Clinical trial NCT03215758
Conditions: Asthma
Keywords: QAW039, uncontrolled asthma
Sponsor: Novartis Pharmaceuticals
Start date: 2017-11-01; Completion date: 2019-07-30
Enrollment: 675 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A randomized, multicenter, double-blind, placebo- controlled parallel-group study to determine the efficacy and safety of QAW039, compared with placebo, when added to standard-of-care (SoC) asthma therapy in adult and adolescent (≥ 12 years) patients with uncontrolled asthma with respect to change from baseline in forced expiratory volume in 1 second (FEV1) at the end of 12 weeks of treatment.

Detailed description:

Arms: arm 1: QAW039 once daily arm 2: Placebo once daily
Interventions: intervention 1: QAW039 intervention 2: Placebo
Intervention descriptions: intervention 1: QAW039 once daily intervention 2: Placebo once daily

Protocol documents:
Prot_001.pdf: 
Global Clinical Development - General Medicine 
QAW039/fevipiprant
Clinical Trial Protocol CQAW039A2316 / NCT03215758
A 12-week, multicenter, randomized, double-blind, placebo-
controlled study to assess the efficacy and safety of 
QAW039 when added to standard-of-care asthma therapy 
in patients with uncontrolled asthma
Document type:
Clinical Trial Protocol
EUDRACT number:
2017-001273-16
Version number:
00 (Original Protocol)
Clinical trial phase:
III
Release date:
10-May-2017
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 3.2 (July 2016)


Novartis
Confidential
Page 2
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................5
List of Abbreviations...........................................................................................................6
Glossary of terms.................................................................................................................9
Protocol summary..............................................................................................................11
1
Introduction .......................................................................................................................15
1.1
Background............................................................................................................15
1.2
Purpose ..................................................................................................................16
2
Study objectives and endpoints .........................................................................................16
2.1
Objectives and related endpoints...........................................................................16
3
Investigational plan ...........................................................................................................18
3.1
Study design...........................................................................................................18
3.2
Rationale for study design .....................................................................................19
3.3
Rationale for dose/regimen, route of administration and duration of treatment....21
3.4
Rationale for choice of comparator .......................................................................21
3.5
Purpose and timing of interim analyses/design adaptations..................................21
3.6
Risks and benefits..................................................................................................21
4
Population..........................................................................................................................22
4.1
Inclusion criteria ....................................................................................................22
4.2
Exclusion criteria...................................................................................................24
5
Treatment...........................................................................................................................27
5.1
Study treatment......................................................................................................27
5.1.1
Investigational and control drugs..........................................................27
5.1.2
Additional treatment..............................................................................28
5.2
Treatment arms ......................................................................................................28
5.3
Treatment assignment and randomization.............................................................28
5.4
Treatment blinding.................................................................................................29
5.5
Treating the patient................................................................................................29
5.5.1
Patient numbering .................................................................................29
5.5.2
Dispensing the study drug.....................................................................30
5.5.3
Handling of study and additional treatment..........................................30
5.5.4
Instructions for prescribing and taking study treatment........................31
5.5.5
Permitted dose adjustments and interruptions of study treatment ........31
5.5.6
Rescue medication ................................................................................32


Novartis
Confidential
Page 3
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
5.5.7
Concomitant medication .......................................................................32
5.5.8
Prohibited medication ...........................................................................34
5.5.9
Emergency breaking of assigned treatment code..................................35
5.6
Study completion and discontinuation...................................................................35
5.6.1
Study completion and post-study treatment..........................................35
5.6.2
Discontinuation of study treatment .......................................................36
5.6.3
Withdrawal of informed consent...........................................................38
5.6.4
Loss to follow-up ..................................................................................38
5.6.5
Early study termination by the sponsor.................................................38
6
Visit schedule and assessments .........................................................................................39
6.1
Information to be collected on screening failures..................................................47
6.2
Patient demographics/other baseline characteristics .............................................47
6.3
Treatment exposure and compliance .....................................................................47
6.4
Efficacy..................................................................................................................48
6.4.1
Spirometry (Pre-dose FEV1 
).................................................48
6.4.2
eDiary for daily asthma symptoms, 
 and rescue 
medication use.......................................................................................48
6.4.3
Asthma exacerbations ...........................................................................50
6.4.4
Appropriateness of efficacy assessments..............................................51
6.5
Safety.....................................................................................................................51
6.5.1
Physical examination ............................................................................52
6.5.2
Vital signs..............................................................................................52
6.5.3
Height and weight .................................................................................52
6.5.4
Laboratory evaluations..........................................................................52
6.5.5
Electrocardiogram (ECG) .....................................................................53
6.5.6
Pregnancy and assessments of fertility .................................................54
6.5.7
Appropriateness of safety measurements..............................................54
6.6
Other assessments..................................................................................................54
6.6.1
Clinical Outcome Assessments (COAs) ...............................................54
56
57
7
Safety monitoring ..............................................................................................................57
7.1
Adverse events.......................................................................................................57
7.2
Serious adverse events...........................................................................................59
7.2.1
Definition of SAE .................................................................................59
7.2.2
SAE reporting........................................................................................60


Novartis
Confidential
Page 4
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
7.3
Liver safety monitoring .........................................................................................60
7.4
Renal safety monitoring.........................................................................................61
7.5
Reporting of study treatment errors including misuse/abuse ................................62
7.6
Pregnancy reporting...............................................................................................62
7.7
Idiosyncratic drug reactions monitoring................................................................63
8
Data review and database management.............................................................................63
8.1
Site monitoring ......................................................................................................63
8.2
Data collection.......................................................................................................64
8.3
Database management and quality control............................................................64
8.4
Data Monitoring Committee..................................................................................65
8.5
Adjudication Committee........................................................................................65
9
Data analysis......................................................................................................................65
9.1
Analysis sets ..........................................................................................................65
9.2
Patient demographics and other baseline characteristics.......................................66
9.3
Treatments .............................................................................................................66
9.4
Analysis of the primary variable(s) .......................................................................66
9.4.1
Primary Variable(s)...............................................................................67
9.4.2
Statistical model, hypothesis, and method of analysis..........................67
9.4.3
Handling of missing values/censoring/discontinuations.......................69
9.4.4
Supportive analyses...............................................................................69
9.5
Analysis of secondary variables ............................................................................70
9.5.1
Efficacy variables..................................................................................70
9.5.2
Safety variables .....................................................................................72
73
73
9.7
Interim analyses .....................................................................................................73
9.8
Sample size calculation..........................................................................................73
9.8.1
Power for the secondary objectives.......................................................74
10 Ethical considerations........................................................................................................75
10.1
Regulatory and ethical compliance........................................................................75
10.2
Informed consent procedures.................................................................................75
10.3
Responsibilities of the investigator and IRB/IEC..................................................76
10.4
Publication of study protocol and results...............................................................76
10.5
Quality Control and Quality Assurance.................................................................76
11 Protocol adherence ............................................................................................................76
11.1
Protocol amendments.............................................................................................77


Novartis
Confidential
Page 5
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
12 References .........................................................................................................................77
13 Appendix 1: Clinically notable laboratory values and vital signs.....................................80
14 Appendix 2: Liver event and laboratory trigger definitions and follow-up 
requirements ......................................................................................................................81
15 Appendix 3: Specific Renal Alert Criteria and Actions ....................................................83
16 Appendix 4:  List of idiosyncratic drug reactions (IDRs) for investigators......................84
17 Appendix 5: Spirometry Guidance....................................................................................85
17.1
References for appendix ........................................................................................87
18 Appendix 6: Estimated equivalence of inhaled corticosteroids ........................................88
19 Appendix 7: Asthma Control Questionnaire (ACQ-5)......................................................89
20 Appendix 8 : Asthma Quality of Life Questionnaire for 12 years and older 
(AQLQ+12) .......................................................................................................................91
97
List of tables
Table 2-1
Objectives and related endpoints ..........................................................16
Table 5-1
Medications allowed under certain conditions......................................32
Table 5-2
Medications to be withheld prior to spirometry....................................34
Table 5-3
Prohibited medication ...........................................................................34
Table 6-1
Assessment schedule.............................................................................41
Table 7-1 
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................62
Table 9-1
Result of power simulations for the primary variable...........................74
Table 9-2
Power simulations for secondary variables...........................................75
Table 14-1
Liver Event and Laboratory Trigger Definitions ..................................81
Table 14-2
Follow Up Requirements for Liver Events and Laboratory Triggers...81
Table 15-1
Specific Renal Alert Criteria and Actions.............................................83
Table 16-1
Definition of potential idiosyncratic drug reactions..............................84
List of figures
Figure 3-1
Study design..........................................................................................18
Figure 9-1
Closed testing procedure for primary and secondary objectives ..........68


Novartis
Confidential
Page 6
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
List of Abbreviations
Abbreviation 
Explanation:
ACR
albumin-creatinine ratio
ACQ
asthma control questionnaire
AE(s)
adverse event(s)
Alb
albumin
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AQLQ+12 
asthma quality of life questionnaire for 12 years and older
ALP
alkaline phosphatase
AST
aspartate aminotransferase
ATC
anatomical therapeutic chemical
ATS/ERS
American Thoracic Society/European Respiratory Society
AV
atrioventricular
BMI
body mass index
BTPS
body temperature and pressure saturated
BUN
blood urea nitrogen  
CFR
Code of Federal Regulations 
CK
creatine kinase
CK-MB
creatine kinase isoenzyme  MB
CPO
Country Pharma Organization
COA
clinical outcome assessment
CRA
clinical research associate
CRF
case report/record form (paper or electronic)
CRO
contract research organization
CRTh2
chemoattractant receptor-homologous molecule expressed on Th2
CT
computed tomography
DAR
dosage administration record
DDE
direct data entry
DNA
deoxyribonucleic acid
DP2
prostaglandin D2 receptor 2
DPI
dry powder inhaler
DMC
Data Monitoring Committee
DRESS
drug reaction with eosinophilia and systemic symptoms
DS&E
Drug Safety & Epidemiology
ECG
electrocardiogram
EDC
electronic data capture
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
ePEF
electronic peak expiratory flow
EU
European Union
FAS
full analysis set
FDA
Food and Drug Administration


Novartis
Confidential
Page 7
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
Abbreviation 
Explanation:
FDC
fixed dose combination
FEV1
forced expiratory volume in 1 second
-GT
gamma-glutamyltransferase
GCP
good clinical practice
GINA
Global Initiative for Asthma
GOLD
Global Initiative For Chronic Obstructive Lung Disease
H0
null hypothesis
Ha
alternative hypothesis
HbA1c
hemoglobin A1c; glycosylated hemoglobin
hCG
human chorionic gonadotropin
HFA
hydrofluoroalkane
HRQOL
health-related quality of life
hsCRP
high sensitivity C-reactive protein
IB
investigator brochure
ICH
international conference on harmonization of technical requirements for 
registration of pharmaceuticals for human use
ICS
inhaled corticosteroid
IDR
idiosyncratic drug reactions
IEC
independent ethics committee
IgE
immunoglobulin E
ImmunoCAP®
specific IgE test
IN
investigator notification
INR
international normalized ratio
IRB
institutional review board
IRT
interactive response technology
ITT
intention-to-treat
IUD
intrauterine device
IUS
intrauterine system
LABA
long-acting -agonist
LAMA
long-acting muscarinic antagonist 
LDH
lactate dehydrogenase
LFT
liver function test
LTRA
leukotriene receptor antagonist
MAR
missing at random
MedDRA
medical dictionary for regulatory activities
MDI
metered dose inhaler
MDRD
modification of diet in renal disease study
MID
minimal important difference
MMRM
mixed model repeated measures
MXR
multi-xenobiotic resistance protein
NYHA
New York Heart Association


Novartis
Confidential
Page 8
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
Abbreviation 
Explanation:
OAT3
organic anion transporter 3
OATP1B3
organic anion transporter P1B3
OC/RDC
Oracle Clinical/Remote Data Capture
PCR
protein-creatinine ratio
PEF
peak expiratory flow
PGD2
prostaglandin D2
P-gp
p-glycoprotein
PPS
per-protocol set
PRO
patient reported outcome
PT
prothrombin time
QM
quality management
QOL
quality of life
QTcF
Fridericia QT correction formula
RAST
radioallergosorbent test
SABA
short-acting -agonist
SAE(s)
serious adverse event(s)
SAF
safety analysis set
sCr
serum creatinine
SCR
screening
SD
standard deviation
SJS
Stevens-Johnson syndrome
SoC
standard of care
SOP
standard operating procedure
SUSAR
suspected unexpected serious adverse reactions
TBL
total bilirubin
TD
treatment discontinuation
TENS
toxic epidermal necrolysis
Th2
T helper 2
UGT
uridinediphosphate glucuronosyltransferase
ULN
upper limit of normal
WoC
withdrawal of consent
WHO
World Health Organisation
US
United States


Novartis
Confidential
Page 9
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
Glossary of terms
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)
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.
eSource
eSource Direct Data Entry (DDE) refers to the capture of clinical 
study data electronically, at the point of care. eSource 
Platform/Applications reduce the use of paper capture source data 
during clinical visits. 
eSource combines source documents and case report forms 
(eCRFs) into one application, allowing for the real time collection of 
clinical trial information to sponsors and other oversight authorities, 
as appropriate.
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)
Epoch/Period
A portion of the study which serves a specific purpose. Typical 
epoch/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.”
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 
with established disease and in those with newly-diagnosed 
disease.
Patient ID 
A unique number assigned to each patient upon signing the 
informed consent 
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


Novartis
Confidential
Page 10
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
Study treatment 
discontinuation (TD)
When the patient permanently stops taking study treatment prior to 
the defined study treatment completion date 
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 11
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
Protocol summary
Protocol number
CQAW039A2316
Full title
A 12-week, multicenter, randomized, double-blind, placebo-controlled study 
to assess the efficacy and safety of QAW039 when added to standard-of-
care asthma therapy in patients with uncontrolled asthma
Brief title
Study of efficacy and safety of QAW039 when added to standard-of-care 
asthma therapy in patients with uncontrolled asthma 
Sponsor and clinical 
phase
Novartis, Phase 3
Investigation type
Drug
Study type
Interventional 
Purpose and rationale
The purpose of this study is to determine the efficacy and safety of 
QAW039 (150 mg once daily), compared with placebo, when added to 
standard-of-care (SoC) asthma therapy in adult and adolescent (≥12 
years) patients with uncontrolled asthma with respect to change from 
baseline in forced expiratory volume in 1 second (FEV1) at the end of 12 
weeks of treatment.
Primary objective
To demonstrate the efficacy of QAW039 150 mg once daily as measured 
by change from baseline in pre-dose FEV1 [in liters], compared with 
placebo, at the end of the 12-week active-treatment period.
Secondary objectives
1. To demonstrate the efficacy of QAW039 150 mg once daily, compared 
with placebo, on daytime asthma symptoms over the 12-week 
active-treatment period.
2. To demonstrate the efficacy of QAW039 150 mg once daily, compared 
with placebo, on total daily short-acting β-agonist (SABA) use over the 12-
week active-treatment period.
3. To demonstrate the efficacy of QAW039 150 mg once daily, compared 
with placebo, on change from baseline in Asthma Quality of Life 
Questionnaire for 12 years and older (AQLQ+12) scores at the end of the 
12-week active-treatment period.
4. To assess the safety of QAW039 150 mg once daily, compared with 
placebo, with respect to adverse events (AEs), electrocardiograms (ECGs), 
vital signs and laboratory tests.
Study design
This study uses a randomized, multicenter, double-blind, placebo-
controlled, parallel-group study design.
Population
The study population will include: 

Males and females aged ≥12 years. 

Asthma patients who are already receiving ICS or ICS with one asthma 
controller medication (see inclusion criterion 4 for allowed ICS doses 
and combinations) are the target population for this study.
Key inclusion criteria

Patients must have a diagnosis of asthma (according to GINA 2016) for 
a period of at least 6 months prior to Visit 1.

Patients who have been treated with:
Medium dose ICS, or
High dose ICS, or
Low dose ICS plus long-acting beta agonist (LABA), or 
Low dose ICS plus leukotriene receptor antagonist (LTRA), or


Novartis
Confidential
Page 12
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
Medium dose ICS plus LABA.
for at least 3 months prior to Visit 1 and the doses have been stable for at 
least 4 weeks prior to Visit 1.  

For patients aged ≥18 years, FEV1 of ≤85% of the predicted normal 
value for the patient, after withholding bronchodilators at Visit 1 and 
Visit 101. For patients aged 12 to <18 years, FEV1 of ≤90% of the 
predicted normal value for the patient, after withholding bronchodilators 
at Visit 1 and Visit 101.

Patients must have a daytime asthma symptom score (0 to 6 scale) of 
≥1 per day during 4 of the last 7 days of the placebo run-in period.

Patients must have a total daily SABA use ≥1 puff per day during 4 of 
the last 7 days of the placebo run-in period.

Demonstrated reversible airway obstruction as determined by the 
central reader from the spirometry vendor at Visit 1 or Visit 101. 
Reversibility is defined as an increase of ≥12% and ≥200 ml in FEV1
approximately 10 to 15 minutes after administration of 400 mcg of 
salbutamol/albuterol (or equivalent).    Spacer devices are permitted for 
administration of salbutamol/albuterol (or equivalent) during reversibility 
testing only. The Investigator or delegate may decide whether or not to 
use a spacer for the reversibility testing.   

If reversibility is not demonstrated at Visit 1, reversibility will be 
attempted at Visit 101. If not achieved at Visit 101, one additional 
attempt to demonstrate reversibility is permitted within 4 days 
following Visit 101 in an ad-hoc visit to meet this eligibility criterion.
Review Visit 1 or Visit 101 or the one additional attempt reversibility 
result from overread by the spirometry vendor central reader prior 
to randomization.

An asthma control questionnaire (ACQ) score ≥ 1.5 at Visit 199.
Key exclusion criteria

Use of other investigational drugs within 5 half-lives of enrollment, or 
within 30 days, whichever is longer.

Patients with a resting QTcF (Fridericia) ≥450 msec (male) or ≥460 
msec (female) at Visit 1.

Patients with a 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, where pregnancy is defined as 
the state of a female after conception and until the termination of 
gestation, confirmed by a positive human chorionic gonadotropin (hCG)
laboratory test.

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 with serious co-morbidities including, but not limited to, 
neurodegenerative diseases, rheumatoid arthritis and other 
autoimmune diseases.

Patients on >20 mg of simvastatin, > 40 mg of atorvastatin, >40 mg of 
pravastatin, or >2 mg of pitavastatin.  Statin doses less than or equal to 


Novartis
Confidential
Page 13
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
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 uridinediphosphate glucuronosyltransferase
(UGT) inhibition and/or inhibition of organic anion transporter 3 (OAT3),
organic anion transporter P1B3 (OATP1B3), multi-xenobiotic resistance 
protein (MXR) and p-glycoprotein (P-gp)).

Patients on any statin therapy with a creatine kinase (CK) level >2 x 
ULN (upper limit of normal) at Visit 1.

Patients with a history of conditions other than asthma or allergic rhinitis
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.
Study treatment
QAW039 150 mg once daily 
Placebo once daily
Key efficacy 
assessments

Lung function (FEV1)

Asthma symptoms

Short-acting β-agonist (SABA) use 

AQLQ+12
Key safety assessments

Adverse event monitoring

Physical examinations

Vital signs 

Laboratory examinations of blood and urine 

ECG
Data analysis
The primary variable for this study is the change from baseline in pre-dose 
FEV1 at the end of 12 weeks of treatment. Pre-dose FEV1 is the average
of the 2 FEV1 assessments taken at 45 minutes and 15 minutes prior to the 
dosing of study drug at the clinic visit. The baseline FEV1 is defined as 
mean of the last two FEV1 assessments prior to the first dose of study 
drug. If any one of these assessments is missing (or is not confirmed to be 
pre-dose), then the remaining non-missing observation will be considered 
as baseline. If both assessments are missing (or are not confirmed to be 
pre-dose) then the last available FEV1 measurement prior to Day 1 on 
study drug will be used for baseline. If the FEV1 measurements are 
missing both on Day 1 and at the placebo run-in or screening visits, the 
respective baseline values will be set to missing. Missing data after 
discontinuation of double-blind study treatment will be imputed using the 
jump-to-reference approach.
The secondary variables are daytime asthma symptoms, total daily SABA 
use, and AQLQ+12. 
Analysis of primary variable: The primary efficacy variable will be analyzed 
on the full analysis set (FAS) using an analysis of covariance (ANCOVA) 
model with factors for treatment group, age group (<18 vs. ≥18 years), use
or non-use of a second asthma controller medication, and region, as well 
as the baseline daytime asthma symptom score, baseline total daily SABA 
use and baseline pre-dose FEV1 as continuous linear covariates. 


Novartis
Confidential
Page 14
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
The least squares mean (“adjusted mean”) change from baseline for each 
treatment group, the difference in the least squares mean changes 
between the two treatment groups (QAW039 150mg – placebo), and the 
two-sided adjusted 95% confidence interval along with the p-value for the 
difference will be obtained and combined from the primary analysis model 
through the multiple imputation approach described in Section 9.4.3. The 
superiority of QAW039 150 mg once daily to placebo as add on to existing 
asthma therapy is established, if the two-sided p-value is less than 0.05 
and the 95% confidence intervals lie entirely to the right of 0 L.
Analysis of secondary variables: The secondary variables of this study are 
change from baseline in daytime asthma symptoms, change from baseline 
in total daily SABA use, and change from baseline in AQLQ+12 over the 
12-week active treatment period.
The mean of change from baseline in the daytime asthma symptom scores 
over the 12 weeks of treatment will be analyzed using an analysis of 
covariance (ANCOVA) model in a similar fashion as for the primary efficacy 
variable.
The mean of change from baseline in the total daily use of SABA over the 
12 weeks of treatment will be analyzed using an ANCOVA model in a 
similar fashion as for the primary efficacy variable.
The change from baseline in AQLQ+12 at week 12 will be analyzed using 
an ANCOVA model in a similar fashion as for the primary efficacy variable.
Six hundred fifty (650) patients (325 per arm) are needed for 90% power to 
observe a statistically significant difference between QAW039 and placebo 
at the two-sided 5% significance level in the primary analysis, assuming a 
treatment difference of 112 mL for the primary endpoint, a standard 
deviation of 380 mL and a treatment discontinuation rate of 15% with half of 
the patients discontinuing from study treatment having week 12 
assessment of the primary variable.
Key words
QAW039, uncontrolled asthma


Novartis
Confidential
Page 15
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
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). Uncontrolled 
asthma has a prevalence of greater than 6 million patients worldwide. 
According to asthma guidelines, the goal of treatment is to “achieve and maintain control of 
the clinical manifestations of the disease for prolonged periods” (GINA pocket guide 2016).  
Current asthma guidelines recognize that the assessment of asthma severity reflects the 
underlying disease state as well as the perceived response to treatment and, based on 
assessment, asthma severity may change over time.  Therefore, current asthma treatment 
guidelines classify patients based on 2 factors: control of asthma and future risk (e.g., risk of 
exacerbations).  For patients older than 5 years with asthma, guidelines recommend 
assignment of patients to 1 of the 5 “treatment steps” based on current asthma controller 
treatment or, if a de novo presentation, assignment based on severity to either Step 2 or Step 3.  
Asthma control is then periodically assessed (~every 3 months) based on a patient’s asthma 
symptoms, severity, response to current medications, and future risk.  Patients are assessed as 
“controlled,” “partly controlled,” or “uncontrolled” according to an algorithm and treatment is 
adjusted to achieve or maintain control at the lowest treatment step (GINA pocket guide 2016). 
The treatment guidelines recommend initiation of short-acting ß-agonists (SABAs) for 
patients older than 5 years with occasional symptoms, followed by addition of controller 
medications (e.g., inhaled corticosteroids (ICS), inhaled corticosteroid/long-acting ß-agonists
(LABA) combinations, leukotriene modifiers etc.) according to the stepwise treatment 
paradigm to achieve and maintain control as described above (GINA pocket guide 2016).  
Following current guidelines, most patients are able to achieve asthma control with currently 
available therapies.  Approximately 5% of patients have a refractory form of asthma which is 
associated with increased risk of hospitalization and death, and about 50% of medical costs 
associated with asthma care (ATS 2005).  
While only an estimated 5% of patients with asthma fulfill criteria for a diagnosis of 
refractory asthma, as many as 40% of patients do not achieve control with currently available 
asthma treatment (Fuhlbrigge et al 2009).  Failure to respond to therapy may be due to 
multiple factors, including poor adherence, inadequate inhaler technique (inhaled therapies) or 
corticosteroid resistance. Thus, there is a need for new, effective anti-inflammatory therapies 
for asthma.
Prostaglandin D2 receptor 2 (DP2) also known as the chemoattractant receptor-homologous 
molecule expressed on Th2 cells (CRTh2) receptor is a receptor for prostaglandin D2 (PGD2) 
which is one of the major prostanoid inflammatory mediators identified in asthma.  
Fevipiprant (QAW039) is a DP2 antagonist expected to provide benefit in asthma by binding 
to prostaglandin D2 receptor 2 (DP2)on eosinophils, basophils, and T lymphocytes in the 


Novartis
Confidential
Page 16
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
blood and tissues; thus, inhibiting migration and activation of these cells into the airway 
tissues and blocking the PGD2-driven release of T helper 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 (fevipiprant) 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 (CQAW039A2201, 
CQAW039A2206, and CQAW039A2208) 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 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 
The purpose of this study is to determine the efficacy and safety of QAW039 (150 mg once 
daily), compared with placebo, when added to standard-of-care (SoC) asthma therapy in adult 
and adolescent (≥12 years) patients with uncontrolled asthma with respect to change from 
baseline in FEV1 at the end of 12 weeks of treatment. 
2
Study objectives and endpoints
2.1
Objectives and related endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary Objective
To demonstrate the efficacy of QAW039 150 mg 
once daily as measured by change from baseline 
in pre-dose FEV1 [in liters], compared with 
placebo, at the end of the 12-week active-
treatment period.
Endpoint for primary objective
Change from baseline in pre-dose FEV1 (L) at 
Week 12.
Secondary Objectives
1.
To demonstrate the efficacy of QAW039 150 
mg once daily, compared with placebo, on 
daytime asthma symptoms over the 12-week 
active-treatment period.
2.
To demonstrate the efficacy of QAW039 150 
mg once daily, compared with placebo, on 
total daily short-acting β-agonist (SABA) use 
over the 12-week active-treatment period.
3.
To demonstrate the efficacy of QAW039 150 
mg once daily, compared with placebo, on 
change from baseline in Asthma Quality of 
Life Questionnaire for 12 years and older
(AQLQ+12) score at the end of  the 12-week 
active-treatment period.
4.
To assess the safety of QAW039 150 mg 
Endpoints for secondary objectives
1.
Change from baseline in daytime asthma 
symptom score over 12 weeks of treatment.
2.
Change from baseline in number of puffs of 
SABA taken per day over 12 weeks of 
treatment.
3.
Change from baseline in AQLQ+12 score at 
Week 12.
4.
Summaries of treatment-emergent adverse 
events, systolic and diastolic blood pressure, 


Novartis
Confidential
Page 17
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
Objective(s)
Endpoint(s)
once daily, compared with placebo, with 
respect to adverse events (AE), 
electrocardiograms (ECGs), vital signs, and 
laboratory tests.
pulse rate, body weight, ventricular rate, RR 
interval, PR interval, QRS duration, heart 
rate, and Fridericia’s QTc, laboratory values 
and change from baseline for continuous 
laboratory values.


Novartis
Confidential
Page 18
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
3
Investigational plan
3.1
Study design
This study uses a randomized, multicenter, double-blind, placebo-controlled parallel-group 
study design in which QAW039 or placebo is added to incoming SoC asthma therapy (Figure 
3-1).  Asthma patients who are already receiving ICS or ICS with one asthma controller 
medication (see inclusion criterion 4 for allowed ICS doses and combinations) are the target 
population for this study. Patients will continue to receive the SoC asthma medication they 
were receiving at Visit 1 throughout the remainder of the study.  No change in SoC asthma 
medication and no dosage adjustments will be permitted throughout the study.
Within 14 days prior to or at Visit 1, an informed consent will be obtained from patients 
before any study related assessments or procedures are performed. All patients signing 
informed consent must be registered in the Interactive Response Technology (IRT). Asthma 
and other medications and eligibility criteria will be reviewed. Patients will be instructed 
regarding medications to be withheld prior to spirometry for Visit 1 (See Section 5.5.7). The 
study will include: 

a Screening period of up to 2 weeks to assess eligibility.  Patients will also practice 
completing the electronic peak expiratory flow (ePEF)/eDiary device during this period.

a Placebo Run-in period of 1 week to collect baseline data for efficacy variables and 
compliance with the ePEF /eDiary device.  Eligibility for randomization will be 
determined during the placebo run-in period.

a Treatment period of 12 weeks; and 

a Follow-up period of 4 weeks, study drug-free, following the last dose of study drug.
Note: the follow-up period applies to all patients except those patients who enter the 
safety study (CQAW039A2315) directly after Visit 299.
Figure 3-1
Study design 


Novartis
Confidential
Page 19
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
Patients experiencing an asthma exacerbation as defined in Section 6.4.3 during the screening
or placebo run-in periods must be designated as screening failure or run-in failure. Patients 
who experience an asthma exacerbation during screening may be re-screened 4 weeks after 
complete recovery from the exacerbation. All patients must demonstrate FEV1 reversibility as 
determined by the central reader from the spirometry vendor for study eligibility. If 
reversibility is not demonstrated at Visit 1, reversibility will be attempted at Visit 101. If not 
achieved at Visit 101, then one additional attempt to demonstrate reversibility is permitted 
within 4 days following Visit 101 in an ad-hoc visit to meet this eligibility criterion.
Clinic visits will be scheduled approximately 2, 4, 8, and 12 weeks after randomization during 
the active-treatment period. Since the primary endpoint is pre-dose FEV1, patients will 
receive witnessed doses of study drug at clinic visits after spirometry is performed for the 
FEV1 assessment.  This will allow for appropriate assessment of pre-dose FEV1.
A follow-up visit will occur approximately 4 weeks (i.e., approximately 30 days) following 
the last dose of study drug to complete safety assessments and pregnancy testing (if 
applicable).  Please refer to the assessment schedule (Section 6) for a list of procedures to be 
conducted at each visit.
A Safety Study of QAW039 is planned.  At sites participating in the Safety Study 
CQAW039A2315, patients who successfully complete 12 weeks of treatment in this study 
(CQAWA0392316 [hereafter referred to as Study A2316]) may be offered participation in the 
Safety Study; patient participation in the Safety Study will be optional. The study design and 
procedures for the Safety Study will be described in a separate protocol.
Periodic unblinded safety reviews will be conducted by an independent Data Monitoring 
Committee (DMC) for the duration of the trial.
3.2
Rationale for study design
The patient population will be described in more detail in Section 4 below.
This randomized, double-blind, parallel-group, placebo-controlled, design supports the 
assessment of efficacy as well as safety of QAW039 as add-on treatment for patients with
asthma inadequately controlled on ICS or ICS with a second controller medication. According 
to Global Initiative for Asthma (GINA) guidelines, the goals of asthma therapy are to attain 
asthma control and reduce future risk of asthma worsening while maintaining minimal side 
effects of therapy.  By maintaining good asthma control in patients with appropriate use of 
therapies, potential future risk to patients may be reduced. The endpoints included in this 
study measure objective and symptomatic parameters of asthma control (objective: lung 
function [FEV1, 
]; symptomatic parameters: daytime 
 asthma 
symptoms, SABA use, quality of life (QOL), 
) in patients over 12 weeks of 
therapy.  
Patient population 
The overall purpose for the study is to determine whether QAW039 150 mg improves lung 
function as measured by change from baseline in pre-dose FEV1 in patients aged ≥12 years.
These patients represent a subset of moderate asthma patients treated according to GINA 


Novartis
Confidential
Page 20
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
2016 (treatment steps 3 and 4).  This study will confirm results from a prior study of 
QAW039 (Study CQAW039A2206).
A prior Phase 2 study of QAW039 (Study CQAW039A2206) in patients with moderate-to-
severe asthma showed a statistically significant improvement in pre-dose FEV1 (L), after 12 
weeks of treatment with QAW039 on top of low-dose ICS, compared with placebo on top of 
low-dose ICS (p=0.0035), with a clinically relevant maximum model-averaged difference to 
placebo of 112 ml.  In this study, a total daily dose of 150 mg provided maximum efficacy as 
determined by pre-dose FEV1.
Screening period  
The screening period allows for assessment of patient entry criteria and for patients to become 
familiar with spirometry measurement and daily eDiary entry prior to the collection of 
baseline values. 
Patients experiencing an asthma exacerbation during the screening period must be designated 
as a screening failure.  Patients who experience an asthma exacerbation during screening may 
be re-screened 4 weeks after complete recovery from the exacerbation.
Re-screening of patients is permitted once during the screening period.
Placebo run-in
The placebo run-in period allows for the determination of level of asthma control based on 
ACQ score, FEV1 reversibility as determined by the central reader at the spirometry vendor, 
SABA use, and daytime asthma symptom scores for eligibility for randomization into the 12-
week active treatment period. This period also allows for the collection of baseline data for all 
efficacy variables. During this period, patients will become familiar with administration of 
investigational treatment and patient’s compliance with an Electronic Peak Flow/ eDiary 
device will be assessed.  
Patients experiencing an asthma exacerbation during the placebo run-in period must be 
designated as a run-in failure. 
Treatment period
During this period, oral QAW039 150 mg or matching placebo (1:1) will be administered 
once daily for 12 weeks added to SoC asthma therapy (as defined in inclusion criterion 4), 
with the last dose given at Week 12 and final assessment for the treatment period at Week 12.  
The 12-week treatment duration is considered sufficient to demonstrate an effect of QAW039 
on the primary endpoint, pre-dose FEV1, in this Phase 3 study since QAW039 has previously 
demonstrated significant effects on pre-dose FEV1 in 12-week Phase 2 studies.
Follow-up period
The 4-week wash out period will monitor the safety and tolerability profile after the last dose 
of study drug.


Novartis
Confidential
Page 21
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
The investigator must provide appropriate advice on the continued use of effective 
contraception for at least one week (at least 5 half-lives of QAW039) after the last dose of 
study drug and follow up with the subject as appropriate.
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment 
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 pre-dose FEV1 in a 
prior dose-ranging study (Study CQAW039A2206) in patients with moderate-to-severe 
asthma (GINA treatment steps 3 and 4) as add-on to low-dose ICS.
3.4
Rationale for choice of comparator
All patients in this study will receive SoC asthma therapy (as defined in inclusion criterion 4) 
during the screening period, the placebo run-in period, and the treatment period. QAW039 or 
placebo will be administered as add-on therapy.
Placebo was chosen as the comparator as it will permit the assessment of improvement in 
terms of pre-dose FEV1 for patients with uncontrolled disease who are treated with QAW039 
plus SoC asthma therapy, in comparison to those solely on SoC asthma therapy. Additionally, 
the use of placebo will permit a controlled evaluation of the safety of QAW039 plus SoC 
asthma therapy, compared with SoC asthma therapy in these patients. Further, patients will be 
allowed the use of SABAs as rescue medication when required.
3.5
Purpose and timing of interim analyses/design adaptations
Not applicable.
3.6
Risks and benefits 
QAW039 is a potent and highly selective oral DP2 antagonist being developed as a potential 
therapy for patients with severe asthma. DP2 is a receptor for PGD2 which mediates the 
activation and migration of T helper 2 (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 QAW039 includes 15 studies: 11 (six in healthy 
volunteers and five in patients) have completed and four (three in patients and one in healthy 
volunteers) are ongoing. The completed phase 2 studies consist of three in patients with 
asthma, one in patients with allergic rhinitis and one in patients with atopic dermatitis (Refer 
to the Investigator’s Brochure (IB) for information on the studies of QAW039). As of 31-Jan-
2016, >1400 patients have been exposed to QAW039.
Three Phase 2 studies in patients with asthma evaluated the effect of QAW039 across the 
range of asthma severities (mild to severe). In these studies, QAW039 demonstrated an effect 
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 


Novartis
Confidential
Page 22
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
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-2016. 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 patients 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 and Niemi 2009), as well as patients on any statins with high
creatine kinase (CK) levels (>2 X ULN (upper limit of normal)) 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 (LFT) 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 risks and 
benefits.
4
Population
The study population will include: 

Males and females aged ≥12 years.

Asthma patients who are already receiving ICS or ICS with one asthma controller 
medication (see inclusion criterion 4 for allowed ICS doses and combinations) are the 
target population for this study.

Approximately 1857 patients will be screened to randomize approximately 650 patients in 
a 1:1 ratio into the study worldwide.

An estimated 15% of patients will discontinue their study drug during the treatment period; 
these patients will not be replaced. 
4.1
Inclusion criteria
Patients eligible for inclusion in this study must fulfill all of the following criteria:


Novartis
Confidential
Page 23
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
1. Written informed consent and assent (if applicable) must be obtained within 14 days prior 
to or at Visit 1 before any assessment is performed including any adjustment to asthma 
medication.
2. Male and female patients at a minimum age of 12 years (or higher minimum age limit as 
allowed by health authority and/or independent ethics committee/institutional review 
board (IEC/IRB) approvals).
3. Patients must have a diagnosis of asthma (according to GINA 2016) for a period of at least 
6 months prior to Visit 1.
4. Patients who have been treated with:

Medium dose ICS, or

High dose ICS, or

Low dose ICS plus long-acting beta agonist (LABA), or 

Low dose ICS plus leukotriene receptor antagonist (LTRA), or

Medium dose ICS plus LABA.
for at least 3 months prior to Visit 1 and the doses have been stable for at least 4 weeks 
prior to Visit 1.  
5. For patients aged ≥18 years, FEV1 of ≤85% of the predicted normal value for the patient, 
after withholding bronchodilators at Visit 1 and Visit 101. For patients aged 12 to <18 
years, FEV1 of ≤90% of the predicted normal value for the patient, after withholding 
bronchodilators at Visit 1 and Visit 101.
NOTE: Withholding of bronchodilators prior to spirometry: 

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 (FDC) of LABA and ICS given twice daily ≥ 12 hours; and

Fixed dose combinations of LABA and ICS given once daily ≥ 24 hours.
6. Patients must have a daytime asthma symptom score (0 to 6 scale) of ≥1 per day during 4 
of the last 7 days of the placebo run-in period.
7. Patients must have a total daily SABA use ≥1 puff per day during 4 of the last 7 days of 
the placebo run-in period.
8. Demonstrated reversible airway obstruction as determined by the central reader from the 
spirometry vendor at Visit 1 or Visit 101.  Reversibility is defined as an increase of ≥12% 
and ≥200 ml in FEV1 approximately 10 to 15 minutes after administration of 400 mcg of 
salbutamol/albuterol (or equivalent).  Spacer devices are permitted for administration of
salbutamol/albuterol (or equivalent) during reversibility testing only. The Investigator or 
delegate may decide whether or not to use a spacer for the reversibility testing.   

If reversibility is not demonstrated at Visit 1, reversibility will be attempted at Visit 
101. If not achieved at Visit 101, then one additional attempt to demonstrate 
reversibility is permitted within 4 days following Visit 101 in an ad-hoc visit to meet 
this eligibility criterion.  


Novartis
Confidential
Page 24
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
Review Visit 1 or Visit 101 or the one additional attempt reversibility result from overread
by the spirometry vendor central reader prior to randomization.
9. An ACQ score ≥ 1.5 at Visit 199.
4.2
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
1. Use of other investigational drugs within 5 half-lives of enrollment, or within 30 days, 
whichever is longer.
2. History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar 
chemical classes to QAW039.
3. History of lactose or milk sensitivity.
4. Patients with a history or current diagnosis of ECG abnormalities indicating significant 
risk of safety for patients participating in the study such as:

Concomitant clinically significant cardiac arrhythmias, e.g., sustained ventricular 
tachycardia, and clinically significant second or third degree atrioventricular (AV)
block without a pacemaker.

History of familial long QT syndrome or known family history of Torsades de Pointes.
5. Patients with a resting QTcF (Fridericia) ≥450 msec (male) or ≥460 msec (female) at Visit 
1. 
6. Use of agents known to prolong the QT interval unless it can be permanently discontinued 
for the duration of the study. 
7. Patients with a 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. 
8. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive human 
chorionic gonadotropin (hCG) laboratory test.
9. 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 an effective method of contraception by local regulations. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception

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 patients on the 
study, the vasectomized male partner must be the sole partner for that subject


Novartis
Confidential
Page 25
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316

Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) if allowed as an effective method of contraception by local 
regulations.  For United Kingdom: 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)
*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.
In case local regulations deviate from the contraception methods listed above, local 
regulations apply and will be described in the informed consent form (ICF).
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy) 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. 
10. 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 cigarette 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.).
11. Patients who have had an asthma exacerbation requiring systemic corticosteroids, 
hospitalization, or emergency room visit within 6 weeks prior to Visit 1.  
12. Patients who have an asthma exacerbation requiring systemic corticosteroids, 
hospitalization or emergency room visit during the screening or placebo run-in periods.
Patients who experience an asthma exacerbation during screening may be re-screened 4 
weeks after complete recovery from the exacerbation.
13. Patients who have had a respiratory tract infection or asthma worsening within 4 weeks of 
Visit 1.  Patients who experience a respiratory tract infection or asthma worsening during 
screening may be re-screened after 4 weeks after recovery.
14. Patients with any chronic condition of the respiratory tract which in the opinion of the 
investigator may interfere with study evaluation or optimal participation in the study.
15. Patients with a history of chronic lung disease other than asthma, including (but not 
limited to) chronic obstructive pulmonary disease (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 
101) computed tomography (CT) scan proof is available), sarcoidosis interstitial lung 
disease, cystic fibrosis, and tuberculosis.
16. Patients with a history of conditions other than asthma or allergic rhinitis that could result 
in elevated eosinophils (e.g., hypereosinophilic syndromes, Churg-Strauss Syndrome, 


Novartis
Confidential
Page 26
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
eosinophilic esophagitis).  Patients with known parasitic infestation within 6 months prior 
to Visit 1 are also excluded.
17. Patients with uncontrolled diabetes having an hemoglobin A1c (HbA1c) test result ≥8% at 
the Visit 1 laboratory test.
18. 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;

Aspartate aminotransferase (AST) or alanine aminotransferase (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 study (MDRD) equation or Bedside Schwartz equation <55 mL/minute/1.73
m2.
19. 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.
20. Patients with a history of myocardial infarction within 12 months of Visit 1.
21. Patients with serious co-morbidities including, but not limited to, neurodegenerative 
diseases, rheumatoid arthritis and other autoimmune diseases.
22. Patients with a history of alcohol or drug abuse within 12 months prior to Visit 1.
23. Patients with a weight <30 kg at Visit 1.
24. Patients aged 12 to <18 years below the third percentile for weight by age at Visit 1 (based 
on local growth charts or the United States Center for Disease Control growth charts 
(Center for Disease Control and Prevention, 2000) if local growth charts are not available).
25. Patients receiving any other asthma treatment that is not stipulated in Inclusion Criterion 
#4. 
26. Patients receiving any medications in the classes listed in Table 5-3 must be excluded 
unless they meet the criteria as specified in Table 5-3.
27. Patients receiving medications in the classes listed in Table 5-1 must be excluded unless 
the medication has been stabilized for the specified period and the stated conditions have 
been met.
28. 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. 
29. Patients with a known history of non-compliance to medication or who are unable or 
unwilling to complete an electronic patient diary or who are unable or unwilling to use the 
Electronic Peak Expiratory Flow (PEF) with eDiary device or who are unable to 
demonstrate good eDiary compliance (defined as >70% compliance) during the placebo 
run-in period.


Novartis
Confidential
Page 27
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
30. Inability to comply with all study requirements and demonstrate good study drug
compliance (≥80% compliance) during the placebo run-in period.
31. Patients with any medical or psychological condition that, in the investigator’s opinion, 
renders the patient unable to understand the nature, scope, and possible consequences of 
the study.
32. Patients with a history of being unable to swallow tablets.
33. Patients who have received methotrexate, oral gold, troleandomycin, cyclosporine 
azathioprine or any experimental anti-inflammatory therapies within 6 months of Visit 101.
34. Patients with regular use of oral or systemic corticosteroids within 12 months or any intra-
articular or short-acting, intramuscular corticosteroid within 1 month or intramuscular, 
long acting depot corticosteroids within 3 months of Visit 101.
35. 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.
36. Patients with a history of immunodeficiency disease or hepatitis B or hepatitis C.
37. 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.
38. Patients on any statin therapy with a CK level >2 x ULN at Visit 1.
39. Patients on rifampin, probenecid, ritonavir and valproic acid (i.e. medications blocking 
several pathways important for the elimination of QAW039 (broad range uridine-
diphosphate glucuronosyltransferase (UGT) inhibition and/or inhibition of organic anion 
transporter 3 (OAT3), organic anion transporter P1B3 (OATP1B3), multi-xenobiotic 
resistance protein (MXR) and p-glycoprotein (P-gp)).
40. No person directly associated with the administration of the study is allowed to participate 
as a study subject.
41. 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 study drug will be supplied by Novartis to the study sites:

Name: QAW039

Formulation: tablet

Unit dose: 1 strength: 150 mg 
Please refer to the Investigator’s Brochure for composition of the QAW039 tablets.

Name: QAW039 placebo

Formulation: tablet

Unit dose: matching placebo to QAW039 150 mg


Novartis
Confidential
Page 28
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
Please refer to the Investigator’s Brochure for composition of the placebo tablets.
The investigational treatment (tablets) will be supplied in bottles. The matching placebos for 
QAW039 will be identical in appearance to their active counterparts and will be identically 
packaged. 
5.1.2
Additional treatment
All patients will continue to receive SoC asthma therapy during the screening period, the 
placebo run-in period and the treatment period throughout the trial. No dosage adjustments of 
the patient’s SoC asthma therapy will be permitted during the study.
Short bursts of rescue systemic corticosteroids are allowed for treatment of asthma 
exacerbations, as clinically indicated (see Section 6.4.3).  
5.2
Treatment arms
During the placebo run-in period, all patients will receive placebo to QAW039 once daily 
(one tablet blinded placebo to QAW039 150 mg).
Patients will be assigned to one of two treatment arms as follows in a 1:1 ratio in the treatment 
period:

QAW039 150 mg once daily

Matching placebo to QAW039 150 mg, once daily 
Patients will be instructed to take their study drug (QAW039 or placebo) once daily in the 
morning without regard to time of food intake. Further instructions on when patients have to 
take the study drug are found in Section 5.5.4.
5.3
Treatment assignment and randomization 
At Visit 201, all eligible patients will be randomized via Interactive Response Technology 
(IRT) to 1 of the 2 treatment arms (QAW039 150 mg once daily or matching placebo once 
daily) in a 1:1 fashion. 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 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 29
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
Randomization will be stratified by patient age at Visit 1 (<18 years or ≥18 years) and use or 
non-use of a second asthma controller medication at Visit 1.  Treatment randomization will be 
stratified at the regional level.
The randomization scheme for patients will be reviewed and approved by a member of the 
Randomization Group.
5.4
Treatment blinding
This study consists of a single-blind run-in period (i.e., only patients will be blinded to the 
identity of the treatment) followed by a double-blind randomized treatment period.
Patients, investigator staff, persons performing the assessments, and data analysts will remain 
blind to the identity of the treatment from the time of randomization until database lock, using 
the following methods: (1) Randomization data are kept strictly confidential until the time of 
unblinding, and will not be accessible by anyone involved in the study with the following 
exceptions: the external DMC, independent of the QAW039 study team, will have access to 
unblinded data. Please refer to Section 8.4 for details. (2) For QAW039, the identity of the 
treatment will be concealed by the use of placebo identical in packaging, labeling, schedule of 
administration, appearance, taste, and odor to QAW039.  
Unblinding should only occur in the case of patient emergencies (see Section 5.6) 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
Each patient is uniquely identified by a Subject Number which is composed by the site 
number assigned by Novartis and a sequential number assigned by the investigator. Once 
assigned to a patient, the Subject Number will not be reused. 
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 mus t 
select the case report form (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 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 are 
assigned consecutive numbers (e.g. the second patient is assigned patient number 2, the third 


Novartis
Confidential
Page 30
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
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.
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 electronic case report 
form (eCRF) should also be completed.
5.5.2
Dispensing the study drug
Each study site will be supplied with study drug in packaging of identical appearance.
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 2 treatment arms and a specific dose. 
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 
Pharma Organization (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 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 
The following non-study treatment (rescue medication) has to be monitored:


Novartis
Confidential
Page 31
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316

SABA (such as salbutamol 100 mcg or albuterol 90 mcg)
The non-study treatment must be handled and stored according to label, kept in a secured 
location and dispensed only in accordance with the protocol.
The investigator must maintain an accurate record of dispensing of the above-mentioned 
treatment in a drug accountability log / inventory log / source documents. Monitoring of drug 
accountability will be performed by monitors during site visits and at the completion of the 
study. Patients will be asked to return all unused SABA treatments and packaging at the end 
of the study or at the time of discontinuation from the study.
5.5.4
Instructions for prescribing and taking study treatment
Study drug will be single-blind during the placebo run-in and double-blind, placebo-
controlled after randomization. At clinic visits, patients will receive a witnessed dose of study 
drug and, therefore, will be instructed to withhold study drug and SoC asthma therapy  prior 
to each clinic visit.  These in-clinic witnessed doses should be given after completion of all 
pre-dose assessments and at approximately the same time at each clinic visit.  Between clinic 
visits, patients will take study drug once daily in the morning.  Patients will be instructed to 
take their study drug at approximately the same time each morning, with or without food.
At Visit 101, all eligible patients will be given oral placebo to QAW039 during the placebo
run-in period for approximately 1 week and will be instructed on the intake of study drug. In 
order to maintain the blind from the patient’s point of view, investigators must not 
divulge information regarding the fact that all individuals will be assigned to placebo 
during the placebo run-in period. At Visit 201, patients will be randomized and stratified 
according to patient age (<18 or ≥18 years) and use or non-use of a second asthma controller 
medication at Visit 1. Treatment randomization will be stratified at the regional level. Each 
randomized patient will then enter a 12-week treatment period where they will receive one of 
the following 2 treatments:  (1) QAW039 150 mg once daily given orally or (2) matching 
placebo to QAW039 150 mg once daily given orally. The study drug will be dispensed in 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 during the study must be recorded on the dosage administration 
record (DAR) CRF. All kits of study drug assigned by IRT will be recorded/databased in the 
IRT system. 
The investigator must promote compliance by instructing the patient to take the study drug 
exactly as prescribed and by stating that compliance is necessary for the patient’s safety and 
the validity of the study. The patient must also be instructed to contact the investigator if 
he/she is unable for any reason to take the study drug as prescribed.
5.5.5
Permitted dose adjustments and interruptions of study treatment
QAW039 and background asthma therapy 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 drug until serum 
β-hCG is performed and found to be negative. 


Novartis
Confidential
Page 32
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316

An investigator considers an interruption is necessary for the treatment of an adverse event. 
Interruption to study drug must be recorded on the dosage administration record eCRF.
5.5.6
Rescue medication
At Visit 1 all patients will be provided with a SABA (such as salbutamol [100 mcg] or 
albuterol [90 mcg]) which they will be instructed to use throughout the study as rescue 
medication on an ‘as needed basis.’ Patients will be advised that between visits they can take 
their rescue medication for symptoms of asthma. Rescue medication (i.e., SABAs) will either
be supplied to the study sites locally by Novartis or provided by the study site to the patient 
and reimbursed by Novartis.
Nebulized salbutamol/albuterol is not allowed as rescue medication and will not be supplied.
No other rescue treatment is permitted and use of a spacer for rescue medication is not 
allowed at any time throughout the study.
To standardize measurements, patients will be instructed not to use their rescue medication 
upon rising in the morning on days requiring spirometric assessments indicated in Table 6-1, 
unless absolutely necessary.  If rescue medication is taken within 6 hours prior to spirometry, 
this information will be recorded by the study site staff using the equipment provided by the 
central spirometry vendor.  Additionally, if rescue medication is taken within 6 hours prior to 
spirometry at any of the scheduled visits, the visit must be rescheduled to the next possible 
day. 
Daily use of rescue medication (the number of puffs taken in the previous 12 hours) will be 
recorded (once in the morning and once in the evening) by the patient using ePEF/ eDiary.
Unless clinically indicated, the type of rescue medication (i.e., SABA) a patient uses, the 
device used to deliver the medication (e.g., dry powder or hydrofluoroalkane (HFA)) and the 
way it is administered (e.g., with a spacer device) must not be adjusted. Any changes relating 
to the above must be recorded on the Concomitant medications eCRF after the start of study 
drug.
5.5.7
Concomitant medication
The medications in Table 5-1 are only permitted under the circumstances given.  This table is 
not considered all-inclusive. Medications should be assessed for adherence to the indication
and other inclusion/exclusion criteria.
Table 5-1
Medications allowed under certain conditions
Class of medication
Condition
Inhaled corticosteroids (ICS) 

Medium dose ICS, or

High dose ICS, or

Low dose ICS plus LABA, or 

Low dose ICS plus LTRA, or

Medium dose ICS plus LABA
Used for at least 3 months prior to Visit 1 and 
dose(s) stable for at least 4 weeks prior to Visit 1.


Novartis
Confidential
Page 33
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
Table 5-2 indicates the wash-out periods for allowed asthma medications prior to spirometry 
assessments. 
Dose adjustments are not permitted throughout the 
study.
Long-acting inhaled β-2 agonists (LABAs)
Allowed as the second asthma controller 
medication when taken with low or medium dose 
ICS.
Used for at least 3 months prior to Visit 1 and dose 
stable for at least 4 weeks prior to Visit 1. 
Dose adjustments are not permitted during the 
study.
Fixed dose combinations of ICS and LABA 
(FDC)
Allowed as ICS (low or medium dose) with a LABA.  
Used for at least 3 months prior to Visit 1 and 
doses stable for at least 4 weeks prior to Visit 1.
Dose adjustments are not permitted during the 
study.
Leukotriene receptor antagonists (LTRAs) 
Allowed as the second asthma controller 
medication when taken with low dose ICS.
Used for at least 3 months prior to Visit 1 and dose 
stable for at least 4 weeks prior to Visit 1.
Dose adjustments are not permitted during the 
study.
Oral corticosteroids for treatment of asthma
Short bursts of rescue systemic corticosteroids are 
allowed for treatment of asthma exacerbations, as 
clinically indicated.  
Short-acting β2-agonist (SABAs)
Rescue medication to be taken as needed.
Maintenance immunotherapy for allergies
Stable dose for at least 3 months prior to 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
Recommended doses and dosage regimens.
Antihistamines (e.g., loratadine, cetirizine)
Recommended doses and dosage regimens
Nasal anticholinergics
Treatment regimen has been stable for at least 1 
month prior to Visit 1.
In the case of as needed use, providing an 
established pattern of use has been documented.
Nasal corticosteroids
Nasal or ophthalmological preparations of 
nedocromil
Nasal or ophthalmological preparations of 
antihistamines
*See Appendix 6 for the GINA 2016 definition of medium and high dose ICS.


Novartis
Confidential
Page 34
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
Table 5-2
Medications to be withheld prior to spirometry
Class of medication
Last dose prior to spirometry
Short-acting β2-agonists  
≥ 6 hours
Long-acting β2-agonists (LABAs) given twice daily
≥ 12 hours
LABAs given once daily
≥ 24 hours
Fixed dose combinations of LABA and inhaled 
corticosteroid (ICS) given twice daily
≥ 12 hours
Fixed-dose combinations of LABA and ICS given 
once daily
≥ 24 hours
The investigator must instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) 
administered after the patient was enrolled into the study must be recorded in the 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.
5.5.8
Prohibited medication
Use of the treatments displayed in Table 5-3 is NOT allowed after Visit 101. Each 
concomitant drug must be individually assessed against all exclusion criteria and the tables 
below to see if it is allowed. If in doubt, the investigator must contact the Novartis medical 
monitor or designee before randomizing a patient or allowing a new medication to be started. 
This table is not considered all-inclusive. Medications must be assessed for adherence to the 
indication and other inclusion/exclusion crtieria.
These medications are also prohibited if administered for other indications.
Table 5-3
Prohibited medication
Class of medication
Minimum cessation prior to Visit 101
Other investigational drugs
30 days or 5 half-lives, whichever is longer 
Live attenuated vaccine
30 days
Other DP2 antagonists (e.g., ramatroban)
7 days or 5 half-lives, whichever is longer
Short-acting anticholinergics
8 hours
Long-acting anticholinergics
7 days
Fixed combinations of short-acting β2 agonists and 
short-acting anticholinergics
8 hours
Mast cell stabilizers (e.g., cromoglycate, 
nedocromil, ketotifen)
7 days
Monoclonal antibodies, investigational or 
approved,  for the treatment of asthma (e.g.,
omalizumab)
5 months
Simvastatin >20 mg, atorvastatin >40 mg, 
pravastatin >40 mg, or pitavastatin >2 mg total 
7 days


Novartis
Confidential
Page 35
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
Class of medication
Minimum cessation prior to Visit 101
daily dose
Rifampin, probenecid, ritonavir and valproic acid 
(i.e., medications blocking several pathways 
important for the elimination of QAW039 (broad 
range UGT inhibition and/or inhibition of OAT3, 
OATP1B3, MXR and P-gp)).
7 days
Methotrexate, gold salts, cyclosporine, 
troleandomycin, azathioprine, other 
immunomodulator drugs or immunomodulatory 
monoclonal antibodies
6 months
Abbreviation: DP2 (prostaglandin D2 receptor 2)
5.5.9
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 (TD) 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.
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. 
Study drug must be discontinued after emergency unblinding. Study drug must also be 
discontinued for any patient whose treatment code has been inadvertently broken or for any 
other non-emergency reason.
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 
Study completion for a patient will occur after he/she has completed 12 weeks of treatment 
(through to Visit 299) or has prematurely withdrawn. Completion of the study will be when 


Novartis
Confidential
Page 36
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
all randomized patients have completed 12 weeks of treatment and the post-treatment Follow-
up visit.
Patients who have been screened when enrolment target has been met will be allowed to 
proceed onto study participation.
A Safety Study of QAW039 is planned.  At sites participating in the Safety Study, patients 
who successfully complete 12 weeks of treatment in this study (Study A2316) may be offered 
participation in the Safety Study; patient participation in the Safety Study will be optional. 
Patients not entering the Safety study will complete the follow-up period and will not be given 
further access to study drug because the risk/benefit ratio will not yet have been substantiated 
and there are already other marketed therapeutic alternatives available to treat these patients.  
At the time of study completion or early termination, all patients will be placed on the 
appropriate asthma treatment as prescribed by the investigator. 
The investigator must provide appropriate advice on the continued use of effective 
contraception for at least one week (at least 5 half-lives of QAW039) after the study 
completion visit (Visit 299) or premature study drug discontinuation and must follow up with 
the subject as appropriate at least to the end of this period.
The investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care.
5.6.2
Discontinuation of study treatment 
Discontinuation of study drug 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. 
Patients may voluntarily discontinue study drug (discontinue double-blind study drug but 
continue with study participation) at any time. Patients who wish to discontinue double-
blind study drug will be asked to remain in the study and complete all study visits.  
Patients withdrawn from study drug will receive SoC asthma therapy according to 
investigator judgment. 
The investigator must discontinue study drug for a given patient if, on balance, he/she 
believes that continuation of study drug would negatively impact the risk/benefit of trial 
participation.
Study drug must be discontinued under the following circumstances: 

Patient wish;

Pregnancy (see Section 6.5.6 and Section 7.6);

Any situation in which study participation might result in a safety risk to the patient;

Female patients non-compliant with the chosen effective method of contraception during 
the study. The investigator must provide appropriate advice on the continued use of 
effective contraception for at least one week (at least 5 half-lives of QAW039) after study 
drug discontinuation and follow up with the subject as appropriate at least to the end of 
this period;

Liver laboratory test abnormality / event (see Appendix 2):

Abnormal liver laboratory results requiring discontinuation – refer to Table 14-2;


Novartis
Confidential
Page 37
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316

If the investigator considers it appropriate after the confirmation of a liver safety 
monitoring signal: 

ALT or AST ≥5xULN, or

ALT or AST ≥2.5xULN and total bilirubin ≥1.5xULN (Appendix 2);

Any laboratory abnormalities that in the judgment of the investigator, taking into 
consideration the subject’s overall status, prevents the subject from continuing 
participation in the study;

Premature unblinding of study drug for a patient for any reason;

Total white blood cell count <1000 cells/µL;

If patients on statin therapy complain of persistent muscle pain without any obvious cause 
for greater than 3 days accompanied by increase in CK levels >10 x ULN or persistent 
intolerable muscle pain regardless of the accompanying CK level;

If a patient develops a medical condition that requires consistent use of prohibited 
treatment as per Section 5.5.8 or if patient exhibits a behavior of non-compliance 
regarding prohibited medication.
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 “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 record eCRF. 
The investigator and study staff must discuss with the patient his/her continued participation 
in the study and request he/she continues attending study visits according to the study visit 
schedule with all assessments completed up to Visit 299. If the patient cannot or is unwilling 
to attend any further visit(s), the site staff should maintain regular phone contact with the 
patient, or with a person pre-designated by the patient. This phone contact should preferably 
be done according to the study visit schedule. 
After study drug discontinuation, at a minimum, in abbreviated visits, the following data 
should to be collected at clinic visits or via telephone visits: 

new / concomitant treatments

adverse events/Serious Adverse Events (SAE)
The investigator must also contact the IRT to register the patient’s discontinuation from study 
drug.
If study drug discontinuation occurs because treatment code has been broken, please refer to 
Section 5.5.9.
5.6.2.1
Asthma worsening alerts
The data captured in the patient eDiary will be used in conjunction with the patient’s asthma 
characteristics to monitor the patient’s asthma.  Patients will be instructed to call the study site 
if they experience symptoms of worsening asthma.  Additionally, the eDiary will be 


Novartis
Confidential
Page 38
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
programed to generate some alerts of signs of possible worsening asthma based on data 
collected. These alerts will be sent to the patient and/or to the investigator. 
The patient’s personal best PEF in the clinic at Visit 101 will be set as the patient’s baseline 
for the placebo run-in period, and the personal best PEF in the clinic at Visit 199 will be set as 
the patient’s baseline for the treatment period. 
5.6.3
Withdrawal of informed consent
Patients 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 the 
assessment table below.
5.6.4
Loss to follow-up 
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of 
telephone calls, registered letters, etc. A 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 discontinued patient. 
The investigator may be informed of additional procedures to be followed in order to ensure 


Novartis
Confidential
Page 39
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
that adequate consideration is given to the protection of the patient’s interests. The 
investigator will be responsible for informing the Institutional Review Board/Independent 
Ethics Committee (IRBs/IECs) of the early termination of the trial.
6
Visit schedule and assessments
Visits must be scheduled to allow randomized study drug to be taken in the morning. 
Table 6-1 lists all of the assessments and indicates with an “X” or “S” when the visits are 
performed. Assessments marked with “S” are documented in source documentation only and 
will not be entered into the eCRF.
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 discontinue 
study drug before completing the study and accept to remain in the study will return for study 
visits as described in Section 5.6.2. If they fail to return for these assessments for unknown 
reasons, every effort should be made to contact them as specified in Section 5.6.2.  At the 
very least, patients should be asked if they can be contacted by phone by study personnel at 
the date they would have been scheduled to end the follow up period (4 weeks after premature 
study drug discontinuation) to ask about concomitant medication use, surgery and procedures, 
SAEs, AEs and asthma exacerbations.
Patients will be required to attend the clinic in the morning at approximately the same 
time, so that pre-dose FEV1 assessments can be performed between 6 AM and 10 AM
±1 hour. Efficacy and safety assessments will be completed prior to QAW039 or placebo 
administration in the clinic.  
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  
If the patient has not withheld medications as specified in the protocol before a particular 
visit, the visit must be rescheduled; 
2. Patient Reported Outcome (PRO) instruments to be completed in the following order:
ACQ-5, AQLQ+12, 
 at certain clinic visits;
3. Vital signs; 
4. ECGs;
5. Samples for urinalysis/hematology/blood chemistry (At Visit 1, there is no specified 
order for collection of samples. At all other applicable visits, collect samples prior to the 
1st pre-dose spirometry [which is the -45 minute pre-dose spirometry] or between the 1st
and 2nd pre-dose spirometry measurements);
6.
 
7. Spirometry. Spirometry assessments must be timed so that the Visit 1 spirometry 
assessment and all pre-dose spirometry assessments can be performed between 6 AM and 


Novartis
Confidential
Page 40
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
10 AM ±1 hour and other tests must be performed as close as possible to those spirometry 
times. During the treatment period, two pre-dose spirometry assessments must be 
performed as follows:

First pre-dose spirometry assessment: approximately 45 minutes prior to the dosing 
of study drug at the clinic visit.

Second pre-dose spirometry assessment: approximately 15 minutes prior to the 
dosing of study drug at the clinic visit.
8. Reversibility at certain visits (spirometry after administration of SABA) may be 
performed after 10 AM ±1 hour.
9. In-clinic witnessed dosing of study drug.


Novartis
Confidential
Page 41
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
Table 6-1
Assessment schedule
Period
Screen
Placebo Run-in
Treatment
Follow-
up
Notes
Visit Number (Site visits)
1
101
199
201
202
203
204
TD
299
301
Follow-up Visit 301 is only applicable for 
patients not participating in the safety study.
Treatment Week
-3
-1
0
0
2
4
8
TD
12
16
Visit 199 and Visit 201 occur on the same 
day.
Treatment Day
-21
-7
1
1
14
28
56
84
112
Informed consent and assent (if 
applicable)
X
ICF must be obtained within 14 days of Visit 1 
or at Visit 1.
Ask question on withholding of 
medication before clinic visits
S
S
S
S
S
S
S
If the patient has not withheld medications as 
specified in the protocol before a particular 
visit, the visit must be rescheduled.
Demographics
X
Medical history
X
Medical History – Protocol 
solicited events for asthma
X
Asthma exacerbation history
X
Smoking history
X
Prior/concomitant medication 
(asthma and non-asthma 
medications) review
X
X
X
X
X
X
X
Inclusion/exclusion criteria
X
X
Review and record surgeries 
and procedures
X
X
X
X
X
X
X
Physical examination 
S
S
S
Abbreviated physical 
examination
S
S
S
S
Heart and lungs only.
ACQ-5 in clinic
X
AQLQ+12 in clinic
X
X
X
X


Novartis
Confidential
Page 42
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
Period
Screen
Placebo Run-in
Treatment
Follow-
up
Notes
Visit Number (Site visits)
1
101
199
201
202
203
204
TD
299
301
Follow-up Visit 301 is only applicable for 
patients not participating in the safety study.
Treatment Week
-3
-1
0
0
2
4
8
TD
12
16
Visit 199 and Visit 201 occur on the same 
day.
Treatment Day
-21
-7
1
1
14
28
56
84
112
Train patient and assess 
patient’s ability to use 
eDiary/ePEF and dispense 
eDiary/ePEF 
S
Review eDiary /ePEF 
compliance 
S
S†
† eDiary/ePEF compliance must be assessed 
prior to randomizing the patient.
Review eDiary/ePEF entries
S
S
S
S
S
S
S
Height
X
X
X
Weight
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
Systolic/diastolic blood pressure, radial pulse 
(sitting), and body temperature.
Electrocardiogram
X
X
Electrocardiogram (Pre-dose)
X
X
Pregnancy test—serum 
(women of child bearing 
potential)
X
Pregnancy testing will begin at the visit a 
patient is first identified as being of child 
bearing potential.
If positive, the patient must not be 
randomized.
Pregnancy test—urine dipstick 
test in clinic (women of child 
bearing potential)
X
X
X
X
X
X
Pregnancy testing will begin at the visit a 
patient is first identified as being of child 
bearing potential.
A positive urine pregnancy test requires 
immediate interruption of study drug until 
serum β-hCG is performed and found to be 


Novartis
Confidential
Page 43
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
Period
Screen
Placebo Run-in
Treatment
Follow-
up
Notes
Visit Number (Site visits)
1
101
199
201
202
203
204
TD
299
301
Follow-up Visit 301 is only applicable for 
patients not participating in the safety study.
Treatment Week
-3
-1
0
0
2
4
8
TD
12
16
Visit 199 and Visit 201 occur on the same 
day.
Treatment Day
-21
-7
1
1
14
28
56
84
112
negative.    If positive, the patient must be 
discontinued from study drug.
Urinalysis  and urine chemistry 
(central laboratory)
X
X
X
X
Blood sample for hematology 
and chemistry (central 
laboratory)
X
X
X
X
No fasting requirement prior to blood 
sampling.
Blood sample for 
RAST/ImmunoCAP test 
(central laboratory)
X
Review Visit 1 laboratory results 
S
If results for chemistry, hematology, HbA1c, 
RAST/ImmunoCAP, urine chemistry and 
urinalysis are missing, obtain a repeat for the 
missing result.
Parasitic screening
S
Only if required by health authority and/or 
ethics committee/ institutional review board.  
Sites should use local laboratories.
Spirometry (centralized)
X
X
1st Pre-dose Spirometry 
(centralized) approximately - 45 
min. pre-dose
X
X
X
X
X
X
To be performed approximately 45 min. prior 
to in-clinic witnessed study drug 
administration.
2nd pre-dose Spirometry 
(centralized) approximately -15 
min. pre-dose
X£
X
X
X
X
X
To be performed approximately 15 min. prior 
to in-clinic witnessed study drug 
administration.


Novartis
Confidential
Page 44
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
Period
Screen
Placebo Run-in
Treatment
Follow-
up
Notes
Visit Number (Site visits)
1
101
199
201
202
203
204
TD
299
301
Follow-up Visit 301 is only applicable for 
patients not participating in the safety study.
Treatment Week
-3
-1
0
0
2
4
8
TD
12
16
Visit 199 and Visit 201 occur on the same 
day.
Treatment Day
-21
-7
1
1
14
28
56
84
112
£To be performed prior to reversibility test.
Reversibility test (spirometry 
after administration of short-
acting β-agonist [SABA])
X**
X,ß **
To be performed prior to in-clinic witnessed 
study drug administration.
ßTo be performed after the second (-15 min.) 
pre-dose spirometry (may be performed after 
10 AM ± 1 h).
**If reversibility is NOT demonstrated at 
Visit 1, reversibility will be attempted at 
Visit 101. If not achieved, then one 
additional attempt allowed within 4 days
following Visit 101.
Review Visit 1 or Visit 101 or 
the one additional attempt 
reversibility result from overread
S
Asthma exacerbation monitoring
X
X
X
X
X
X
X
X
X
X
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 
arranged.
Serious adverse event 
monitoring
X
X
X
X
X
X
X
X
X
X
Adverse event monitoring
X
X
X
X
X
X
X
X
X
Liver event monitoring
X
X
X
X
X
X
X
X
X
X
If applicable, review lab results and clinical 
events as per Section 7.3.
Renal event monitoring
X
X
X
X
If applicable, review lab results as per Section 
7.4.


Novartis
Confidential
Page 45
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
Period
Screen
Placebo Run-in
Treatment
Follow-
up
Notes
Visit Number (Site visits)
1
101
199
201
202
203
204
TD
299
301
Follow-up Visit 301 is only applicable for 
patients not participating in the safety study.
Treatment Week
-3
-1
0
0
2
4
8
TD
12
16
Visit 199 and Visit 201 occur on the same 
day.
Treatment Day
-21
-7
1
1
14
28
56
84
112
Record deaths
X
X
X
X
X
X
X
X
X
X
Contact IRT 
S
S
S
S
S
S
S
S
S
S
Randomize patient through IRT 
S
Assess and dispense rescue 
SABA to be used on an as-
needed basis 
S*
S
S
S
S
S
S
S
S**
*dispense SABA only
**assess SABA only
Dispense study drug
S
S
S
S
S
Patients will be instructed to take study drug 
in the morning.
Assess compliance with study 
drug (count tablets in returned 
bottles) 
S
S
S
S
S
S
In-clinic witnessed study drug 
intake
X
X
X
X
X
X
Complete Dosage Administration Record 
(DAR)-Visit – at site visit.
Complete Study Drug Dosage 
Administration Record-
Summary page
X
X
X
X
X
X
Complete DAR- Summary at each indicated 
visit to record compliance
Complete Study Disposition 
page (screening)
X
Complete Study Disposition 
page (run-in)
X
Complete Study Disposition 
page (end of treatment )
X
Complete Study Disposition 
page (follow-up )
X
For patients not participating in the safety 
study.
Complete Withdrawal of 
X
X
X
X
X
X
X
X
X
X


Novartis
Confidential
Page 46
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
Period
Screen
Placebo Run-in
Treatment
Follow-
up
Notes
Visit Number (Site visits)
1
101
199
201
202
203
204
TD
299
301
Follow-up Visit 301 is only applicable for 
patients not participating in the safety study.
Treatment Week
-3
-1
0
0
2
4
8
TD
12
16
Visit 199 and Visit 201 occur on the same 
day.
Treatment Day
-21
-7
1
1
14
28
56
84
112
informed consent form (if patient 
withdraws consent)
Re-screening of patient
X
Re-screening of patients is permitted once. 
Once a patient enters the placebo run-in 
period, the patient may not be re-
screened. If a patient is re-screened, a new 
informed consent (and assent if applicable) 
must be obtained.
Appointment for next clinic visit 
S
S
S
S
S
S
S
S
Dispense patient card
S
Discuss optional participation in 
safety study
S
Collect patient card 
S*
S
* If participating in the safety study.
Abbreviations: TD (treatment discontinuation), ICF (informed consent form), ACQ-5 (asthma control questionnaire-5), AQLQ+12 (asthma quality of life questionnaire for 
12 years and older, 
 eDiary/ePEF (electronic peak expiratory flow), ECG (electrocardiogram), RAST (radioallergosorbent test), 
HbA1c (hemoglobulin A1c), 
 IRT (interactive response technology).


Novartis
Confidential
Page 47
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
6.1
Information to be collected on screening failures 
All patients who have signed informed consent but have not entered into the placebo run-in
period will have the study completion page for the screening period, demographics, 
inclusion/exclusion, and serious adverse event (SAE) data collected. Adverse events that are 
not SAEs will be followed by the investigator and collected only in the source data.
All patients who have signed informed consent and have received placebo study medication, 
but discontinue prior to randomization (run-in failures) must have all data for the visits they 
attended, the summary pages (adverse event, concomitant medication, dosage administrative 
record), and screening and placebo run-in disposition pages completed. All adverse events 
occurring after informed consent is signed must be recorded on the Adverse Event eCRF. 
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 Yes/No (RAST/ImmunoCap)

Smoking history

Reversibility (demonstrated)

FEV1

Baseline ACQ-5

Baseline AQLQ+12

ICS use alone/ICS plus a second controller

Relevant medical history/current medical condition present before signing informed 
consent. Where possible, diagnoses and not symptoms will be recorded.
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.
6.3
Treatment exposure and compliance
Study drug compliance will be assessed by the investigator and/or study personnel at 
designated visits by recording tablet counts from the previously dispensed bottles. This 


Novartis
Confidential
Page 48
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
information must be captured in the source document at each visit. All study drug dispensed 
and returned must be recorded in the Drug Accountability Log.
Start and end dates of doses of study drug administered since the last dispensing visit will be 
recorded in the eCRFs (study drug dosage administration record (DAR)-summary page) at 
visits specified in the table of assessments (Table 6-1).   
All doses of study drug taken at the clinic visits must be from the newly assigned medication 
bottles, except at Visit 299 when the medication returned by the patient should be used.
6.4
Efficacy
6.4.1
Spirometry (Pre-dose FEV1 
)
All clinic visits must occur in the morning. Please refer to Section 6 and Table 6-1 for full 
details of the scheduling of spirometry measurements.
Equipment for spirometry assessments will be provided to all study sites by a Central 
Spirometry vendor, and overread of spirometry assessments will be performed by trained 
spirometry technicians at the central vendor.
Please refer to the Spirometry Guidance, in Appendix 5 (Spirometry Guidance), for full 
details on scheduling and performing spirometry. Reversibility testing must be conducted in 
the morning.
6.4.2
eDiary for daily asthma symptoms, 
 and rescue medication 
use
The study will use the asthma diary reported by Santanello et al (1997).  This asthma diary 
was validated in studies of patients aged 18 to 65 years (Santanello et al. 1997).  The diary 
was subsequently included as a measure in placebo-controlled studies of montelukast in 
patients aged 15 years and older (Reiss et al. 1998, Malmstrom et al. 1999) and shown to be 
responsive to both montelukast and inhaled beclomethasone therapy in this age range.  All 
patients will complete the asthma diary regardless of age.
All patients will be provided with a patient electronic diary (referred to as eDiary or 
eDiary/ePEF) to record daily asthma symptoms, 
, and SABA (salbutamol/albuterol) use.  
Patients will be instructed to routinely complete the patient diary twice daily – at the same 
time each morning and each evening, approximately 12 hours apart.  The eDiary/ePEF 
recordings are to be reviewed at each clinic visit as detailed in Table 6-1 until study 
completion. Sites and patients will receive appropriate training and guidance on the use of the 
eDiary/ePEF device.
The information detailed below will be collected in the eDiary/ePEF.  Daytime asthma 
symptoms will be rated on a 0 to 6 scale and nocturnal asthma symptoms will be rated on a 0 
to 3 scale.
6.4.2.1
Daily symptom scores
The asthma diary contains daytime and nocturnal asthma symptom questions as delineated 
below.  The format of the electronically administered asthma diary may vary.


Novartis
Confidential
Page 49
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
Daytime symptom diary scale questions
How often did you experience asthma symptoms today?
0
1
2
3
4
5
6
None of
All of 
the time
the time
How much did your asthma symptoms bother you today?
0
1
2
3
4
5
6
Not at all
Severely
bothered
bothered
How much activity could you do today?
0
1
2
3
4
5
6
More than
Less than 
usual activity
usual activity
How often did your asthma affect your activities today?
0
1
2
3
4
5
6
None of
All of 
the time
the time
6.4.2.2
Number of inhalations of rescue medication
The total number of inhalations used of SABA (number of puffs taken in the previous 12 
hours) will be recorded morning and evening by the patient, in the eDiary/ePEF.


Novartis
Confidential
Page 50
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
6.4.2.4
Worsening of asthma (and related eDiary alerts)
Asthma worsening criteria will be programmed into the eDiary/ePEF. 
The data captured in the eDiary/ePEF will be used to alert the patient and/or investigator to 
possible signs of worsening asthma.  These alerts include:

An increase in SABA use on at least 2 of any 3 consecutive days exceeding the equivalent 
of 8 puffs/day (diary alert).

Night time awakenings requiring SABA use on at least 2 out of any 3 consecutive nights
(diary alert).

<60% of PEF compared to baseline (diary alert).
The patient’s personal best PEF in the clinic at Visit 101 will be set as the patient’s baseline 
for the placebo run-in period, and the personal best PEF in the clinic at Visit 199 before 
dosing will be set as the patient’s baseline for the treatment period. 
If patients develop any of the above criteria, the patient should notify the investigator and be 
evaluated by the investigator and treated as clinically appropriate.
If any of these criteria are met while a patient is in the screening, placebo run-in, or treatment 
periods of the study, they may be withdrawn if, in the opinion of the investigator, it is 
appropriate to do so. 
Worsening of asthma symptoms may require unscheduled evaluation between visits.  Study 
site personnel must be available to monitor and document the patient’s progress until the 
asthma worsening has resolved.
6.4.3
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.


Novartis
Confidential
Page 51
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
Scheduled spirometry must not be performed during an exacerbation until it has completely 
resolved.
Patients experiencing an asthma exacerbation during the screening or placebo run-in periods 
must be designated as screening or run-in failures. Patients who experience an asthma 
exacerbation during screening may be re-screened 4 weeks after complete recovery from the 
exacerbation. 
6.4.4
Appropriateness of efficacy assessments
The measurements described above are standard outcome measures in asthma trials.
6.5
Safety
The following safety assessments as delineated in Table 6-1 will be performed:

History and physical examination

Vital signs

Hematology

Blood chemistry including but not limited to 

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 (Alb), gamma-glucoronyl transferase (γ-GT), alkaline phosphatase (ALP), 
lactate dehydrogenase (LDH), creatine kinase (CK), iron, uric acid, cholesterol, 
triglycerides

amylase, lipase

High sensitivity C-reactive protein (hsCRP)

Creatine kinase isoenzyme–MB (CK-MB) and Troponin-I (in response to CK results 
outside of the normal range)

Glycosylated hemoglobin (HbA1c) (collected at Visit 1 only)

Urinalysis and urine chemistry 

Pregnancy test (Pregnancy testing will begin at  the visit when  a patient is first identified 
as being of child bearing potential)

ECG

Adverse events including serious adverse events
Spirometry will also be used to monitor the safety of patients during the study. Patients will 
be provided with an eDiary/ePEF. The data captured in the eDiary/ePEF will be used to alert 
the patient and/or investigator to possible signs of worsening asthma. 
A central laboratory will be used to analyze and report blood chemistry/hematology and 
urinalysis/ urine chemistry. A central ECG vendor will be used to collect, assess and report 
ECGs.
A Data Monitoring Committee will be set up to overview safety. See Section 8.4 for details.


Novartis
Confidential
Page 52
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
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 as indicated in Table 6-1. 
These will include the examination of the lungs and heart.
Information for all physical examinations must be included in the source documentation at the 
study site. Significant findings that are present prior to informed consent being granted must 
be included in the Relevant Medical History/Current Medical Conditions screen on the 
patient’s eCRF. Significant findings made after informed consent is given which meet the 
definition of an Adverse Event must be recorded on the Adverse Event screen of the patient’s 
eCRF.
6.5.2
Vital signs
Vital signs will be performed at visits specified in the table of assessments (Table 6-1). 
Measurements will include systolic and diastolic blood pressure, pulse rate, and body 
temperature. 
6.5.3
Height and weight
Height in centimeters (cm) will be measured at the visits specified in the table of assessments 
(See Table 6-1).
Body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, but without shoes) will be 
measured at the visits specified in the table of assessments (See Table 6-1).
Body Mass Index (BMI) will be calculated as the weight in kg divided by the height in meters 
squared. 
6.5.4
Laboratory evaluations
A central laboratory will be used for analysis of all specimens detailed in this section. Details 
on the collections, shipment of samples and reporting of results by the central laboratory are 
provided to investigators in the laboratory manual.
Clinically notable laboratory findings are defined in Appendix 1.
6.5.4.1
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential, and 
platelet count will be measured according to the assessment schedule in Table 6-1. Other 
reflex testing will be performed as outlined in the laboratory manual.


Novartis
Confidential
Page 53
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
6.5.4.2
Clinical chemistry
BUN/urea, creatinine, creatine kinase, total bilirubin, AST, ALT, alkaline phosphatase, 
gamma-glutamyl transpeptidase, lactate dehydrogenase, sodium, potassium, chloride, calcium, 
magnesium, iron, bicarbonate, cholesterol, triglycerides, high-sensitivity C-reactive protein, 
phosphorus, total protein, albumin, glucose, uric acid, amylase, lipase, CK-MB and Troponin-
I (in response to CK results outside of the normal range), HbA1c (collected at Visit 1 only) 
 (
, 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 must be 
followed until the values return to within the normal ranges or until a clinical explanation is 
identified, even after study drug 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 15-1 “Specific Renal Alert Criteria 
and Actions” in Section 7.4 “Renal Safety Monitoring” of this protocol”. Other reflex testing 
will be performed as outlined in the laboratory manual.
6.5.5
Electrocardiogram (ECG) 
ECGs will be measured according to the assessment schedule in Table 6-1.  At Visit 1, an 
ECG will be measured to test for eligibility for trial inclusion.
ECGs must be recorded according to the ECG investigator manual 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) must be used for clinical decisions.
Single 12 lead ECGs are to be collected with ECG machines supplied by the core laboratory.  
Full details of all procedures relating to the ECG collection and reporting will be contained in 
an investigator manual to be provided to each investigator site.
The original trace will be sent electronically for central review directly from the ECG 
machine. Two ‘identical’ duplicate print-outs will be generated and kept at the investigator 
site as source documentation and as back-up for submission to the central laboratory in case 
of problems with the electronic transmission.  Each page of the ECG tracing must be labeled 
with study number (CQAW039A2316), subject initials (where this is allowed according to 
local regulations), subject number, date and time, and filed in the study site source documents.


Novartis
Confidential
Page 54
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
For any ECGs with subject safety concerns, two additional ECGs must be performed to 
confirm the safety finding and copies forwarded to the central ECG laboratory for assessment.
Clinically significant ECG findings prior to dosing with study drug must be discussed with the 
Novartis responsible person or designee.
Clinically significant abnormalities must be recorded on the relevant section of the medical 
history/Current medical conditions/AE CRF / e(CRF) page as appropriate.
In the event that the central cardiologist reports that an ECG is abnormal, then the investigator 
must comment as to whether the ECG abnormality is either clinically significant or clinically 
insignificant. If necessary a cardiologist may be consulted.
6.5.6
Pregnancy and assessments of fertility 
All women 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 a 
patient is first identified as being of child bearing potential.
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 drug 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
In addition to patient reported outcomes at the visits indicated in Table 6-1, 
 
6.6.1
Clinical Outcome Assessments (COAs)
6.6.1.1
Patient Reported Outcomes (PRO)
The impact of QAW039 on various aspects of patient’s health status will be assessed by the 
following measures:

Asthma Control Questionnaire-5 (ACQ-5) to assess improvement in asthma symptom 
control;

Asthma Quality of Life Questionnaire+12 (AQLQ+12) to measure health-related quality 
of life (HRQOL); and
All questionnaires will be completed in the language most familiar to the respondent, at the 
scheduled study visit prior to the patient seeing the investigator for any clinical assessment or 
evaluation. The patient must be given sufficient instruction, space, time and privacy to 
complete the questionnaire. The study coordinator must check the responses to the 
questionnaire for completeness and encourage the patient to complete any missing responses.
Available training materials related to the administrative procedures of the questionnaires will 
be provided to the sites.


Novartis
Confidential
Page 55
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
All patients will complete the PRO questions via a handheld electronic device or an electronic 
tablet. Patients must be given sufficient space and time to complete all study PROs. If patients 
experience any difficulties with submission after they complete the PROs, the study staff must 
assist them with submitting their PRO responses.  Attempts must be made to collect responses 
to all PROs for all patients, including from those who prematurely discontinue prior to the 
study evaluation completion visit, however, if patients refuse to complete PROs, this must be 
documented in study source records. Patient’s refusal to complete study PROs are not 
protocol deviations.
Completed questionnaires will be reviewed and examined by the investigator, before the 
clinical examination, for responses that may indicate potential adverse events (AEs) or serious 
adverse events (SAEs). The investigator must review not only the responses to the questions 
in the questionnaires 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. 
The PROs ACQ-5, AQLQ+12, 
questionnaires should always be completed before 
any other assessments and in the following order when done at the same visits (see Section 6):

ACQ-5

AQLQ+12
Asthma Control Questionnaire (ACQ-5)
In this study, the ACQ-5 will be used to assess improvements in asthma symptom control.
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 will be self-administered at the clinic and only takes a few minutes to complete.
Patients will be asked to recall how their asthma has been during the previous week and to 
respond to the symptom questions on a 7-point scale (0=no impairment, 6=maximum 
impairment). The questions are equally weighted and the ACQ-5 score is the mean of the 5
questions: therefore, between 0 (totally controlled) and 6 (severely uncontrolled) (Juniper et al 
1999; Juniper et al 2005; Juniper et al 2006).
The ACQ will be collected in an electronic format. The ACQ will be completed by patients at 
the visits specified in the table of assessments (See Table 6-1). The questionnaire must be 
completed before the AQLQ+12 and before any other assessments (see Section 6). The 
appropriate language version(s) of the questionnaire will be used in each participating country. 
The same language version of the questionnaire must be used by a particular patient 
throughout the study.   


Novartis
Confidential
Page 56
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
The study coordinator must be familiar with the instrument and the associated user guides and 
training materials provided.  Patients must complete the questionnaire in a quiet area and are 
allowed to ask questions; however the site staff must take care not to influence the patient’s 
response. In response to a question, patients must be instructed to provide the truest or best 
response for them. 
Asthma Quality of Life Questionnaire for 12 years and older (AQLQ+12)
In this study, the disease-specific AQLQ+12 will be used to measure health-related quality of 
life in patients. The measure was originally validated for use in patients with asthma aged “12 
to 80 years (Juniper et al 2005)”.  
The AQLQ+12 comprises a total of 32 individual questions that span a total of four domains: 
symptoms, activity limitation, emotional function, and environmental stimuli. Test-retest 
reliability, construct validity (cross-sectional and longitudinal), and responsiveness have been 
demonstrated (see Appendix 8).  
The AQLQ+12 will be self-administered at the clinic. It takes about 4 to 5 minutes to 
complete.  Patients are asked to recall their experiences during the previous 2 weeks and to 
score each item on a 7-point scale (7 = not at all impaired to 1 = severely impaired). The  
AQLQ+12 yields individual domain scores, which is the mean of all items in each domain, 
and an overall score, which is the mean of all 32 individual responses. Higher scores indicate 
less impairment in HRQOL.
The AQLQ+12 will be collected in an electronic format. The questionnaire will be completed 
by patients at the visits specified in the table of assessments (See Table 6-1).
The appropriate language version(s) of the questionnaire will be used in each participating 
country. The same language version of the questionnaire must be used by a particular patient 
throughout the study.  
The study coordinator must be familiar with the instrument and the associated user guides and 
training materials provided. The patient must complete the questionnaire in a quiet area and 
be allowed to ask questions; however site staff must take care not to influence the patient’s 
responses. The patient will be instructed to provide the truest and for them best response. 


Novartis
Confidential
Page 57
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
7
Safety monitoring
7.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study 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.
In addition, all reports of intentional misuse and abuse of the product are also considered an 
adverse event irrespective if a clinical event has occurred.
The occurrence of adverse events must 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 findings, laboratory 
test findings, 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 must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying adverse events. Alert ranges for laboratory and other test abnormalities 
are included in Appendix 1.


Novartis
Confidential
Page 58
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
Adverse events must be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information:

The severity grade:

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities

its relationship to the study treatment 

Yes

No

its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved must 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 must be treated appropriately. Treatment may include one or more of the 
following: 

no action taken (e.g. further observation only) 

investigational treatment dosage increased/reduced

investigational treatment interrupted/withdrawn

concomitant medication or non-drug therapy given 

non-drug therapy given 

patient hospitalized/patient’s hospitalization prolonged (see Section 7.2 for definition of 
an SAE)

its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown)
Once an adverse event is detected, it must be followed until its resolution or until it is judged 
to be permanent, and assessment must 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 (IN) 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 must 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 must be recorded in the 


Novartis
Confidential
Page 59
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
investigator’s source documents; however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis.
7.2
Serious adverse events
7.2.1
Definition of SAE 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)]
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the 
following criteria:

is fatal or life-threatening 

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (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 (please refer to 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 (please refer to Annex IV, ICH-E2D Guideline).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.


Novartis
Confidential
Page 60
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
7.2.2
SAE reporting
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days after the last study visit must be reported to 
Novartis safety within 24 hours of learning of its occurrence. Any SAEs experienced after the 
30 day period after the last study visit should only be reported to Novartis safety 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.
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.
Note: SAEs must be reported to Novartis within 24 hours of the investigator learning of its 
occurrence/receiving follow-up information.
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):


Novartis
Confidential
Page 61
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316

Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter

Liver events, which will require close observation, follow-up monitoring and completion 
of the standard base liver CRF pages
Please refer to Table 14-1 in Appendix 2 for complete definitions of liver laboratory triggers 
and liver events. 
Every liver laboratory trigger or liver event as defined in Table 14-1 of Appendix 2 should be 
followed up by the investigator or designated personal at the trial site as summarized below. 
Detailed information is outlined in Table 14-2 in Appendix 2.
For the liver laboratory trigger:

Repeating the 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 
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.
Repeat laboratory tests must be entered on the appropriate unscheduled local laboratory CRF 
page.

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 ≥24 hours) increase in serum creatinine (sCr) of ≥25% compared to 
baseline during normal hydration status.

Urine event

Albumin-creatinine ratio (ACR) ≥1g/g or ≥100 mg/mmol.


Novartis
Confidential
Page 62
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316

Protein-creatinine ratio (PCR )≥1g/g or ≥100 mg/mmol.
Every renal laboratory trigger or renal event as defined in Table 15-1 should be followed up 
by the investigator or designated personnel at the trial site as summarized in Appendix 3. 
7.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient or 
consumer (European Medicine Agency (EMA) definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the DAR (dosage 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.
Table 7-1 
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error 
type
Document in Dose 
Administration (DAR) 
eCRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with an 
SAE
Misuse/Abuse
Yes
Yes, 
Yes, even if not associated 
with a SAE
Abbreviation: eCRF (electronic case report form), AE (adverse event), SAE (serious adverse event).
7.6
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 the birth of the newborn 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 63
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
7.7
Idiosyncratic drug reactions monitoring 
IDRs are adverse drug reactions that do not occur in most patients (i.e., they are rare, 
occurring 1 in 10,000 to 1 in 100,000 patients) and do not result from known pharmacological 
effects of a drug. Their onset is unpredictable and they may involve one or more organ 
systems, most notably the immune system, liver and blood cells.  
The investigator should pay special attention to any adverse events which may be a potential 
IDR reported by a patient.  If such an event occurs, the investigator should report the event as 
per standard adverse event reporting procedures (i.e., serious adverse events for those meeting 
serious criteria and non-serious adverse events for those meeting non-serious adverse event 
criteria as defined in the protocol). 
The investigator may be also be contacted by Novartis regarding AEs that may resemble an 
IDR. A list of terms considered IDRs are provided in Appendix 4.  
Events with potential to be IDRs will be identified thorough a pre-specified search algorithm 
based on the standardized medical dictionary for regulatory activities (MedDRA) Queries as 
described in the study analysis plan. These events will be reviewed by the DMC on a regular 
basis.
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 data capture requirements (i.e. eSource or eCRFs) 
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 data capture / data entry, the adherence to the protocol and to Good Clinical 
Practice, the progress of enrollment, and to ensure that study treatment is being stored, 
dispensed, and accounted for according to specifications. Key study personnel must be 
available to assist the field monitor during these visits.  Continuous remote monitoring of each 
site’s data may be performed by a centralized Novartis 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 data capture and/or data entry. Novartis monitoring standards 
require full verification for the presence of informed consent, adherence to the 


Novartis
Confidential
Page 64
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
inclusion/exclusion criteria, documentation of SAEs, and of data that will be used for all 
primary variables. Additional checks of the consistency of the source data with the CRFs are 
performed according to the study-specific monitoring plan. No information in source 
documents about the identity of the patients will be disclosed.
8.2
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. 
8.3
Database management and quality control
Novartis staff (or contract research organization (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.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the anatomical therapeutic chemical (ATC) 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).
Spirometry and ECG readings will be processed centrally and the results will be sent 
electronically to Novartis (or a designated CRO).
Diary data will be entered into an electronic diary by the patient and patients will fill in their 
PRO data in a site-based tablet. The system will be supplied by a vendor(s), who will also 
manage the database. The database will be sent electronically to Novartis personnel (or 
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. 


Novartis
Confidential
Page 65
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
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, external data monitoring committee (DMC) will be set up to review safety 
data (including specific safety summaries for adolescent participants) from this trial and other 
Phase 3 trials in the QAW039 asthma development program. The DMC will consist of a 
group of experts independent of the sponsor; analyses for the DMC will be prepared by 
individuals independent of the sponsor and sponsor personnel will remain fully blinded to 
results until the final clinical database lock as described in Section 5.4. Based on the safety 
implications of the data, the DMC may recommend modification or termination of the study. 
No statistical adjustment will be made to the final analysis. Full details on procedures, the 
DMC and futility criteria will be specified in a DMC charter.
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 primary efficacy analysis of this pivotal trial will be based on the data of this trial alone. 
In addition, efficacy data will also be pooled with the other identical Phase 3 trial and the 
pooled data will be used to fully characterize efficacy in the asthma patient population studied 
in these trials.
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. It was considered reasonable to limit the FAS to patients who took trial 
medication, because the decision on whether or not study drug is started will not be influenced 
by the treatment group assignment due to the effective treatment blinding procedures 
described in Section 5.4. Following the intent-to-treat principle, patients will be analyzed 
according to the treatment they were assigned to at randomization.
The per-protocol set (PPS) will include all patients in the FAS without any major protocol 
deviations such as violation of major entry criteria or low compliance. Patients may also be 
considered censored for the PPS analysis at the time of major post-baseline protocol 
deviations. Major protocol deviations will be defined in the study specification document


Novartis
Confidential
Page 66
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
prior to database lock and the un-blinding of the study. Patients will be analyzed according to 
the treatment they received.
The safety set (SAF) will include all patients who received at least one dose of double-blind 
study drug. Patients will be analyzed according to the treatment they received.
The analysis of the primary objective will be performed on the FAS. The PPS will be used for 
the supportive analysis of the primary and the secondary variables. The FAS will be used for 
the analysis of all other efficacy variables. The SAF will be used in the analysis of all safety 
variables.
9.2
Patient demographics and other baseline characteristics
Patient demographics and baseline characteristics measured before randomization including 
age (calculated from date of birth to date of Visit 1), sex, race, ethnicity, height, weight, body 
mass index (BMI), relevant medical history,  including smoking history, asthma duration, use 
of long-acting beta-agonists, ICS dose ranges (medium, high) pre- and post- bronchodilator 
FEV1, percent predicted FEV1, 
, ACQ score, AQLQ+12 score, 
, 
number of exacerbations in the previous year, and daytime asthma symptom scores will be 
summarized by treatment group for the FAS. Categorizations of age will include at least the 
categories of <18, 18 to <65, 65-74, 75-84 and ≥85 years of age.
9.3
Treatments
The duration of exposure, the number of patients randomized who completed the foreseen 
course of study drug and the number of patients who discontinued from the study drug will be 
summarized.
Medications started and stopped prior to study drug, taken concomitantly, and started 
following last study drug dose (if applicable) will be summarized by treatment group in 
separate tables in the SAF. Concomitant therapies will be recorded, listed and summarized 
separately for asthma related medications / non-drug therapies and other medications.  
Concomitant asthma related medications will be summarized by pre-defined category.  
Concomitant medications not related to asthma will be summarized by anatomical therapeutic 
chemical (ATC) class and preferred term. More than one ATC class per medication is 
possible and the medication will be reported under all applicable classes.
SABA usage (number of puffs) during the placebo run-in period will be summarized. 
Usage of asthma medication (e.g., LABA, ICS) at baseline will be summarized (if applicable). 
Patients taking prohibited concomitant medications will be noted in the summary of protocol 
deviations.
Compliance with study drug over the entire study will be summarized as the percentage of 
days with study drug intake during the period from first intake to last intake.
9.4
Analysis of the primary variable(s)
The primary analysis for this study will be conducted according the intention to treat (ITT)
principle.


Novartis
Confidential
Page 67
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
9.4.1
Primary Variable(s)
The primary variable for this study is the change from baseline in pre-dose FEV1 at the end of
12 weeks of treatment. Pre-dose FEV1 is the average of the two FEV1 assessments taken at 
45 minutes and 15 minutes prior to the dosing of study drug at the clinic visit. The baseline 
FEV1 is defined as mean of the two FEV1 assessments prior to the first dose of study drug at 
the randomization visit. If any one of these assessments is missing (or is not confirmed to be 
pre-dose), then the remaining non-missing observation will be considered as baseline. If both 
assessments are missing (or are not confirmed to be pre-dose) then the last available FEV1 
measurement prior to Day 1 on study drug will be used for baseline. If the FEV1 
measurements are missing both on Day 1 and at the placebo run-in or screening visits, the 
respective baseline values will be set to missing.
The secondary variables are daytime asthma symptoms, total daily SABA use and AQLQ+12. 
Their definition and analysis is described in Section 9.5.
Efficacy measurements (i.e., daily asthma symptom scores, FEV1) taken within 7 days of 
systemic corticosteroid use and/or within 6 hours of rescue medication (SABA) use will be 
censored (set to missing). Additionally, if the pre-dose FEV1 is taken within 12 hours of 
LABA (including fixed dose combinations of LABA and ICS) use or 24 hours of tiotropium, 
then the individual FEV1 value will be set to missing.
9.4.2
Statistical model, hypothesis, and method of analysis
The primary objective of the study is to evaluate superiority of QAW039 150 mg once daily
over placebo (with SoC asthma therapy as the background therapy) by testing the following 
null hypothesis (H0) versus the alternative hypothesis (Ha):
H0: There is no difference in the change from baseline in pre-dose FEV1 at week 12 post-
baseline for the patients treated with QAW039 150 mg once daily compared with placebo.
Ha: There is a difference in the change from baseline in pre-dose FEV1 at week 12 post-
baseline for the patients treated with QAW039 150 mg once daily compared with placebo.
Familywise type I error rate control
The familywise type I error rate will be controlled at the two-sided 5% level across the 
primary and secondary null hypotheses using the closed testing procedure shown in Figure 9-
1 using the graphical method of  Bretz et al 2009. In this closed testing procedure, the primary 
null hypothesis about pre-dose FEV1 acts as a gatekeeper for the secondary null hypotheses. 


Novartis
Confidential
Page 68
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
Figure 9-1
Closed testing procedure for primary and secondary objectives
Vertices with associated weights denote the individual null hypotheses and their local significance 
levels. Directed edges between the vertices specify how the local significance levels are propagated in 
case of significant results. ε is set to a very small number in practice. Abbreviations: FEV1 (forced 
expiratory volume in 1 second); AQLQ+12 (asthma quality of life questionnaire for 12 years and older).
Initially, the alpha is assigned to the primary null hypothesis. Once the primary null 
hypothesis has been rejected, then 98% of the alpha will be distributed equally amongst the 
secondary null hypotheses of daytime asthma symptoms and total daily SABA use, 
respectively, and 2% of the alpha will be assigned to the null hypothesis for AQLQ+12. If one 
of the secondary null hypotheses is rejected, its local significance level will be propagated to 
the other secondary null hypotheses as illustrated in Figure 9-1. 
Statistical model for primary variable
The primary efficacy variable will be analyzed on FAS using an analysis of covariance 
(ANCOVA) model with factors for treatment group, age group (<18 vs. ≥18 years), use or 
non-use of a second asthma controller medication at study entry, and region, as well as the 
baseline daytime asthma symptom score, baseline total daily SABA use and baseline pre-dose
FEV1 as continuous linear covariates.
The least squares mean (“adjusted mean”) change from baseline for each treatment group, the 
difference in the least squares mean changes between the two treatment groups (QAW039
150mg – placebo), and the two-sided adjusted 95% confidence interval along with the p-value 
for the difference will be obtained and combined from the primary analysis model through the 
multiple imputation approach described in Section 9.4.3. The superiority of QAW039 150 mg 
once daily to placebo as add on to SoC asthma therapy is established if the two-sided p-value 
is less than 0.05 and the 95% confidence intervals lie entirely to the right of 0 L.
Summary statistics for the primary variable
Summaries of absolute values and change from baseline in pre-dose FEV1 by treatment group 
and visit will be presented. Figures will be produced to visually show the mean pre-dose 


Novartis
Confidential
Page 69
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
FEV1 and the mean change from baseline in pre-dose FEV1 by visit over study period for 
each treatment group.
9.4.3
Handling of missing values/censoring/discontinuations
Despite all attempts to ensure complete follow-up for all patients, some patients may not be 
followed for pre-dose FEV1 for the whole planned study duration. Missing data after 
discontinuation of double-blind study treatment will be imputed using the jump to reference 
approach (Carpenter et al 2013). Intermittent missing data prior to discontinuation of double-
blind study treatment will be imputed under a missing at random assumption.
A large number of imputed datasets will be created, with their number chosen based on 
computational feasibility, but at least 1,000. Each dataset will be analyzed using the model 
described in Section 9.4.2 and the results will be combined using Rubin’s rule (Barnard and 
Rubin 1999) for final inference.
The average of the two FEV1 assessments will only be formed after multiple imputations so 
that if one of the two FEV1 assessments at a visit is missing, the average will be between the 
one available assessment and a second imputed assessment. In the situation when both FEV1 
values at the randomization visit are missing, the values from preceding visits will be used as 
described in Section 9.4.1. Retrieved data after the discontinuation of study drug (retrieved 
drop-out) will remain in the analysis without further imputation for all treatment groups. 
9.4.4
Supportive analyses 
The primary and the secondary analyses will be repeated for the PPS.
The analysis results and the imputed data for different methods for imputing missing data will 
be compared.
In a sensitivity analysis, data will be analyzed in the same manner as for the primary analysis, 
but with missing data imputed using pattern mixture approach combining the jump to 
reference and the randomized-arm missing at random approaches (Carpenter, et al 2013) by 
distinguishing the following two cases:
1. A continued treatment effect for QAW039 150 mg patients being lost to follow-up for 
reasons likely to be unrelated to study drug (e.g. lost to follow-up, withdrew consent) will 
be assumed (randomized-arm missing at random).
2. Same treatment effect as placebo will be imputed for QAW039 150 mg patients that 
discontinue study drug and are lost to follow-up due to (or following a study drug 
discontinuation due to) lack of efficacy, adverse events or death (jump to reference).
If feasible, retrieved drop-out will be used to impute missing post-study drug discontinuation 
data as a sensitivity analysis. While retrieved drop-outs may be a particularly suitable basis 
for imputing data for non-retrieved drop-outs as it is most close to the ITT principal, this 
analysis may not be feasible or may require simplification of the imputation model, because 
observed post-study drug discontinuation data may be sparse.
The primary efficacy variable will also be analyzed using a repeated measurement analysis 
model in which treatment, age group (<18 vs. ≥18 years), use or non-use of a second asthma 
controller medication at study entry, region, visit (where FEV1 measurement is taken per 


Novartis
Confidential
Page 70
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
assessment schedule Table 6-1) and treatment-by-visit interaction will be included as fixed-
effect factors, and baseline pre-dose FEV1 value as well as the baseline daytime asthma 
symptom score, baseline total daily SABA use and visit-by-baseline FEV1 as covariates. A
common unstructured covariance matrix among visits for each treatment group will be used. 
The analysis will be performed based on all available on-treatment data up to week 12 and 
based on a likelihood method with an assumption of missing at random (MAR) for missing 
data assuming a hypothetical situation of continued treatment. On-treatment data is defined as 
all available data collected while patients took the study drug up to the Week 12 visit. The 
estimated treatment differences for all treatment comparisons will be tabulated along with the 
associated 95% confidence intervals and two-sided p-values.
In a tipping point analysis it will be explored by how much the imputed continuous missing 
data for the investigational and the placebo arm would have had to change compared to the 
imputations in the primary analysis in order to alter the trial conclusions. This will include an 
exploration of  the possibility that patients with missing data from the investigational arm has 
worse outcomes than patients with missing data from the placebo arm.
In a further rank-based sensitivity analysis for the primary endpoint, patients will be ranked 
from smallest to largest in the following sequence with high ranks denoting greater efficacy.
1. patients that died
2. patients that withdrew from the trial 
3. patients that completed the trial 
Within category 3, patients with higher FEV1 change from baseline will be ranked greater 
than patients with lower change from baseline. Within categories 1 and 2, patients that 
withdraw from the trial later will get higher ranks than patients that withdraw early. In case 
patients withdraw at same study day, patients with higher FEV1 change from baseline at the 
last assessment are assigned a higher rank. In case of ties in the FEV1 values or no available 
post-baseline assessments of the primary variable, we use midranks. A Wilcoxon rank-sum 
test stratified by age group (<18 vs. ≥18 years), use or non-use of a second asthma controller 
medication, and region will be used to analyze the ranked data.
Subgroups
The primary and secondary analyses will also be conducted by subgroup including for key 
demographic (e.g., age, sex, race, BMI, geographic region) and disease related subgroups (e.g. 
number of exacerbations in the previous year, use or non-use of a second asthma controller 
medication, baseline FEV1 tertiles, ACQ tertiles, 
).
9.5
Analysis of secondary variables
9.5.1
Efficacy variables
The secondary variables of this study are change from baseline in daytime asthma symptoms,
change from baseline in total daily SABA use, and change from baseline in AQLQ+12 over 
the 12 weeks of treatment. The local significance level for each secondary null hypothesis will 
be determined based on the closed testing procedure specified by Figure 9-1. A range of 


Novartis
Confidential
Page 71
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
sensitivity analyses will be conducted on secondary endpoints under different missing data 
handling approaches in a similar fashion as those described in Section 9.4.4. 
9.5.1.1
Daytime asthma symptoms in patients 
Daytime asthma symptoms are evaluated through four questions and each of them will be
rated on a scale of 0 to 6. Higher scores indicate more severe asthma-related symptoms. A 
mean score will be calculated for the responses to 4 questions. The main analysis of the 
secondary endpoint of daytime symptoms will be performed for all patients over the entire age 
range (12 years and older). The baseline of daytime asthma symptoms will be defined as the 
average of the mean daytime asthma symptom score during the placebo run-in period. The 
mean of change from baseline in the daytime symptom scores over the 12 weeks of treatment 
will be analyzed using an analysis of covariance (ANCOVA) model in a similar fashion as the 
primary efficacy variable. The null hypothesis is that the treatment difference compared to 
placebo over the 12 weeks of treatment = 0, while the alternative hypothesis is that the 
treatment difference to placebo over the 12 weeks of treatment ≠ 0. This model will be fitted 
to each of multiple imputations generated using a jump-to-reference approach as for the 
primary analysis.
The asthma diary included in this study to measure daytime asthma symptoms was validated 
in studies of patients aged 18 to 65 years (Santanello et al 1997).  It was subsequently 
included as a measure in placebo-controlled studies of montelukast in patients aged 15 years 
and older (Reiss et al. 1998 and Malmstrom et al. 1999) and shown to be responsive to both 
montelukast and inhaled beclomethasone therapy in this age range. Given the performance 
characteristics, particularly the responsiveness to asthma therapies, of the asthma diary are 
known for patients aged 15 years and older, a supportive analysis of the secondary endpoint of 
daytime symptoms will be included and be limited to patients aged 15 years and older.  
9.5.1.2
Total daily use of SABA
Total daily use of SABA (the number of puffs taken in the previous 24 hours) by the patient 
will be analyzed using ePEF/ eDiary data. The baseline of SABA use will be defined as the 
average of total daily SABA use during the placebo run-in period. The mean of change from 
baseline in the total daily use of SABA over the 12 weeks of treatment will be analyzed using 
an ANCOVA model in a similar fashion as the primary efficacy variable. The null hypothesis 
is that the treatment difference compared to placebo over the 12 weeks of treatment = 0, while 
the alternative hypothesis is that the treatment difference to placebo over the 12 weeks of 
treatment ≠ 0. This model will be fitted to each of multiple imputations generated using a 
jump-to-reference approach as for the primary analysis.
9.5.1.3
AQLQ+12
The change from baseline in AQLQ+12 at week 12 will be analyzed using an ANCOVA 
model in a similar fashion as the primary efficacy variable. The baseline of AQLQ+12 is 
defined as the last assessment prior to the first dose of study drug. Missing data of AQLQ+12 
overall score will be imputed a jump-to-reference approach as for the primary analysis.


Novartis
Confidential
Page 72
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
9.5.1.4
Summary statistics for the secondary variables
Summaries of absolute values and change from baseline in the three secondary variables will 
be presented by visit and by treatment group. Figures will be produced to visually show the 
mean and the mean change from baseline by visit over study period for each treatment group. 
9.5.2
Safety variables
All safety data will be summarized for the safety set.
9.5.2.1
Adverse events
Adverse events after informed consent including asthma exacerbations will be summarized 
and listed.
Adverse events starting on or after the time of the first intake of study drug will be classified 
as treatment-emergent adverse events. Any adverse events that started during the study after 
informed consent before the time of the first intake of study drug will be classified as a prior 
adverse events and not included in tabulations of treatment emergent adverse events. 
The following treatment emergent adverse event summaries will be produced, overall by 
system organ class and preferred term, overall by system organ class, preferred term and 
maximum severity, suspected drug-related adverse events by system organ class and preferred 
term, serious adverse events by system organ class and preferred term, and adverse events 
leading to permanent discontinuation of study-drug by system organ class and preferred term.
The number and percentage of patients with the most frequent AEs will be summarized by 
treatment. 
Selected adverse events of special interest may be summarized and analyzed as well.
9.5.2.2
Vital signs
Data of the vital signs (systolic blood pressure, diastolic blood pressure, and pulse rate) will 
be summarized by treatment and scheduled visit. The maximum and minimum systolic blood 
pressure, diastolic blood pressure, and pulse rate post-baseline (including values from post-
baseline unscheduled and premature discontinuation visits) can also be summarized by 
treatment. Absolute body weight will be summarized by scheduled visit. The change from 
baseline to each scheduled post-baseline visit will be summarized by vital sign parameter, 
scheduled visit and treatment with standard descriptive statistics.
Notable values and notable changes from baseline in vital signs will be summarized.
9.5.2.3
Electrocardiogram (ECG) 
The changes from baseline will be summarized by ECG parameter, schedule visit where 
baseline and post baseline values are both available. 
The following quantitative variables will be summarized by treatment at each scheduled post-
baseline visit: ventricular rate, QT interval, RR interval, PR interval, QRS duration, heart rate, 
and Fridericia’s QTc. The maximum QTc (including values from post-baseline unscheduled 
and premature discontinuation visits) will also be summarized. 


Novartis
Confidential
Page 73
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
Notable values and notable changes from baseline in quantitative ECG variables will be 
summarized.
9.5.2.4
Laboratory data
All laboratory data will be listed with abnormal values flagged. The laboratory values and the 
change from baseline for continuous laboratory parameters will be summarized at each visit. 
A frequency table of results for categorical laboratory parameters will be produced for the 
whole study duration. 
Shift tables relative to the normal reference ranges will be used to summarize the change from 
baseline to post-baseline for each laboratory parameter. For each 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 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 value meeting the clinically notable criteria 
will be counted under the applicable criteria. 
9.7
Interim analyses
Not applicable.
9.8
Sample size calculation
The primary objective is to demonstrate that QAW039 150 mg is superior to placebo in pre-
dose FEV1 following 12 weeks of post-baseline treatment. A difference of 112 mL in pre-
dose FEV1 during treatment was assumed, which is similar to the model-averaged effect seen 
in study QAW039A2206. The standard deviation (SD) of 380 mL and between-visit 
correlation for pre-dose FEV1 was based on study QAW039A2206 in a similar population. A 
treatment discontinuation rate of 15% was assumed based on QAW039A2206 and it was 
assumed that half of the patients discontinuing study treatment would have week 12 FEV1 


Novartis
Confidential
Page 74
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
values. Simulations were used to determine the sample size due to the complex jump-to-
reference missing data imputation approach for the primary analysis.
Under the outlined assumptions, a sample size of 650 patients (325 per arm) will be needed to 
have 90% power to observe a statistically significant difference between QAW039 and 
placebo at the two-sided 5% significance level in the primary analysis as shown in Table 9-1.
The table also shows the sensitivity of the power to deviations from the assumptions.
Table 9-1
Result of power simulations for the primary variable
Treatment effect (mL)
Discontinuation rate
Sample size
Power
112
15%
650
90.3
112
20%
650
85.9
100
15%
650
80.9
Based on 10,000 simulated trials per scenario and 250 multiple imputations for each trial. Simulations 
were conducted using SAS/STAT® 13.1 software, Version 9.4 of the SAS System for Linux.
9.8.1
Power for the secondary objectives
If statistical significance is achieved in the primary test, the tests for the secondary variables 
will be performed. The local significance level for each secondary null hypothesis will be 
determined based on the closed testing procedure shown in Figure 9-1. 
As differences in FEV1 to placebo for QAW039 150 mg once daily and montelukast 10 mg 
once daily appeared to be of similar magnitudes in study QAW039A2206, the power 
calculations for the two secondary objectives (change from baseline in daytime asthma 
symptoms and change from baseline in total daily SABA use) are based on the assumptions 
from the results of two studies comparing montelukast 10 mg once daily with placebo (Reiss 
et al 1998, Malmstrom et al 1999). These studies suggest an averaged difference of 0.26 for 
change from baseline in daytime asthma symptoms between montelukast and placebo after 12
weeks of treatment and a SD of 0.94. The two studies also suggest an averaged difference of -
1.34 point difference in the change from baseline in the number of daily SABA puffs between
montelukast and placebo with a standard deviation of 3.82. We assume a clinically important 
true improvement of at least 0.5 in AQLQ+12 after 12 weeks treatment for patients that 
remain on treatment and a standard deviation (SD) of 1. As shown in Table 9-2 all secondary 
endpoints have an adequate conditional power once the primary null hypothesis has been 
rejected, but will each have an even higher conditional power once the null hypotheses 
relating to the other secondary variables have been rejected.


Novartis
Confidential
Page 75
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
Table 9-2
Power simulations for secondary variables
Daytime asthma 
symptoms
Total daily rescue 
medication use
AQLQ+12
Difference of effect (δ)
-0.26
--1.34 number of puffs
0.5
SD (σ)
0.94
3.82 number of puffs
1
Local two-sided significance level once 
primary null hypothesis is rejected
0.0245
0.0245
0.001
Power
74%
97%
98%
Local two-sided significance level once 
primary and the other two secondary 
hypotheses are rejected
0.05
0.05
0.05
Power
83%
98%
> 99%
Power statements are based on 10,000 simulated trials per scenario and 250 multiple imputations 
using a jump-to-reference approach for each simulated trial. Simulations were conducted using 
SAS/STAT® 13.1 software, Version 9.4 of the SAS System for Linux. We assumed a treatment 
discontinuation rate of 15% with half of the patients discontinuing from study treatment completing 
the trial. The correlation structure was assumed to be the same as for the primary endpoint. 
Abbreviation: AQLQ+12 (asthma quality of life questionnaire for 12 years and older).
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, United States Code of 
Federal Regulations (US CFR) 21, and Japanese Ministry of Health, Labor, and Welfare), and 
with the ethical principles laid down in the Declaration of Helsinki.
10.2
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if applicable after 
such consent has been provided by a legally acceptable representative(s) of the patient. 
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.


Novartis
Confidential
Page 76
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
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. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Quality Assurance representatives, designated 
agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the 
clinical site is requested by a regulatory authority, the investigator must inform Novartis 
immediately that this request has been made.
10.4
Publication of study protocol and results
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, 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 should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 


Novartis
Confidential
Page 77
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction, data, information, observation 
would be incidentally collected, the investigator shall immediately disclose it to Novartis and 
not use it for any purpose other than the study, except for the appropriate monitoring on study 
participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented. 
11.1
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate 
hazard to patients may be implemented immediately provided the health authorities are 
subsequently notified by protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7 Safety Monitoring must be followed.
12
References 
References are available upon request.
ATS/ERS (2005) Recommendations for Standardized Procedures for Online and Offline 
Measurement of Exhaled Lower Respiratory Nitric Oxide and Nasal Nitric Oxide. AJRCCM; 
171: 912-930.
Barnard J and Rubin DB (1999) Small-sample degrees of freedom with multiple imputation. 
Biometrika; 86:948–955.
Bretz F, Maurer W, Brannath W et al. (2009) A graphical approach to sequentially rejective 
multiple test procedures. Statistics in Medicine; 28(4): 586-604.
Carpenter JR, Roger JH, Kenward MG (2013) Analysis of Longitudinal Trials with Protocol 
Deviation: A Framework for Relevant, Accessible Assumptions, and Inference via Multiple 
Imputation. Journal of Biopharmaceutical Statistics, 23 (6), 1352-1371
Center for Disease Control and Prevention (Cdc.gov) (2000). Growth Charts - Homepage. 
Available from: http://www.cdc.gov/growthcharts/.
Chevalier E, Stock J, Fisher T et al. (2005) Cutting edge: chemoattractant receptor-
homologous molecule expressed on Th2 cells plays a restricting role on IL-5 production and 
eosinophil recruitment. J Immunol; 175: 2056–2060.
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.


Novartis
Confidential
Page 78
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
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.
Fuhlbrigge A, Reed ML, Stempel DA et al (2009) The status of asthma control in the U.S. 
adult population.  Allergy Asthma Proc 30: 529-533.
Global Initiative for Asthma (GINA) (2016). Global Strategy for Asthma Management and 
Prevention.  Available from http://www.ginasthma.org/. 
Global Initiative for Asthma (GINA) (2016). Pocket guide for asthma management and 
prevention for adults and children older than 5 years.  Available from 
http://www.ginasthma.org/. 
 
Jacobson TA (2008) Toward “pain-free” statin prescribing: clinical algorithm for diagnosis 
and management of myalgia. Mayo Clin Proc; 83: 687-700.
Juniper EF, O'Byrne PM, Guyatt GH et al. (1999) Development and validation of a
questionnaire to measure asthma control. Eur Resp J; 14: 902-907.
Juniper EF, Svensson K, Moerk AC, et al (2005) Modification of the Asthma Quality of Life 
Questionnaire (standardised) for patients 12 years and older. Health and Quality 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) Asthma Control Questionnaire in 
children: 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.
Malmstrom K, Rodriguez-Gomez G, Guerra J et al (1999)  Oral montelukast, inhaled 
beclomethasone, and placebo for chronic asthma. Ann Intern Med; 130: 487-495.
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.
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.
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; 31:367-395.


Novartis
Confidential
Page 79
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
Reiss TF, Chervinsky P, Dockhorn RJ et al (1998) Montelukast, a once-daily leukotriene 
receptor antagonist, in the treatment of chronic asthma: a multicenter, randomized, double-
blind trial. Montelukast Clinical Research Study Group. Arch Intern Med; 158:1213-1220.
Santanello NC, Barber BL, Reiss TF et al (1997) Measurement characteristics of two asthma 
symptom diary scales for use in clinical trials.  Eur Resp J; 10: 646-651.


Novartis
Confidential
Page 80
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
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 electronic case report form (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 3 for specific renal alert criteria and actions.
For electrocardiograms (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 contract research organization (CRO) and require assessment for clinical relevance 
and continuance of the patient by the Investigator.  


Novartis
Confidential
Page 81
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
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.
Abbreviations: ULN (upper limit of normal), ALT (alanine aminotransferase), AST (aspartate aminotransferase), 
TBL (total bilirubin), ALP (alkaline phosphatase), INR (international normalized ratio).
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)
> 3 × ULN 
accompanied by 
symptomsb
Discontinue the study treatment immediately
Hospitalize if clinically appropriate
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)


Novartis
Confidential
Page 82
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
Criteria
Actions required
Follow-up monitoring
Establish causality
Complete liver CRF
> 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.
Abbreviations: ULN (upper limit of normal), ALT (alanine aminotransferase), AST (aspartate aminotransferase), 
TBL (total bilirubin), ALP (alkaline phosphatase), INR (international normalized ratio), PT, Alb (albumin), LFT (lung 
function test), CRF (case report form).


Novartis
Confidential
Page 83
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
15
Appendix 3: Specific Renal Alert Criteria and Actions
Table 15-1
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 84
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
16
Appendix 4:  List of idiosyncratic drug reactions (IDRs) for 
investigators
Table 16-1
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 85
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
17
Appendix 5: Spirometry Guidance
Equipment
Spirometers must meet the specifications and performance criteria recommended in the 
American Thoracic Society (ATS)/European Respiratory Society (ERS) Standardization of 
Spirometry1. Spirometers must have the capacity to print forced vital capacity (FVC) tracings.  
All spirometry values should be reported at body temperature and pressure saturated (BTPS)
by the method established by the manufacturer.
Calibration
The spirometer should be calibrated every morning before any spirometric measurements for 
the study are performed. Calibration reports should be printed and stored as source data at the 
site. 
Preparing the test subject
On study days when spirometry will be performed, patients should refrain from the following:

Coffee, tea, chocolate, cola and other caffeine-containing beverages and foods and ice-
cold beverages  for 4 hours prior to spirometry

Alcohol for 4 hours prior to spirometry

Strenuous activity for 12 hours prior to spirometry 

Exposure to environmental smoke, dust or areas with strong odors
Every effort should be made to assure consistent testing conditions throughout the study.  A 
seated position with nose clips is recommended to reduce risks related to dizziness or syncope.  
When possible, spirometry should be conducted by the same technician using the same 
spirometer.  To minimize the effects of diurnal variation on lung function, spirometry visits 
should start at approximately the same time of day at each visit.  
Performing Spirometry
The subject’s age, height and gender will be entered into the spirometer.  It is important that 
the height is measured accurately at the study site. Spirometry, an effort-dependent test, 
requires careful instruction and cooperation of the subject.  The technician should ensure a 
good seal around the mouthpiece, and confirm that the subject’s posture is correct. The 
subject should be instructed to perform a maximal inspiration, followed by maximum forced 
expiration until no more air can be exhaled or for at least 6 seconds. Expiration must be rapid 
with exertion of maximal effort. The results of spirometry should meet the ATS/ERS criteria 
for acceptability and repeatability. Acceptability criteria should be applied before repeatability 
is determined.  


Novartis
Confidential
Page 86
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
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.
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 and no volume change for at least 1 second) or the subject cannot continue 
to exhale further. Overall acceptability will be determined by expert over-read by 
spirometry vendor.
Repeatability
The 2 largest forced expiratory volume in 1 second (FEV1) values from 3 acceptable 
maneuvers should not vary by more than 0.150 L.
If patient does not meet the repeatability or acceptability criteria during the screening period, 
patient may be rescreened once or allow one spirometry retest. 
Recording of data
The greatest FEV1 
 from any of the acceptable curves are recorded. (The greatest 
FEV1 
 may not necessarily result from the same acceptable curve).  
Predicted normal
For all patients, this study will utilize the global lung function 2012 equations (GLI2012) 
published by Quanjer et al 20122 or Japanese Respiratory Society3.
Reversibility
All reversibility evaluations should follow the recommendations of the ATS/ERS Task force: 
Standardization of Lung Function Testing1. A pre-bronchodilator spirometry* assessment 
should be performed after withholding of specified medications as specified in Table 5-2
“Medications to be withheld prior to spirometry”.
Administer 400µg of salbutamol/albuterol (or equivalent) following the completion of the pre-
bronchodilator assessment*. Spacers will be allowed for the administration of 
salbutamol/albuterol (or equivalent) for reversibility testing.  Post-bronchodilator spirometry 
assessment is then performed approximately 10 to 15 minutes after administration of the 
salbumatol/albuterol. 
Reversibility is calculated as: 


Novartis
Confidential
Page 87
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
100 x       FEV1 (post-bronchodilator) – FEV1 (pre-bronchodilator)*
                                     FEV1 (pre-bronchodilator)*
Patients will be considered reversible if an increase of at least 12% (and 200 mL) is 
demonstrated after administration of the salbutamol/albuterol.
*NOTE: At visits with two pre-dose spirometry assessments (please see Table 6-1 for 
schedule of assessments) the FEV1 from the 2nd pre-dose spirometry assessment (performed 
approximately 15 min prior to in-clinic witnessed study drug administration) should be used 
for FEV1 (pre-bronchodilator).
17.1
References for appendix
1Miller 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.
3Kubota, 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 88
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
18
Appendix 6: Estimated equivalence of inhaled 
corticosteroids
From the Global Strategy for Asthma Management and Prevention 2016, © Global Initiative 
for Asthma (GINA) all rights reserved. Available from http://www.ginasthma.org.
For the purposes of calculating total daily dose for the study, if the table has the medication 
dose listed by dry powder inhaler (DPI), but not metered dose inhaler (MDI), then use the DPI 
classification as a reference and vice versa (i.e., if the table has the medication dose listed by
MDI, but not DPI, then use the MDI classification). 


Novartis
Confidential
Page 89
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
19
Appendix 7: Asthma Control Questionnaire (ACQ-5)
A SAMPLE of the Asthma Control Questionnaire – 5 is included below.  The format of the 
administered test may vary.


Novartis
Confidential
Page 90
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316


Novartis
Confidential
Page 91
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316
20
Appendix 8 : Asthma Quality of Life Questionnaire for 12 
years and older (AQLQ+12)
A SAMPLE of the Asthma Quality of Life Questionnaire for 12 years and older is included 
below.  The format of the administered test may vary.


Novartis
Confidential
Page 92
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316


Novartis
Confidential
Page 93
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316


Novartis
Confidential
Page 94
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316


Novartis
Confidential
Page 95
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316


Novartis
Confidential
Page 96
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316


Novartis
Confidential
Page 97
Clinical Trial Protocol (Version 00)
Protocol No. CQAW039A2316

SAP_000.pdf: 
Clinical Development 
QAW039/fevipiprant 
CQAW039A2316 / NCT03215758
A 12-week, multicenter, randomized, double-blind, placebo-
controlled study to assess the efficacy and safety of 
QAW039 when added to standard-of-care asthma therapy 
in patients with uncontrolled asthma 
Statistical Analysis Plan (SAP) 
Author: 
, Trial Statistician 
Document type: 
SAP Documentation 
Document status: 
Amendment 1 
Release date: 
25-Aug-2019
Number of pages: 
49 
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 
 
CQAW039A2316 
 
Document History – Changes compared to previous final version of SAP 
 
Date 
Reason for update 
Section and title 
impacted (Current) 
20-Jun-
2019 
Updated time window for eDiary data baseline 
Table 2-1 
 
Added summary of estimand table for primary endpoint to 
explicitly describe the primary estimand 
Table 2-2 
 
Provided more details on rank-based analysis 
Section 2.5.5 
 
Added the responder analysis for AQLQ improvement 
Section 2.6.3 
 
Updated the treatment emergent flags in order to maintain 
consistency with the submission documents 
 
Section 2.7 
 
Updated rule of exclusion criteria of analysis sets 
Section 6.4 
16-Aug-
2019 
Extended box-plot to all laboratory parameters to 
investigate the tendency of treatment effect  
Section 2.7.3.2 
 
Added more details to liver function tests including eDISH 
plot 
Section 2.7.3.3 
 
Added analysis for renal events and liver events according 
to project level alignment 
Section 2.7.5 and 
Section 2.7.6 


Novartis 
For business use only 
Page 3 
SAP 
 
CQAW039A2316 
 
Table of contents 
Table of contents ................................................................................................................. 3 
List of abbreviations ............................................................................................................ 5 
1 
Introduction ......................................................................................................................... 7 
1.1 
Study design............................................................................................................. 7 
1.2 
Study objectives and endpoints ............................................................................... 8 
1.2.1 
Study Objectives and Endpoints ............................................................. 8 
2 
Statistical methods ............................................................................................................. 10 
2.1 
Data analysis general information ......................................................................... 10 
2.1.1 
General definitions ................................................................................ 10 
2.2 
Analysis sets .......................................................................................................... 13 
2.2.1 
Subgroup of interest .............................................................................. 14 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 15 
2.3.1 
Patient disposition ................................................................................. 15 
2.3.2 
Patient demographics and baseline characteristics  .............................. 15 
2.3.3 
Medical history ...................................................................................... 17 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 17 
2.4.1 
Study treatment / compliance ................................................................ 17 
2.4.2 
Prior, concomitant and post therapies ................................................... 18 
2.5 
Analysis of the primary and secondary endpoint .................................................. 18 
2.5.1 
Primary endpoint ................................................................................... 18 
2.5.2 
Secondary endpoints ............................................................................. 20 
2.5.3 
Statistical hypothesis, model, and method of analysis .......................... 20 
2.5.4 
Handling of missing values/censoring/discontinuations ....................... 21 
2.5.5 
Supportive analyses ............................................................................... 22 
2.5.6 
Multiplicity adjustment ......................................................................... 23 
2.6 
Analysis of secondary efficacy objective(s) .......................................................... 24 
2.6.1 
Daytime asthma symptoms in patients .................................................. 24 
2.6.2 
Total daily use of SABA ....................................................................... 25 
2.6.3 
AQLQ+12 ............................................................................................. 26 
2.6.4 
Handling of missing values/censoring/discontinuations ....................... 27 
2.7 
Safety analyses ....................................................................................................... 28 
2.7.1 
Adverse events (AEs) ............................................................................ 28 
2.7.2 
Deaths .................................................................................................... 29 
2.7.3 
Laboratory data ..................................................................................... 29 
2.7.4 
Other safety data ................................................................................... 32 


Novartis 
For business use only 
Page 4 
SAP 
 
CQAW039A2316 
 
2.7.5 
Renal events .......................................................................................... 34 
2.7.6 
Liver events ........................................................................................... 34 
2.8 
Pharmacokinetic endpoints .................................................................................... 34 
2.9 
PD and PK/PD analyses......................................................................................... 34 
 
 34 
 
 34 
 
 34 
 
 35 
 
 35 
 
 36 
 
 36 
 
 37 
 
 38 
2.12 
Interim analysis ...................................................................................................... 38 
3 
Sample size calculation ..................................................................................................... 38 
Power for the secondary objectives ....................................................................... 39 
4 
Change to protocol specified analyses .............................................................................. 40 
 
 41 
 
 41 
 
 41 
 
 41 
 
 42 
 
 42 
6 
Appendix ........................................................................................................................... 42 
6.1 
Imputation rules ..................................................................................................... 42 
6.1.1 
Study drug ............................................................................................. 42 
6.1.2 
AE date imputation ............................................................................... 42 
6.1.3 
Concomitant medication date imputation ............................................. 42 
6.2 
AEs and Concomitant medications coding/grading .............................................. 43 
6.3 
Visit remapping and assessment windows ............................................................ 43 
6.4 
Laboratory parameters derivations ........................................................................ 43 
6.5 
Vital signs – definition of clinically notable and relevant values .......................... 46 
6.6 
Statistical methodology and assumptions .............................................................. 47 
6.6.1 
Multiple imputations for primary and secondary variables .................. 47 
6.7 
Rule of exclusion criteria of analysis sets.............................................................. 49 
7 
Reference ........................................................................................................................... 51 


Novartis 
For business use only 
Page 5 
SAP 
 
CQAW039A2316 
 
List of abbreviations 
ACQ-5 
Asthma Control Questionnaire 
AE 
Adverse event 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
AMAC 
Asia-Pacific, Middle East and African Countries 
ANCOVA 
Analysis of Covariance 
AQLQ 
Asthma Quality of Life Questionnaire 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Classification 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
CM 
Concomitant Medication 
CRS 
Case Retrieval Strategy 
DAR 
Dosage Administration Records 
DBP 
Diastolic Blood Pressure 
DMC 
Data Monitoring Committee  
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
FAS 
Full Analysis Set 
FEV1 
Forced Expiratory Volume in 1 Second 
 
 
ICS 
Inhaled Corticosteroid 
IgE 
Immunoglobulin E 
IRT 
interactive response technology 
ITT 
Intension-to-treat 
LABA 
Long Acting Beta-2 Agonist 
LFT 
Liver Function Test 
MAR 
Missing at Random 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
mg 
milligram 
MI 
Multiple Imputation 
MMRM 
Mixed Model for Repeated Measures 
MNAR 
Missing Not at Random 
PD 
Pharmacodynamics 
PDS 
Programming Dataset Specification 
PEF 
Peak Expiratory Flow 
PK 
Pharmacokinetics 
PPS 
Per protocol set 
PR 
Pulse Rate 
PT 
Preferred Term 
Qd 
Qua’que di’e / once a day 
QTc 
Corrected QT interval 


Novartis 
For business use only 
Page 6 
SAP 
 
CQAW039A2316 
 
QTcF 
Fridericia QT correction formula 
RAN 
Randomized set 
SABA 
Short Acting Beta2 Agonist 
SAE 
Serious Adverse Event 
SAF 
Safety analysis set 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SI 
SoC 
International System of Units 
Standard of Care 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TFL 
Tables, Figures, Listings 
WHO-DD 
World Health Organization- Drug Dictionary 
 


Novartis 
For business use only 
Page 7 
SAP 
 
CQAW039A2316 
 
1 
Introduction 
This document contains details of the statistical methods that will be used in the phase III 
clinical trial CQAW039A2316. This study is designed to determine efficacy and safety of 
QAW039 (150 mg once daily), compared with placebo, when added to standard-of-care (SoC) 
asthma therapy in adult and adolescent (≥12 years) patients with uncontrolled asthma with 
respect to change from baseline in FEV1 at the end of 12 weeks of treatment. 
Data will be analyzed according to Section 9 of the study protocol.  
Important information is given in the following sections and details are provided, as applicable, 
in Section 6: Appendix. 
1.1 
Study design 
This study uses a randomized, multicenter, double-blind, placebo-controlled parallel-group 
study design in which QAW039 or placebo is added to incoming SoC asthma therapy (Figure 
1).  
The study will include: 
• a Screening period of up to 2 weeks to assess eligibility. Patients will also practice 
completing the electronic peak expiratory flow (ePEF)/eDiary device during this period. 
• a Placebo Run-in period of 1 week to collect baseline data for efficacy variables and 
compliance with the ePEF /eDiary device. Eligibility for randomization will be 
determined during the placebo run-in period. 
• a Treatment period of 12 weeks; and 
• a Follow-up period of 4 weeks, study drug-free, following the last dose of study drug. 
Note: the follow-up period applies to all patients except those patients who enter the 
safety study (CQAW039A2315) directly after Visit 299. 
 


Novartis 
For business use only 
Page 8 
SAP 
 
CQAW039A2316 
 
Figure 1 
Study design  
 
 
1.2 
Study objectives and endpoints 
All objectives will consider the following comparison: 
QAW039 (150 mg once daily) compared with placebo, when added to standard-of-care (SoC) 
asthma therapy in adult and adolescent (≥12 years) patients with uncontrolled asthma. 
1.2.1 
Study Objectives and Endpoints 
Table 1-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary Objective 
To demonstrate the efficacy of QAW039 150 
mg once daily as measured by change from 
baseline in pre-dose FEV1 [in liters], 
compared with placebo, at the end of the 12-
week active-treatment period. 
Endpoint for primary objective 
Change from baseline in pre-dose FEV1 (L) 
at week 12. 
Secondary Objectives 
1. To demonstrate the efficacy of QAW039 
150 mg once daily, compared with 
placebo, on daytime asthma symptoms 
over the 12-week active-treatment 
period. 
2. To demonstrate the efficacy of QAW039 
150 mg once daily, compared with 
placebo, on total daily short-acting β-
Endpoints for secondary objectives 
1. Change from baseline in daytime asthma 
symptom score over 12 weeks of 
treatment. 
 
2. Change from baseline in number of 
puffs of SABA taken per day over 12 
weeks of treatment. 
 


Novartis 
For business use only 
Page 9 
SAP 
 
CQAW039A2316 
 
Objective(s) 
Endpoint(s) 
agonist (SABA) use over the 12-week 
active-treatment period. 
3. To demonstrate the efficacy of QAW039 
150 mg once daily, compared with 
placebo, on change from baseline in 
Asthma Quality of Life Questionnaire 
for 12 years and older (AQLQ+12) score 
at the end of  the 12-week active-
treatment period. 
4. To assess the safety of QAW039 150 mg 
once daily, compared with placebo, with 
respect to adverse events (AE), 
electrocardiograms (ECGs), vital signs, 
and laboratory tests.   
 
 
3. Change from baseline in AQLQ+12 
score at week 12. 
 
 
 
 
4. Summaries of treatment-emergent 
adverse events, systolic and diastolic 
blood pressure, pulse rate, body weight, 
RR interval, PR interval, QRS duration, 
heart rate, and Fridericia’s QTc, 
laboratory values and change from 
baseline for continuous laboratory 
values. 


Novartis 
For business use only 
Page 10 
SAP 
 
CQAW039A2316 
 
 
2 
Statistical methods 
 
2.1 
Data analysis general information 
 
The statistical analysis will be performed by Novartis. The most recent version of SAS® (SAS 
Institute Inc., Cary, NC, USA) available in the statistical programming environment of Novartis 
will be used for the analysis.  
2.1.1 
General definitions  
In this document, although investigational treatment is given in addition to background standard 
of care therapy, ‘study medication’, ‘study treatment’ or ‘study drug’ will be used to refer to 
investigational therapy assigned to a patient. Specifically, for the double-blind treatment period, 
study treatment refers to QAW039 or placebo as assigned to a patient at randomization.  
The date of the first administration of the investigational treatment (QAW039 or matching 
placebo) is referred to as the date of first administration of study treatment in the study. The 
evaluations which have complete date and time values are assigned to pre or post-dose 
assessment based on the actual date/time. However, evaluations with missing date/time are 
assigned to their respective scheduled visit date and time given the visit number and time point 
are non-missing. If an evaluation scheduled as pre-dose is actually performed post-dose, or vice 


Novartis 
For business use only 
Page 11 
SAP 
 
CQAW039A2316 
 
versa, the data will not be used for inferential analysis and summary statistics but will be 
included in the summaries of the notable values and extreme values.  
Study day will be defined as the number of days since the date of first dose of study medication. 
The date of first dose of study medication will be defined as Day 1 and the day before the first 
dose of study medication is defined as Day -1.  
Therefore, for a particular date, study day will be calculated as follows: 
• 
for dates on or after the first date of study medication, 
Study day = Assessment date – Date of first dose of study medication + 1; 
• 
for dates prior to the first date of study medication, 
Study day = Assessment date – Date of first dose of study medication. 
If a patient never took any study medication, the randomization date will be used instead of the 
date of first dose of study medication. In this case, the randomization date is defined as Day 1 
and the day prior to randomization is defined as Day -1. 
2.1.1.1 
Baseline definition 
Data from unplanned visits prior to screening are not included in analysis. In general, baseline 
is defined as the last assessment taken prior to the first dose of study drug at Day 1 (Visit 201).  
Checks will be performed to ensure the assessments were taken prior to the first dose of study 
drug on Day 1 (Visit 201). If the assessment is missing or not confirmed to be pre-dose, then 
the last available non-missing assessment will be used as baseline. Missing baseline pre-dose 
FEV1, daytime asthma symptoms, total daily SABA use and AQLQ+12 will be assumed to be 
missing at random as assessments are performed prior to any knowledge of treatment allocation 
and will be imputed using the mean value of all randomized patients.  
Table 2-1 Baseline definition of analysis parameters 
Parameter 
Baseline assessment 
Detail 
ACQ-5, AQLQ 
  
  
Last assessment  prior to 
the first dose of study drug 
on Day 1 
If the Day 1 assessment is 
missing the last available 
assessment (scheduled or 
unscheduled) taken prior to the 
first dose of study drug will be 
used.  


Novartis 
For business use only 
Page 12 
SAP 
 
CQAW039A2316 
 
Lung function (FEV1) 
Average of the two FEV1 
assessments taken at 45 
minutes and 15 minutes 
prior to the first dose of 
study drug on Day 1 
 
Checks will be performed to 
ensure both values were taken 
prior to the first dose of study 
drug. If one of the 45 and 15 min 
values is missing (or is not 
confirmed to be pre-dose) then 
the remaining non-missing value 
will be taken as the baseline.  
If both assessments are missing 
(or are not confirmed to be pre-
dose) then the last available 
FEV1 measurement (scheduled 
or unscheduled) prior to Day 1 
will be used for baseline.  
 
 
eDiary data (Daytime 
asthma symptoms) 
Average 
of 
the 
mean 
daytime asthma symptom 
score from Visit 101 to Day 
1  
 
The baseline score will be 
calculated as long as there are at 
least 4 days with non-missing 
eDiary data. Noted that the 
morning assessment for Day 1 
counts towards the baseline.  
eDiary data (Total daily 
use of SABA) 
Average of total daily 
SABA use from Visit 101 
to Day 1 
The baseline score will be 
calculated as long as at least 4 
days with non-missing eDiary 
data. Noted that the morning 
assessment for Day 1 counts 
towards the baseline  while the 
evening assessment for Day 1 
counts as the treatment period. 


Novartis 
For business use only 
Page 13 
SAP 
 
CQAW039A2316 
 
Laboratory data 
(hematology, clinical 
chemistry, urine analysis) 
Last available assessment 
(scheduled or unscheduled) 
prior to dosing on Day 1 
 
Vital signs  (pulse rate 
and systolic & diastolic 
blood pressures) 
Last available assessment 
(scheduled or unscheduled) 
prior to dosing on Day 1 
 
Height and weight 
Last available assessment 
(scheduled or unscheduled) 
prior to dosing on Day 1  
 
ECG 
Last available assessment 
(scheduled or unscheduled) 
prior to dosing on Day 1  
 
2.1.1.2 
Post-baseline measurement 
Post-baseline measurements are defined as those assessments after the start of the study 
treatment. 
When change from baseline is of interest, the following formula will be used for each visit and 
time-point where baseline and post-baseline values are both available: 
Change from baseline = post baseline value – baseline value. 
2.2 
Analysis sets  
The following analysis sets are defined: 
• The screened set (SCR) will include all patients who provided informed consent. 
• The randomized (RAN) set will consist of all patients who were assigned a 
randomization number, regardless of whether or not they actually received study 
medication. Patients in RAN will be analyzed according to the treatment they were 
randomized to.  
• The Full Analysis Set (FAS) will consist of all randomized patients who received at 
least one dose of study medication. It was considered reasonable to limit the FAS to 
patients who took trial medication, because the decision on whether or not study drug is 
started will not be influenced by the treatment group assignment due to the effective 
treatment blinding procedures. Following the intent-to-treat principle, patients will be 
analyzed according to the treatment they were assigned to at randomization. The FAS 
will be used for the analysis of all efficacy endpoints, and for the summaries of patient 
disposition, demographic and baseline characteristics. 
• The Per-Protocol Set (PPS) will include all patients in the FAS who did not have any 
major protocol deviations such as violation of major entry criteria. Protocol deviations 
will be defined in the data review plan document prior to database lock and the un-
blinding of the study. Protocol deviations leading to exclusion from analysis sets are 


Novartis 
For business use only 
Page 14 
SAP 
 
CQAW039A2316 
 
defined in Section 6.7. Patients in the PPS will be analyzed according to the treatment 
they actually received. The PPS may be used for supportive analysis of the primary 
efficacy endpoint. 
• The Safety Set (SAF) will consist of all patients who received at least one dose of 
double-blind study drug. Patients will be analyzed according to the treatment they 
received. The SAF will be used in the analysis of all safety variables. If due to a 
dispensing error a patient erroneously receive received any study treatment which is 
different from the randomized treatment, the patient will be analyzed according to the 
treatment they were randomized to. 
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. 
In cases where an incorrect randomization stratum is entered in the IRT (interactive response 
technology), the corrected stratum information as per the CRF data will be used for reporting 
and analysis. 
2.2.1 
Subgroup of interest  
Subgroup analyses will be performed for primary endpoint and secondary endpoints using the 
same model as for the primary analysis (mentioned in section 2.5.3) but with additional model 
terms for the subgroup (if not already included in the model) and subgroup-by-treatment 
interaction terms. The subgroup variables are listed below:  
Key demographic subgroups: 
• Age at entry into study (<18,  ≥18 years) 
• Sex (Male, Female) 
• Race (Caucasian, Black, Asian, Other) 
• Geographic region (Europe, Latin America, North America, China/AMAC)  
The definition of geographic region will be same as the definition of region at the 
randomization 
Disease related subgroups: 
• Use or non-use of a second asthma controller medication 
• Baseline FEV1 (tertiles 1, tertiles 2, tertiles 3)   
• Baseline %predicted FEV1 (> 70%, ≤ 70%)  
Subgroup analyses will be conducted on the FAS for exploratory purposes. Formal multiplicity 
adjusted testing on the subgroups will not be performed. 
Subgroup analyses contributing key regulatory information will be provided for relevant 
country or region to meet regulatory requirements. Analyses required to fulfil health authority 
commitments or submission requirements for specific countries will be reported separately and 
outside of CSR. 


Novartis 
For business use only 
Page 15 
SAP 
 
CQAW039A2316 
 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
2.3.1 
Patient disposition  
The number of patients screened, randomized, completed and discontinued from the study will 
be summarized for each study phase (i.e., screening, run-in, and treatment). In addition, the 
number of patients randomized, completed and discontinued from the 12-week treatment period 
will be summarized by country. Screened set and its subset of patients who received placebo 
study medication during the run-in period will be used for screening period and run-in period 
disposition tables, respectively.  RAN will be used for treatment disposition outputs.  Patients 
discontinued from the 12-week treatment period will also be summarized with reasons for 
discontinuation. Patients who discontinued study treatment but stayed in the study will be 
considered as completing the 12-week treatment period. Patients who discontinued study 
treatment but stay in the study are defined as patients with the date of study discontinuation or 
Visit 299 - the end date of study treatment > 0. Patient randomization numbers and whether 
they completed or discontinued from the study will be listed, with date of last dose and primary 
reason for discontinuation, including the unblinding date if applicable. 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 using a 
Kaplan-Meier curve for the FAS. The date of study discontinuation is defined as the maximum 
of the last known visit date for treatment period and the date of last dose of study medication. 
Patients who completed the study will be censored at the final study visit. 
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.  
The number of patients included in each analysis set will be tabulated by treatment group for 
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). 
2.3.2 
Patient demographics and baseline characteristics  
Demographics and baseline characteristics will be summarized by treatment group using the 
FAS set. Summaries will include age, gender, race, ethnicity, height, weight, BMI, pre- and 
post-bronchodilator FEV1, percent predicted FEV1,  
 
, FEV1 reversibility, duration of asthma, number of asthma 
exacerbations in prior year, atopic asthma at entry into the study (Yes/No), smoking history 
(never/former), number of pack years, baseline ACQ-5, baseline AQLQ+12, 
 
, and ICS use (alone, plus LABA, plus LTRA), ICS dose ranges (low, medium, 
high), 
 
and daytime asthma symptom scores.  
Background asthma therapy will be categorized into GINA steps and will be summarized at 
baseline. Background asthma therapy is defined as concomitant medication start date on or 
before Visit 1 and end date after Visit 1. Continuous variables will be summarized using 


Novartis 
For business use only 
Page 16 
SAP 
 
CQAW039A2316 
 
descriptive statistics (number of non-missing data, mean, standard deviation, median, first and 
third quartiles, minimum, and maximum)  and categorical variables will be summarized in terms 
of the number and percentage of patients in each category including a category for missing data 
if any for the treatment group. 
No statistical analyses will be provided for baseline comparability among the treatment groups. 
 
In addition, the following categorizations of continuous variables will be done: 
• Age: <18, 18 to <65, and ≥65 years; 
• BMI:  ≤ 30.0 kg/m2 and > 30.0 kg/m2; 
• Duration of asthma: < 1 year, 1 - 5 years, > 5 - 10 years, > 10 - 15 years, > 15 – 20 years, 
and > 20 years; 
• Number of asthma exacerbations in prior year: 0, 1-2, 3, 4, ≥ 5  
• pre-bronchodilator percent predicted FEV1: <= 40 %, >40% - ≤ 50%, >50% - ≤ 
60%, >60% - ≤ 70%, >70% - ≤ 80%, >80% 
• ACQ-5: 1.5- < 2, 2 – < 2.5, ≥ 2.5 (< 1.5 will be added in case of protocol deviations) 
• 
 
 
 
Derivation of the demographics and baseline characteristics 
• BMI is calculated as: BMI (kg/m2) = Weight (kg) / [Height (m) * Height (m)] 
• Estimated number of pack years is calculated by the total years of smoking multiplied by 
cigarette packs smoked per day. This will be summarized as recorded on the eCRF. Smoking 
history in package years will be calculated as: (1 pack year = 20 cigarettes/day x 1 year or 
10 cigarettes/day x 2 years).  
• % of (pre-bronchodilator) predicted FEV1 is obtained as a percentage of FEV1 relative to 
the predicted normal value.  
• FEV1 reversibility is calculated as percentage increase of FEV1 values after inhalation of 
bronchodilator relative to FEV1 values prior to the inhalation. At visits with two pre-dose 
spirometry assessments, the FEV1 from the 2nd pre-dose spirometry assessment (15 min 
prior to in-clinic witnessed study drug administration) should be considered the pre-
bronchodilator FEV1 value. A patient is considered to have demonstrated reversibility at 
clinic at baseline if there is an increase of 12% and >=200 ml any particular visit prior to 
Day 1. 
• Duration of asthma is calculated from the date of asthma first diagnosed recorded on the 
eCRF until the 1st visit. If the date is missing in day and/or month, it will be imputed as 
follows. If the year is before the first visit, the missing days will be imputed as the first of 
the month and the missing months will be imputed as July. If the year is the current year of 
the first visit, the missing days will be imputed as the first of the month and the missing 
months will be imputed as January. 


Novartis 
For business use only 
Page 17 
SAP 
 
CQAW039A2316 
 
• The total daily ICS dose at baseline will be categorized as low, medium, high based on the 
Appendix 6 in study protocol.  
 
2.3.3 
Medical history  
Medical history will be coded with the Medical Dictionary for Regulatory Activities 
terminology (MedDRA) using the most recent version at the time of database lock. 
History/conditions as well as protocol solicited events for asthma will be summarized for the 
FAS set by primary system organ class and preferred term. Verbatim recorded 
history/conditions will be listed together with the coded terms, date of diagnosis/surgery and 
whether the problem was ongoing at start of the study. 
 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
 Study treatment / compliance  
2.4.1.1 
Duration of exposure  
Duration of exposure to a treatment will be calculated as the number of days between the first  
dose date and the last dose date exposed to that treatment over the specified period (expressed 
as: Duration of exposure = Date of last known dose of study drug – Date of first dose of study 
drug + 1). 
The duration of exposure will be summarized by treatment group for the safety set as a 
continuous variable with the standard descriptive statistics. 
The number of patients who completed the 12-week study treatment and who discontinued 
prematurely will be shown including the reasons for discontinuation of study treatment. In 
addition, the duration of exposure will be summarized as a categorical variable classified into 
<4 weeks, >=4 to <12 weeks, >=12 weeks. 
2.4.1.2 
Compliance 
Study drug compliance will be assessed. The overall compliance will be calculated as the 
percentage of days with study medication intake during the period from first intake to last intake 
taking into account the duration of the drug interruptions. 
Percentage of days with study medication intake = 100 x number of days with study medication 
intake as per protocol / (Date of last known dose of study drug – Day 1 + 1).  
Compliance will be categorized as <80%, 80% -100% and summarized by treatment group for 
the safety set. 
Time to study treatment discontinuation will be displayed graphically for each treatment group 
using a Kaplan-Meier curve for the SAF. The date of study treatment discontinuation is defined 
as the date of last dose of study medication. Patients who completed the study treatment will be 
censored at the final visit for treatment period. 


Novartis 
For business use only 
Page 18 
SAP 
 
CQAW039A2316 
 
2.4.2 
Prior, concomitant and post therapies  
Medications started and stopped prior to study drug and taken concomitantly will be 
summarized by treatment group in separate tables in the SAF. The medication will be classified 
into “prior”, “concomitant” and “post” based on the start/end dates. 
Prior: Any medication with a start date before Day 1.  
Concomitant: Any medication with end date on or after Day 1 or ongoing at the end of trial or 
missing end date and start date on or before the end of the Treatment + 1 day. 
Post: Any medication with start date after the end of treatment + 1 day, 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. 
 
Short acting beta2 agonist (SABA) rescue medication usage (mean number of puffs) during the 
placebo run-in period will be summarized. Patients taking prohibited concomitant medications 
will be noted in the summary of protocol deviations. 
 
All summaries will be by treatment group on the Safety Set. 
2.5 
Analysis of the primary and secondary endpoint  
2.5.1 
Primary endpoint 
The definition and rationale for the estimand for the primary endpoint are given in Table 2-2. 
Novartis proposes the most informative estimand to be one that considers the maintenance 
treatment effect that could be expected in clinical practice. The statistical strategy to handle 
each intercurrent event is described in more detail in Section 2.5.4. 
 
 
 
 
 
 


Novartis 
For business use only 
Page 19 
SAP 
 
CQAW039A2316 
 
Table 2-2 
Summary of estimand for the primary endpoint 
Population 
Male or female patients aged 12 years and older with asthma, who are uncontrolled with 
SoC therapy and receive at least one dose of study treatment. For this study, SOC is defined 
as ICS or ICS with a second controller medication (LABA or LTRA) 
 
Variables 
Change from baseline in pre-dose FEV1 at the end of 12 weeks of treatment  
 
Intercurrent event 
Description 
Strategy to handle event 
Justification 
Asthma 
medications with an 
effect on FEV1 are 
taken within 
washout periods 
prior to spirometry 
assessment. 
Allowed asthma 
medications 
(including SABA 
and SoC 
treatment) are 
taken within 
washout periods 
prior to spirometry 
assessment. 
Wash-out periods 
for allowed asthma 
medications prior 
to spirometry 
assessments are 
defined in Protocol 
Table 5-2.  
A hypothetical strategy will 
be used for the days on 
which these medications 
are taken within the 
washout periods.  
Asthma medications that 
taken within washout 
periods may have a 
transient impact on FEV1 
but interest is primarily in 
the effect of longer-term 
maintenance therapy. 
 
Discontinuation of 
fevipiprant for any 
reason 
Discontinuation of 
fevipiprant for any 
reason regardless 
of relation to 
fevipiprant 
A treatment policy strategy 
will be used. All efforts will 
be made to retain patients 
in the trial and adhere to 
the schedule even after 
discontinuation of 
fevipiprant/placebo. 
Where those efforts are 
not successful, the 
missing observations will 
be imputed as described 
in Section 2.5.4  
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.  
Discontinuation of 
placebo for any 
reason 
Discontinuation of 
placebo for any 
reason 
A treatment policy strategy 
will be used. All efforts will 
be made to retain patients 
in the trial and adhere to 
the schedule even after 
discontinuation of 
fevipiprant/placebo. 
Where those efforts are 
not successful, the 
missing observations will 
be imputed as described 
in Section 2.5.4 
In clinical practice, 
patients receive SoC 
without additional 
treatment and the 
approach for placebo 
reflects this. 
 


Novartis 
For business use only 
Page 20 
SAP 
 
CQAW039A2316 
 
Summary measures 
mean difference in change from baseline in pre-dose FEV1 (L) at week 12 between treatment 
groups 
2.5.2 
Secondary endpoints 
The secondary endpoints are daytime asthma symptoms, total daily SABA use and AQLQ+12. 
Their definition and analysis is described in Section 2.6. 
2.5.3 
Statistical hypothesis, model, and method of analysis  
2.5.3.1 
Primary endpoint  
The primary objective of the study is to evaluate superiority of QAW039 150 mg once daily 
over placebo (with SoC asthma therapy as the background therapy) by testing the following 
null hypothesis (H0) versus the alternative hypothesis (Ha): 
H0: There is no difference in the change from baseline in pre-dose FEV1 (L) at week 12 post-
baseline for the patients treated with QAW039 150 mg once daily compared with placebo (μ1 
– μ2 = 0) 
Ha: There is a difference in the change from baseline in pre-dose FEV1 (L) at week 12 post-
baseline for the patients treated with QAW039 150 mg once daily compared with placebo (μ1 
– μ2 ≠ 0). 
where;  
 μ1 = Mean change from baseline in pre-dose FEV1 (L) at week 12 of QAW039 150 mg once 
daily treatment; 
μ2 = Mean change from baseline in pre-dose FEV1 (L) at week 12 of Placebo treatment; 
 
The primary efficacy variable will be analyzed on the FAS using an analysis of covariance 
(ANCOVA) model with factors for treatment group, randomization strata [age group (<18 vs. 
≥18 years), use or non-use of a second asthma controller medication at study entry, and region], 
as well as the baseline daytime asthma symptom score, baseline total daily SABA use and 
baseline pre-dose FEV1 as continuous linear covariates. The variables contributing to the 
randomization strata (i.e. age group (<18 vs. ≥18 years), use or non-use of a second asthma 
controller medication at study entry, and region) are included separately in the model. 
The least squares mean (“adjusted mean”) change from baseline for each treatment group, the 
difference in the least squares (LS) mean changes between the two treatment groups (QAW039 
150 mg – placebo), and the two-sided 95% confidence interval along with the p-value for the 
difference will be obtained and combined from the primary analysis model through the multiple 
imputation approach described in Section 2.5.4.  
The superiority of QAW039 150 mg once daily to placebo as add on to SoC asthma therapy is 
established if the two-sided p-value is less than 0.05 and the 95% confidence intervals lie 
entirely to the right of 0 L. 
Summary statistics for the primary endpoint  
Summaries of observed absolute values and change from baseline in pre-dose FEV1 (L) by 
treatment group and visit will be presented.  


Novartis 
For business use only 
Page 21 
SAP 
 
CQAW039A2316 
 
2.5.4 
Handling of missing values/censoring/discontinuations 
Retrieved data after the discontinuation of study drug (retrieved drop-out) will remain in the 
analysis without further imputation for all treatment groups. 
Despite all attempts to ensure complete follow-up for all patients, some patients may not be 
followed for pre-dose FEV1 for the whole planned study duration. Missing baseline pre-dose 
FEV1 will be assumed to be missing at random (MAR) as assessments are performed prior to 
any knowledge of treatment allocation and will be imputated using the mean value of all 
randomized patients included in the FAS.  
The FEV1 value analyzed at each visit is based on the average of the two FEV1 assessments 
taken at approximately 45 minutes and approximately 15 minutes prior to the dosing of study 
drug at clinic visits. In cases where one of the values is missing, this will be imputed within 
treatment group via multiple imputation and the average will be calculated based on the one 
available assessment and a second imputed assessment. 
Once these imputations are complete, subsequent missing data will be imputed based on a jump-
to-reference (J2R) approach according to following assumptions:  
• Continued treatment effect will be imputed for QAW039 patients with intermittent 
missing data under a MAR assumption 
• For QAW039 patients with missing data after discontinuation of double-blind treatment , 
imputation will be done based on placebo group under a J2R assumption 
• Missing data in placebo group will  be imputed under MAR assumption 
The imputation and analysis will be implemented using the “five macros” available from 
www.missingdata.org.uk (for a full description see Carpenter et al (2013)). The first step in 
implementing this pattern mixture imputation approach is to fit a Bayesian Normal repeated 
measures model to estimate parameters from the observed on-study values (including on-
treatment and off-treatment data). The model will include the same covariates as the primary 
model. Then use the estimated parameters to build possible predicted profiles for the 
unobserved values in a separate imputation model, one for each pattern of withdrawal. These 
profiles represent what we expect would happen to patients after they withdraw. Missing values 
for an individual are then imputed based on the profile of predicted means that matches their 
treatment, their time of withdrawal and other covariates. A large number of imputed datasets 
will be created, with their number chosen based on computational feasibility, but at least 1000. 
Observed and imputed data will be contrasted graphically.  Each dataset will be analyzed using 
the model described in Section 2.5.3.1 and the results will be combined using Rubin’s rule 
(Barnard and Rubin 1999) for final inference. A fuller description is given in the Section 6.6.1 
of the Appendix. 
Unless otherwise specified,  for efficacy parameters, on-treatment data are defined as data on 
or after the first day of treatment with double-blind medication, but before or on the day of the 
last day of treatment with double-blind study medication; on-study data are defined as data on 
or after the first day of treatment with double-blind medication, but before or on the day of the 
last day of treatment period. 


Novartis 
For business use only 
Page 22 
SAP 
 
CQAW039A2316 
 
2.5.5 
Supportive analyses  
Sensitivity analysis  
Two-dimensional tipping point analysis will be performed corresponding to the primary 
analysis on the FAS. Missing data after study treatment discontinuation will be firstly imputed 
in the same way as for the primary analysis. Then it will be explored by how much the imputed 
continuous missing data for the QAW039 treatment and the placebo arms would have had to 
change compared to the imputation values in the primary analysis in order to overturn 
conclusions from the primary analysis. After such tipping point(s) is determined, clinical 
judgment can be applied as to the plausibility of the assumptions underlying this tipping point. 
This methodology will provide a good picture of what it would take to overturn study 
conclusions based on varying assumptions about missing data.   
Supplementary analysis  
The primary efficacy variable will also be analyzed using a repeated measures (MMRM) 
analysis model in which treatment, age group (<18 vs. ≥18 years), use or non-use of a second 
asthma controller medication at study entry, region, visit and treatment-by-visit interaction will 
be included as fixed-effect factors, and baseline pre-dose FEV1 value as well as the baseline 
daytime asthma symptom score, baseline total daily SABA use and visit-by-baseline FEV1 as 
covariates. A common unstructured covariance matrix among visits for each treatment group 
will be used. If this model does not converge, a heterogeneous AR (1) covariance structure will 
be used. If this model still does not converge, a heterogeneous compound symmetry covariance 
structure will be used. The analysis will be performed based on all available on-treatment data 
up to week 12 and based on a likelihood method with an assumption of MAR for missing data 
assuming a hypothetical situation of continued treatment. On-treatment data is defined as all 
available data collected while patients took the study drug up to the week 12 visit. The estimated 
treatment differences for all treatment comparisons will be tabulated along with the associated 
95% confidence intervals and their two-sided p-values. 
Rank-based analysis 
In a further rank-based supportive analysis for the primary endpoint, patients will be ranked 
from largest to smallest in the following sequence with high ranks denoting greater efficacy. 
1. patients who completed the trial  
2. patients who withdrew from the trial and did not die  
3. patients who died  
Note: death refers to adverse events with fatal outcome on-study. 
Within category 1, patients with higher change from baseline FEV1 at Week 12 will be ranked 
greater than patients with lower change from baseline. Patients who completed the trial with 
missing FEV1 data at Week 12 will be ranked lower than anyone who completed the trial with 
non-missing FEV1 data at Week 12. Within that, patients with higher change from baseline in 
FEV1 at a later visit will get higher ranks. In case of ties in the visits with last available FEV1 
data, patients with higher change from baseline in FEV1 are assigned a higher rank. In case of 
ties in the FEV1 values, midranks will be used.  


Novartis 
For business use only 
Page 23 
SAP 
 
CQAW039A2316 
 
Within categories 2 and 3, patients that withdraw from the trial later will get higher ranks than 
patients that withdraw early. In cases in which patients withdraw at same study day, patients 
with higher change from baseline in FEV1 at a later visit will get higher ranks. In case of ties in 
the FEV1 values or no available post-baseline assessments of the primary variable, midranks 
will be used.  
A Wilcoxon rank-sum test (Van Elteren test) stratified by age group (<18 vs. ≥18 years), use or 
non-use of a second asthma controller medication, and region will be used to analyze the ranked 
data. 
Per-protocol analysis 
The primary analysis may be repeated for the PPS. 
2.5.6 
Multiplicity adjustment 
Familywise type I error rate control 
The following null hypotheses are included in the testing strategy: 
Primary objective: H1 (see Section 2.5.3.1) 
Secondary objectives: 
     H2: QAW039 150 mg is not different to Placebo with respect to mean change from baseline 
in daytime asthma symptoms over the 12 weeks of treatment 
     H3: QAW039 150 mg is not different to Placebo with respect to mean change from baseline 
in total daily SABA use over the 12 weeks of treatment 
     H4: QAW039 150 mg is not different to Placebo with respect to change from baseline in 
AQLQ+12 at week 12 
The familywise type I error rate will be controlled at the two-sided 5% level across the 
primary and secondary null hypotheses using the closed testing procedure shown in Figure 2 
using the graphical method of  Bretz et al 2009. In this closed testing procedure, the primary 
null hypothesis about pre-dose FEV1 acts as a gatekeeper for the secondary null hypotheses.  


Novartis 
For business use only 
Page 24 
SAP 
 
CQAW039A2316 
 
Figure 2 
Closed testing procedure for primary and secondary objectives 
 
 
Vertices with associated weights denote the individual null hypotheses and their local significance 
levels. Directed edges between the vertices specify how the local significance levels are propagated in 
case of significant results. ε is set to a very small number in practice. Abbreviations: FEV1 (forced 
expiratory volume in 1 second); AQLQ+12 (asthma quality of life questionnaire for 12 years and older). 
Initially, the alpha is assigned to the primary null hypothesis. Once the primary null hypothesis 
has been rejected, then 98% of the alpha will be distributed equally amongst the secondary null 
hypotheses of daytime asthma symptoms and total daily SABA use, respectively, and 2% of the 
alpha will be assigned to the null hypothesis for AQLQ+12. If one of the secondary null 
hypotheses is rejected, its local significance level will be propagated to the other secondary null 
hypotheses as illustrated in Figure 2.  
2.6 
Analysis of secondary efficacy objective(s) 
2.6.1 
Daytime asthma symptoms in patients  
Daytime asthma symptoms are evaluated through four questions and each of them will be rated 
on a scale of 0 to 6. Higher scores indicate more severe asthma-related symptoms. A mean score 
will be calculated for the responses to 4 questions. The main analysis of the secondary endpoint 
of daytime symptoms will be performed for all patients over the entire age range (12 years and 
older).  
The mean of change from baseline in the daytime symptom scores over the 12 weeks of 
treatment will be analyzed based on on-study data (including on-treatment and off-treatment 
data) using an analysis of covariance (ANCOVA) model in a similar fashion as the primary 
efficacy variable.  
The model will include factors for treatment group, age group (<18 vs. ≥18 years), use or non-
use of a second asthma controller medication at study entry, and region, as well as the baseline 


Novartis 
For business use only 
Page 25 
SAP 
 
CQAW039A2316 
 
daytime asthma symptom score, baseline total daily SABA use and baseline pre-dose FEV1 as 
continuous linear covariates. 
The least squares mean (“adjusted mean”) change from baseline for each treatment group, the 
difference in the least squares mean changes between the two treatment groups (QAW039 150 
mg – placebo), and the two-sided 95% confidence interval along with the superiority p-value 
for the difference will be obtained. This model will be fitted to each of multiple imputations 
generated using the approach described in Section 2.6.4. 
In addition, the mean of change from baseline in the daytime symptom scores by 4-week 
intervals over the 12 weeks of treatment will be analyzed based on on-treatment data using a 
MMRM model in which treatment, age group (<18 vs. ≥18 years), use or non-use of a second 
asthma controller medication at study entry, region, interval and treatment-by-interval 
interaction will be included as fixed-effect factors, and baseline pre-dose FEV1 value as well 
as the baseline daytime asthma symptom score, baseline total daily SABA use and interval-by-
baseline daytime asthma symptom score as covariates. A common unstructured covariance 
matrix among visits for each treatment group will be used. The analysis will be performed based 
on all available on-treatment data up to week 12. The estimated treatment differences for all 
treatment comparisons will be tabulated along with the associated 95% confidence intervals and 
their two-sided p-values. 
Summaries of absolute values and change from baseline will be presented by 4-week intervals 
and overall 12 weeks of treatment based on on-treatment data.  
The average score for each time interval is defined as the sum of daily scores divided by the 
number of days where eDiary records have been made on daytime score for that interval. The 
non-missing data within that interval will be used to calculate the mean value, as long as there 
are at least 4 days with non-missing eDiary data for baseline scores and 14 days with non-
missing data for post-baseline scores in a 4-week period. Otherwise, the value will be set as 
missing for that interval. For Weeks 1 – 12, summary values will be calculated as long as a 
patient has at least 50% of their diary days and at least 42 diary days with evaluable data for 
that variable in the period of interest.  
The asthma diary included in this study to measure daytime asthma symptoms was validated in 
studies of patients aged 18 to 65 years (Santanello et al 1997).  It was subsequently included as 
a measure in placebo-controlled studies of montelukast in patients aged 15 years and older 
(Reiss et al. 1998 and Malmstrom et al. 1999) and shown to be responsive to both montelukast 
and inhaled beclomethasone therapy in this age range. Given the performance characteristics, 
particularly the responsiveness to asthma therapies, of the asthma diary are known for patients 
aged 15 years and older, a supportive analysis of the secondary endpoint of daytime symptoms 
will be included and be limited to patients aged 15 years and older.   
2.6.2 
Total daily use of SABA  
Total daily use of SABA (the number of puffs taken in the previous 24 hours) by the patient 
will be analyzed using ePEF/ eDiary data. The mean of change from baseline in the total daily 
use of SABA over the 12 weeks of treatment will be analyzed based on on-study data (including 
on-treatment and off-treatment data) using an ANCOVA model in a similar fashion as the 
primary efficacy variable. The model will include factors for treatment group, age group (<18 


Novartis 
For business use only 
Page 26 
SAP 
 
CQAW039A2316 
 
vs. ≥18 years), use or non-use of a second asthma controller medication at study entry, and 
region, as well as the baseline daytime asthma symptom score, baseline total daily SABA use 
and baseline pre-dose FEV1 as continuous linear covariates. 
The least squares mean (“adjusted mean”) change from baseline for each treatment group, the 
difference in the least squares mean changes between the two treatment groups (QAW039 150 
mg – placebo), and the two-sided 95% confidence interval along with the superiority p-value 
for the difference will be obtained. This model will be fitted to each of multiple imputations 
generated using the approach described in Section 2.6.4.  
In addition, the mean of change from baseline in the total daily use of SABA by 4-week intervals 
over the 12 weeks of treatment will be analyzed based on on-treatment data using a MMRM 
model in a similar fashion as mentioned in Section 2.6.1 except only one change is to replace 
interval-by-baseline daytime asthma symptom score interaction with interval-by-baseline total 
daily use of SABA interaction. 
Summaries of absolute values and change from baseline will be presented by 4-week interval 
and overall 12 weeks of treatment based on on-treatment data. If the number of puffs of SABA 
use is missing but the rest of the eDiary has non-missing data, the number of puffs will be 
assumed zero. The total number of puffs of SABA use will be divided by the total number of 
days with non-missing SABA use data to derive the mean daily number of puffs of SABA use 
for each given visit interval (every 4 weeks). The non-missing data within that interval will be 
used to calculate the mean value, as long as there are at least 4 days with non-missing eDiary 
data for baseline scores and 14 days with non-missing data for post-baseline scores in a 4-week 
period. Otherwise, the value will be set as missing for that interval. If the number of puffs is 
missing for part of the day (either morning or evening) then a half day will be used in the 
denominator. For Weeks 1 – 12, summary values will be calculated as long as a patient has at 
least 50% of their diary days and at least 42 diary days with evaluable data for that variable in 
the period of interest.  
2.6.3 
AQLQ+12  
The 32 items in the AQLQ+12 are divided into 4 domain-specific scores and a total score as 
follows:  
• Symptoms = Mean of Items 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 29, 30 (12 items)  
• Activity limitation  = Mean of Items 1, 2, 3, 4, 5, 11, 19, 25, 28, 31, 32 (11 items)  
• Emotional function  = Mean of Items 7, 13, 15, 21, 27 (5 items)  
• Environmental Stimuli = Mean of Items 9, 17, 23, 26 (4 items)  
• Overall Score = Mean of Items 1 to 32 (32 items)  
Each item of the AQLQ+12 is equally weighted and scored along a 7-point scale, where 1 
indicates maximal impairment and 7 indicates no impairment. Thus, higher scores indicate 
better asthma-related HRQOL (Health-Related Quality of Life). There is a mean score 
calculated for each of the four domains, as well as an overall quality-of-life score, which is the 
mean score of all 32 items. The resultant overall scores will be between 1 and 7. 
The developer suggests no more than 10% of missing data. This means no more than 3 missing 
responses for the overall score and no more than 1 missing response per domain.  For the 


Novartis 
For business use only 
Page 27 
SAP 
 
CQAW039A2316 
 
symptoms and activity domain scores, one missing value per domain is allowed.  For the 
emotional function and environmental stimuli domain scores, no missing values are allowed. If 
these limits for missing questions are exceeded, the variable will be considered missing and will 
be imputed as described in Section 2.6.4.  
The minimal important difference (MID), defined as “the smallest difference in score which 
patients perceive as beneficial and would mandate, in the absence of troublesome side effects 
and excessive cost, a change in the patient’s management,” of 0.5 has been established for this 
questionnaire as clinically significant (Juniper, et al 1994). 
The change from baseline in AQLQ+12 at week 12 will be analyzed using an ANCOVA model 
in a similar fashion as the primary efficacy variable, based on on-study data (including on-
treatment and off-treatment data). The model will include factors for treatment group, age group 
(<18 vs. ≥18 years), use or non-use of a second asthma controller medication at study entry, 
and region, as well as the baseline daytime asthma symptom score, baseline total daily SABA 
use, baseline pre-dose FEV1 , and baseline AQLQ as continuous linear covariates. 
The least squares mean (“adjusted mean”) change from baseline for each treatment group, the 
difference in the least squares mean changes between the two treatment groups (QAW039 150 
mg – placebo), and the two-sided 95% confidence interval along with the superiority p-value 
for the difference will be obtained. This model will be fitted to each of multiple imputations 
generated using the same approach as for the primary analysis.  
In addition, the mean of change from baseline in AQLQ +12 at Week12 will be analyzed based 
on on-treatment data using a MMRM model in which treatment, age group (<18 vs. ≥18 years), 
use or non-use of a second asthma controller medication at study entry, region, visit and 
treatment-by-visit interaction will be included as fixed-effect factors, and baseline pre-dose 
FEV1 value as well as the baseline daytime asthma symptom score, baseline total daily SABA 
use, baseline AQLQ and visit-by- baseline AQLQ as covariates. A common unstructured 
covariance matrix among visits for each treatment group will be used. The analysis will be 
performed based on all available on-treatment data up to week 12. The estimated treatment 
differences for all treatment comparisons will be tabulated along with the associated 95% 
confidence intervals and their two-sided p-values. 
Summaries of absolute values and change from baseline will be presented by visit and by 
treatment group based on on-treatment data.  
In addition, the proportion of patients with a change from baseline (improvement) in AQLQ+12 
score of at least +0.5 unit based on on-treatment data will be analyzed using logistic regression 
by visit. The model will include treatment, age group (<18 vs. ≥18 years), use or non-use of a 
second asthma controller medication at study entry and region as a fixed class effects, and the 
baseline AQLQ+12 as continuous linear covariates. Estimates of the odds ratios between 
QAW039 group and placebo will be displayed along with associated 95% confidence intervals 
and two-sided p-values by visit.  
 
2.6.4 
Handling of missing values/censoring/discontinuations 
Handling of missing daytime asthma symptom scores and total daily SABA use 


Novartis 
For business use only 
Page 28 
SAP 
 
CQAW039A2316 
 
The weekly mean will be calculated based on the non-missing post-baseline assessments as 
long as there are at least 4 days with non-missing data in a one-week period. Otherwise, the 
weekly mean will be set to missing. The multiple imputations will be carried out on the weekly 
mean data using J2R approach in a similar fashion as primary analysis described in Section 
2.5.4. The completed weekly mean data after imputation will be used in the model to calculate 
the mean of change from baseline over 12 weeks of treatment. 
Handling of missing AQLQ+12 values 
The missing data of AQLQ+12 will be imputed using the same approach as primary analysis 
described in Section 2.5.4.  
2.7 
Safety analyses 
All safety evaluation will be based on the safety analysis set. 
2.7.1 
Adverse events (AEs)  
 
All adverse events, including asthma exacerbations, coded with MedDRA using the most actual 
version at the time of database lock, will be listed. Unless otherwise specified, summaries will 
include treatment-emergent adverse events (TEAEs) only. AEs starting on or after the time of 
the first intake of study drug and not later than 7 days (30 days in the case of a serious AE) after 
the last intake of study drug will be classified as a TEAE. For those patients who enter the safety 
study (CQAW039A2315) directly after Visit 299, AEs (including serious AEs) starting after 
Visit 299 will not be considered as TEAEs in this study as they will be reported in 
CQAW039A2315.  
As a general rule of censoring, patients who either completed the study or discontinue treatment 
prematurely 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. The number and 
percentage of patients who reported TEAEs will be summarized by primary system organ class 
(SOC), preferred term (PT), and treatment group for 
• all adverse events (AEs) 
• all AEs by maximum severity 
• AEs suspected to be related to study drug 
• AEs by standardized MedDRA query (SMQ) level 
• serious AEs (SAEs) 
• AEs leading to permanent study drug discontinuation 
• AEs of special interest 
Unless otherwise specified, primary system organ classes will be sorted alphabetically and, 
within each primary system organ class, the preferred terms will be sorted in descending order 
of frequency in the QAW039 150 mg once daily treatment group. If a patient reported more 
than one AE with the same preferred term, the AE will be counted only once. If a patient 
reported more than one AE within the same primary system organ class, the patient will be 
counted only once at the system organ class level. 


Novartis 
For business use only 
Page 29 
SAP 
 
CQAW039A2316 
 
In addition, the most frequent AEs will be presented by preferred term in descending order of 
frequency in the QAW039 150 mg once daily treatment group. 
2.7.1.1 
Adverse events of special interest / grouping of adverse events 
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 and treatment. 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 
2.7.1.2 
AE reporting for CT.gov and EudraCT 
For the legal requirements of clinicaltrials.gov, two required tables on TEAEs which are not 
SAEs with an incidence greater than a certain threshold based on the final database and on 
TESAEs and SAEs suspected to be related to study treatment will be provided by system organ 
class and PT on the safety set population. 
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT: 
• 
a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE 
• 
more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE 
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE. 
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT. 
2.7.2 
Deaths 
The number 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.  
2.7.3 
Laboratory data  
 
Laboratory data consist of hematology, biochemistry and urinalysis measurements.  


Novartis 
For business use only 
Page 30 
SAP 
 
CQAW039A2316 
 
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. Laboratory data measured more than 7 days 
after last intake of study drug are regarded as post-treatment data and will not be summarized. 
All data will be included in the analyses regardless of rescue medication use. Results from local 
labs will be collected but not included in any analyses or summary tables because the reporting 
from local labs cannot be standardized.  Results from central laboratories will be included in 
analyses and summary tables. Baseline laboratory data is defined in Section 2.1.1.1. The 
following sub-sections will describe the method of summary.  
2.7.3.1 
Summary of absolute values 
For all continuous laboratory parameters, the absolute on-treatment laboratory values, including 
the worst case post-baseline values (including values from post-baseline unscheduled and 
premature discontinuation visits), will be summarized with standard descriptive statistics by 
parameter, scheduled visit and time-point, and treatment group.  
The direction of interest for worst case post-baseline for selected hematology and biochemistry 
parameters is tabulated in Table 6-4-1. For continuous urinalysis parameters, the direction of 
interest is always High. 
A frequency table of results for categorical on-treatment laboratory parameters will be 
produced. For categorical urinalysis laboratory parameters, a frequency table of results will be 
produced by laboratory parameter, scheduled visit and time-point, and treatment. Worst-case 
on-treatment post-baseline values (including values from post-baseline unscheduled and 
premature discontinuation visits) will also be included.  
For summary tables and figures on laboratory parameters considering values, which are lower 
or greater than the limit of quantification, the following approach will be taken. For values 
which are flagged as lower than the lower limit of quantification, the values presented in 
summary tables should be multiplied by 0.5 and for values that are flagged as greater than upper 
limit of quantification as 1.5, the values presented in summary tables should be multiplied by 
1.5. 
2.7.3.2 
Summary of change from baseline  
For continuous laboratory parameters, the on-treatment change from baseline at each scheduled 
visit and time-point, and the on-treatment change from baseline to the worst case post-baseline 
values (including values from post-baseline unscheduled and premature discontinuation visits) 
will be summarized by laboratory parameter, scheduled visit and time-point, and treatment 
group with standard descriptive statistics. 
In order to observe the tendency of treatment effect on mean values, box plots by treatment arm 
for post-baseline values and worst case post-baseline will be presented on the change from 
baseline for all laboratory parameters. Albumin: Creatinine ratio (ACR) value will be 
considered missing if either the albumin or the creatinine values are missing. Similarly, Protein: 
Creatinine ratio (PCR) will be considered missing if either the protein or the creatinine values 
are 
missing. 
 
 


Novartis 
For business use only 
Page 31 
SAP 
 
CQAW039A2316 
 
2.7.3.3 
Notable values 
For selected laboratory parameters, abnormalities occurring at any time-point over the treatment 
period, considering all post-baseline 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 not clinically notable and have a worse post-baseline value. For patients with a 
missing baseline value, any post-baseline notable value will be considered as newly occurring.  
The criteria for clinically notable values are presented in Table 6-4-2. 
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 (the international system of units) 
results. Therefore, both BUN and Urea parameters will be included in the data. 
 
BUN is always reported as mg/dL and Urea as mmol/L. BUN and Urea are the same 
measurement in the lab and should be considered the same test. Hence, for the summary 
tables, it is expressed in SI units.  Conversion to SI units includes the factor that 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. 
Liver function tests 
To evaluate potential drug-induced liver injury, newly occurring or worsening abnormalities in 
liver function tests will be evaluated (see Table 6-4-3 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. 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. 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 32 
SAP 
 
CQAW039A2316 
 
2.7.4 
Other safety data 
2.7.4.1 
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 
root). Furthermore, an overall interpretation of the central cardiologist will be provided as well 
as a specification of abnormal findings. 
ECG data measured more than 7 days after last intake of study drug are regarded as post 
treatment data and will not be summarized. All data will be included in the analyses regardless 
of rescue medication use. 
 
Summary of absolute values and change from baseline 
Absolute values and change from baseline summarized by parameter, and visit.  
Clinically notable values 
• The number and percentage of patients with newly occurring or worsening clinical notable 
QTcF values (see Table 2-3) 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 2-3 Clinically notable criteria for QTcF (Fridericia's formula) 
ECG parameter (unit) 
Clinically notable range 
Value considering newly occurring or worsening cases 
QTc (msec) 
≥ 450 (male) 
QTc (msec) 
≥ 460 (female) 
QTc (msec) 
 > 500 (both)  
Change from baseline 
QTc 
1 - < 30  
QTc 
30 – 60 
QTc 
> 60 
 
 
Clinically relevant values 
 
• A summary table will also be produced for number and percentage of subjects with 
clinically relevant 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 


Novartis 
For business use only 
Page 33 
SAP 
 
CQAW039A2316 
 
d. QTcF increase from baseline of ≥ 60 ms plus QTcF interval ≥ 450 ms, > 480 ms or > 
500 ms 
• The number and percentage of subjects with noteworthy PR, QRS and HR interval 
changes will be reported using the below categories: 
a. New PR > 200 ms to <= 220 ms; and > 220 ms  
b. New QRS > 110 ms to <= 120 ms; and > 120 ms 
c. PR increase > 25% to a value > 200 ms  
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 the parameters: QTcF and summary (mean) heart rate  
will be presented.   
2.7.4.2 
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 the time of the first intake of 
study drug and until 7 days after the last intake of study drug are regarded as on-treatment data. 
Vital signs data measured more than 7 days after last intake of study drug are regarded as post-
treatment data and will not be summarized. All data will be included in the analyses regardless 
of rescue medication use. 
The following analyses will be performed by treatment group: 
• absolute on-treatment values and change from baseline summarized by parameter, and visit  
• the number and percentage of patients with newly occurring or worsening notable vital signs 
on-treatment values (see Table 6-5-1 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 


Novartis 
For business use only 
Page 34 
SAP 
 
CQAW039A2316 
 
3. Diastolic blood pressure: < 50 mm Hg, 50 – 90 mm Hg, and > 90 mm Hg. 
 
Number and percentage of patients with clinically relevant on-treatment vital signs values that 
occur at any time post-baseline will be summarized for minimum and maximum post-baseline 
values. 
2.7.5 
Renal events 
Summary of treatment emergent renal event overview data by treatment will be presented. All 
renal event overview data will be listed.  
2.7.6 
Liver events 
Summary of treatment emergent liver event overview data by treatment will be presented. All 
liver event overview data will be listed. 
2.8 
Pharmacokinetic endpoints   
Not Applicable  
2.9 
PD and PK/PD analyses 
Not Applicable 


Novartis 
For business use only 
Page 35 
SAP 
 
CQAW039A2316 
 


Novartis 
For business use only 
Page 36 
SAP 
 
CQAW039A2316 


Novartis 
For business use only 
Page 37 
SAP 
 
CQAW039A2316 


Novartis 
For business use only 
Page 38 
SAP 
 
CQAW039A2316 
2.12 
Interim analysis 
No interim analysis for efficacy is planned in this study. An independent, external DMC has 
been set up to review safety data (including specific safety summaries for adolescent 
participants) for this trial. No statistical adjustment will be made to the final analysis. 
3 
Sample size calculation 
The primary objective is to demonstrate that QAW039 150 mg is superior to placebo in pre-
dose FEV1 following 12 weeks of post-baseline treatment. A difference of 112 mL in pre-dose 
FEV1 during treatment was assumed, which is similar to the model-averaged effect seen in 


Novartis 
For business use only 
Page 39 
SAP 
 
CQAW039A2316 
 
study QAW039A2206. The standard deviation (SD) of 380 mL and between-visit correlation 
for pre-dose FEV1 was based on study QAW039A2206 in a similar population. A treatment 
discontinuation rate of 15% was assumed based on QAW039A2206 and it was assumed that 
half of the patients discontinuing study treatment would have week 12 FEV1 values. 
Simulations were used to determine the sample size due to the complex J2R missing data 
imputation approach for the primary analysis. 
Under the outlined assumptions, a sample size of 650 patients (325 per arm) would be needed 
to have 90% power to observe a statistically significant difference between QAW039 and 
placebo at the two-sided 5% significance level in the primary analysis as shown in Table 3-1. 
The table also shows the sensitivity of the power to deviations from the assumptions. 
Table 3-1 
Result of power simulations for the primary variable 
Treatment effect (mL) 
Discontinuation rate 
Sample size 
Power 
112 
15% 
650 
90.3 
112 
20% 
650 
85.9 
100 
15% 
650 
80.9 
Based on 10,000 simulated trials per scenario and 250 multiple imputations for each trial. Simulations 
were conducted using SAS/STAT® 13.1 software, Version 9.4 of the SAS System for Linux. 
Power for the secondary objectives 
If statistical significance is achieved in the primary test, the tests for the secondary variables 
will be performed. The local significance level for each secondary null hypothesis will be 
determined based on the closed testing procedure shown in Figure 2.  
As differences in FEV1 to placebo for QAW039 150 mg once daily and montelukast 10 mg 
once daily appeared to be of similar magnitudes in study QAW039A2206, the power 
calculations for the two secondary objectives (change from baseline in daytime asthma 
symptoms and change from baseline in total daily SABA use) are based on the assumptions 
from the results of two studies comparing montelukast 10 mg once daily with placebo (Reiss et 
al 1998, Malmstrom et al 1999). These studies suggest an averaged difference of 0.26 for change 
from baseline in daytime asthma symptoms between montelukast and placebo after 12 weeks 
of treatment and a SD of 0.94. The two studies also suggest an averaged difference of -1.34 
point difference in the change from baseline in the number of daily SABA puffs between 
montelukast and placebo with a standard deviation of 3.82. We assume a clinically important 
true improvement of at least 0.5 in AQLQ+12 after 12 weeks of treatment for patients that 
remain on treatment and a standard deviation (SD) of 1. As shown in Table 3-2 all secondary 
endpoints have an adequate conditional power once the primary null hypothesis has been 
rejected, but will each have an even higher conditional power once the null hypotheses relating 
to the other secondary variables have been rejected. 


Novartis 
For business use only 
Page 40 
SAP 
 
CQAW039A2316 
 
Table 3-2 
Power simulations for secondary variables 
 
Daytime asthma 
symptoms 
Total daily rescue 
medication use 
AQLQ+12 
Difference of effect (δ) 
-0.26 
-1.34 number of puffs 
0.5 
SD (σ) 
0.94 
3.82 number of puffs 
1 
Local two-sided significance level once 
primary null hypothesis is rejected 
0.0245 
0.0245 
0.001 
Power 
74% 
97% 
98% 
Local two-sided significance level once 
primary and the other two secondary 
hypotheses are rejected 
0.05 
0.05 
0.05 
Power 
83% 
98% 
> 99% 
Power statements are based on 10,000 simulated trials per scenario and 250 multiple imputations 
using a jump-to-reference approach for each simulated trial. Simulations were conducted using 
SAS/STAT® 13.1 software, Version 9.4 of the SAS System for Linux. We assumed a treatment 
discontinuation rate of 15% with half of the patients discontinuing from study treatment completing 
the trial. The correlation structure was assumed the same as for the primary endpoint. Abbreviation: 
AQLQ+12 (asthma quality of life questionnaire for 12 years and older). 
4 
Change to protocol specified analyses 
• Section 9.2 in the study protocol states that the age of the patient will be calculated from 
the date of birth to date of Visit 1. However, since date of birth is not captured on the CRF 
page and age (in years) at the time of informed consent is entered into CRF, there is no 
need to re-calculate age.   
• 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.  
• Study protocol defines treatment emergent adverse events as those events starting on or 
after the time of the first intake of study drug and until the day after the last intake of study 
drug. However, in order to maintain consistency with the submission documents, for 
analysis purposes the following updated definitions are considered: 
AEs starting on or after the time of the first intake of study drug and not later than 7 days 
(30 days in the case of a serious AE) after the last intake of study drug will be classified as 
a TEAE. 
• 
Added the responder analysis for AQLQ improvement 
• 
Added more details to liver function tests including eDISH plot 
• Added analysis for renal events and liver events according to project level alignment 
• The following analyses, though pre-specified in the protocol, may not be critical for 
decision making purposes and hence will be reported outside of CSR: 
• 
 
   


Novartis 
For business use only 
Page 41 
SAP 
 
CQAW039A2316 
 
• In protocol 9.4.4, supportive analysis for the primary endpoint based on other missing 
data imputation approaches: pattern mixture approach combining the jump to 
reference and missing at random approaches by distinguishing reasons for 
discontinuation of treatment and retrieved dropout imputation approach. 
• In protocol Section 9.4.4, subgroup analyses for BMI, number of exacerbations in the 
previous year, ACQ tertiles, 
. 
• Summaries on post-treatment discontinuation events to be produced for adverse events 
and serious adverse events by system organ class and preferred term. 


Novartis 
For business use only 
Page 42 
SAP 
 
CQAW039A2316 
6 
Appendix 
This appendix gives details about statistical methods in addition to the report text. All analyses 
will be performed by using SAS Version 9.4. 
Note: The SAS version that will be actual on the NOVARTIS platform at the time when the study 
is completed will be stated here. 
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 
Rules for imputing AE end date or start date will be provided in Programming Dataset 
Specification (PDS) document in details. 
6.1.3 
Concomitant medication date imputation 
Rules for imputing concomitant medication start or end dates will be provided in Programming 
Dataset Specification (PDS) document in details. 


Novartis 
For business use only 
Page 43 
SAP 
 
CQAW039A2316 
 
6.1.3.1 
Prior therapies date imputation 
Rules for imputing the prior therapies end date or start date will be provided in Programming 
Dataset Specification (PDS) document in details. 
6.1.3.2 
Post therapies date imputation 
Rules for imputing the post therapies end date or start date will be provided in Programming 
Dataset Specification (PDS) document in details. 
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. 
6.3 
Visit remapping and assessment windows 
If a scheduled visit did not occur, the data from the treatment discontinuation or study 
discontinuation visit may be used as the data from the scheduled visit, if the treatment 
discontinuation or study discontinuation visit 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 so that no missing data imputation will be necessary. Otherwise, 
the data from any scheduled visit that did not occur will be dealt with like any other missing 
data. If the treatment discontinuation or study discontinuation visit is not re-mapped to any 
scheduled visit, it will be treated as an unscheduled visit that does not appear in by-visit 
summaries. 
6.4 
Laboratory parameters derivations 
The following table shows the criteria for clinically notable laboratory values. Not all 
parameters have notable criteria defined.  


Novartis 
For business use only 
Page 44 
SAP 
 
CQAW039A2316 
 
Table 6-4-1 
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 6-4-2 
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 aged 12-17 
     Male aged 18-65 
     Male aged >=66 
     Female aged 12-65 
     Female aged >=66 
 
0.34 
0.37 
0.34 
0.32 
0.31 
 
 


Novartis 
For business use only 
Page 45 
SAP 
 
CQAW039A2316 
 
Laboratory parameter (unit) 
Bound for notably low 
values 
Bound for notably high 
values 
Hemoglobin (g/L) 
    Male aged 12-17 
    Male aged >=18 
    Female 
 
100 
110 
95 
 
 
Thrombocytes (x10E9/L 
75  
700 
WBC’s (x109/L) 
2.8 
16.0 
Chemistry 
 
 
Alkaline Phosphatase (IU/L) 
- 
3xULN 
Total Bilirubin (µmol/L) 
- 
34.2 
Creatinine (µmol/L) 
 
176.8 
Potassium (mmol/L) 
3 
6 
Glucose (mmol/L) 
2.78 
9.99 
ALT/SGPT (U/L) 
- 
3 x ULN 
AST/SGOT (U/L) 
- 
3 x ULN 
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  
 


Novartis 
For business use only 
Page 46 
SAP 
 
CQAW039A2316 
 
Table 6-4-3 
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. 
 
6.5 
Vital signs – definition of clinically notable and relevant values 
The following table shows the clinical notable criteria for vital signs. 


Novartis 
For business use only 
Page 47 
SAP 
 
CQAW039A2316 
 
Table 6-5-1 Vital signs - clinical notable values 
Vital sign parameter (unit) 
Lower bound of clinically 
notable range 
Upper bound of 
clinically notable range 
Notable value considering newly occurring or worsening cases 
Systolic blood pressure (mmHg) 
< 75  
> 200 
Diastolic blood pressure (mmHg) 
< 40 
 
> 115 
Pulse rate (bpm) 
< 40 
> 130 
Notable change from baseline 
Systolic blood pressure (mmHg) 
≤ 90 and decrease from 
baseline by ≥ 20  
≥ 180 and increase 
from baseline by ≥ 20 
Diastolic blood pressure (mmHg) 
≤ 50 and decrease from 
baseline by ≥ 15 
≥ 105 and increase 
from baseline by ≥ 15 
Pulse rate (bpm) 
≤ 50 and decrease from 
baseline by ≥ 15 
≥ 120 and increase 
from baseline by ≥ 15 
Weight (kg) 
Decrease ≥ 7% from 
baseline 
Increase ≥ 7% from 
baseline 
6.6 
Statistical methodology and assumptions 
SAS codes for all statistical methodology described in this section will be included in Table, 
Figure, Listing (TFL) Shells as programming note. 
6.6.1 
Multiple imputations for primary and secondary variables 
The imputation and analysis of primary and secondary variables will be implemented using 
the “five macros” available from www.missingdata.org.uk (for a full description see 
Carpenter et al (2013)). The purpose and activities of each of the five macros is described 
below. 
Part1A declares the parameter estimation model and checks consistency with the input dataset. 
It builds a master dataset which holds details of the current job and also builds indexes for the 
classification variables, which may be either numeric or character. 
Part1B fits the parameter estimation model using the MCMC procedure and draws a pseudo- 
independent sample from the joint posterior distribution for the linear predictor parameters and 
the covariance parameters. 
Part2A calculates the predicted mean under MAR, and under MNAR for each subject based on 
their withdrawal pattern once for each draw of the linear predictor parameter estimates. The 
choice of MNAR is controlled by the method used, which may vary from subject to subject. 
Part2B imputes the intermediate missing values using MAR and the trailing missing values 
using MNAR, by deriving the conditional distribution for the missing values conditional on the 
observed values and covariates, using the appropriate sampled covariance parameter estimates. 


Novartis 
For business use only 
Page 48 
SAP 
 
CQAW039A2316 
 
Part3 carries out a univariate ANOVA analysis at selected time points usually based on the same 
covariates as the parameter estimation model. It then combines the least-squares means and their 
differences using the MIANALYZE procedure to provide final results. 
This is example code to implement the primary analysis: 
%part1A(Jobname=fev1 
,Data=RE 
,Subject=subjid 
,Response=aval 
,Time=visit 
,Treat=trt01pn 
,Covbytime= basefev basescore basesaba 
,Catcov=stratum 
, 
); 
 
Where subjid = subject identifier 
aval = change from baseline in  FEV1 value at visit during the treatment epoch 
visit = treatment period visit number 
trt01pn = planned treatment 
basefev = baseline FEV1 value 
basescore = baseline daytime asthma symptom score  
basesaba = baseline total daily SABA use 
stratum = randomization strata (patient age (<18 years or ≥18 years), use or not use a second 
asthma controller at study entry, region) 
 
%part1B(Jobname=fev1 
,Ndraws=1000 
,thin=750 
,seed=12345 
); 
%part2A(Jobname=fev1_J2R 
,inname=fev1 
,methodV=Mymethod 
,refV=Myreference 
); 
where Mymethod = Method used to impute missing data: J2R for QAW patients who 
discontinued treatment and MAR otherwise. Myreference = Placebo 


Novartis 
For business use only 
Page 49 
SAP 
 
CQAW039A2316 
 
%part2B(Jobname=fev1_J2R 
,seed=832216); 
 
%part3(Jobname=fev1_J2R 
,ANTreat=trt01pn 
,label=Mixed MAR and J2R); 
Results will be presented as Least Squares Means (LSM) and standard errors (SE) for treatment 
effects and LSM, SE, associated two-sided 95% confidence interval, and two-sided p-value for 
all relevant treatment contrasts.  
 
 
6.7 
Rule of exclusion criteria of analysis sets  
Subject classification in the analysis sets (FAS, Safety, Per Protocol, SCR, and RAN) will be 
based on protocol deviation specifications and non-protocol deviation classification criteria as 
following. 
Table 6-7-1 
Protocol deviations that cause subjects to be excluded 
Deviation 
ID 
Description of Deviation 
Exclusion in Analyses 
INCL01a 
Informed consent was not obtained 
SCR, RAN, FAS, PPS, SAF 
INCL02 
Age < 12 years 
PPS 
INCL03 
No current diagnosis of Asthma of at 
least 6 months prior to V1 
PPS 
INCL05a 
For patients aged >= 18 years, % 
predicted FEV1 was not <= 85% at both 
V1 & V101 
PPS 
INCL05b 
For patients aged 12 years to <18 
years, % predicted FEV1 was not <= 
90% at V1 & V101 
PPS 
INCL05c 
Spirometry done for assessing study 
eligibility is not meeting ATS/ERS criteria 
for acceptability or repeatability. 
PPS 
INCL08 
Reversibility not demonstrated before 
randomization 
PPS 
EXCL01 
Other investigational drug used within 30 
days or within 5 half-lives prior to 
Screening 
PPS 
EXCL10b 
Smoking history of greater than 10 pack 
years 
PPS 
EXCL11 
Patient had an asthma exacerbation 
requiring systemic corticosteroids, 
hospitalization, or emergency room 
visit within 6 weeks prior to Visit 1 
PPS 


Novartis 
For business use only 
Page 50 
SAP 
 
CQAW039A2316 
 
Deviation 
ID 
Description of Deviation 
Exclusion in Analyses 
EXCL12 
Patient had an asthma exacerbation 
requiring systemic corticosteroids, 
hospitalization or emergency room 
visit during the screening or placebo 
run-in periods.  
PPS 
EXCL13 
Patients had respiratory tract Infection or 
asthma worsening within 4 weeks prior to 
V1. 
PPS 
COMD01 
Prohibited 
asthma 
related 
ConMed 
during treatment epoch  
PPS 
COMD04 
Permitted asthma related medication not 
taken 
as 
allowed 
under 
certain 
conditions during treatment epoch 
PPS 
COMD05 
Baseline asthma medication or their 
dose was changed after Visit 1 
PPS 
OTH04 
Patient randomized in error 
PPS 
 
Table 6-7-2 
Subject Classification 
Analysis Set 
PD ID that 
    
cause subjects to be excluded 
Non-PD criteria that cause  
subjects to be excluded 
SCR 
INCL01a,  
NA 
RAN 
INCL01a 
NA 
FAS 
INCL01a 
Not in RAN; 
Randomized and no double-blind study drug 
taken 
PPS 
INCL01a,INCL02,INCL03, 
INCL05a,INCL05b,INCL05c,
INCL08,EXCL01,EXCL10b,
EXCL11,EXCL12, 
EXCL13,COMD01,COMD04
,COMD05,OTH04 
Not in FAS; 
 
SAF 
INCL01a 
No double-blind study drug taken 
 
 
 
 


Novartis 
For business use only 
Page 51 
SAP 
 
CQAW039A2316 
 
7 
Reference 
Elizabeth Juniper (2004). Asthma Control Questionnaire: Background, Administration and 
Analysis 
Kenward MG and Roger JH (1997). Small sample inference for fixed effects from restricted 
maximum likelihood. Biometrics 53(3):983-97 
Scott L. Zeger; Kung Yee Liang; Paul S. Albert (1988). Models for Longitudinal Data: A 
generalized Estimating Equation Approach. Biometrics, Volume 44, Issue 4, 1049-1060 
Bretz F, Maurer W, Brannath W et al. (2009) A graphical approach to sequentially rejective 
multiple test procedures. Statistics in Medicine; 28(4): 586-604. 
Barnard J, Rubin D (1999) Small-sample degrees of freedom with multiple imputation. 
Biometrika; 86:948–955. 
Committee for Medicinal Products for Human Use (2010) Guideline on Missing Data in 
Confirmatory Clinical Trials. 
Carpenter JR, Roger JH and Kenward MG (2013) Analysis of Longitudinal Trials with Protocol 
Deviation: A Framework for Relevant, Accessible Assumptions, and Inference via Multiple 
Imputation. Journal of Biopharmaceutical Statistics, 23:6, 1352-1371 
Reiss TF, Chervinsky P, Dockhorn RJ et al (1998) Montelukast, a once-daily leukotriene 
receptor antagonist, in the treatment of chronic asthma: a multicenter, randomized, double-blind 
trial. Montelukast Clinical Research Study Group. Arch Intern Med; 158:1213-1220. 
Santanello NC, Barber BL, Reiss TF et al (1997) Measurement characteristics of two asthma 
symptom diary scales for use in clinical trials. Eur Resp J; 10: 646-651. 
Malmstrom K, Rodriguez-Gomez G, Guerra J et al (1999) Oral montelukast, inhaled 
beclomethasone, and placebo for chronic asthma. Ann Intern Med; 130: 487-495.