epoch of the prior Phase 3 study will serve as the Visit 1 assessment for Study A2315. 
NP = New patients not previously participating in a phase 3 study of QAW039; PP = patients completing a prior Phase 3 study of QAW039; TD = study 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; 
Epoch 1 Informed consent
(IC) and assent (if 
applicable) 
Note: IC and assent (if 
applicable) may be obtained 
within 14 days prior to or at 
V1. 
For patients completing a 
prior phase 3 study of 
QAW039, IC and assents (if 
applicable) for Treatment 
Epoch 1 may be obtained on
the last day of treatment in 
the prior study’s treatment 
epoch.
X
X


Novartis
Confidential
Page 54
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
Screening 
Treatment
Foll
ow-
up
Treatment Epoch 1 
Treatment Epoch 2 
Visit Number (Site visits)1
12, 3
2
201
202
203
204
205
TD
2994,5
301
302
303
304
305
306
307
308
TD
399
4016
NP
PP
Treatment Week
-2
1
1
4
13
26
39
TD
52
52
65
78
91
104
117
130
143
TD
156
160
Treatment Day 
Note: *Visit 2 and 201 will 
occur on the same day if the 
patient is randomized
-14
-1
1*
1*
28
91
182
273
TD
364
364
455
546
637
728
819
910
1001
TD
1092
1120
1Scheduled clinic visits (starting at Visit1 and thereafter) are to occur in the morning at approximately the same time, so that the specified FEV1 assessments can be performed between 06:00 A.M. and 10:00 A.M (±1 
hour).
2For patients who have not previously participated in a study of QAW039: patients experiencing an asthma exacerbation during the Screening Epoch may be re-screened ≥6 weeks after recovery from the exacerbation.
3 For patients completing a prior Phase 3 study of QAW039, Visit 1 will occur on the same day as the last day of treatment in the prior study.
4 For patients continuing into Treatment Epoch 2, Visit 299 and Visit 301 will occur on the same day.
5For the witnessed dose at Visit 299, patients will take a tablet from the study drug dispensed at Visit 205.
6Visit 401 will occur after Visit 299 for patients not continuing into Treatment Epoch 2 or after Visit 399 for patients completing Treatment Epoch 2.
†For patients completing a prior Phase 3 study of QAW039; consult the CRF Completion Guidelines for patient data to be moved from the prior Phase 3 study eCRFs to the Study A2315 eCRFs.
‡For patients completing a prior Phase 3 study of QAW039, the assessment from the last visit of the Treatment Epoch of the prior Phase 3 study will serve as the Visit 1 assessment for Study A2315. 
NP = New patients not previously participating in a phase 3 study of QAW039; PP = patients completing a prior Phase 3 study of QAW039; TD = study 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; 
Epoch 2 Informed consent
(IC) and assent (if 
applicable) 
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 should be rescheduled.
X
X
X
X
X
X
X
X
Demographics
X
X†, ‡ 
Previous Trial, Site and 
Subject Identifiers (if 
applicable)
X†


Novartis
Confidential
Page 55
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
Screening 
Treatment
Foll
ow-
up
Treatment Epoch 1 
Treatment Epoch 2 
Visit Number (Site visits)1
12, 3
2
201
202
203
204
205
TD
2994,5
301
302
303
304
305
306
307
308
TD
399
4016
NP
PP
Treatment Week
-2
1
1
4
13
26
39
TD
52
52
65
78
91
104
117
130
143
TD
156
160
Treatment Day 
Note: *Visit 2 and 201 will 
occur on the same day if the 
patient is randomized
-14
-1
1*
1*
28
91
182
273
TD
364
364
455
546
637
728
819
910
1001
TD
1092
1120
1Scheduled clinic visits (starting at Visit1 and thereafter) are to occur in the morning at approximately the same time, so that the specified FEV1 assessments can be performed between 06:00 A.M. and 10:00 A.M (±1 
hour).
2For patients who have not previously participated in a study of QAW039: patients experiencing an asthma exacerbation during the Screening Epoch may be re-screened ≥6 weeks after recovery from the exacerbation.
3 For patients completing a prior Phase 3 study of QAW039, Visit 1 will occur on the same day as the last day of treatment in the prior study.
4 For patients continuing into Treatment Epoch 2, Visit 299 and Visit 301 will occur on the same day.
5For the witnessed dose at Visit 299, patients will take a tablet from the study drug dispensed at Visit 205.
6Visit 401 will occur after Visit 299 for patients not continuing into Treatment Epoch 2 or after Visit 399 for patients completing Treatment Epoch 2.
†For patients completing a prior Phase 3 study of QAW039; consult the CRF Completion Guidelines for patient data to be moved from the prior Phase 3 study eCRFs to the Study A2315 eCRFs.
‡For patients completing a prior Phase 3 study of QAW039, the assessment from the last visit of the Treatment Epoch of the prior Phase 3 study will serve as the Visit 1 assessment for Study A2315. 
NP = New patients not previously participating in a phase 3 study of QAW039; PP = patients completing a prior Phase 3 study of QAW039; TD = study 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; 
Medical history
X
X†,‡
Medical History – Protocol 
solicited events for 
asthma
X
X†,‡
Asthma exacerbation 
history
X
Smoking history
X
X†,‡
Prior/concomitant 
medication (asthma and 
non-asthma medications) 
review
X
X†,‡
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Inclusion/exclusion criteria
X
X
X
Review and record 
surgeries and procedures
X
X†,‡
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination (S)
S
S‡
S
S
S
S


Novartis
Confidential
Page 56
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
Screening 
Treatment
Foll
ow-
up
Treatment Epoch 1 
Treatment Epoch 2 
Visit Number (Site visits)1
12, 3
2
201
202
203
204
205
TD
2994,5
301
302
303
304
305
306
307
308
TD
399
4016
NP
PP
Treatment Week
-2
1
1
4
13
26
39
TD
52
52
65
78
91
104
117
130
143
TD
156
160
Treatment Day 
Note: *Visit 2 and 201 will 
occur on the same day if the 
patient is randomized
-14
-1
1*
1*
28
91
182
273
TD
364
364
455
546
637
728
819
910
1001
TD
1092
1120
1Scheduled clinic visits (starting at Visit1 and thereafter) are to occur in the morning at approximately the same time, so that the specified FEV1 assessments can be performed between 06:00 A.M. and 10:00 A.M (±1 
hour).
2For patients who have not previously participated in a study of QAW039: patients experiencing an asthma exacerbation during the Screening Epoch may be re-screened ≥6 weeks after recovery from the exacerbation.
3 For patients completing a prior Phase 3 study of QAW039, Visit 1 will occur on the same day as the last day of treatment in the prior study.
4 For patients continuing into Treatment Epoch 2, Visit 299 and Visit 301 will occur on the same day.
5For the witnessed dose at Visit 299, patients will take a tablet from the study drug dispensed at Visit 205.
6Visit 401 will occur after Visit 299 for patients not continuing into Treatment Epoch 2 or after Visit 399 for patients completing Treatment Epoch 2.
†For patients completing a prior Phase 3 study of QAW039; consult the CRF Completion Guidelines for patient data to be moved from the prior Phase 3 study eCRFs to the Study A2315 eCRFs.
‡For patients completing a prior Phase 3 study of QAW039, the assessment from the last visit of the Treatment Epoch of the prior Phase 3 study will serve as the Visit 1 assessment for Study A2315. 
NP = New patients not previously participating in a phase 3 study of QAW039; PP = patients completing a prior Phase 3 study of QAW039; TD = study 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; 
Abbreviated physical 
examination (heart and 
lung only) (S)
S
S
S
S
S
S
S
S
S
S
S
S
Height
Note: Height must be 
collected using a standard 
measurement device (such 
as a stadiometer)
X
X†,‡
X
X
Weight
X
X†,‡
X
X
X
X
Vital signs
(systolic/diastolic blood 
pressure, radial pulse 
[sitting], and body 
temperature)
X
X†,‡
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Electrocardiogram 
X
X†,‡
X
X


Novartis
Confidential
Page 57
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
Screening 
Treatment
Foll
ow-
up
Treatment Epoch 1 
Treatment Epoch 2 
Visit Number (Site visits)1
12, 3
2
201
202
203
204
205
TD
2994,5
301
302
303
304
305
306
307
308
TD
399
4016
NP
PP
Treatment Week
-2
1
1
4
13
26
39
TD
52
52
65
78
91
104
117
130
143
TD
156
160
Treatment Day 
Note: *Visit 2 and 201 will 
occur on the same day if the 
patient is randomized
-14
-1
1*
1*
28
91
182
273
TD
364
364
455
546
637
728
819
910
1001
TD
1092
1120
1Scheduled clinic visits (starting at Visit1 and thereafter) are to occur in the morning at approximately the same time, so that the specified FEV1 assessments can be performed between 06:00 A.M. and 10:00 A.M (±1 
hour).
2For patients who have not previously participated in a study of QAW039: patients experiencing an asthma exacerbation during the Screening Epoch may be re-screened ≥6 weeks after recovery from the exacerbation.
3 For patients completing a prior Phase 3 study of QAW039, Visit 1 will occur on the same day as the last day of treatment in the prior study.
4 For patients continuing into Treatment Epoch 2, Visit 299 and Visit 301 will occur on the same day.
5For the witnessed dose at Visit 299, patients will take a tablet from the study drug dispensed at Visit 205.
6Visit 401 will occur after Visit 299 for patients not continuing into Treatment Epoch 2 or after Visit 399 for patients completing Treatment Epoch 2.
†For patients completing a prior Phase 3 study of QAW039; consult the CRF Completion Guidelines for patient data to be moved from the prior Phase 3 study eCRFs to the Study A2315 eCRFs.
‡For patients completing a prior Phase 3 study of QAW039, the assessment from the last visit of the Treatment Epoch of the prior Phase 3 study will serve as the Visit 1 assessment for Study A2315. 
NP = New patients not previously participating in a phase 3 study of QAW039; PP = patients completing a prior Phase 3 study of QAW039; TD = study 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; 
Electrocardiogram (Pre-
dose)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy test—serum 
(women of child bearing 
potential)
Note: Pregnancy testing will 
begin at the first visit a 
patient is identified as being 
of child bearing potential and 
then performed at all 
subsequent visits.
X


Novartis
Confidential
Page 58
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
Screening 
Treatment
Foll
ow-
up
Treatment Epoch 1 
Treatment Epoch 2 
Visit Number (Site visits)1
12, 3
2
201
202
203
204
205
TD
2994,5
301
302
303
304
305
306
307
308
TD
399
4016
NP
PP
Treatment Week
-2
1
1
4
13
26
39
TD
52
52
65
78
91
104
117
130
143
TD
156
160
Treatment Day 
Note: *Visit 2 and 201 will 
occur on the same day if the 
patient is randomized
-14
-1
1*
1*
28
91
182
273
TD
364
364
455
546
637
728
819
910
1001
TD
1092
1120
1Scheduled clinic visits (starting at Visit1 and thereafter) are to occur in the morning at approximately the same time, so that the specified FEV1 assessments can be performed between 06:00 A.M. and 10:00 A.M (±1 
hour).
2For patients who have not previously participated in a study of QAW039: patients experiencing an asthma exacerbation during the Screening Epoch may be re-screened ≥6 weeks after recovery from the exacerbation.
3 For patients completing a prior Phase 3 study of QAW039, Visit 1 will occur on the same day as the last day of treatment in the prior study.
4 For patients continuing into Treatment Epoch 2, Visit 299 and Visit 301 will occur on the same day.
5For the witnessed dose at Visit 299, patients will take a tablet from the study drug dispensed at Visit 205.
6Visit 401 will occur after Visit 299 for patients not continuing into Treatment Epoch 2 or after Visit 399 for patients completing Treatment Epoch 2.
†For patients completing a prior Phase 3 study of QAW039; consult the CRF Completion Guidelines for patient data to be moved from the prior Phase 3 study eCRFs to the Study A2315 eCRFs.
‡For patients completing a prior Phase 3 study of QAW039, the assessment from the last visit of the Treatment Epoch of the prior Phase 3 study will serve as the Visit 1 assessment for Study A2315. 
NP = New patients not previously participating in a phase 3 study of QAW039; PP = patients completing a prior Phase 3 study of QAW039; TD = study 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—urine 
(women of child bearing 
potential)
Note: Pregnancy testing will 
begin at the first visit if a 
patient is identified as being 
of child bearing potential and 
then performed at all 
subsequent visits. 
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
X
X
X
X
X
X
X


Novartis
Confidential
Page 59
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
Screening 
Treatment
Foll
ow-
up
Treatment Epoch 1 
Treatment Epoch 2 
Visit Number (Site visits)1
12, 3
2
201
202
203
204
205
TD
2994,5
301
302
303
304
305
306
307
308
TD
399
4016
NP
PP
Treatment Week
-2
1
1
4
13
26
39
TD
52
52
65
78
91
104
117
130
143
TD
156
160
Treatment Day 
Note: *Visit 2 and 201 will 
occur on the same day if the 
patient is randomized
-14
-1
1*
1*
28
91
182
273
TD
364
364
455
546
637
728
819
910
1001
TD
1092
1120
1Scheduled clinic visits (starting at Visit1 and thereafter) are to occur in the morning at approximately the same time, so that the specified FEV1 assessments can be performed between 06:00 A.M. and 10:00 A.M (±1 
hour).
2For patients who have not previously participated in a study of QAW039: patients experiencing an asthma exacerbation during the Screening Epoch may be re-screened ≥6 weeks after recovery from the exacerbation.
3 For patients completing a prior Phase 3 study of QAW039, Visit 1 will occur on the same day as the last day of treatment in the prior study.
4 For patients continuing into Treatment Epoch 2, Visit 299 and Visit 301 will occur on the same day.
5For the witnessed dose at Visit 299, patients will take a tablet from the study drug dispensed at Visit 205.
6Visit 401 will occur after Visit 299 for patients not continuing into Treatment Epoch 2 or after Visit 399 for patients completing Treatment Epoch 2.
†For patients completing a prior Phase 3 study of QAW039; consult the CRF Completion Guidelines for patient data to be moved from the prior Phase 3 study eCRFs to the Study A2315 eCRFs.
‡For patients completing a prior Phase 3 study of QAW039, the assessment from the last visit of the Treatment Epoch of the prior Phase 3 study will serve as the Visit 1 assessment for Study A2315. 
NP = New patients not previously participating in a phase 3 study of QAW039; PP = patients completing a prior Phase 3 study of QAW039; TD = study 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; 
In countries where 
monthly pregnancy testing 
is required for women of 
child-bearing potential by 
local laws and 
regulations: 
Home Pregnancy testing-
urine 
Note: These female patients will report the results of monthly home urine pregnancy test as “positive” or “negative” to study site staff as part of 
a monthly telephone call from the site to the patient between in clinic study visits (S)
Urinalysis and urine 
chemistry (central 
laboratory)
X
X†,‡
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


Novartis
Confidential
Page 60
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
Screening 
Treatment
Foll
ow-
up
Treatment Epoch 1 
Treatment Epoch 2 
Visit Number (Site visits)1
12, 3
2
201
202
203
204
205
TD
2994,5
301
302
303
304
305
306
307
308
TD
399
4016
NP
PP
Treatment Week
-2
1
1
4
13
26
39
TD
52
52
65
78
91
104
117
130
143
TD
156
160
Treatment Day 
Note: *Visit 2 and 201 will 
occur on the same day if the 
patient is randomized
-14
-1
1*
1*
28
91
182
273
TD
364
364
455
546
637
728
819
910
1001
TD
1092
1120
1Scheduled clinic visits (starting at Visit1 and thereafter) are to occur in the morning at approximately the same time, so that the specified FEV1 assessments can be performed between 06:00 A.M. and 10:00 A.M (±1 
hour).
2For patients who have not previously participated in a study of QAW039: patients experiencing an asthma exacerbation during the Screening Epoch may be re-screened ≥6 weeks after recovery from the exacerbation.
3 For patients completing a prior Phase 3 study of QAW039, Visit 1 will occur on the same day as the last day of treatment in the prior study.
4 For patients continuing into Treatment Epoch 2, Visit 299 and Visit 301 will occur on the same day.
5For the witnessed dose at Visit 299, patients will take a tablet from the study drug dispensed at Visit 205.
6Visit 401 will occur after Visit 299 for patients not continuing into Treatment Epoch 2 or after Visit 399 for patients completing Treatment Epoch 2.
†For patients completing a prior Phase 3 study of QAW039; consult the CRF Completion Guidelines for patient data to be moved from the prior Phase 3 study eCRFs to the Study A2315 eCRFs.
‡For patients completing a prior Phase 3 study of QAW039, the assessment from the last visit of the Treatment Epoch of the prior Phase 3 study will serve as the Visit 1 assessment for Study A2315. 
NP = New patients not previously participating in a phase 3 study of QAW039; PP = patients completing a prior Phase 3 study of QAW039; TD = study 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. Refer to 
Section 6.5.4
Notes: No fasting 
requirement prior to blood 
sampling.
X
X†,‡
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood for 
RAST/ImmunoCap test:
Only performed for
patients who have not 
previously participated in 
a prior study of QAW039.
X


Novartis
Confidential
Page 61
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
Screening 
Treatment
Foll
ow-
up
Treatment Epoch 1 
Treatment Epoch 2 
Visit Number (Site visits)1
12, 3
2
201
202
203
204
205
TD
2994,5
301
302
303
304
305
306
307
308
TD
399
4016
NP
PP
Treatment Week
-2
1
1
4
13
26
39
TD
52
52
65
78
91
104
117
130
143
TD
156
160
Treatment Day 
Note: *Visit 2 and 201 will 
occur on the same day if the 
patient is randomized
-14
-1
1*
1*
28
91
182
273
TD
364
364
455
546
637
728
819
910
1001
TD
1092
1120
1Scheduled clinic visits (starting at Visit1 and thereafter) are to occur in the morning at approximately the same time, so that the specified FEV1 assessments can be performed between 06:00 A.M. and 10:00 A.M (±1 
hour).
2For patients who have not previously participated in a study of QAW039: patients experiencing an asthma exacerbation during the Screening Epoch may be re-screened ≥6 weeks after recovery from the exacerbation.
3 For patients completing a prior Phase 3 study of QAW039, Visit 1 will occur on the same day as the last day of treatment in the prior study.
4 For patients continuing into Treatment Epoch 2, Visit 299 and Visit 301 will occur on the same day.
5For the witnessed dose at Visit 299, patients will take a tablet from the study drug dispensed at Visit 205.
6Visit 401 will occur after Visit 299 for patients not continuing into Treatment Epoch 2 or after Visit 399 for patients completing Treatment Epoch 2.
†For patients completing a prior Phase 3 study of QAW039; consult the CRF Completion Guidelines for patient data to be moved from the prior Phase 3 study eCRFs to the Study A2315 eCRFs.
‡For patients completing a prior Phase 3 study of QAW039, the assessment from the last visit of the Treatment Epoch of the prior Phase 3 study will serve as the Visit 1 assessment for Study A2315. 
NP = New patients not previously participating in a phase 3 study of QAW039; PP = patients completing a prior Phase 3 study of QAW039; TD = study 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 Visit 1 laboratory 
results or laboratory 
results from previous 
study if applicable 
(chemistry, hematology, 
hemoglobin HbA1c, 
RAST/ImmunoCAP, urine 
chemistry and urinalysis 
as applicable).
Note: If results for one of the 
laboratory tests is missing, 
obtain a repeat for the 
missing result.
X


Novartis
Confidential
Page 62
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
Screening 
Treatment
Foll
ow-
up
Treatment Epoch 1 
Treatment Epoch 2 
Visit Number (Site visits)1
12, 3
2
201
202
203
204
205
TD
2994,5
301
302
303
304
305
306
307
308
TD
399
4016
NP
PP
Treatment Week
-2
1
1
4
13
26
39
TD
52
52
65
78
91
104
117
130
143
TD
156
160
Treatment Day 
Note: *Visit 2 and 201 will 
occur on the same day if the 
patient is randomized
-14
-1
1*
1*
28
91
182
273
TD
364
364
455
546
637
728
819
910
1001
TD
1092
1120
1Scheduled clinic visits (starting at Visit1 and thereafter) are to occur in the morning at approximately the same time, so that the specified FEV1 assessments can be performed between 06:00 A.M. and 10:00 A.M (±1 
hour).
2For patients who have not previously participated in a study of QAW039: patients experiencing an asthma exacerbation during the Screening Epoch may be re-screened ≥6 weeks after recovery from the exacerbation.
3 For patients completing a prior Phase 3 study of QAW039, Visit 1 will occur on the same day as the last day of treatment in the prior study.
4 For patients continuing into Treatment Epoch 2, Visit 299 and Visit 301 will occur on the same day.
5For the witnessed dose at Visit 299, patients will take a tablet from the study drug dispensed at Visit 205.
6Visit 401 will occur after Visit 299 for patients not continuing into Treatment Epoch 2 or after Visit 399 for patients completing Treatment Epoch 2.
†For patients completing a prior Phase 3 study of QAW039; consult the CRF Completion Guidelines for patient data to be moved from the prior Phase 3 study eCRFs to the Study A2315 eCRFs.
‡For patients completing a prior Phase 3 study of QAW039, the assessment from the last visit of the Treatment Epoch of the prior Phase 3 study will serve as the Visit 1 assessment for Study A2315. 
NP = New patients not previously participating in a phase 3 study of QAW039; PP = patients completing a prior Phase 3 study of QAW039; TD = study 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; 
Parasitic screening 
Notes:
Only for patients who HAVE 
NOT PREVIOUSLY 
PARTICIPATED IN A 
PHASE 3 STUDY OF 
QAW039.
Only if required by health 
authority and/or ethics 
committee/institutional review 
board.  Sites should use local 
laboratories.
S
Serious adverse event 
recording
X
X†,‡
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
X
X
Record deaths
X
X
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
X
X
X
X
X
X
X
X


Novartis
Confidential
Page 63
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
Screening 
Treatment
Foll
ow-
up
Treatment Epoch 1 
Treatment Epoch 2 
Visit Number (Site visits)1
12, 3
2
201
202
203
204
205
TD
2994,5
301
302
303
304
305
306
307
308
TD
399
4016
NP
PP
Treatment Week
-2
1
1
4
13
26
39
TD
52
52
65
78
91
104
117
130
143
TD
156
160
Treatment Day 
Note: *Visit 2 and 201 will 
occur on the same day if the 
patient is randomized
-14
-1
1*
1*
28
91
182
273
TD
364
364
455
546
637
728
819
910
1001
TD
1092
1120
1Scheduled clinic visits (starting at Visit1 and thereafter) are to occur in the morning at approximately the same time, so that the specified FEV1 assessments can be performed between 06:00 A.M. and 10:00 A.M (±1 
hour).
2For patients who have not previously participated in a study of QAW039: patients experiencing an asthma exacerbation during the Screening Epoch may be re-screened ≥6 weeks after recovery from the exacerbation.
3 For patients completing a prior Phase 3 study of QAW039, Visit 1 will occur on the same day as the last day of treatment in the prior study.
4 For patients continuing into Treatment Epoch 2, Visit 299 and Visit 301 will occur on the same day.
5For the witnessed dose at Visit 299, patients will take a tablet from the study drug dispensed at Visit 205.
6Visit 401 will occur after Visit 299 for patients not continuing into Treatment Epoch 2 or after Visit 399 for patients completing Treatment Epoch 2.
†For patients completing a prior Phase 3 study of QAW039; consult the CRF Completion Guidelines for patient data to be moved from the prior Phase 3 study eCRFs to the Study A2315 eCRFs.
‡For patients completing a prior Phase 3 study of QAW039, the assessment from the last visit of the Treatment Epoch of the prior Phase 3 study will serve as the Visit 1 assessment for Study A2315. 
NP = New patients not previously participating in a phase 3 study of QAW039; PP = patients completing a prior Phase 3 study of QAW039; TD = study 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; 
Renal events monitoring
X
X†,‡
X
X
X
X
X
X
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
X
X
X


Novartis
Confidential
Page 64
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
Screening 
Treatment
Foll
ow-
up
Treatment Epoch 1 
Treatment Epoch 2 
Visit Number (Site visits)1
12, 3
2
201
202
203
204
205
TD
2994,5
301
302
303
304
305
306
307
308
TD
399
4016
NP
PP
Treatment Week
-2
1
1
4
13
26
39
TD
52
52
65
78
91
104
117
130
143
TD
156
160
Treatment Day 
Note: *Visit 2 and 201 will 
occur on the same day if the 
patient is randomized
-14
-1
1*
1*
28
91
182
273
TD
364
364
455
546
637
728
819
910
1001
TD
1092
1120
1Scheduled clinic visits (starting at Visit1 and thereafter) are to occur in the morning at approximately the same time, so that the specified FEV1 assessments can be performed between 06:00 A.M. and 10:00 A.M (±1 
hour).
2For patients who have not previously participated in a study of QAW039: patients experiencing an asthma exacerbation during the Screening Epoch may be re-screened ≥6 weeks after recovery from the exacerbation.
3 For patients completing a prior Phase 3 study of QAW039, Visit 1 will occur on the same day as the last day of treatment in the prior study.
4 For patients continuing into Treatment Epoch 2, Visit 299 and Visit 301 will occur on the same day.
5For the witnessed dose at Visit 299, patients will take a tablet from the study drug dispensed at Visit 205.
6Visit 401 will occur after Visit 299 for patients not continuing into Treatment Epoch 2 or after Visit 399 for patients completing Treatment Epoch 2.
†For patients completing a prior Phase 3 study of QAW039; consult the CRF Completion Guidelines for patient data to be moved from the prior Phase 3 study eCRFs to the Study A2315 eCRFs.
‡For patients completing a prior Phase 3 study of QAW039, the assessment from the last visit of the Treatment Epoch of the prior Phase 3 study will serve as the Visit 1 assessment for Study A2315. 
NP = New patients not previously participating in a phase 3 study of QAW039; PP = patients completing a prior Phase 3 study of QAW039; TD = study 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; 
Spirometry (centralized)
To be performed prior to 
reversibility test if 
reversibility test is 
required. 
Note: This spirometry 
assessment must be 
performed between 6:00 AM 
and 10:00 AM (±1 hour).
X
X


Novartis
Confidential
Page 65
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
Screening 
Treatment
Foll
ow-
up
Treatment Epoch 1 
Treatment Epoch 2 
Visit Number (Site visits)1
12, 3
2
201
202
203
204
205
TD
2994,5
301
302
303
304
305
306
307
308
TD
399
4016
NP
PP
Treatment Week
-2
1
1
4
13
26
39
TD
52
52
65
78
91
104
117
130
143
TD
156
160
Treatment Day 
Note: *Visit 2 and 201 will 
occur on the same day if the 
patient is randomized
-14
-1
1*
1*
28
91
182
273
TD
364
364
455
546
637
728
819
910
1001
TD
1092
1120
1Scheduled clinic visits (starting at Visit1 and thereafter) are to occur in the morning at approximately the same time, so that the specified FEV1 assessments can be performed between 06:00 A.M. and 10:00 A.M (±1 
hour).
2For patients who have not previously participated in a study of QAW039: patients experiencing an asthma exacerbation during the Screening Epoch may be re-screened ≥6 weeks after recovery from the exacerbation.
3 For patients completing a prior Phase 3 study of QAW039, Visit 1 will occur on the same day as the last day of treatment in the prior study.
4 For patients continuing into Treatment Epoch 2, Visit 299 and Visit 301 will occur on the same day.
5For the witnessed dose at Visit 299, patients will take a tablet from the study drug dispensed at Visit 205.
6Visit 401 will occur after Visit 299 for patients not continuing into Treatment Epoch 2 or after Visit 399 for patients completing Treatment Epoch 2.
†For patients completing a prior Phase 3 study of QAW039; consult the CRF Completion Guidelines for patient data to be moved from the prior Phase 3 study eCRFs to the Study A2315 eCRFs.
‡For patients completing a prior Phase 3 study of QAW039, the assessment from the last visit of the Treatment Epoch of the prior Phase 3 study will serve as the Visit 1 assessment for Study A2315. 
NP = New patients not previously participating in a phase 3 study of QAW039; PP = patients completing a prior Phase 3 study of QAW039; TD = study 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; 


Novartis
Confidential
Page 66
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
Screening 
Treatment
Foll
ow-
up
Treatment Epoch 1 
Treatment Epoch 2 
Visit Number (Site visits)1
12, 3
2
201
202
203
204
205
TD
2994,5
301
302
303
304
305
306
307
308
TD
399
4016
NP
PP
Treatment Week
-2
1
1
4
13
26
39
TD
52
52
65
78
91
104
117
130
143
TD
156
160
Treatment Day 
Note: *Visit 2 and 201 will 
occur on the same day if the 
patient is randomized
-14
-1
1*
1*
28
91
182
273
TD
364
364
455
546
637
728
819
910
1001
TD
1092
1120
1Scheduled clinic visits (starting at Visit1 and thereafter) are to occur in the morning at approximately the same time, so that the specified FEV1 assessments can be performed between 06:00 A.M. and 10:00 A.M (±1 
hour).
2For patients who have not previously participated in a study of QAW039: patients experiencing an asthma exacerbation during the Screening Epoch may be re-screened ≥6 weeks after recovery from the exacerbation.
3 For patients completing a prior Phase 3 study of QAW039, Visit 1 will occur on the same day as the last day of treatment in the prior study.
4 For patients continuing into Treatment Epoch 2, Visit 299 and Visit 301 will occur on the same day.
5For the witnessed dose at Visit 299, patients will take a tablet from the study drug dispensed at Visit 205.
6Visit 401 will occur after Visit 299 for patients not continuing into Treatment Epoch 2 or after Visit 399 for patients completing Treatment Epoch 2.
†For patients completing a prior Phase 3 study of QAW039; consult the CRF Completion Guidelines for patient data to be moved from the prior Phase 3 study eCRFs to the Study A2315 eCRFs.
‡For patients completing a prior Phase 3 study of QAW039, the assessment from the last visit of the Treatment Epoch of the prior Phase 3 study will serve as the Visit 1 assessment for Study A2315. 
NP = New patients not previously participating in a phase 3 study of QAW039; PP = patients completing a prior Phase 3 study of QAW039; TD = study 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; 


Novartis
Confidential
Page 67
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
Screening 
Treatment
Foll
ow-
up
Treatment Epoch 1 
Treatment Epoch 2 
Visit Number (Site visits)1
12, 3
2
201
202
203
204
205
TD
2994,5
301
302
303
304
305
306
307
308
TD
399
4016
NP
PP
Treatment Week
-2
1
1
4
13
26
39
TD
52
52
65
78
91
104
117
130
143
TD
156
160
Treatment Day 
Note: *Visit 2 and 201 will 
occur on the same day if the 
patient is randomized
-14
-1
1*
1*
28
91
182
273
TD
364
364
455
546
637
728
819
910
1001
TD
1092
1120
1Scheduled clinic visits (starting at Visit1 and thereafter) are to occur in the morning at approximately the same time, so that the specified FEV1 assessments can be performed between 06:00 A.M. and 10:00 A.M (±1 
hour).
2For patients who have not previously participated in a study of QAW039: patients experiencing an asthma exacerbation during the Screening Epoch may be re-screened ≥6 weeks after recovery from the exacerbation.
3 For patients completing a prior Phase 3 study of QAW039, Visit 1 will occur on the same day as the last day of treatment in the prior study.
4 For patients continuing into Treatment Epoch 2, Visit 299 and Visit 301 will occur on the same day.
5For the witnessed dose at Visit 299, patients will take a tablet from the study drug dispensed at Visit 205.
6Visit 401 will occur after Visit 299 for patients not continuing into Treatment Epoch 2 or after Visit 399 for patients completing Treatment Epoch 2.
†For patients completing a prior Phase 3 study of QAW039; consult the CRF Completion Guidelines for patient data to be moved from the prior Phase 3 study eCRFs to the Study A2315 eCRFs.
‡For patients completing a prior Phase 3 study of QAW039, the assessment from the last visit of the Treatment Epoch of the prior Phase 3 study will serve as the Visit 1 assessment for Study A2315. 
NP = New patients not previously participating in a phase 3 study of QAW039; PP = patients completing a prior Phase 3 study of QAW039; TD = study 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 
(spirometry after 
administration of SABA)
Notes: 
If reversibility is not 
demonstrated at Visit 1, 
historical information 
demonstrating reversibility 
may be used.
X
Contact IRT (S)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomize patient 
through IRT (S)
X


Novartis
Confidential
Page 68
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
Screening 
Treatment
Foll
ow-
up
Treatment Epoch 1 
Treatment Epoch 2 
Visit Number (Site visits)1
12, 3
2
201
202
203
204
205
TD
2994,5
301
302
303
304
305
306
307
308
TD
399
4016
NP
PP
Treatment Week
-2
1
1
4
13
26
39
TD
52
52
65
78
91
104
117
130
143
TD
156
160
Treatment Day 
Note: *Visit 2 and 201 will 
occur on the same day if the 
patient is randomized
-14
-1
1*
1*
28
91
182
273
TD
364
364
455
546
637
728
819
910
1001
TD
1092
1120
1Scheduled clinic visits (starting at Visit1 and thereafter) are to occur in the morning at approximately the same time, so that the specified FEV1 assessments can be performed between 06:00 A.M. and 10:00 A.M (±1 
hour).
2For patients who have not previously participated in a study of QAW039: patients experiencing an asthma exacerbation during the Screening Epoch may be re-screened ≥6 weeks after recovery from the exacerbation.
3 For patients completing a prior Phase 3 study of QAW039, Visit 1 will occur on the same day as the last day of treatment in the prior study.
4 For patients continuing into Treatment Epoch 2, Visit 299 and Visit 301 will occur on the same day.
5For the witnessed dose at Visit 299, patients will take a tablet from the study drug dispensed at Visit 205.
6Visit 401 will occur after Visit 299 for patients not continuing into Treatment Epoch 2 or after Visit 399 for patients completing Treatment Epoch 2.
†For patients completing a prior Phase 3 study of QAW039; consult the CRF Completion Guidelines for patient data to be moved from the prior Phase 3 study eCRFs to the Study A2315 eCRFs.
‡For patients completing a prior Phase 3 study of QAW039, the assessment from the last visit of the Treatment Epoch of the prior Phase 3 study will serve as the Visit 1 assessment for Study A2315. 
NP = New patients not previously participating in a phase 3 study of QAW039; PP = patients completing a prior Phase 3 study of QAW039; TD = study 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; 
ACQ-5 in clinic
Note: Only for patients who 
HAVE NOT PREVIOUSLY 
PARTICIPATED IN A 
PHASE 3 STUDY OF 
QAW039.
X
Dispense rescue SABA to 
be used on an as-needed 
basis (S) 
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
Return and assess rescue 
SABA (to be used on an 
as-needed basis) (S)
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S


Novartis
Confidential
Page 69
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
Screening 
Treatment
Foll
ow-
up
Treatment Epoch 1 
Treatment Epoch 2 
Visit Number (Site visits)1
12, 3
2
201
202
203
204
205
TD
2994,5
301
302
303
304
305
306
307
308
TD
399
4016
NP
PP
Treatment Week
-2
1
1
4
13
26
39
TD
52
52
65
78
91
104
117
130
143
TD
156
160
Treatment Day 
Note: *Visit 2 and 201 will 
occur on the same day if the 
patient is randomized
-14
-1
1*
1*
28
91
182
273
TD
364
364
455
546
637
728
819
910
1001
TD
1092
1120
1Scheduled clinic visits (starting at Visit1 and thereafter) are to occur in the morning at approximately the same time, so that the specified FEV1 assessments can be performed between 06:00 A.M. and 10:00 A.M (±1 
hour).
2For patients who have not previously participated in a study of QAW039: patients experiencing an asthma exacerbation during the Screening Epoch may be re-screened ≥6 weeks after recovery from the exacerbation.
3 For patients completing a prior Phase 3 study of QAW039, Visit 1 will occur on the same day as the last day of treatment in the prior study.
4 For patients continuing into Treatment Epoch 2, Visit 299 and Visit 301 will occur on the same day.
5For the witnessed dose at Visit 299, patients will take a tablet from the study drug dispensed at Visit 205.
6Visit 401 will occur after Visit 299 for patients not continuing into Treatment Epoch 2 or after Visit 399 for patients completing Treatment Epoch 2.
†For patients completing a prior Phase 3 study of QAW039; consult the CRF Completion Guidelines for patient data to be moved from the prior Phase 3 study eCRFs to the Study A2315 eCRFs.
‡For patients completing a prior Phase 3 study of QAW039, the assessment from the last visit of the Treatment Epoch of the prior Phase 3 study will serve as the Visit 1 assessment for Study A2315. 
NP = New patients not previously participating in a phase 3 study of QAW039; PP = patients completing a prior Phase 3 study of QAW039; TD = study 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 study drug
Note: Study drug dispensed 
at Visit 201 will be re-
dispensed at Visit 202 as kits 
are provided for 13 weeks of 
treatment.
X
X
X
X
X
X
X
X
X
X
X
X
X
Return and assess 
compliance with study 
drug (count tablets in 
returned bottles) (S)
S
S
S
S
S
S
S
S
S
S
S
S
S
S
Patient to bring all bottles 
of study medication to 
clinic 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


Novartis
Confidential
Page 70
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
Screening 
Treatment
Foll
ow-
up
Treatment Epoch 1 
Treatment Epoch 2 
Visit Number (Site visits)1
12, 3
2
201
202
203
204
205
TD
2994,5
301
302
303
304
305
306
307
308
TD
399
4016
NP
PP
Treatment Week
-2
1
1
4
13
26
39
TD
52
52
65
78
91
104
117
130
143
TD
156
160
Treatment Day 
Note: *Visit 2 and 201 will 
occur on the same day if the 
patient is randomized
-14
-1
1*
1*
28
91
182
273
TD
364
364
455
546
637
728
819
910
1001
TD
1092
1120
1Scheduled clinic visits (starting at Visit1 and thereafter) are to occur in the morning at approximately the same time, so that the specified FEV1 assessments can be performed between 06:00 A.M. and 10:00 A.M (±1 
hour).
2For patients who have not previously participated in a study of QAW039: patients experiencing an asthma exacerbation during the Screening Epoch may be re-screened ≥6 weeks after recovery from the exacerbation.
3 For patients completing a prior Phase 3 study of QAW039, Visit 1 will occur on the same day as the last day of treatment in the prior study.
4 For patients continuing into Treatment Epoch 2, Visit 299 and Visit 301 will occur on the same day.
5For the witnessed dose at Visit 299, patients will take a tablet from the study drug dispensed at Visit 205.
6Visit 401 will occur after Visit 299 for patients not continuing into Treatment Epoch 2 or after Visit 399 for patients completing Treatment Epoch 2.
†For patients completing a prior Phase 3 study of QAW039; consult the CRF Completion Guidelines for patient data to be moved from the prior Phase 3 study eCRFs to the Study A2315 eCRFs.
‡For patients completing a prior Phase 3 study of QAW039, the assessment from the last visit of the Treatment Epoch of the prior Phase 3 study will serve as the Visit 1 assessment for Study A2315. 
NP = New patients not previously participating in a phase 3 study of QAW039; PP = patients completing a prior Phase 3 study of QAW039; TD = study 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; 
In-clinic witnessed study 
drug intake 
Note:  Complete Dose 
administration record (DAR) 
– at site visit.
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete Dose 
administration record -
Summary page
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Screening Phase 
Disposition page 
(screening)
X
Study Phase Completion 
page 
X
X
End of Study Treatment 
page
X
X


Novartis
Confidential
Page 71
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
Screening 
Treatment
Foll
ow-
up
Treatment Epoch 1 
Treatment Epoch 2 
Visit Number (Site visits)1
12, 3
2
201
202
203
204
205
TD
2994,5
301
302
303
304
305
306
307
308
TD
399
4016
NP
PP
Treatment Week
-2
1
1
4
13
26
39
TD
52
52
65
78
91
104
117
130
143
TD
156
160
Treatment Day 
Note: *Visit 2 and 201 will 
occur on the same day if the 
patient is randomized
-14
-1
1*
1*
28
91
182
273
TD
364
364
455
546
637
728
819
910
1001
TD
1092
1120
1Scheduled clinic visits (starting at Visit1 and thereafter) are to occur in the morning at approximately the same time, so that the specified FEV1 assessments can be performed between 06:00 A.M. and 10:00 A.M (±1 
hour).
2For patients who have not previously participated in a study of QAW039: patients experiencing an asthma exacerbation during the Screening Epoch may be re-screened ≥6 weeks after recovery from the exacerbation.
3 For patients completing a prior Phase 3 study of QAW039, Visit 1 will occur on the same day as the last day of treatment in the prior study.
4 For patients continuing into Treatment Epoch 2, Visit 299 and Visit 301 will occur on the same day.
5For the witnessed dose at Visit 299, patients will take a tablet from the study drug dispensed at Visit 205.
6Visit 401 will occur after Visit 299 for patients not continuing into Treatment Epoch 2 or after Visit 399 for patients completing Treatment Epoch 2.
†For patients completing a prior Phase 3 study of QAW039; consult the CRF Completion Guidelines for patient data to be moved from the prior Phase 3 study eCRFs to the Study A2315 eCRFs.
‡For patients completing a prior Phase 3 study of QAW039, the assessment from the last visit of the Treatment Epoch of the prior Phase 3 study will serve as the Visit 1 assessment for Study A2315. 
NP = New patients not previously participating in a phase 3 study of QAW039; PP = patients completing a prior Phase 3 study of QAW039; TD = study 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; 
Follow-up Phase 
Completion page (follow-
up )
X


Novartis
Confidential
Page 72
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
Screening 
Treatment
Foll
ow-
up
Treatment Epoch 1 
Treatment Epoch 2 
Visit Number (Site visits)1
12, 3
2
201
202
203
204
205
TD
2994,5
301
302
303
304
305
306
307
308
TD
399
4016
NP
PP
Treatment Week
-2
1
1
4
13
26
39
TD
52
52
65
78
91
104
117
130
143
TD
156
160
Treatment Day 
Note: *Visit 2 and 201 will 
occur on the same day if the 
patient is randomized
-14
-1
1*
1*
28
91
182
273
TD
364
364
455
546
637
728
819
910
1001
TD
1092
1120
1Scheduled clinic visits (starting at Visit1 and thereafter) are to occur in the morning at approximately the same time, so that the specified FEV1 assessments can be performed between 06:00 A.M. and 10:00 A.M (±1 
hour).
2For patients who have not previously participated in a study of QAW039: patients experiencing an asthma exacerbation during the Screening Epoch may be re-screened ≥6 weeks after recovery from the exacerbation.
3 For patients completing a prior Phase 3 study of QAW039, Visit 1 will occur on the same day as the last day of treatment in the prior study.
4 For patients continuing into Treatment Epoch 2, Visit 299 and Visit 301 will occur on the same day.
5For the witnessed dose at Visit 299, patients will take a tablet from the study drug dispensed at Visit 205.
6Visit 401 will occur after Visit 299 for patients not continuing into Treatment Epoch 2 or after Visit 399 for patients completing Treatment Epoch 2.
†For patients completing a prior Phase 3 study of QAW039; consult the CRF Completion Guidelines for patient data to be moved from the prior Phase 3 study eCRFs to the Study A2315 eCRFs.
‡For patients completing a prior Phase 3 study of QAW039, the assessment from the last visit of the Treatment Epoch of the prior Phase 3 study will serve as the Visit 1 assessment for Study A2315. 
NP = New patients not previously participating in a phase 3 study of QAW039; PP = patients completing a prior Phase 3 study of QAW039; TD = study 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; 
Re-screening of patient
Note: Re-screening of 
patients who have not 
previously participated in 
a study of QAW039 is 
permitted once. 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. Patients 
completing a prior Phase 
3 study of QAW039 may 
not be re-screened.
X


Novartis
Confidential
Page 73
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
Screening 
Treatment
Foll
ow-
up
Treatment Epoch 1 
Treatment Epoch 2 
Visit Number (Site visits)1
12, 3
2
201
202
203
204
205
TD
2994,5
301
302
303
304
305
306
307
308
TD
399
4016
NP
PP
Treatment Week
-2
1
1
4
13
26
39
TD
52
52
65
78
91
104
117
130
143
TD
156
160
Treatment Day 
Note: *Visit 2 and 201 will 
occur on the same day if the 
patient is randomized
-14
-1
1*
1*
28
91
182
273
TD
364
364
455
546
637
728
819
910
1001
TD
1092
1120
1Scheduled clinic visits (starting at Visit1 and thereafter) are to occur in the morning at approximately the same time, so that the specified FEV1 assessments can be performed between 06:00 A.M. and 10:00 A.M (±1 
hour).
2For patients who have not previously participated in a study of QAW039: patients experiencing an asthma exacerbation during the Screening Epoch may be re-screened ≥6 weeks after recovery from the exacerbation.
3 For patients completing a prior Phase 3 study of QAW039, Visit 1 will occur on the same day as the last day of treatment in the prior study.
4 For patients continuing into Treatment Epoch 2, Visit 299 and Visit 301 will occur on the same day.
5For the witnessed dose at Visit 299, patients will take a tablet from the study drug dispensed at Visit 205.
6Visit 401 will occur after Visit 299 for patients not continuing into Treatment Epoch 2 or after Visit 399 for patients completing Treatment Epoch 2.
†For patients completing a prior Phase 3 study of QAW039; consult the CRF Completion Guidelines for patient data to be moved from the prior Phase 3 study eCRFs to the Study A2315 eCRFs.
‡For patients completing a prior Phase 3 study of QAW039, the assessment from the last visit of the Treatment Epoch of the prior Phase 3 study will serve as the Visit 1 assessment for Study A2315. 
NP = New patients not previously participating in a phase 3 study of QAW039; PP = patients completing a prior Phase 3 study of QAW039; TD = study 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; 
Withdrawal of informed 
consent
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Appointment for next 
clinic visit (S)
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
Dispense patient card (S)
S
S
Collect patient card (S)
S


Novartis
Confidential
Page 74
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
6.1
Information to be collected on screening failures 
All patients/subjects who have signed informed consent but not entered into the next period
will have the study completion page for the Screening Period, demographics, 
inclusion/exclusion, and SAE data collected. Adverse events that are not SAEs will be 
followed by the investigator and collected only in the source data.
All AEs 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

Participation in a prior Phase 3 study of QAW039
    

Relevant medical history/current medical condition present before signing informed 
consent. Where possible, diagnoses and not symptoms will be recorded.
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.


Novartis
Confidential
Page 75
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
All doses of study drug taken at the clinic visits should be from the newly assigned 
medication kits, except at Visit 202 and Visit 299 when the medication returned by the 
patient should be used.
6.4
Efficacy
6.4.1
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. Spirometry will be performed between 
6:00 AM and 10:00 AM (±1 hour), 
 
 
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 4, for full details on scheduling and 
performing spirometry. Reversibility testing must be conducted in the morning.
6.4.2
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.
Patients who have not previously participated in a study of QAW039 may be rescreened once.
If a patient who has not previously participated in a study of QAW039 experiences an asthma 
exacerbation requiring systemic corticosteroids, hospitalization, or emergency room visit 
during the Screening Period, rescreening of the patient should occur ≥6 weeks after recovery 


Novartis
Confidential
Page 76
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
from the asthma exacerbation. Patients completing a prior Phase 3 study of QAW039 may not 
be re-screened.
6.4.3
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:

Vital signs

History and physical examinations

Hematology

Blood chemistry including but not limited to 

Liver function tests: ALT, AST, total bilirubin

Metabolic panel: sodium, potassium, chloride, bicarbonate, blood urea nitrogen 
(BUN)/urea, creatinine, glucose, calcium, phosphorus, magnesium, total protein, 
albumin, γ-GT, alkaline phosphatase, lactose dehydrogenase (LDH), CK, iron, uric 
acid, cholesterol, triglycerides

amylase, lipase

High reactive C-reactive protein (hsCRP)

CK-MB and Troponin-I (in response to CK results outside of the normal range)

Glycated hemoglobin (HbA1c) (collected at Visit 1 for new patients only)

Urinalysis and urine chemistry 

Pregnancy test (females of childbearing potential)

ECG

AEs including SAEs
A central laboratory will be used to analyze and report blood chemistry/hematology and 
urinalysis/ urine chemistry. A central ECG vendor will be used to collect, assess and report 
ECGs.
A Data Monitoring Committee will overview safety during the study. See Section 8.4 for 
details.
6.5.1
Physical examination
A complete physical examination will be performed at visits specified in the table of 
assessments (Table 6-1). 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 specified in Table 6-1. The 
abbreviated physical examination will include examination of the lungs and heart.


Novartis
Confidential
Page 77
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
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 performed at visits specified in the table of assessments (Table 6-1). 
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 once using an automated 
validated device, e.g. OMRON, with an appropriately sized cuff. 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.
6.5.3
Height and weight 
Height in centimeters (cm) will be measured at visits specified in the table of assessments 
(Table 6-1). Body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, but without 
shoes) will be measured at visits specified in the table of assessments (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, volume of samples, shipment of samples and reporting of results by the 
central laboratory are provided to investigators in the laboratory manual.
Clinically notable laboratory findings are defined in Appendix 1.
6.5.4.1
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential, and 
platelet count will be measured at visits specified in the table of assessments (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 for new 


Novartis
Confidential
Page 78
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
patients only) and immunoglobulins (IgE, RAST/ImmunoCAP test), will be measured 
according to the assessment schedule (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.
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 17-1 “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.
Three 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.
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 (CQAW039A2315), 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 ECG overreaders of the central ECG 
core laboratory. 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.


Novartis
Confidential
Page 79
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
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 and adolescent girls of child bearing potential will have serum pregnancy test 
according to the assessment schedule in Table 6-1. Pregnancy testing will begin at the visit 
when a patient is identified as being of child bearing potential. 
For patients completing a prior phase 3 study of QAW039, the urine pregnancy test from Visit 
299 of the previous study will serve as the required Visit 1 pregnancy test for Study A2315.
There will be a urine pregnancy test at all other site visits (except Visit 201, since Visit 2 and 
201 should occur on the same day.
In countries where monthly pregnancy testing is required for women of child-bearing 
potential, these patients will perform home urine pregnancy testing monthly as instructed by 
the study site. These female patients will report the results of their home urine pregnancy test 
as “positive” or “negative” to study site staff via a monthly telephone call made by the study 
staff to the patient. The results will be recorded in source documents.
A positive urine pregnancy test requires immediate interruption of study drug until serum β-
hCG is performed and found to be negative. If positive, the patient must be discontinued from 
study treatment and the patient is followed to understand the outcome of the pregnancy.
6.5.7
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/patient population.
6.6
Other assessments
6.6.1
Clinical Outcome Assessments (COAs)
Asthma Control Questionnaire (ACQ)
The study coordinator should be familiar with the instrument and the associated user guides 
and training materials provided. 
In this study, the ACQ-5 will be used to assess asthma symptom control as an inclusion 
criterion for patients who have not previously participated in a study of QAW039.
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, et al 1999, Juniper, et 
al 2006), and 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, et al 2010) and including a minimal important difference (MID) or smallest change 
that can be considered clinically important (0.5).
The ACQ-5 (see Appendix 6) 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 


Novartis
Confidential
Page 80
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
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 who have not previously participated in a study of 
QAW039 at Visit 1 (See Table 6-1). The questionnaire should be completed before any other 
assessments (see Section 6). The appropriate language version(s) of the questionnaire will be 
used in each participating country. 
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. The original questionnaire will be kept with the patient’s file 
as the source document. 
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.


Novartis
Confidential
Page 81
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
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 
study until the end of study visit. 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


Novartis
Confidential
Page 82
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315

its relationship to the study treatment (no/yes), or 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 investigational 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) 

investigational treatment dosage increased/reduced

investigational treatment interrupted/withdrawn 

concomitant medication or non-drug therapy given 

patient hospitalized/patient’s hospitalization prolonged 

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). This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. Any 
new information regarding the safety profile of the medicinal product that is identified 
between IB updates will be communicated as appropriate, for example, via an Investigator 
Notification or an Aggregate Safety Finding. New information might require an update to the 
informed consent and has then to be discussed with the patient.
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 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:


Novartis
Confidential
Page 83
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315

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 (specify what this includes)

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, e.g. 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.
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 it were 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.
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 following the last administration of study must 
be reported to Novartis within 24 hours of learning of its occurrence. Any SAEs experienced 
after the 30 day period following the last administration of study treatment should only be 
reported to Novartis if the investigator suspects a causal relationship to study treatment. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at 
a different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.


Novartis
Confidential
Page 84
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
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 study treatment a Drug Safety and 
Epidemiology (DS&E) Department associate may urgently require further information from 
the investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study 
treatment that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with European Union (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 (irrespective of whether classified/reported as (S)AE):

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 for complete definitions of liver laboratory triggers and liver events. 
Every liver laboratory trigger or liver event as defined in Table 14-1 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.
For the liver laboratory trigger:

Repeating the liver function test (LFT) within the next week to confirm elevation.
These LFT repeats must 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 must then be performed at central laboratory as soon as possible. If 


Novartis
Confidential
Page 85
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
a liver event is subsequently reported, any local LFTs previously conducted that are 
associated with this event must 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 must be recorded on appropriate CRF pages, including the liver 
event overview CRF pages.
7.4
Renal safety monitoring 
The following two categories of abnormal renal laboratory values have to be considered 
during the course of the study:

Serum event:

confirmed (after ≥24h) increase in serum creatinine of ≥25% compared to baseline 
during normal hydration status

Urine event

Albumin-creatinine ratio (ACR) ≥1g/g or ≥100 mg/mmol;

Protein-creatinine ratio (PCR )≥1g/g or ≥100 mg/mmol
Every renal laboratory trigger or renal event as defined in Table 17-1 should be followed up 
by the investigator or designated personnel at the trial site as summarized in Appendix 5. 
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 is provided in Appendix 3.


Novartis
Confidential
Page 86
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
Events with potential to be IDRs will be identified thorough a pre-specified search algorithm 
based on the Standardized MedDRA Queries as described in the study analysis plan. These 
events will be reviewed by the DMC on a regular basis.
7.6
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient or 
consumer (European Medicines Agency definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the DAR (dose administration record) eCRF irrespective of whether or not associated with an 
AE/SAE and reported to Safety only if associated with an SAE. Misuse or abuse will be 
collected and reported in the safety database irrespective of it being associated with an 
AE/SAE.
Treatment error 
type
Document in Dose 
Administration (DAR) 
eCRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with an 
SAE
Misuse/Abuse
Yes
Yes, 
Yes, even if not associated 
with a SAE
7.7
Pregnancy reporting 
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications.
Pregnancy must 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 study treatment.
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.


Novartis
Confidential
Page 87
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
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 Good Clinical Practice 
(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 Clinical Research Associate (CRA) organization, additionally; a central analytics 
organization may analyze data and identify risks and trends for site operational parameters, 
and provide reports to Novartis Clinical Teams to assist with trial oversight.
The investigator must maintain source documents for each 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/subjects will be disclosed.
8.2
Data collection 
Designated investigator staff will enter the data required by the protocol into the Oracle 
Clinical/Remote Data Capture (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. 


Novartis
Confidential
Page 88
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
8.3
Database management and quality control 
Novartis staff [or 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).
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).
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.
8.4
Data Monitoring Committee 
An independent, (DMC) will review safety data (including specific safety summaries for 
adolescent participants) from this study and other Phase 3 studies in the QAW039 asthma 
development program. The DMC consists 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 blinded to the interim results 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, because the primary purpose of the study is the assessment of long-term safety. 


Novartis
Confidential
Page 89
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
Therefore, no statistical adjustment will be made to the final analysis due to safety DMC 
reviews of the data. Full details on procedures for the DMC are specified in the DMC charter.
The charter for the Data Monitoring Committee (DMC) is available as a separate document. 
The DMC is the autonomous data and safety advisory group for Novartis. Novartis is
described as the “Sponsor” in the charter, though the Sponsor of the study in any particular 
country may in fact be an affiliate of this entity. 
The DMC charter defines: 
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 study 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.
8.5
Adjudication Committee 
Not required.
9
Data analysis 
The analysis will be conducted on all subject data at the time the trial ends. Any data analysis 
carried out independently by the investigator should be submitted to Novartis before 
publication or presentation. The reporting at the end of Treatment Period 1 will be solely 
based on all Treatment Period 1 data while the reporting at the end of Treatment Period 2 will 
be based on all the data from both Treatment Period 1 and Treatment Period 2. Analyses 
combining data from prior studies of QAW039 will not be a part of the clinical study report 
but may be presented as a part of the separate pooled analyses.
9.1
Analysis sets 
The screened set (SCR) will include all patients who provided informed consent.
The full analysis set (FAS) will include all randomized patients who received at least one dose 
of study drug during this study. Following the intent-to-treat principle, patients will be 
analyzed according to the treatment they were assigned to at randomization. 
The safety set (SAF) will include all patients who received at least one dose of study drug 
during this study. Patients will be analyzed according to the treatment they received during 
this study.


Novartis
Confidential
Page 90
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
The analysis of the primary and secondary safety variables will be performed on the SAF. The 
FAS will be used for the analysis of all 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.
Major protocol deviations will be defined in the data handling plan prior to database lock and 
the un-blinding of the study and will be listed.
9.2
Patient demographics and other baseline characteristics 
Baseline age will be defined as the age of the patient at study entry in Study A2315. For all 
other variables in patients completing a prior phase 3 study of QAW039, the baseline value 
from the prior study will be used as the baseline value for this study (Study A2315). For all 
variables in patients who have not previously participated in a study of QAW039, the last pre-
treatment assessment in the current study (Study A2315) will be used as the baseline value.
Patient demographics and baseline characteristics including age, sex, race, ethnicity, height, 
weight, body mass index (BMI), relevant medical history, smoking history, asthma duration, 
background therapies, pre- and post-bronchodilator FEV1, percent predicted FEV1, 
 
, number of exacerbations in the previous year prior to screening will be 
summarized by treatment group for the FAS. Categorizations of age will include at least the 
categories of <18 years of age and ≥18 years of age.
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 prior to study drug, taken concomitantly, and started following last study 
drug dose (if applicable) will be summarized by treatment group in separate tables for 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.
Usage of asthma medication (e.g., LABA, ICS) at baseline will be summarized. Usage of oral 
corticosteroids, 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 on the SAF.


Novartis
Confidential
Page 91
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
9.4.1
Variables
The primary variables for the study are:

Time-to-first treatment emergent AE;

Time-to-first treatment emergent SAE; and

Time-to-first treatment emergent AE leading to discontinuation from study treatment.
Adverse events (including asthma exacerbations), 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 
treatment emergent AEs. Any AEs that started during the study after informed consent and 
before the time of the first intake of study drug will be classified as a prior AE and not 
classified as treatment emergent AE. The time-to-first treatment emergent AE will be defined 
as the time to the occurrence of an AE from the treatment start date, and will be computed as 
time to AE=AE start date-treatment start date+1 day. Treatment emergent SAEs and AEs 
leading to discontinuation from study treatment will be defined in a similar manner. 
9.4.2
Statistical model, hypothesis, and method of analysis
The time-to-first treatment emergent AE will be considered from the start of Study A2315 
only and the clinical study report will be based solely on the data from Study A2315. 
The primary variable will be analyzed by a Cox regression model stratified by randomization 
stratum (but not by region):

patients on QAW039 150 mg once daily treatment in Studies QAW039A2307 and
QAW039A2314,  

patients on QAW039 450 mg once daily treatment in Studies QAW039A2307 and
QAW039A2314, 

patients on placebo in Studies QAW039A2307 and QAW039A2314, 

patients on QAW039 150 mg once daily treatment in Studies QAW039A2316 and 
QAW039A2317, 

patients on placebo in Studies QAW039A2316 and QAW039A2317, 

patients who have not previously participated in a study of QAW039, 
and treatment group, severity of asthma (GINA treatment steps 3, 4 and 5), and region as 
fixed class effects. 
Hazard ratios comparing QAW039 450 mg once daily, QAW039 150 mg, once daily, and 
placebo treatments with regard to time to first treatment emergent AEs and their 
corresponding 95% profile likelihood confidence intervals will be presented. The other 
primary variables, treatment emergent SAEs and AEs leading to study treatment 
discontinuation, will be analyzed in a similar fashion. 
The detailed statistical analysis plan will pre-specify how strata would be pooled for analysis 
purposes, if this is necessary. 
The same analyses will be performed based on the Treatment Period 1 data and based on the 
entirety of the study (Treatment Period 1 and Treatment Period 2 combined). A multiplicity 
adjustment for these two separate assessments is not foreseen.


Novartis
Confidential
Page 92
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
Summary statistics for the primary variable
The primary variables will be summarized for the SAF by treatment group in terms of the 
number of patients experiencing a treatment emergent AE, as well as the exposure-adjusted 
incidence rate (patients with treatment emergent AEs per patient year of follow-up to first 
event [AE or censoring]). The duration of on-treatment follow-up in years will be calculated 
for each patient as (treatment end date - treatment start date + 2 days)/365.25 without taking 
into account treatment interruptions. Summaries of the other primary variables, treatment 
emergent SAEs and AEs leading to study treatment discontinuation, will be similarly 
presented.  Additionally, incidence rates may be compared with epidemiological background 
rates in appropriately matched populations.
Estimates of the cumulative incidence of the primary outcomes will be displayed graphically 
for the SAF.
9.4.3
Handling of missing values/censoring/discontinuations
Patients that do not experience a treatment emergent AE prior to study end or the day after 
treatment discontinuation will be considered censored at the time of study end or the day after 
the last intake of study drug. For the analysis of the 52-week data from Treatment Period 1, 
patients without a treatment emergent AE during Treatment Period 1 will be considered 
censored on the day after their last intake of study drug in Treatment Period 1 or on the day of 
the completion visit (Visit 299) in Treatment Period 1, if the patient continued into Treatment 
Period 2.
The primary Cox regression model will implicitly impute the censored data under the 
assumption of independent censoring (conditional on the baseline covariates). That is, a 
censored patient is assumed to be no more or less likely to experience an event in any future 
time interval than other patients in the same stratum that continue to be at risk for a first event 
and that have the same model covariates. The implied assumption of a continued treatment 
effect after treatment discontinuation is considered conservative for the purpose of the 
evaluation of safety outcomes that are assumed to be more likely to occur while active 
treatment is ongoing. The sensitivity analyses described in Section 9.4.4 will evaluate the 
impact of these assumptions on the trial conclusions.


Novartis
Confidential
Page 93
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
9.5
Analysis of secondary variables
9.5.1
Efficacy variables 
The primary and secondary objectives of the study are based on safety variables and hence no 
efficacy variables are stated in this section.
9.5.2
Safety variables 
All safety data will be summarized for the SAF.
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 data based safety data 
will be listed. 
Secondary safety endpoints
The secondary endpoint of the rate of patients with at least one treatment emergent AE by 
primary system organ class will be presented descriptively and analyzed using a Cox 
regression model in a similar manner as the primary endpoint. A supportive analysis on the 
rate of patients with at least one AE by primary system organ class will be conducted 
similarly including all AEs starting on or after the time of the first intake of study drug (i.e., 
treatment emergent AEs and AEs occurring during the post-treatment follow-up).
The secondary endpoint of the rate of treatment emergent patient deaths and patient 
hospitalizations (any visit to the hospital requiring an overnight stay or an emergency room 
visit greater than 24 hours) due to an asthma exacerbation will be analyzed using a negative 
binomial regression model. The model will include randomization stratum (as in the analysis 
on primary endpoint), treatment group, severity of asthma (GINA steps 3, 4 and 5), and region 
as fixed class effects, with the natural logarithm of the duration of on-treatment follow-up in 
years as an offset variable. The duration of on-treatment follow-up in years will be calculated 


Novartis
Confidential
Page 94
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
for each patient as (treatment end date - treatment start date + 2 days)/365.25 without taking 
into account treatment interruptions. A supportive analysis of the rate of patient deaths and 
patient hospitalizations due to asthma exacerbations treatment emergent and after treatment 
discontinuation will be conducted similarly with the natural logarithm of the duration of 
follow-up in years as an offset variable. 
In addition to the inferential analysis, summary statistics on the secondary safety variables 
will be presented as described below.
Adverse events
Adverse events after informed consent including asthma exacerbations will be summarized 
and listed. Summaries will include the number of patients with an event, exposure-adjusted 
incidence rates (patients with an event per patient year of follow-up to first event or censoring) 
and the percentage of patients with an event.
The following treatment emergent AE summaries will be produced:

overall by system organ class and preferred term, 

overall by system organ class, preferred term and maximum severity, 

suspected drug-related AEs by system organ class and preferred term, 

SAEs by system organ class and preferred term, and 

AEs leading to permanent discontinuation of study-drug by system organ class and 
preferred term. 
Additionally, 
summaries 
including 
both 
treatment 
emergent 
and 
post-treatment 
discontinuation events will be produced for AEs and SAEs by system organ class and 
preferred term. Similarly, summaries will also be presented on patient deaths and patient 
hospitalizations (any visit to the hospital requiring an overnight stay or an emergency room 
visit greater than 24 hours) due to an asthma exacerbation.
The number and percentage of patients with treatment emergent AEs of special interest (e.g., 
IDRs), 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 regressions 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 study.
Vital signs
On-treatment data from the vital signs (body temperature, 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) will 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.


Novartis
Confidential
Page 95
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
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, scheduled 
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: 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 
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. 


Novartis
Confidential
Page 96
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315


Novartis
Confidential
Page 97
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
9.7
Interim analyses
As described in Section 3.5, periodic unblinded safety reviews by the DMC (see Section 8.4) 
using data (including specific safety summaries for adolescent participants) from this study 
and other Phase 3 studies in the QAW039 asthma development program will be conducted. 
No stopping for demonstrated efficacy or safety prior to the completion of the study is 
foreseen, because the purpose of the study is to assess long-term safety. Thus, no statistical 
adjustment will be made to any of the interim analyses or the analysis after all patients have 


Novartis
Confidential
Page 98
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
completed the study. No adjustment is foreseen to account for these two reporting times. To 
support the worldwide registration of QAW039 and to address health authority requests, 
interim analyses are foreseen and the results may be submitted to health authorities. Interim 
analyses will focus on presentation of safety data, including partial data for patients ongoing 
in the study; analyses on efficacy endpoints will not be performed. After all patients have 
completed or discontinued Treatment Period 1, a report based on Treatment Period 1 data will 
be produced and results may be published.
9.8
Sample size calculation
Approximately 1000 patients are expected to complete prior QAW039 Phase 3 studies and 
join the current Study A2315, based on the following assumptions.

In the prior QAW039 Phase 3 studies, 85% of randomized patients are expected to 
complete the prior study and eligible for participation in the current study.

It is estimated that 50% of those eligible patients from Studies A2307 and A2314 will 
enter in the current study.

It is estimated that 25% of those eligible patients from Studies A2316 and A2317 will 
enter in the current study.
New patients (i.e., patients who have not previously participated in a study of QAW039) will 
also be recruited according to local regulatory requirements in certain countries. It is currently 
anticipated that approximately 570 newly recruited patients will be enrolled in the current 
study. Thus, the anticipated total sample size of this study is approximately 1,570 patients.
This number of patients participating in the safety study will ensure 6-month exposure for 
each QAW039 dose clearly across the whole Phase 3 program in excess of the 300 to 600 
patients (as well as in excess of 100 patients exposed for at least 1 year) suggested by ICH E1 
at the time of the first regulatory submission for QAW039. The number of new patients and 
total patients may be subject to change depending on the actual participation of patients from 
prior QAW039 Phase 3 studies, the actual dropout rate in the current study and the local 
regulatory requirements.
While no formal hypothesis testing is foreseen for the primary safety objectives, if both 
QAW039 doses have a 50% relative hazard increase for treatment emergent events, compared 
with placebo, then there will be approximately > 99%, 94% and 38% power that the two-sided 
95% confidence interval not adjusted for multiplicity for one of the two QAW039 doses 
would exclude no effect for the primary safety variables of time-to-first treatment emergent
AE, time-to-first treatment emergent SAE, and time-to-first treatment emergent AE leading to 
study treatment discontinuation analyzed across Treatment Period 1 and Treatment 2 
combined, respectively. The power was estimated using 10,000 simulations based on 1,570
patients being randomized into the current study. In addition, the sensitivity of the power is 
further assessed for different scenarios of sample size (1470 patients and 1670 patients).This 
power will be higher, if more patients are randomized (e.g., due to additional new patients 
being enrolled) or more patients completing prior Phase 3 studies of QAW039 elect to 
participate in the current study. 


Novartis
Confidential
Page 99
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
The underlying assumptions for the power simulations were an exponential censoring rate in 
the placebo group of 0.22 and of 0.16 in the QAW039 treatment groups. The assumptions on 
the exponential event rate in each treatment group are shown in Table 9-1. These assumptions 
are based on the, DREAM (Pavord et al. 2012) and MENSA (Ortega et al. 2014) trials, as 
well as a QAW039 Phase 2 study in moderate-to-severe asthma. The detailed power 
calculations are shown in the Table 9-2 and Table 9-3. 
Table 9-1 
Assumed placebo event rates for power calculations
Endpoint
Previous study patients were 
enrolled in or new patients
Assumed 
exponential 
event rate (per patient-
year)
Rate of AEs
QAW039A2316/
QAW039A2317
3.01
QAW039A2307/ 
QAW039A2314
2.86
New patients
2.86
Rate of SAEs
QAW039A2316/
QAW039A2317
0.07
QAW039A2307/ 
QAW039A2314
0.24
New patients
0.24
Rate of AEs leading to study treatment
discontinuation
QAW039A2316/
QAW039A2317
0.03
QAW039A2307/ 
QAW039A2314
0.03
New patients
0.03


Novartis
Confidential
Page 100
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
Table 9-2
Power (%) for a non-multiplicity adjusted confidence interval to 
exclude no-difference versus placebo for the primary safety variables 
Primary Endpoint
Treatment 
Period
QAW039 150 
mg versus 
placebo
QAW39 450 
mg versus 
placebo
Both QAW039 150 
mg and 450 mg 
versus placebo
One of the 
two 
QAW039 
doses 
versus 
placebo
Time-to-first AE
1
>99
>99
>99
>99
1 & 2
>99
>99
>99
>99
Time-to-first SAE
1
65
65
54
76
1 & 2
89
89
84
94
Time-to-first AE 
leading to study
treatment 
discontinuation
1
16
16
9
22
1 & 2
29
28
19
38
Power results are based on the sample size of 1570 randomized patients (1000 rollover patients plus 
570 new patients).
Simulations were performed in SAS 9.4.
Table 9-3
power (%) for a non-multiplicity adjusted confidence interval to 
exclude no-difference versus placebo for the primary safety variables 
based on different sample size scenarios
Primary Endpoint
Treatment 
Period
QAW039 150 
mg versus 
placebo
QAW39 450 
mg versus 
placebo
Both QAW039 150 
mg and 450 mg 
versus placebo
One of the 
two 
QAW039 
doses 
versus 
placebo
Time-to-first AE
1
>99
>99
>99
>99
>99
>99
>99
>99
1 & 2
>99
>99
>99
>99
>99
>99
>99
>99
Time-to-first SAE
1
62
68
62
68
50
57
73
79
1 & 2
87
92
87
91
81
87
93
96
Time-to-first AE 
leading to study 
treatment 
discontinuation
1
14
17
14
16
8
10
21
23
1 & 2
27
30
27
30
17
20
36
40
Power results in the upper rows are based on the sample size of 1470 randomized patients (1000 
rollover patients plus 470 new patients).
Power results in the lower rows are based on the sample size of 1670 randomized patients (1000 
rollover patients plus 670 new patients).
Simulations were performed in SAS 9.4.


Novartis
Confidential
Page 101
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
10
Ethical considerations 
10.1
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in 
accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with 
applicable local regulations (including European Directive 2001/20/EC, US CFR 21, and 
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/subjects 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 must be informed 
about the study to the extent possible given his/her understanding. If the patient is capable of 
doing so, he/she must 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 (e.g. all of the procedures described in the protocol). 
The process of obtaining informed consent must be documented in the patient source 
documents. 
For trials using an Electronic Informed Consent system where a date/timestamp is 
automatically generated, the system-generated date/timestamp is sufficient; additional input of 
the date at the time of consent is not required by the patient. 
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 must be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
must not be entered in the study.
10.3
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment 
procedures (e.g., advertisements) and any other written information to be provided to 
patients/subjects. Prior to study start, the investigator is required to sign a protocol signature 


Novartis
Confidential
Page 102
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
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
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 Assurance 
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.
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 standard operating procedures (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/subjects 
should be administered as deemed necessary on a case by case basis. Under no circumstances 
is an investigator allowed to collect additional data or conduct any additional procedures for 
any research related purpose involving any investigational drugs under the protocol.
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. 
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 


Novartis
Confidential
Page 103
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
hazard to patients/subjects 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 must be followed.
12
References 
References are available upon request.
ATS (2000) Proceedings of the ATS workshop on refractory asthma: current understanding, 
recommendations, and unanswered questions. Am J Respir Crit Care Med; 162: 2341-51.
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.
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 elevated blood eosinophil counts: results from two, multicentre, parallel, double-
blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med; Published Online: 
23 February 2015.
Cdc.gov, 
(2000). 
Growth 
Charts 
-
Homepage. 
[online] 
Available 
at: 
http://www.cdc.gov/growthcharts/ [Accessed 26 Feb. 2016].
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.
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.
Jacobson TA (2008) Toward “pain-fee” statin prescribing: clinical algorithm for diagnosis
and management of myalgia. Mayo Clin Proc; 83: 687-700.


Novartis
Confidential
Page 104
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
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.
 
 
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.
 
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.


Novartis
Confidential
Page 105
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
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.


Novartis
Confidential
Page 106
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
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.  See Appendix 5 for specific renal alert Criteria and actions
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 107
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
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 treatment 
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 treatment 
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 treatment 
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

If elevation persists for more than 2 
weeks, discontinue the study drug

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)


Novartis
Confidential
Page 108
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
Criteria
Actions required
Follow-up monitoring
> 3 × ULN 
accompanied by 
symptomsb

Discontinue the study treatment 
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 treatment 
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 treatment 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 109
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
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 110
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
16
Appendix 4: Spirometry Guidance
Equipment
Spirometers must meet the specifications and performance criteria recommended in the 
American Thoracic Society (ATS)/European Respiratory Society (ERS) Standardization of 
Spirometry1. Spirometers must have the capacity to print FVC tracings.  All spirometry values 
should be reported at 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.  
Number of trials
A minimum of 3 acceptable forced vital capacity (FVC) maneuvers should be performed.  If a 
subject is unable to perform a single acceptable maneuver after 8 attempts, testing may be 
discontinued. 


Novartis
Confidential
Page 111
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
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 FVC and 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 at Visit 1, patient may be 
rescreened or allow one spirometry retest. 
Recording of data
The greatest FEV1 and FVC from any of the acceptable curves are recorded. (The greatest 
FEV1 and FVC may not necessarily result from the same acceptable curve).  
Predicted normal
For all subjects, this study will utilize the global lung function 2012 spirometric prediction 
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 a witheld period as indicated in Table 5-2.
Administer 400µg of salbutamol/albuterol (or equivalent) following the completion of the pre-
bronchodilator assessment*. Post-bronchodilator spirometry assessment is then performed 
approximately 10 to 15 minutes after administration of the salbumatol/albuterol. 
Reversibility is calculated as: 
100 x       FEV1 (post-bronchodilator) – FEV1 (pre-bronchodilator)*
                                     FEV1 (pre-bronchodilator)*
Subjects will be considered reversible if an increase of at least 12% (and 200 ml) is
demonstrated after administration of the salbutamol/albuterol.


Novartis
Confidential
Page 112
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
 
 
 
16.1
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 113
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
17
Appendix 5: Specific Renal Alert Criteria and Actions
Table 17-1
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 study treatment 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 study treatment interruption / or discontinuation 
For all renal events:
Document contributing factors in the CRF: co-medication, other co-morbid conditions, and additional diagnostic 
procedures performed 
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 114
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315
18
Appendix 6: 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 115
Amended Protocol Version v01 – Clean
Protocol No. CQAW039A2315

SAP_000.pdf: 
Clinical Development
QAW039/Fevipiprant
CQAW039A2315 / NCT03052517
A 2-treatment period, randomized, placebo-controlled, 
multicenter parallel-group study to assess the safety of 
QAW039 when added to existing asthma therapy in GINA 
steps 3, 4 and 5 patients with uncontrolled asthma
Statistical Analysis Plan (SAP)
Author:
Trial Statistician, 
Document type:
SAP Amendment 3
Document status:
Final
Release date:
21-Mar-2020
Number of pages:
47
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
CQAW039A2315
Document History – Changes compared to previous final version of SAP
Date
Time
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
July 
12, 
2017
Amd 
0.1
draft
Core 
study 
2319 
cancelled 
Remove the 2319 related content and 
modify the comparisons for continued 
therapy, 
withdrawal 
therapy 
and 
change of doses. 
Aug 
18, 
2017
0.2
Country 
list 
and 
background 
therapy 
definition
Define the subgroup of background 
therapy as double therapy, triple 
therapy and other. Update the country 
list.
Sep
2, 
2018
Amd 
0.3 
draft
Protocol 
amendment
 
 
 
Align 
with 
A2307/A2314, 
A2316/A2317 
SAP wherever 
possible
Remove shift table analysis
Only 
cover 
first IA in this 
document
Specify the scope of analysis
Nov 
30, 
2018
Amd 
0.4 
draft
Subgroup
Revise the subgroups of interest.
Dec 
30, 
2018
Amd 
0.5 
draft
Analysis 
scope 
and 
DDI analysis
Analysis scope is updated to include the 
possibility of multiple data cuts based 
on country specific needs. DDI analysis 
is removed as it will be covered in the 
SCS.
Jan 
23, 
2019
Amd 
1
Final
Nov 
20, 
2019
Amd 
2
Updated 
based on dry 
run comments
Created modified full analysis set  


Novartis
For business use only
Page 3
SAP
CQAW039A2315
Date
Time
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
Mar 
16, 
2020
Amd 
3
Removed 
IA 
related 
wording, 
subgroup 
analyses 
of 
safety 
variables, and 
additional 
cuts at Week 
26 and Week 
52


Novartis
For business use only
Page 4
SAP
CQAW039A2315
Table of contents
Table of contents .................................................................................................................4
List of abbreviations............................................................................................................6
1
Introduction .........................................................................................................................7
1.1
Study design.............................................................................................................7
1.1.1
Study Design ...........................................................................................7
1.1.2
Randomization scheme ...........................................................................8
1.2
Study objectives and endpoints ...............................................................................9
1.2.1
Primary Objective ...................................................................................9
1.2.2
Secondary objective(s)............................................................................9
10
2
Statistical methods.............................................................................................................10
2.1
Data analysis general information .........................................................................10
2.1.1
General definitions................................................................................10
12
2.2
Analysis sets ..........................................................................................................13
2.2.1
Subgroup of interest ..............................................................................13
2.3
Patient disposition, demographics and other baseline characteristics ...................14
2.3.1
Patient disposition.................................................................................14
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................15
2.4.1
Study treatment / compliance................................................................15
2.4.2
Prior, concomitant and post therapies...................................................15
2.5
Analysis of the primary objective..........................................................................16
2.5.1
Primary endpoint...................................................................................16
2.5.2
Statistical hypothesis, model, and method of analysis..........................19
2.5.3
Handling of missing values/censoring/discontinuations.......................19
2.6
Analysis of the key secondary objective ...............................................................20
2.7
Analysis of secondary efficacy objective(s)..........................................................20
2.8
Safety analyses.......................................................................................................20
2.8.1
Adverse events (AEs)............................................................................20
2.8.2
Deaths....................................................................................................22
2.8.3
Laboratory data .....................................................................................22
2.8.4
Other safety data ...................................................................................26
2.8.5
Renal events ..........................................................................................29
2.8.6
Liver events...........................................................................................29
29


Novartis
For business use only
Page 5
SAP
CQAW039A2315
29
.29
29
30
30
32
33
33
2.14
Other Interim analyses...........................................................................................34
3
Sample size calculation .....................................................................................................34
4
Change to protocol specified analyses ..............................................................................37
38
38
38
39
6
Appendix ...........................................................................................................................39
6.1
Imputation rules.....................................................................................................39
6.1.1
Study drug.............................................................................................39
6.1.2
AE date imputation ...............................................................................39
6.2
AEs and Concomitant medications coding/grading ..............................................42
42
42
44
6.4
Background asthma therapy ..................................................................................45
6.4.1
Prednisone equivalent OCS doses.........................................................45
6.5
Rule of exclusion criteria of analysis sets..............................................................46
6.6
Atopic and non-atopic status .................................................................................46
7
Reference...........................................................................................................................46


Novartis
For business use only
Page 6
SAP
CQAW039A2315
List of abbreviations
AE
Adverse event
ATC
Anatomical Therapeutic Classification
AUC
Area Under the Curve
Bid
bis in diem/twice a day
CM
Concomitant Medication
CSR
Clinical Study report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data Monitoring Committee 
FAS
Full Analysis Set
eCRF
Electronic Case Report Form
IA
Interim analysis
IVR
Interactive Voice Response
IWR
Interactive Web Response
MedDRA
Medical Dictionary for Drug Regulatory Affairs
NCI
National Cancer Institute
o.d.
Once Daily
OS
Overall Survival
PFS
Progression-Free Survival
PK
Pharmacokinetics
PPS
Per-Protocol Set
PRO
Patient-reported Outcomes
qd
Qua’que di’e / once a day
QoL
Quality of Life
RAP
Report and Analysis Process
RECIST
Response Evaluation Criteria in Solid Tumors 
SAP                     Statistical Analysis Plan
SCS
Systemic corticosteroid
SOC
System Organ Class
TFLs
Tables, Figures, Listings
WHO
World Health Organization


Novartis
For business use only
Page 7
SAP
CQAW039A2315
1
Introduction
This document contains details of the statistical methods that will be used in the final analysis 
of phase III clinical trial CQAW039A2315. Data will be analyzed 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
1.1.1
Study Design
This study is a 2-treatment period, randomized, multicenter parallel-group safety study (Figure 
1-1). Treatment Period 1 is a 52-week, double-blind treatment period in which QAW039 or 
placebo is added to Global Initiative of Asthma (GINA) steps 3, 4 and 5 standard-of-care (SoC) 
asthma therapy. Treatment Period 2 is an optional 104-week, single-blind treatment period in 
which patients will receive QAW039 or placebo added to GINA steps 3, 4 and 5 SoC asthma 
therapy. 
Note: For the purpose of this study, single-blind means investigators and patients will remain 
blinded while all Novartis personnel will be unblinded.
Two categories of patients will be enrolled:

Rollover patients: patients completing a prior Phase 3 study (A2307, A2314, A2316, or 
A2317) of QAW039 on active study treatment (i.e., did not discontinue blinded study 
treatment prematurely); and
New patients: patients with inadequately controlled asthma who had not previously 
participated in a study of QAW039. 
Patients who successfully complete the treatment period of a prior Phase 3 study of QAW039 
will be permitted to enter Study A2315 directly upon the completion of the treatment period of 
the prior study without completing an off drug follow-up period in the prior study. For these 
patients completing a prior Phase 3 study of QAW039, the last visit of the treatment period in 
the prior study and Visit 1 of Study 2315 will occur on the same day (i.e., on the last day of 
study drug treatment in the prior study). Additionally, for patients completing a prior Phase 3 
study of QAW039, Visit 201 of Study 2315 will occur the following day (1 day after completion 
of the last visit of the treatment period of the prior study and Visit 1 of this study [Study A2315]) 
so that there is no interruption in study drug treatment. 


Novartis
For business use only
Page 8
SAP
CQAW039A2315
Figure 1-1
Study design
1.1.2
Randomization scheme
Overall, there is an approximately 85% chance patients will receive QAW039 in Study 
A2315. For patients who participated in a prior Phase 3 study, there is at least 57% chance 
a patient will remain on the same QAW039 dose they received in the prior study in Study 
A2315. 
Table 1-1 shows the randomized allocation of patients into treatment groups in Study A2315.
Table 1-1 Randomized Allocation of Patients into Treatment groups
Patients completing A PRIOR PHASE 3 STUDY OF QAW039: treatment allocation in Study 
A2315
Prior study
Treatment group in prior 
study
Randomization ratio in 
Study A2315
Treatment group in Study 
A2315
CQAW039A2307
CQAW039A2314
450 mg once daily
5
QAW039 450 mg once daily
1
QAW039 150 mg once daily
1
Placebo
150 mg once daily
1
QAW039 450 mg once daily
5
QAW039 150 mg once daily
1
Placebo
Placebo
3
QAW039 450 mg once daily
3
QAW039 150 mg once daily
1
Placebo
CQAW039A2316
CQAW039A2317
150 mg once daily
2
QAW039 450 mg once daily
4
QAW039 150 mg once daily
1
Placebo


Novartis
For business use only
Page 9
SAP
CQAW039A2315
Placebo
4
QAW039 450 mg once daily
2
QAW039 150 mg once daily
1
Placebo
Patients who HAVE NOT PREVIOUSLY PARTICIPATED IN A STUDY OF QAW039: treatment 
allocation in Study A2315
Prior study
Treatment group in prior 
study
Randomization ratio in 
Study A2315
Treatment group in Study 
A2315
Not applicable
Not applicable
3
QAW039 450 mg once daily
3
QAW039 150 mg once daily
1
Placebo
Treatment randomization will be stratified at the regional level.
1.2
Study objectives and endpoints
1.2.1
Primary Objective
Treatment Period 1 (52-week treatment period):
In patients with moderate-to-severe asthma receiving SoC asthma therapy, to evaluate the 
long-term safety of QAW039 (150 mg once daily and 450 mg once daily), compared with 
placebo, as assessed by:

treatment emergent adverse events (AEs);

treatment emergent serious adverse events (SAEs); and

study treatment discontinuations due to treatment emergent AEs.
Treatment Period 1 and Treatment Period 2 combined:
In patients with moderate-to-severe-asthma receiving SoC asthma therapy, to evaluate the 
long-term safety of QAW039 (150 mg once daily and 450 mg once daily), compared with 
placebo, as assessed by:

treatment emergent AEs

treatment emergent SAEs; and

study treatment discontinuations due to treatment emergent AEs.
1.2.2
Secondary objective(s)
Treatment Period 1 (52-week treatment period):
In patients with moderate-to-severe asthma receiving SoC asthma therapy, to evaluate the 
long-term safety of QAW039 (150 mg once daily and 450 mg once daily), compared with 
placebo, as assessed by:

the rate of patients with at least 1 treatment emergent AE by primary system organ class; 
and

the rate of treatment emergent patient deaths and patient hospitalizations (any visit to the 
hospital requiring an overnight stay or an emergency room visit greater than 24 hours) due 
to an asthma exacerbation.


Novartis
For business use only
Page 10
SAP
CQAW039A2315
Treatment Period 1 and Treatment Period 2 combined:
In patients with moderate-to-severe-asthma receiving SoC asthma therapy, to evaluate the 
long-term safety of QAW039 (150 mg once daily and 450 mg once daily), compared with 
placebo, as assessed by:

the rate of patients with at least 1 treatment emergent AE by primary system organ class; 
and

the rate of treatment emergent patient deaths and patient hospitalizations (any visit to the 
hospital requiring an overnight stay or an emergency room visit greater than 24 hours) due 
to an asthma exacerbation.
2
Statistical methods
2.1
Data analysis general information
2.1.1
General definitions 
2.1.1.1
Study 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

Name: placebos to QAW039 150 mg and QAW039 450 mg 

Formulation: tablet


Novartis
For business use only
Page 11
SAP
CQAW039A2315

Unit dose: matching placebo to QAW039 150 mg, matching placebo to QAW039 
450mg
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. No additional maintenance asthma treatment beyond investigational treatment will 
be provided for this trial.
Hence for this study the investigational treatment will be referred to as study treatment/drug.
The date of the first administration of the investigational treatment (QAW039 or matching 
placebo) in Study A2315 is referred to as the date of first administration of study treatment in 
the study.
2.1.1.2
Study day
The first day of administration of randomized study treatment (first dose) is defined as Day 1. 
All other study days will be labeled relative to Day 1.  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.
2.1.1.3
Baseline definition
Baseline age will be defined as the age of the patient at study entry in Study A2315 for all 
patients. Baseline values of other variables are defined as follows for rollover patients and new 
patients, respectively.
Rollover patients: For laboratory, vital signs, and ECG variables, the last pre-treatment 
assessment in current study (A2315 baseline) will be used as a primary baseline value for safety 
monitoring purpose, and prior study baseline (i.e., the baseline value from the previous 
QAW039 Phase 3 study) will be used as a supplementary baseline value. For other variables, 
prior study baseline will be used. 
New patients: the last pre-treatment assessment in the current study will be used as the baseline 
value.
Post-baseline measurements are defined as those assessments on or after the start of study 
treatment in Study A2315.  


Novartis
For business use only
Page 12
SAP
CQAW039A2315
2.1.1.4
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.
2.1.1.5
Study completion and last contact
A patient will be considered to have completed the study when the patient has completed the 
last visit planned in the protocol.
Study completion for a patient can occur after he/she has completed 52 weeks of treatment in 
Treatment Period 1, or after the additional 104 weeks of treatment in optional Treatment Period
2 (total of 156 weeks of treatment) or if they have prematurely withdrawn. Completion of the 
study will be when all randomized patients have met the definition of study completion 
described above and have completed the post-treatment follow-up visit.
For all patients/subjects a safety follow-up visit (visit 401) should be conducted (e.g. by 
telephone) 30 days after last visit (299, Week 52 for patients not continuing into Treatment 
Period 2 and visit 399, week 156 for patients completing Treatment Period 2). 
The maximum of the date of last visit, date of last phase completion, date of withdrawal of 
consent would be the date of last contact for the patient participating in the study.
2.1.1.6
Data pooling 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 occurred 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. 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 scheduled visit, it will be treated as an unscheduled 
visit that does not appear in by-visit summaries.


Novartis
For business use only
Page 13
SAP
CQAW039A2315
 
 
2.2
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 to the study. 
Following the intent-to-treat principle, patients will be analyzed according to the treatment 
they were assigned to at randomization. 
The full analysis set (FAS) will include all randomized patients who received at least one dose 
of study drug during this study. Following the intent-to-treat principle, patients will be analyzed 
according to the treatment they were assigned to at randomization. 
The modified full analysis set (mFAS) will include all randomized patients in the FAS who 
either rolled over from Study A2307 or A2314 or were newly randomized. This analysis set
consists of a more homogeneous group of patients with moderate-severe asthma.
The safety set (SAF) will include all patients who received at least one dose of study drug during 
this study. Patients will be analyzed according to the treatment they received during this study.
If patients switch double-blind treatment during the study, they will be analyzed according to 
the treatment they have been randomized to.
The analysis of the primary and secondary safety variables will be performed on the SAF. The 
mFAS will be used for the analysis of all 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.
Protocol deviations will be defined in the data review plan document prior to database lock.
2.2.1
Subgroup of interest
Subgroup analyses will be performed for summaries of treatment emergent AE incidence rate 
and exposure adjusted AE incidence rate
:
 
 
 


Novartis
For business use only
Page 14
SAP
CQAW039A2315
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 China will be considered as the Chinese patients. 
Separate analyses on Chinese patients will be performed and the specific outputs will be marked 
by suffix ‘C’ in the study TFL shells. Patients randomized to the study in the sites in China, 
Japan, Taiwan, and Korea will be considered as Asian patients. Separate analyses on Asia 
region subgroup will be performed and the specific outputs will be marked by suffix ‘AS’ in 
the study TFL shells.
2.3
Patient disposition, demographics and other baseline 
characteristics
Patient demographics and baseline characteristics including age, sex, race, ethnicity, height, 
weight, body mass index (BMI), relevant medical history, smoking history, asthma duration, 
background therapies, pre- and post-bronchodilator FEV1,
, percent predicted 
FEV1, 
, number of exacerbations in the previous year prior to screening
will be summarized by treatment group for the SAF. Categorizations of age will include the 
categories of <18 years, >=18- <65 years and >=65 years of age. For rollover patients, 
summaries mentioning the number of patients who were adolescents (< 18 years age) at the start 
of the previous Phase 3 study but are adults (>= 18 years age) at the start of study A2315 will 
also be presented. 
For rollover patients, relevant medical histories and adverse events that started and stopped in 
the prior phase 3 study will be recorded in Medical History CRF page of this study per 
investigator’s judgement. Ongoing AEs in the prior phase 3 study will be recorded in Prior 
Study Adverse Event Outcome CRF page of this study and considered as medical history. 
2.3.1
Patient disposition
The number of patients screened, randomized, completed and discontinued from the study (in 
overall treatment period, treatment period 1 and treatment period 2 separately) will be 
summarized on overall population and by source of patients (i.e., rollover patients from Study 
A2307/A2314, rollover patients from Study A2316/A2317, and new patients). In addition, a
similar summary for overall population will be provided by country. Overall treatment period 
is defined as combined treatment period 1 and treatment period 2 (treatment period 1 only in 
the case of patients not continuing into treatment period 2). Patients discontinued from the study 
will be summarized with reasons for discontinuation. Rescreening information will also be 
summarized mentioning the number of patients who were rescreened and how many of them 
were randomized.
Time to study discontinuation will be displayed graphically for each treatment group by source 
of patients using a Kaplan-Meier curve for the FAS. The date of study discontinuation is defined 
as the maximum of the last known visit date in treatment period and the date of last dose of 
study medication. Patients who completed the study will be censored at the final visit.
Number of patients with protocol deviations and protocol deviations that lead to exclusion from 
analysis sets will be tabulated by deviation category and treatment group for the RAN. 


Novartis
For business use only
Page 15
SAP
CQAW039A2315
The number of patients included in each analysis set will be tabulated by treatment group on
overall population and by source of patients on the RAN. Reasons for exclusions from analysis 
sets will be tabulated. Patient exclusion from analysis sets will be listed for all patients with 
reasons for exclusion (including protocol deviations).
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
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 on overall population, by source of patients, by source of 
patients and prior treatment in a prior Phase 3 study. 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 for each treatment while compliance will be 
presented by treatment arm for each of the bottles separately.
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 – <12 weeks, ≥12 – <26 weeks, ≥26 – <52 weeks, ≥52 – <104
weeks, ≥104 – <156 weeks, ≥156 weeks.
Patients in the randomized set who received any wrong study medications 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.
Study compliance will be calculated as the percentage of days with study medication intake 
(taking into account the duration of the drug interruptions) during the period from first intake 
to last intake.
Study compliance = 100 x number of days with study medication intake as per protocol/ (Day 
of the last treatment – Day 1 +1). 
Compliance will be categorized as <80%, 80% -100%, and summarized by treatment arm and 
source of patients for each of the bottles separately based on the SAF.
2.4.2
Prior, concomitant and post therapies
Medications started prior to study drug in Study A2315, taken concomitantly in Study A2315, 
and started following last study drug dose (if applicable) in Study A2315 will be summarized 
by treatment group in separate tables for the SAF. The medication will be classified into “prior”, 
“concomitant” based on the start/end dates.
Prior: Any medication with a start date before Day 1 in Study A2315.


Novartis
For business use only
Page 16
SAP
CQAW039A2315
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 on or before the end of the treatment .
Post: Any medication with start date after the end of treatment, including medications taken in 
the follow-up period. Medications can be considered both prior and concomitant.
Concomitant therapies will be recorded 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.
Patients taking prohibited concomitant medications will be noted in the summary of protocol 
deviations.
2.5
Analysis of the primary objective
2.5.1
Primary endpoint
Primary endpoints for the study are:
Treatment Period 1:

Time-to-first treatment emergent adverse events (AEs);

Time-to-first treatment emergent serious adverse events (SAEs); and

Time-to-first treatment emergent AE leading to discontinuation from study treatment.
of  QAW039 (150 mg once daily and 450 mg once daily), compared with placebo in patients 
with moderate-to-severe asthma receiving SoC asthma therapy.
Treatment Period 1 and Treatment Period 2 combined:

Time-to-first treatment emergent adverse events (AEs);

Time-to-first treatment emergent serious adverse events (SAEs); and

Time-to-first treatment emergent AE leading to discontinuation from study treatment.
of  QAW039 (150 mg once daily and 450 mg once daily), compared with placebo in patients 
with moderate-to-severe asthma receiving SoC asthma therapy.
As this study has been early terminated, the primary endpoint will be analyzed in the way of 
combined treatment period 1 and treatment period 2. Treatment emergent AEs are defined as
adverse events (including asthma exacerbations), starting on or after the day of the first intake 
of study drug in this study and until the earlier date out of: date of last intake of study drug +7 
days (30 days in the case of a serious AE) and final visit. 
Any AEs that started during the study after informed consent and before the time of the first 
intake of study drug will be classified as a prior AE and not classified as treatment emergent 
AE. The time-to-first treatment emergent AE is defined as the time to the occurrence of an AE 
from the treatment start date, and computed as time to AE=AE start date −treatment start date
+1 day. As a general rule of censoring, patients who either completed the study or discontinued 


Novartis
For business use only
Page 17
SAP
CQAW039A2315
treatment prematurely or continued treatment and without the event of interest will be censored 
at the minimum out of the dates of last medication intake + 30 days, final visit date, and date of 
death. Time-to-first treatment emergent SAEs and time-to-first treatment emergent AEs leading 
to discontinuation from study treatment are defined in a similar manner as time-to-first 
treatment emergent AE.
The definition and rationale for the estimand for the primary endpoint are given in Table 2-1. 
The statistical strategy to handle each intercurrent event is described in more detail in Section
2.5.3.


Novartis
For business use only
Page 18
SAP
CQAW039A2315
Table 2-1
Summary of estimand for the primary endpoint
Population
Justification
Male or female patients aged 12 years and older 
with moderate-to-severe asthma on standard-of-
care asthma therapy and receive at least one dose 
of study treatment, including two categories of 
patients:

Rollover patients: patients completing a prior 
Phase 3 study (A2307, A2314, A2316, or 
A2317) of fevipiprant; and

New patients: patients with inadequately 
controlled asthma who had not previously 
participated in a study of fevipiprant. 
Fevipiprant (QAW039) is a Prostaglandin D2 
receptor 2 (DP2) antagonist expected to
provide benefit in asthma by impacting major 
effector cells and soluble factors driving airway 
inflammation in asthma. Treatment with 
fevipiprant should result in a decrease in these 
parameters of airway inflammation as well as 
a clinical improvement in asthma.
Variables
Justification

Time-to-first treatment emergent AEs

Time-to-first treatment emergent SAEs and

Time-to-first treatment emergent AE leading to 
discontinuation from study treatment.
The primary endpoints provide safety 
assessments with respect to the timing of first 
occurrence of treatment emergent AEs, SAEs, 
and AEs leading to study treatment 
discontinuation. 
Intercurrent event
Description
Strategy to handle event
Justification
Discontinuation of 
fevipiprant for any 
reason without 
experiencing a 
safety outcome as 
defined in the 
primary variables
Discontinuation of 
fevipiprant for any 
reason regardless 
of relation to 
fevipiprant without 
experiencing a 
safety outcome as 
defined in the 
primary variables
A hypothetical strategy will 
be used assuming a 
continued risk for a first 
event after study 
treatment discontinuation
as described in Section 
2.5.3
These patients may
discontinue therapy in 
clinical practice. Any 
fevipiprant treatment 
effect would cease almost 
instantly after 
discontinuation of 
fevipiprant, and only SoC 
effect is expected. 
The safety outcomes
would be no more or less 
likely to occur after 
discontinuation of 
fevipiprant. 
Discontinuation of 
placebo for any 
reason without 
experiencing a 
safety outcome as 
defined in the 
primary variables
Discontinuation of 
placebo for any 
reason without 
experiencing a 
safety outcome as 
defined in the 
primary variables
A hypothetical strategy will 
be used assuming a 
continued risk for a first 
event after discontinuation
of placebo as described in 
Section 2.5.3
In clinical practice patients 
receive SoC without 
additional treatment and 
the approach for placebo 
reflects this.
Summary measures
Hazard ratios comparing QAW039 450 mg once daily, QAW039 150 mg, once daily, and placebo 
treatments with regard to primary variables.


Novartis
For business use only
Page 19
SAP
CQAW039A2315
2.5.2
Statistical hypothesis, model, and method of analysis
The time-to-first treatment emergent AE will be considered from the start of study treatment 
for Study A2315 only and the clinical study report will be based solely on the data from Study 
A2315. 
The primary variable will be analyzed by a Cox regression model stratified by randomization 
stratum (but not by region):

patients on QAW039 150 mg once daily treatment in Studies QAW039A2307, 
QAW039A2314,  

patients on QAW039 450 mg once daily treatment in Studies QAW039A2307 and
QAW039A2314, 

patients on placebo in Studies QAW039A2307 and  QAW039A2314

patients on QAW039 150 mg once daily treatment in Studies QAW039A2316 and 
QAW039A2317, 

patients on placebo in Studies QAW039A2316 and QAW039A2317, 

patients who have not previously participated in a study of QAW039, 
and treatment group, severity of asthma (GINA treatment steps 3, 4, and 5), and region as fixed 
class effects. 
Hazard ratios comparing QAW039 450 mg once daily, QAW039 150 mg, once daily, and 
placebo treatments with regard to time to first treatment emergent AEs and their corresponding 
95% profile likelihood confidence intervals (CIs) will be presented. Time to first treatment 
emergent SAEs and time to first treatment emergent AEs leading to study treatment 
discontinuation, will be analyzed in a similar fashion. 
If the model does not converge, then the primary variable will be analyzed similar to the primary 
analysis but after removing stratification factors from the model. Hence in case of non-
convergence, primary variable will be analyzed by a Cox regression model having treatment 
group, severity of asthma (GINA treatment steps 3, 4, and 5), and region as fixed class effects. 
If then also the model does not converge the variable will be analyzed after removing region as 
a fixed class effect in the model. If the resulting model also fails to converge then the variable 
will be analyzed considering only treatment group as a fixed class effect in the Cox regression 
model. Efron’s method for handling ties will be used.
Summary statistics for the primary variable(s)
Ascending Kaplan-Meier curves will be constructed by treatment arm on overall population and by 
source of patients. The number of subjects with an event, number of subjects remaining at risk 
in the treatment group, estimate of the event rate and its estimated standard error, as estimable, 
will be provided for each treatment group. Median time to event and quartiles including 95% 
confidence intervals will be summarized as well.
2.5.3
Handling of missing values/censoring/discontinuations
The primary Cox regression model will implicitly impute the censored data under the 
assumption of independent censoring (conditional on the baseline covariates). That is, a 
censored patient is assumed to be no more or less likely to experience an event in any future 


Novartis
For business use only
Page 20
SAP
CQAW039A2315
time interval than other patients in the same stratum that continue to be at risk for a first event 
and that have the same model covariates. The implied assumption of a continued treatment 
effect after treatment discontinuation is considered conservative for the purpose of the 
evaluation of safety outcomes that are assumed to be more likely to occur while active treatment 
is ongoing. 
2.6
Analysis of the key secondary objective
The study does not have any key secondary objectives.
2.7
Analysis of secondary efficacy objective(s)
The secondary objectives of the study are based on safety variables and hence no efficacy 
variables are stated in this section.
2.8
Safety analyses
The primary and secondary objectives of the study are based on safety variables. All safety data 
will be summarized for the SAF.
2.8.1
Adverse events (AEs)
Adverse events after informed consent including asthma exacerbations will be recorded. 
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 following treatment emergent AE summaries will be produced by system organ class 
(SOC), preferred term (PT), treatment on overall population, by source of patients for:
1. all AEs, 
2. all AEs by maximum severity, 
3. suspected drug-related AEs, 
4. AEs by standardized MedDRA query (SMQ) level
5. SAEs, and 
6. AEs leading to permanent discontinuation of study-drug. 
The number of patients experiencing an event, as well as the exposure-adjusted incidence rate 
(patients with events per 100 patient year of follow-up) will be provided in above summaries. 
Patient year of follow-up  will be computed as (sum of the duration of exposure over patients, 
in days)/365.25. This method will account for the length of follow-up time under the assumption 
that events would occur with the same frequency at any point in time. 
Summaries described above will also be produced by source of patients.
 
 


Novartis
For business use only
Page 21
SAP
CQAW039A2315
Post-treatment discontinuation AEs (events that start more than 7 days (30 days in the case of 
a serious AE) after the last intake of study drug) will be summarized separately in terms of 
number and percentage of patients with at least one AE. 
Secondary endpoint: the rate of patients with at least one treatment emergent 
AE by primary system organ class 
The number and proportion of patients with at least one treatment emergent AE by primary 
system organ class will be presented descriptively and analyzed using a logistic regression 
model stratified by randomization stratum (but not by region) and treatment group, severity of 
asthma (GINA treatment step 3, 4, and 5), and region as fixed class effects. Estimates of the 
odds ratios between QAW039 groups and placebo will be displayed along with associated 95% 
confidence intervals. Firth’s penalized likelihood will be utilized for logistic regression for rare 
events.
Secondary endpoint: the rate of treatment emergent severe asthma exacerbation
episodes requiring hospitalizations 
In safety analysis, each record of asthma exacerbation episode will be considered as an adverse 
event regardless of the interval between two episodes, i.e., no collapsing of multiple records
(this differs from how asthma exacerbations are included in efficacy analyses – see Section 
2.13.1). Number of treatment emergent severe asthma exacerbation episodes requiring 
hospitalizations (any visit to the hospital requiring an overnight stay or an emergency room visit 
greater than 24 hours) will be summarized by source of patients. 
Adverse events of special interest / grouping of AEs
AEs of special interest definitions are found in the compound electronic Case Retrieval Strategy 
(eCRS). The classification reflects the current version of the dSPP and 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 treatment emergent AEs of special interest will be 
summarized by risk category, PT, treatment on overall population and by source of patients. In 
addition, summaries will be provided for 

Treatment emergent AEs of special interest by maximum severity

Treatment emergent serious AEs of special interest

Treatment emergent AEs of special interest that are suspected to be related to study drug
AE reporting for CT.gov and EudraCT
For the legal requirements of clinicaltrials.gov and EudraCT, two required tables on treatment 
emergent adverse events which are not serious adverse events with an incidence greater than 
X% 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.


Novartis
For business use only
Page 22
SAP
CQAW039A2315
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.
2.8.2
Deaths
The number and percentage of deaths resulting from TEAEs will be summarized by SOC and 
PT. All the deaths in the clinical database including those occurring during screening will be 
listed.
Secondary endpoint: the rate of patient deaths due to a treatment emergent 
asthma exacerbation 
The number and percentage of deaths due to a treatment emergent asthma exacerbation will 
be summarized.
2.8.3
Laboratory data
Laboratory data consist of hematology, biochemistry and urinalysis. On-treatment laboratory 
data will be summarized. Laboratory data measured on or after first intake of study drug and 
until 7 days after last intake of study drug are regarded as on-treatment data. All data will be 
included in the analyses regardless of rescue medication use. The following sub-sections will 
describe the method of summary. For rollover patients, the last pre-treatment assessment in the 
current study (A2315 baseline) will be used in summary tables and figures. Prior study baseline 
will be considered as a supplementary baseline value presented in figures as well.
2.8.3.1
Summary of absolute values
For all continuous laboratory parameters, the absolute 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 by parameter, 
scheduled visit and treatment. The direction of interest for worst case post-baseline for selected 
hematology and biochemistry parameters is tabulated in Table 2-2.
For categorical urinalysis laboratory parameters, a frequency table of results will be produced 
by laboratory parameter, scheduled visit, and treatment for the whole study duration.


Novartis
For business use only
Page 23
SAP
CQAW039A2315
2.8.3.2
Summary of change from baseline
For continuous laboratory parameters, the change from baseline at each scheduled visit, and the 
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 treatment with standard descriptive statistics.
2.8.3.3
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 missing value in baseline, any post-
baseline notable value will be considered as newly occurring. 
Guidelines for clinically notable criteria for laboratory tests are based on the FDA Guidelines 
for adults in SI units. The criteria for clinically notable values are presented in Table 2-3. 
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 listings. 
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.
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. If either albumin or protein or creatinine is below the limit of quantification then the 
raw values would be imputed and ratios will be computed.
Additionally, box plot over time for Albumin: Creatinine ratio (ACR), Protein: Creatinine ratio 
(PCR) will be presented. Box plot of creatinine change from baseline values for the post-
baseline visits will also be presented. Albumin: Creatinine ratio (ACR) value will be considered 


Novartis
For business use only
Page 24
SAP
CQAW039A2315
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.
Mean change from baseline in creatinine will be plotted for the post-baseline visits.
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
     Female 12-65
     Female >=66
0.34
0.37
0.34
0.32
0.31
Hemoglobin (g/L)
    Male 12-17
100


Novartis
For business use only
Page 25
SAP
CQAW039A2315
Laboratory parameter (unit)
Bound for notably low values
Bound for notably high values
    Male >=18
    Female
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
BUN/ 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 
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).
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 
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 by source of patients. 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 source of 
patients and treatment in prior study for rollover for rollover patients. The eDish plot will reflect 
the worst value of each of the parameters; they do not need to occur at the same visit.


Novartis
For business use only
Page 26
SAP
CQAW039A2315
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.
2.8.4
Other safety data
2.8.4.1
ECG 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 


Novartis
For business use only
Page 27
SAP
CQAW039A2315
root). Furthermore, an overall interpretation of the central cardiologist will be provided as well 
as a specification of abnormal findings.
ECG data measured on or after first intake of study drug and until 7 days after last intake of 
study drug are regarded as on-treatment data. All on-treatment data will be included in the 
analyses regardless of rescue medication use. For rollover patients, the last pre-treatment 
assessment in the current study (A2315 baseline) will be used in summary tables and figures. 
Prior study baseline will be considered as a supplementary baseline value presented in figures 
as well.
Summary of absolute values and change from baseline
Absolute values and change from baseline summarized by parameter, and visit. 
Clinically relevant values

The number and percentage of patients with newly occurring or worsening clinical relevant 
QTcF values (see Table 2-5) summarized by scheduled post-baseline visit and additionally 
at any time on treatment considering all post-baseline data from scheduled, unscheduled 
and premature discontinuation visits. Table 2-5 Clinically relevant criteria for QTcF 
(Fridericia's formula)
ECG parameter (unit)
Clinically relevant range
Value considering newly occurring or worsening cases
QTc (msec)
≥ 450 (male)
QTc (msec)
≥ 460 (female)
QTc (msec)
> 500 (both) 
Change from baseline
QTc
30 – 60
QTc
> 60
Clinically notable values

A summary table will also be produced for number and percentage of subjects with 
notable QT and QTcF intervals (irrespective of the time point) 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


Novartis
For business use only
Page 28
SAP
CQAW039A2315

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 
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
Overall ECG interpretation

Summary of ECG abnormalities will be produced on following variables: the number and 
percentage of subjects with newly occurring or persistent/recurrent on-treatment ECG 
abnormalities in overall ECG interpretation at any time point.

The number and percentage of subjects with newly occurring or persistent/recurrent on-
treatment ECG abnormalities by evaluation type and abnormality finding at any time 
point. 
If patients had at least once ECG abnormality at baseline, the baseline flag will be 
abnormal. Similarly for post baseline visits, if patients had at least once ECG abnormality 
at a visit, then ECG is abnormal at that visit else normal.
Patients with notable post-baseline ECG values will be listed. Box plots of ECG by scheduled 
visit and treatment for each parameter will be presented.  
2.8.4.2
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 first intake of study drug and 
until 7 days after 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. For rollover patients, the last pre-treatment assessment in the current study 
(A2315 baseline) will be used in summary tables and figures. Prior study baseline will be 
considered as a supplementary baseline value presented in figures as well.
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 
parameter (except height), at any time on-treatment considering all post-baseline data from 
scheduled, unscheduled and premature discontinuation visits. 

Vital signs will also be summarized by clinically relevant categories: 
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.


Novartis
For business use only
Page 29
SAP
CQAW039A2315
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.
Table 2-6
Clinical notable criteria for vital signs
Vital sign parameter (unit)
Lower bound of clinically 
notable range
Upper bound of clinically 
notable range
Notable value considering newly occurring or worsening cases
Systolic blood pressure (mmHg)
< 75
> 200
Diastolic blood pressure (mmHg)
< 40
> 115
Pulse rate (bpm)
< 40
> 130
Notable change from baseline
Systolic blood pressure (mmHg)
≤ 90 and decrease from 
baseline by ≥ 20 
≥ 180 and increase from 
baseline by ≥ 20
Diastolic blood pressure (mmHg)
≤ 50 and decrease from 
baseline by ≥ 15
≥ 105 and increase from 
baseline by ≥ 15
Pulse rate (bpm)
≤ 50 and decrease from 
baseline by ≥ 15
≥ 120 and increase from 
baseline by ≥ 15
Weight (kg)
Decrease ≥ 7% from baseline
Increase ≥ 7% from baseline
2.8.5
Renal events
Summary of renal event overview data by treatment and source of patients will be presented.
2.8.6
Liver events
Summary of treatment emergent liver event overview data by treatment and source of patients
will be presented. All liver event overview data will be listed.
2.9
Pharmacokinetic endpoints  
The study does not have any pharmacokinetic endpoints.


Novartis
For business use only
Page 30
SAP
CQAW039A2315


Novartis
For business use only
Page 31
SAP
CQAW039A2315


Novartis
For business use only
Page 32
SAP
CQAW039A2315


Novartis
For business use only
Page 33
SAP
CQAW039A2315


Novartis
For business use only
Page 34
SAP
CQAW039A2315
2.14
Other Interim analyses
An independent Data Monitoring Committee will conduct periodic unblinded safety reviews 
of the accumulating data from this study and other Phase 3 studies of the QAW039 asthma 
development program to ensure safety of study participants. 
Periodic unblinded safety reviews by the DMC using data (including specific safety summaries 
for adolescent participants) from this study and other Phase 3 studies in the QAW039 asthma 
development program will be conducted. No stopping for demonstrated efficacy or safety prior 
to the completion of the study is foreseen, because the purpose of the study is to assess long-
term safety. Thus, no statistical adjustment will be made to any of the interim analyses or the 
analysis after all patients have completed the study. No adjustment is foreseen to account for 
these different reporting times. 
3
Sample size calculation
Approximately 1000 patients are expected to complete prior QAW039 Phase 3 studies and join 
the current Study A2315, based on the following assumptions. 


Novartis
For business use only
Page 35
SAP
CQAW039A2315

In the prior QAW039 Phase 3 studies, 85% of randomized patients are expected to 
complete the prior study and eligible for participation in the current study.

It is estimated that 50% of those eligible patients from Studies A2307 and A2314 will 
enter in the current study.

It is estimated that 25% of those eligible patients from Studies A2316 and A2317 will 
enter in the current study.
New patients (i.e., patients who have not previously participated in a study of QAW039) will 
also be recruited according to local regulatory requirements in certain countries. It is currently 
anticipated that approximately 570 newly recruited patients will be enrolled in the current study. 
Thus, the anticipated total sample size of this study is approximately 1,570 patients. This 
number of patients participating in the safety study will ensure 6-month exposure for each 
QAW039 dose clearly across the whole Phase 3 program in excess of the 300 to 600 patients 
(as well as in excess of 100 patients exposed for at least 1 year) suggested by ICH E1 at the 
time of the first regulatory submission for QAW039. The number of new patients and total 
patients may be subject to change depending on the actual participation of patients from prior 
QAW039 Phase 3 studies, the actual dropout rate in the current study and the local regulatory 
requirements. 
While no formal hypothesis testing is foreseen for the primary safety objectives, if both 
QAW039 doses have a 50% relative hazard increase for treatment emergent events, compared 
with placebo, then there will be approximately > 99%, 94% and 38% power that the two-sided 
95% confidence interval not adjusted for multiplicity for one of the two QAW039 doses would 
exclude no effect for the primary safety variables of time-to-first treatment emergent AE, time-
to-first treatment emergent SAE, and time-to-first treatment emergent AE leading to study 
treatment discontinuation analyzed across Treatment Period 1 and Treatment 2 combined, 
respectively. The power was estimated using 10,000 simulations based on 1,570 patients being 
randomized into the current study. In addition, the sensitivity of the power is further assessed 
for different scenarios of sample size (1470 patients and 1670 patients).This power will be 
higher, if more patients are randomized (e.g., due to additional new patients being enrolled) or 
more patients completing prior Phase 3 studies of QAW039 elect to participate in the current 
study. 
The underlying assumptions for the power simulations were an exponential censoring rate in 
the placebo group of 0.22 and of 0.16 in the QAW039 treatment groups. The assumptions on 
the exponential event rate in each treatment group are shown in Table 3-1. These assumptions 
are based on the, DREAM (Pavord et al. 2012) and MENSA (Ortega et al. 2014) trials, as well 
as a QAW039 Phase 2 study in moderate-to-severe asthma. The detailed power calculations are 
shown in the Table 3-2 and Table 3-3. 
Table 3-1 
Assumed placebo event rates for power calculations
Endpoint
Previous study patients were 
enrolled in or new patients
Assumed exponential event 
rate (per patient-year)
Rate of AEs
QAW039A2316/
QAW039A2317
3.01


Novartis
For business use only
Page 36
SAP
CQAW039A2315
QAW039A2307/ 
QAW039A2314
2.86
New patients
2.86
Rate of SAEs
QAW039A2316/
QAW039A2317
0.07
QAW039A2307/ 
QAW039A2314
0.24
New patients
0.24
Rate of AEs leading to study treatment 
discontinuation
QAW039A2316/
QAW039A2317
0.03
QAW039A2307/ 
QAW039A2314
0.03
New patients
0.03
Table 3-2
Power (%) for a non-multiplicity adjusted confidence interval to 
exclude no-difference versus placebo for the primary safety variables 
Primary Endpoint
Treatment 
Period
QAW039 150 
mg versus 
placebo
QAW39 450 
mg versus 
placebo
Both QAW039 150 
mg and 450 mg 
versus placebo
One of the 
two 
QAW039 
doses 
versus 
placebo
Time-to-first AE
1
>99
>99
>99
>99
1 & 2
>99
>99
>99
>99
Time-to-first SAE
1
65
65
54
76
1 & 2
89
89
84
94
Time-to-first AE 
leading to study 
treatment 
discontinuation
1
16
16
9
22
1 & 2
29
28
19
38
Power results are based on the sample size of 1570 randomized patients (1000 rollover patients plus 
570 new patients).
Simulations were performed in SAS 9.4.


Novartis
For business use only
Page 37
SAP
CQAW039A2315
Table 3-3
power (%) for a non-multiplicity adjusted confidence interval to 
exclude no-difference versus placebo for the primary safety variables 
based on different sample size scenarios
Primary Endpoint
Treatment 
Period
QAW039 150 
mg versus 
placebo
QAW39 450 
mg versus 
placebo
Both QAW039 150 
mg and 450 mg 
versus placebo
One of the 
two 
QAW039 
doses 
versus 
placebo
Time-to-first AE
1
>99
>99
>99
>99
>99
>99
>99
>99
1 & 2
>99
>99
>99
>99
>99
>99
>99
>99
Time-to-first SAE
1
62
68
62
68
50
57
73
79
1 & 2
87
92
87
91
81
87
93
96
Time-to-first AE 
leading to study 
treatment 
discontinuation
1
14
17
14
16
8
10
21
23
1 & 2
27
30
27
30
17
20
36
40
Power results in the upper rows are based on the sample size of 1470 randomized patients (1000 
rollover patients plus 470 new patients).
Power results in the lower rows are based on the sample size of 1670 randomized patients (1000 rollover 
patients plus 670 new patients).
Simulations were performed in SAS 9.4.
4
Change to protocol specified analyses

In protocol, the secondary endpoints are stated in one sentence, i.e., the rate of treatment 
emergent patient deaths and patient hospitalizations (any visit to the hospital requiring 
an overnight stay or an emergency room visit greater than 24 hours) due to an asthma 
exacerbation. In the analysis plan, the endpoints are presented separately:
-
The rate of patient deaths due to a treatment emergent asthma exacerbation
-
The rate of treatment emergent severe asthma exacerbation episodes requiring 
hospitalizations

In protocol, it is mentioned that the treatment emergent adverse events and prior adverse 
events are defined based on the time of the adverse event and intake of study drug. 
However since the time of start and end of adverse events are not captured for this study, 
the definition has been updated considering only the day of the adverse event and intake 
of study drug.

The supportive analyses specified in protocol Section 9.4.4 will be performed for 
exposure incidence rate summaries rather than the primary outcome.


Novartis
For business use only
Page 38
SAP
CQAW039A2315

Non-treatment emergent adverse events  (AEs) in post-treatment follow-up period will 
be summarized separately.

AEs of special interest are only presented descriptively. Time-to-first-event analyses 
using Kaplan-Meier plots and Cox regressions as well as incidence for recurrent events 
per patient year will not be not presented.

The secondary endpoint of the rate of patients with at least one treatment emergent AE 
by primary system organ class will be analyzed using a logistic regression model instead 
of a Cox regression model. 

Shift tables relative to the normal reference ranges to summarize the on-treatment 
change from baseline to post-baseline for each laboratory parameter or ECG parameter 
or vital sign assessments will not be presented. 
 
 

In protocol, treatment emergent adverse events (TEAEs) were defined as AEs starting 
on or after the time of the first intake of study drug and until the day after the last intake 
of study drug. This definition was updated in analysis based on clinical and safety 
consideration as follows: adverse events (including asthma exacerbations), starting on 
or after the day of the first intake of study drug in this study and until the dates of last 
intake of study drug +7 days (30 days in the case of a serious AE) .
 
 

Subgroup analyses on primary outcomes are removed. 


Novartis
For business use only
Page 39
SAP
CQAW039A2315
6
Appendix
6.1
Imputation rules
6.1.1
Study drug
Missing/partial start date or end date of study treatment will not be imputed.
6.1.2
AE date imputation
6.1.2.1
AE end date imputation
Rules for imputing  AE end dates are stated below. Date of last contact in the study is defined 
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.
6.1.2.2
AE start date imputation
Rules for imputing the AE 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 Adverse Event Start Date
Not used
MON
YYYY
Treatment Start Date 
Not used
TRTM
TRTY


Novartis
For business use only
Page 40
SAP
CQAW039A2315
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).
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).


Novartis
For business use only
Page 41
SAP
CQAW039A2315
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).
5. 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. Prior and Concomitant medication date imputation
6.1.2.3
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.
6.1.2.4
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.
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


Novartis
For business use only
Page 42
SAP
CQAW039A2315
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.
6.2
AEs and Concomitant medications coding/grading
The MedDRA version which will be available at the time of database lock, will be used for the 
coding purpose of the adverse events. For coding purpose of the concomitant medications, the 
available WHO-DD (World Health Organization- Drug Dictionary) version at the time of 
database lock, will be used.


Novartis
For business use only
Page 43
SAP
CQAW039A2315


Novartis
For business use only
Page 44
SAP
CQAW039A2315


Novartis
For business use only
Page 45
SAP
CQAW039A2315
6.4
Background asthma therapy
6.4.1
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 46
SAP
CQAW039A2315
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
6.5
Rule of exclusion criteria of analysis sets 
The following protocol deviations will be considered as major and will lead to exclusion of 
patients from analysis sets: 
Table 6-1
Protocol deviations that cause patients to be excluded
Deviation ID
Description of Deviation  
Exclusion in Analyses
INCL01ab
Patient did not sign informed consent for EPOCH 1
Exclude from all analysis sets for 
epoch 1 data
INCL01ba
Patient did not sign informed consent for EPOCH 2
Exclude from all analysis sets for 
epoch 2 data
6.6
Atopic and non-atopic status
RAST or ImmunoCAP test at Screening visit will be used to determine the atopic and non-
atopic status. If at least one allergen test (including ‘Other’) is positive, the patient is atopic, 
otherwise the patient is non-atopic. 
7
Reference
Bel EH, Wenzel SE, Thompson PJ et al (2014) Oral Glucocorticoid-Sparing Effect of 
Mepolizumab in Eosinophilic Asthma. The New England Journal of Medicine; 371:1189-
1197. 
Efron, B. (1977), “The Efficiency of Cox’s Likelihood Function for Censored Data,” Journal 
of the American Statistical Association, 72, 557–565.
Greenland S, Rothman KJ (2008). Introduction to categorical statistics. In: Rothman, K. J., 
Greenland, S. and Lash, T. T. (Eds.), Modern Epidemiology. Lippincott Williams &Wilkins, 
Philadelphia, PA, pp. 267-268
 
 
 


Novartis
For business use only
Page 47
SAP
CQAW039A2315
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.