Conditions: Nasal Polyps
Keywords: Nasal Polyposis Asthma Nasal polyp score (NPS) Nasal congestion score (NCS) Bronchial Diseases Lung Diseases Nose Diseases Respiratory Hypersensitivity Fevipiprant QAW039
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 98
Healthy volunteers: no

Brief summary:
A Phase 3b Proof-of-Concept study to evaluate the ability of fevipiprant 150 mg and 450 mg, compared with placebo, as add-on to nasal spray standard-of-care (SoC), in reducing endoscopic nasal polyp score in adult (≥ 18 years) patients with nasal polyposis and concomitant asthma.

Detailed description:
This was a Phase 3b, Proof-of-concept study with a randomized, multicenter, double-blind, placebo-controlled, parallel-group study design to determine the ability of fevipiprant plus standard of care (SoC) compared to placebo plus SoC to reduce the size of nasal polyps. The study enrolled adult male and female patients diagnosed with nasal polyposis with a nasal polyp score assessed by nasal endoscopy ≥ 4 at baseline with a minimum score of 2 in each nostril and a concomitant diagnosis of asthma. Patients who meet the inclusion/exclusion criteria were randomized in 1:1:1 ratio in either of the 3 arms fevipiprant 450 mg dose once daily (o.d.), fevipiprant 150 mg dose o.d. or placebo o.d. in addition to SoC (mometasone furoate spray).

The study included:

* a Screening period of 2 weeks to assess eligibility
* a Run-in period of 4 weeks where patients utilized mometasone furoate spray (200 μg once daily, administered as two 50 μg actuations into each nostril)
* a Treatment period of 16 weeks. Patients continued to use the mometasone furoate SoC throughout the treatment period.
* a Follow-up period of 2 weeks following the last dose of study drug to collect additional data for safety variables.

The purpose of this study was to evaluate the efficacy and safety of fevipiprant 150 mg and 450 mg compared to placebo in the reduction of nasal polyps size and the effect on symptoms, quality of life and smell via patient-reported outcomes in patients with nasal polyposis and concomitant asthma.

Arms:
arm 1: Fevipiprant (QAW039) 150 mg once daily orally arm 2: Fevipiprant (QAW039) 450 mg once daily orally arm 3: Placebo once daily orally

Interventions: intervention 1: Fevipiprant 150 mg intervention 2: Fevipiprant 450 mg intervention 3: Placebo
Intervention descriptions: intervention 1: Fevipiprant (QAW039) 150 mg once daily administered orally as tablet intervention 2: Fevipiprant (QAW039) 450 mg once daily administered orally as tablet intervention 3: Placebo once daily administered orally as tablet

Protocol document:
Prot_001.pdf: 
Novartis Global Medical Affairs
QAW039
Clinical Trial Protocol CQAW039A2322 / NCT03681093
A multicenter, randomized, double-blind, parallel-group, 
placebo-controlled study of fevipiprant once daily plus 
standard-of-care (SoC) for assessment of the efficacy in 
reduction of nasal polyps size in patients with nasal 
polyposis and concomitant asthma
Document type:
Amended Protocol Version
EUDRACT number:
2018-002073-22
Version number:
03 (Clean)
Clinical Trial Phase:
III
Release date:
24-Sep-2019
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template version 1.0 dated 01-Dec-2017


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................10
Amendment 3 ....................................................................................................................12
Amendment 2 ....................................................................................................................13
Amendment 1 ....................................................................................................................14
Protocol summary..............................................................................................................15
1
Introduction .......................................................................................................................18
1.1
Background............................................................................................................18
1.2
Purpose ..................................................................................................................19
2
Objectives and endpoints...................................................................................................19
3
Study design ......................................................................................................................20
4
Rationale............................................................................................................................20
4.1
Rationale for study design .....................................................................................20
4.1.1
Rationale for choice of background therapy.........................................21
4.2
Rationale for dose/regimen and duration of treatment ..........................................21
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................21
4.4
Purpose and timing of interim analyses/design adaptations..................................21
4.5
Risks and benefits..................................................................................................22
5
Population..........................................................................................................................24
5.1
Inclusion criteria ....................................................................................................24
5.2
Exclusion criteria...................................................................................................24
6
Treatment...........................................................................................................................28
6.1
Study treatment......................................................................................................28
6.1.1
Investigational and control drugs..........................................................28
6.1.2
Additional study treatments ..................................................................28
6.1.3
Treatment arms/group ...........................................................................28
6.1.4
Treatment duration................................................................................29
6.2
Other treatment(s)..................................................................................................29


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6.2.1
Concomitant therapy.............................................................................29
6.2.2
Prohibited medication ...........................................................................30
6.2.3
Rescue medication ................................................................................31
6.3
Subject numbering, treatment assignment, randomization....................................31
6.3.1
Subject numbering ................................................................................31
6.3.2
Treatment assignment, randomization ..................................................31
6.4
Treatment blinding.................................................................................................32
6.5
Dose escalation and dose modification..................................................................32
6.5.1
Dose modifications................................................................................33
6.5.2
Follow-up for toxicities.........................................................................33
6.6
Additional treatment guidance...............................................................................33
6.6.1
Treatment compliance...........................................................................33
6.6.2
Emergency breaking of assigned treatment code..................................33
6.7
Preparation and dispensation.................................................................................34
6.7.1
Handling of study treatment and additional treatment..........................34
6.7.2
Instruction for prescribing and taking study treatment .........................35
7
Informed consent procedures ............................................................................................36
8
Visit schedule and assessments .........................................................................................36
8.1
Screening ...............................................................................................................39
8.1.1
Information to be collected on screening failures.................................39
8.2
Subject demographics/other baseline characteristics.............................................39
8.3
Efficacy..................................................................................................................39
8.3.1
Nasal Polyp Score .................................................................................40
8.3.2
Patient Reported Outcomes...................................................................40
8.3.3
Smell (UPSIT).......................................................................................41
8.3.4
Appropriateness of efficacy assessments..............................................41
8.4
Safety.....................................................................................................................41
8.4.1
Laboratory evaluations..........................................................................42
8.4.2
Electrocardiogram (ECG) .....................................................................42
8.4.3
Pregnancy..............................................................................................43
8.4.4
Appropriateness of safety measurements..............................................43
8.5
Additional assessments..........................................................................................43
8.5.1
Clinical Outcome Assessments (COAs) ...............................................43


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9
Study discontinuation and completion ..............................................................................44
9.1
Discontinuation......................................................................................................44
9.1.1
Discontinuation of study treatment .......................................................44
9.1.2
Withdrawal of informed consent...........................................................46
9.1.3
Lost to follow-up...................................................................................46
9.1.4
Early study termination by the sponsor.................................................46
9.2
Study completion and post-study treatment ..........................................................47
10 Safety monitoring and reporting........................................................................................47
10.1
Definition of adverse events and reporting requirements......................................47
10.1.1
Adverse events ......................................................................................47
10.1.2
Serious adverse events ..........................................................................49
10.1.3
SAE reporting........................................................................................50
10.1.4
Pregnancy reporting ..............................................................................50
10.1.5
Reporting of study treatment errors including misuse/abuse................50
10.2
Additional Safety Monitoring................................................................................51
10.2.1
Liver safety monitoring.........................................................................51
10.2.2
Renal safety monitoring........................................................................52
11 Data Collection and Database management......................................................................52
11.1
Data collection.......................................................................................................52
11.2
Database management and quality control............................................................53
11.3
Site monitoring ......................................................................................................53
12 Data analysis and statistical methods ................................................................................54
12.1
Analysis sets ..........................................................................................................54
12.2
Subject demographics and other baseline characteristics......................................55
12.3
Treatments .............................................................................................................55
12.4
Analysis of the primary endpoint(s) ......................................................................55
12.4.1
Definition of primary endpoint(s).........................................................56
12.4.2
Statistical model, hypothesis, and method of analysis..........................56
12.4.3
Handling of missing values/censoring/discontinuations.......................57
12.4.4
Sensitivity and Supportive analyses......................................................57
12.5
Analysis of secondary endpoints ...........................................................................58
12.5.1
Safety Variables ....................................................................................59


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12.7
Interim analyses.....................................................................................................60
12.8
Sample size calculation..........................................................................................61
12.8.1
Primary endpoint(s)...............................................................................61
13 Ethical considerations and administrative procedures ......................................................61
13.1
Regulatory and ethical compliance........................................................................61
13.2
Responsibilities of the investigator and IRB/IEC..................................................61
13.3
Publication of study protocol and results...............................................................62
13.4
Quality Control and Quality Assurance.................................................................62
14 Protocol adherence ............................................................................................................62
14.1
Protocol Amendments ...........................................................................................63
15 References .........................................................................................................................64
16 Appendices ........................................................................................................................66
16.1
Appendix 1: Clinically notable laboratory values and vital signs .........................66
16.2
Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.........................................................................................................67
16.3
Appendix 3: Specific Renal Alert Criteria and Actions and Event Follow-up......69
16.4
Appendix 4: Nasal Congestion Score Questionnaire.............................................70
16.5
Appendix 5: SNOT-22 Questionnaire ...................................................................71
16.6
Appendix 6: ACQ-5 Questionnaire .......................................................................72
16.7
Appendix 7: Nasal Endoscopy...............................................................................74
List of tables
Table 1-1
Nasal Polyp Scale..................................................................................18
Table 2-1
Objectives and related endpoints ..........................................................19
Table 6-1
Medications allowed under certain conditions......................................29
Table 6-2
Prohibited Medication...........................................................................30
Table 6-3
Blinding and unblinding plan................................................................32
Table 8-1
Assessment Schedule ............................................................................37
Table 8-2
Nasal Polyp Scale..................................................................................40
Table 8-3
Physical Assessments............................................................................41
Table 8-4
Laboratory Assessments........................................................................42
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................51


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Table 16-1
Liver Event and Laboratory Trigger Definitions ..................................67
Table 16-2
Follow Up Requirements for Liver Events and Laboratory Triggers...67
Table 16-3
Specific Renal Alert Criteria and Actions.............................................69
List of figures
Figure 3-1
Study Schematic....................................................................................20
Figure 12-1
Representation of Approach to Test Hypotheses..................................56
Figure 16-1
Nasal Congestion Score ........................................................................70
Figure 16-2
SNOT-22 Questionnaire........................................................................71
Figure 16-3
Asthma Control Questionnaire - 5 - Page 1 ..........................................72
Figure 16-4
Asthma Control Questionnaire - 5 - Page 2 ..........................................73


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List of abbreviations
ACQ-5
asthma control questionnaire - 5 questions
ACR
albumin-creatinine ratio
ADME
absorption, distribution, metabolism, excretion
AE
adverse event
AESI
adverse event of special interest
Alb
albumin
ALP
alkaline phosphatase
ALT
alanine aminotransferase
APTT
activated partial thromboplastin time
AST
aspartate aminotransferase
ATC
anatomical therapeutic chemical
AUC
area under the curve
AV
atrioventricular
BMI
body mass index
BSACI
British society for allergy and clinical immunology
BUN
blood urea nitrogen
CFR
code of federal regulation
CK
creatinine kinase
Cmax
maximum concentration
COAs
clinical outcome assessments
CPO
country pharma organisation
CRA
clinical research associate
CRF
case report/record form (paper or electronic)
CT
computerized tomography
CTT
clinical trial team
DAR
dose administration record
DMC
data monitoring committee
DP2
prostaglandin D2 receptor
EC
ethics committee
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
eGFR
estimated glomerular filtration rate
EMA
European medicines agency
ENT
ear, nose, throat
EOT
end of treatment
EU
European Union
FAS
full analysis sets
FCT
film-coated tablets
FEV1
forced expiratory volume in 1 second
FVC
forced vital capacity


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GCP
good clinical practice
GGT
gamma-glutamyl-transferase
GINA
global initiative for asthma
HbA1c
hemoglobin A1c
IB
Investigator's brochure
ICH
international conference on harmonization of technical requirements for registration of 
pharmaceuticals for human use
ICS
inhaled corticosteroids
IDR
idiosyncratic drug reactions
IEC
independent ethics committee
IgE
immunoglobulin E
IL5
interleukin 5
ILC2
innate lymphoid cell type 2
IN
Investigator notification
INR
international normalized ratio
IRB
institutional review board
IRT
interactive response technology
IUD
intrauterine device
IUS
intrauterine system
LABA
long-acting bronchodilator
LAMA
long-acting muscarinic antagonist
LDH
lactate dehydrogenase
LFT
liver function test
LOCF
last observation carried forward
LTRA
leukotriene receptor antagonist
MAR
missing at random
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MDRD
modification of diet in renal disease
MedDRA
Medical dictionary for regulatory activities
MFS
mometasone furoate nasal spray
MMRM
mixed model repeated measures
MXR
multixenobiotic resistance
NCS
nasal congestion score
NIMP
non-investigational medicinal product
NP
nasal polyposis
NPS
nasal polyp score
NYHA
New York Heart Association
OAT
organic anion transporter
OATP
organic anion transporting polypeptide
OCS
oral corticosteroids


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P-gp
P-glycoprotein
PASS
power analysis software
PCR
protein-creatinine ratio
PK
pharmacokinetic
PRO
patient-reported outcome
PT
prothrombin time
QMS
quality management system
QoL
quality of life
QTc
QT interval
QTcF
QT interval - Fridericia correction
RoW 
rest of world
SABA
short-acting bronchodilator
SAE
serious adverse event
SAF
safety analysis set
sCr
serum creatinine
SCS
systemic corticosteroids
SD
standard deviation
SNOT-
22
sino-nasal outcome test - 22 questions
SoC
standard of care
SOP
standard operating procedure
SUSARs
suspected unexpected serious adverse reactions
TBL
total bilirubin
Th2
T helper cell type 2
UK
United Kingdom
ULN
upper limit of normal
UPSIT
University of Pennsylvania smell identification test
US
United States
USB
universal serial bus
WHO
world health organization
WoC
withdrawal of consent


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Cohort
A specific group of subjects fulfilling certain criteria
Control drug
Any drug (an active drug or an inactive drug, such as a placebo) which is 
used as a comparator to the investigational drug being tested in the trial
Dosage
Dose of the study treatment given to the subject in a time unit (e.g. 100 mg 
once a day, 75 mg twice a day)
Enrollment
Point/time of subject entry into the study at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol)
Epoch
Interval of time in the planned conduct of a study. An epoch is associated 
with a purpose (e.g. screening, randomization, treatment, follow-up), which 
applies across all arms of a study.
Investigational drug
The study drug whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and Directive 2001/20/EC and is 
synonymous with “investigational new drug” or “test substance”
Investigational 
treatment
All investigational drug(s) whose properties are being tested in the study as 
well as their associated treatment controls. This includes any placebos, any 
active controls, as well as approved drugs used outside of their 
indication/approved dosage or tested in a fixed combination. Investigational 
treatment generally does not include other treatments administered as 
concomitant background therapy required or allowed by the protocol when 
used within approved indication/dosage.
Medication number
A unique identifier on the label of each study drug package in studies that 
dispense study drug using an IRT system.
Non-investigational 
medicinal Product 
(NIMP)
Products which are not the object of investigation (e.g. any background 
therapy administered to each of the clinical trial subjects, regardless of 
randomization group, rescue medication, active drug run-ins etc.)
Patient
An individual with the condition of interest
Period
A minor subdivision of the study timeline; divides phases into smaller 
functional segments such as screening, baseline, titration, washout, etc.
Premature subject 
withdrawal
Point/time when the subject exits from the study prior to the planned 
completion of all study drug administration and assessments; at this time all 
study drug administration is discontinued and no further assessments are 
planned.
Randomization 
number
A unique identifier assigned to each randomized subject, corresponding to a 
specific treatment arm assignment
Screen Failure
A subject who is screened but is not treated or randomized
Stage
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc.
Study completion
Point/time at which the subject came in for a final evaluation visit or when 
study drug was discontinued whichever is later.
Study 
drug/treatment
Any drug (or combination of drugs) administered to the subject as part of the 
required study procedures; includes investigational drug, active drug run-ins 
or background therapy.
Study treatment
Any drug administered to the study participants as part of the required study 
procedures; includes investigational drug (s), control(s) or non-investigational 
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Study treatment 
discontinuation
When the subject permanently stops taking study treatment prior to the 
defined study treatment completion date
Subject
An individual who has consented to participate in this study. The term 
Subject may be used to describe either a healthy volunteer or a patient.
Subject number
A unique number assigned to each subject upon signing the informed 
consent. This number is the definitive, unique identifier for the subject and 
should be used to identify the subject throughout the study for all data 
collected, sample labels, etc.
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 subject 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, 
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Amendment 3
Amendment rationale
The protocol is being amended to provide clarification on the process for assessment of nasal 
endoscopy at baseline and management of protocol deviations in relation to the statistical 
analysis sets. These changes include: 

Changes in Section 8.3.1 to remove the constraint around the performance of the nasal 
endoscopy at the end of run-in/baseline visit along with confirming that patient 
eligibility will be based on the central reading score

Change to the text in Section 12.1 to highlight that the Full Analysis Set will only 
comprise of patients with a baseline NPS ≥4, confirmed by central reading

Addition of text in Section 12.4 to clarify that the central reading score is what will be 
used for the primary endpoint analysis

Addition of text in Appendix 7 to clarify that the central reading score is the final 
determination of eligibility at both screening and end of run-in/baseline. 
IRB Section
The changes described in this protocol have been classed as non-substantial and will not require 
additional IRB/HA approval, unless required by local regulations. 


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Amendment 2
Amendment rationale
The protocol is being amended to align the safety requirements with other studies in the 
QAW039 program. These changes include:

Addition of exclusion criteria to align with other QAW039 studies in Section 5.2

Update to contraception exclusion criteria to reference that any local deviations from the 
contraception requirements will apply and will be described within the patient informed 
consent form. Updates also included to align exclusion criteria with the prohibited 
medications in Table 6-2

Update to asthma inclusion criteria throughout the protocol to remove reference to Global 
Initiative for Asthma (GINA) Step 3 in order to remove any contradiction and discrepancy 
with other QAW039 trials given this is a new population.

Inclusion of Table 6-1 - Medications allowed under certain conditions - in Section 6.2.1

Inclusion of renal safety monitoring in Section 10.2.2 and additional details as an 
appendix in Section 16.3

Addition of urine pregnancy testing at each treatment visit

Addition of liver event and renal event monitoring to each visit in Table 8-1

Inclusion of clinical chemistry reflex testing in the event of elevated creatine kinase (CK) 
results in Table 8-4

Addition of hemoglobin A1c (HbA1c) testing at Screening and end of treatment (EOT) 
with updates to Table 8-1 and Table 8-4
Changes to the protocol
The described changes in the aforementioned amendment rationale are implemented throughout 
the protocol in the sections noted. 
The opportunity was also taken to make the following changes in the protocol:

Changes made in Table 8-1 to clarify which assessments are performed prior to the start 
of treatment at the Week 1 visit. Other minor clarification changes also included in this 
table. 

Addition of patient withdrawal criteria in Section 9.1.1 relating to the need for nasal 
surgery during the trial, use of corticosteroids during the trial and also for persistent 
muscle pain, with or without elevated CK levels. 

Clarification of Nasal Endoscopy readings / assessments being performed centrally and 
locally

Addition of sensitivity analyses in Section 12.4.4

Typographical changes throughout for spelling/consistency. 
IRB Section
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) and Health Authorities.


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The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval, a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
Amendment 1
Amendment rationale
The protocol is being amended based on health authority feedback - the following changes have 
been implemented:

Added additional exclusion criteria to Section 5.2 to ensure that patients taking any of the 
prohibited medications outlined in Table 6-2 are appropriately excluded.
Changes to the protocol
The described changes in the aforementioned amendment rationale are implemented throughout 
the protocol in the sections noted.
The opportunity was also taken to amend typographical items in the protocol:

Rewording of the text for the restriction on nasal corticosteroids in Table 6-2 to better 
clarify the specific types that are excluded along with the restricted statin therapies

Minor revision to the wording in Section 8.3.3


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Protocol summary
Protocol number
CQAW039A2322
Full Title
A multicenter, randomized, double-blind, parallel-group, placebo-controlled 
study of fevipiprant once daily plus standard-of-care (SoC) for assessment of 
the efficacy in reduction of nasal polyp size in patients with nasal polyposis and 
concomitant asthma.
Brief title
Study of efficacy of fevipiprant in patients with nasal polyposis and asthma
Sponsor and 
Clinical Phase
Novartis
Phase 3b
Investigation 
type
Drug
Study type
Interventional
Purpose and 
rationale
Nasal polyposis is a common disorder, affecting up to 4% of the population. 
Although the causes remain unclear, nasal polyposis has been associated with 
a number of conditions including, asthma, infection, cystic fibrosis and aspirin 
sensitivity. Nasal polyposis with concomitant asthma has a prevalence ranging 
from 2%-66% although it is usually in the region of 30% of those nasal 
polyposis patients who are referred to (ear, nose, throat) ENT departments.
The purpose of this study is to evaluate the efficacy and safety of fevipiprant 150 
mg and 450 mg compared to placebo in the reduction of nasal polyps size and 
the effect on symptoms, quality of life and smell via patient-reported outcomes 
in patients with nasal polyposis (NP) and concomitant asthma.
Primary 
Objective(s) 

In patients with nasal polyps with a polyp size score ≥ 4 at baseline, to 
demonstrate a difference in mean change from baseline in polyp size at 
Week 16, measured by the nasal polyp score (NPS, assessed by nasal 
endoscopy with central reading), between fevipiprant (150 mg or 450 mg 
once daily, separately) and placebo
Secondary 
Objectives

To evaluate the effect on symptoms as measured by the nasal congestion 
score (NCS) with fevipiprant (150 mg or 450 mg once daily), compared 
with placebo following 16 weeks of treatment.

To evaluate the effect on quality of life as measured by the Sino-Nasal 
Outcome Test - 22 (SNOT-22) with fevipiprant (150 mg or 450 mg once 
daily), compared with placebo following 16 weeks of treatment.

To evaluate the effect on Smell as measured by the university of 
Pennsylvania smell identification test (UPSIT) with fevipiprant (150 mg or 
450 mg once daily), compared with placebo following 16 weeks of 
treatment.

To evaluate the effect of fevipiprant 150 mg and 450 mg compared with 
placebo in terms of general safety/tolerability following 16 weeks of 
treatment.
Study design
This is a Phase 3b, Proof-of-concept study with a randomized, multicenter, 
double-blind, placebo-controlled, parallel-group study design to determine the 
ability of fevipiprant plus SoC compared to placebo plus SoC to reduce the size 
of NPs. The study will include: Screening period of 2 weeks to assess eligibility; 
Run-in period of 4 weeks where patients will utilize mometasone furoate spray 
(200 µg once daily, administered as two 50 µg actuations into each nostril); 
Treatment period of 16 weeks (with visits held every month for study 
procedures) and a Follow-up period of 2 weeks following the last dose of study 


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drug to collect additional data for safety variables. Patients will continue to use 
the mometasone furoate SoC throughout the treatment period.
Population
The study population will consist of approximately 93 male and female patients 
aged 18 and above, diagnosed with nasal polyposis with nasal polyp size score 
≥ 4 (nasal polyp score, assessed by nasal endoscopy) with a minimum score of 
2 in each nostril; and a concomitant diagnosis of asthma.
Key Inclusion 
criteria

Written informed consent must be obtained before any assessment is 
performed.

Patients aged ≥ 18 years with a diagnosis of nasal polyposis with nasal 
polyp size score ≥ 4 and a minimum score of 2 in each nostril, measured 
by nasal endoscopy at screening and prior to randomization on Run-
in/Treatment Day 1 (to ensure no reduction in NPS following the use of the 
mometasone furoate SoC therapy).

Patients with a concomitant diagnosis of asthma for a period of at least 6 
months prior to screening.

Have been on a stable asthma treatment regimen of at least inhaled 
corticosteroids (ICS, any dose), alone for at least 6 months prior to 
Screening or ICS for 6 months prior to Screening with any other required 
inhaled asthma medication (long-acting bronchodilator (LABA), long-acting 
muscarinic antagonist (LAMA)) added at least 6 weeks prior to Screening.
Key Exclusion 
criteria

Asthma exacerbation, within 6 weeks prior to Screening that required 
systemic corticosteroids, hospitalization, or emergency room visit. When 
patients experience an exacerbation between screening and the end of the 
4 week Run-in period, and prior to randomization, they will be considered 
screen failures and can be eligible for re-screening only once the required 
6 weeks post-exacerbation window has passed.

Chronic/maintenance use of oral corticosteroids (OCS) defined as any 
continuous use of OCS for a period of 1 month or more within 1 year of 
Screening.

Use of biologics (omalizumab, mepolizumab, reslisumab, dupilumab, 
benralizumab etc., for asthma or any other indications) that has potential to 
interfere/affect asthma or NP disease progression, within 6 months of the 
start of the Run-in period.

Use of medication for sino-nasal symptoms (antibiotics with or without 
OCS) within 30 days of Screening or during the Run-in period.

Any contra-indications to inhaled or nasal steroids e.g. narrow angle 
glaucoma, or any other as decided by the Investigator.

History of nasal surgery (including polypectomy) within 6 months prior to 
screening.

Patients with asthma control questionnaire - 5 questions (ACQ-5) ≥ 1.5 at 
Screening
Study treatment

QAW039 150 mg and QAW039 450 mg once daily

Matching placebo to QAW039 150 mg and QAW039 450 mg once daily
Efficacy 
assessments

Assessment of nasal polyp score by nasal endoscopy

Assessment of nasal congestion using the nasal congestion score 
questionnaire

Assessment of quality of life using the SNOT-22 questionnaire

Assessment of smell using the university of Pennsylvania smell 
identification test


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Key safety 
assessments

Medical history and physical examination

Adverse events (AEs) including serious adverse events (SAEs)

Vital signs

Electrocardiogram (ECG)

Laboratory evaluations (hematology, blood chemistry, urinalysis)

Pregnancy (female patients)
Data analysis
Approximately 93 patients will be randomized in 1:1:1 ratio in either of the 3 
arms fevipiprant 450 mg dose, fevipiprant 150 mg dose or placebo in addition 
to standard of care.
Primary Objective:
The primary aim of the study is to evaluate a change in nasal polyp size with 
fevipiprant (150mg or 450mg once daily, separately) as compared to placebo. 
This will be evaluated by using the NPS) which is assessed by nasal endoscopy. 
The total NPS is recorded as the sum of the right and left nostril scores with a 
range of 0 to 8. A decrease in the NPS is considered a favorable outcome.
The analysis of the primary endpoint will be conducted according to the intention 
to treat principle using the full analysis set (FAS) population and using a mixed 
model repeated measures (MMRM) approach.
Secondary Objectives:

Nasal Congestion Score: The change in NCS will be analyzed using an 
MMRM model.

Quality of Life (SNOT-22): The treatment group difference in terms of 
change from baseline at Week 16 in SNOT-22 will be estimated using an 
MMRM model.

Smell (UPSIT): The treatment group difference in terms of change from 
baseline at Week 16 in UPSIT will be estimated using an MMRM model.

Safety and Tolerability: For all safety analyses, the safety set will be 
used. All listings and tables will be presented by treatment group. Safety 
summaries will be primarily based on on-treatment data with selected 
tables also presented for the all data after the first intake of study drug, 
while all databased safety data will be listed. The on-treatment period lasts 
from the date of first administration of study treatment to 30 days after the 
date of the last actual administration of any study treatment.
Key words
Efficacy and safety of QAW039, nasal polyp score, nasal congestion score, 
quality of life, smell, nasal polyposis, concomitant asthma, female and male 
patients ≥ 18 years


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1
Introduction
1.1
Background
The purpose of this study is to evaluate the efficacy and safety of fevipiprant 150 mg and 450 
mg compared to placebo in the reduction of nasal polyps size and the effect on symptoms, 
quality of life and smell via patient-reported outcomes in patients with nasal polyposis and 
concomitant asthma.
Nasal Polyposis (NP) is a common disorder, affecting up to 4% of the population. Although the 
causes remain unclear, NP has been associated with a number of conditions including asthma, 
infection, cystic fibrosis and aspirin sensitivity. The polyps themselves are benign lesions 
arising from the mucosa of the nasal cavity, which present typically as single or multiple 
polypoid masses, causing symptoms including nasal obstruction, anosmia, post nasal drip, 
rhinorrhea and, less commonly, facial pain (Newton and Ah-See 2008). NP is diagnosed either 
by a clinical examination or more commonly via nasal endoscopy. Computerized tomography 
(CT) scans are useful but do not provide optimal understanding of the disease extension, as the 
polyps can be indistinguishable of the anatomy, so endoscopic direct observation is more 
accurate for diagnosis. Treatment can range from the use of corticosteroid nasal sprays (e.g. 
mometasone furoate) to surgical interventions. It is common for patients to have relapses, 
requiring repeated surgeries.
NP with concomitant asthma has a prevalence ranging from 2%-66% (Orlandi et al 2016), 
usually considered in the range of 30% of the NP patients for those referred to ENT departments 
(Larsen); and it is 58% in those patients with a nasal polyps score ≥ 4 (Bachert et al 2016). 
Nasal polyp score is assessed by nasal endoscopy using the following scale (Gevaert et al 2013):
Table 1-1
Nasal Polyp Scale
Polyp Score
Polyp Size
0
No polyps
1
Small polyps in the middle meatus not reaching below the inferior border of the middle 
turbinate
2
Polyps reaching below the lower border of the middle turbinate
3
Large polyps reaching the lower border of the inferior turbinate or polyps medial to the 
middle turbinate
4
Large polyps causing complete obstruction of the inferior nasal cavity
Prostaglandin D2 (PGD2) is one of the major prostanoid inflammatory mediators identified in 
airway inflammatory diseases. The PGD2 type 2 receptor (DP2) usually mediates these pro-
inflammatory effects. There is evidence that the DP2 pathway and PGD2 have an effect on NP 
physiopathology:

The in-vitro study by Perez-Novo et al showed that in nasal polyps taken from 10 patients 
there was an increased release of PGD2. Pre-treatment with IgE/anti-IgE was significantly 
impacted by pre-incubation with diclofenac. This suggests that in immunologically 
activated NP tissue, PGD2 produced by mast cells promotes the migration of Th2 cells 
through a DP2 dependent mechanism (Pérez-Novo et al 2010).


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
The study by Mjosberg et al showed that tissue taken from nasal polyps in patients with 
chronic rhinosinusitis contained larger proportions of DP2 than mucosa from uninflamed 
nasal cavities from healthy donors (Mjösberg et al 2011).

It has been shown that the expression of DP2 receptors is associated with the 
pathophysiology of Chronic Rhinosinusitis along with NP formation 
(Yamamoto et al 2009).

Elevated percentages of mast cells are found in the sino-nasal mucosa of chronic 
rhinosinusitis patients with NPs (Shaw et al) when compared to a healthy control group.
Fevipiprant (QAW039) is a DP2 competitive antagonist in investigation in severe asthma. It 
exerts its effect by binding to DP2 receptors on eosinophils, Th2 and ILC2 cells in the blood 
and tissues; thus, inhibiting migration and activation of these cells into the airway tissues and 
reducing the release of pro-inflammatory cytokines (Chevalier et al 2005). It is proposed that 
fevipiprant will also be a suitable treatment for NP. Moreover it's once daily oral regimen could 
increase compliance when compared with the current standard of care of nasal sprays.
1.2
Purpose
A Phase 3b Proof-of-Concept study to evaluate the efficacy of fevipiprant (QAW039) (150 mg 
and 450 mg once daily) compared with placebo, as add-on to mometasone furoate treatment 
standard-of-care (SoC), in reducing endoscopic nasal polyp score (NPS) and nasal congestion 
score (NCS) in adult (≥ 18 years) patients with nasal polyposis (NP) and concomitant asthma.
2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

In patients with nasal polyps with a polyp size 
score ≥ 4, to demonstrate a difference in mean 
change from baseline in polyp size at week 16, 
measured by the nasal polyp score (NPS, 
assessed by nasal endoscopy with central 
reading), between fevipiprant (150 mg or 450 mg 
once daily, separately ) and placebo.

Reduction (in terms of change from baseline to 
week 16) in NPS for fevipiprant (150 mg or 450 
mg once daily, separately) as compared to 
placebo.
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To evaluate the effect of fevipiprant 150 mg and 
450 mg compared with placebo in terms of 
general safety/tolerability

Adverse events, ECG, vital signs and laboratory 
analysis following 16 weeks of treatment.

To evaluate the effect on Quality of Life as 
measured by the Sino-Nasal Outcome Test 
(SNOT 22) with fevipiprant (150 mg or 450 mg 
once daily), compared with placebo.

Increase (in terms of change from baseline to 
week 16) in QoL score for fevipiprant (150 mg or 
450 mg once daily, separately) as compared to 
placebo.

To evaluate the effect on Smell as measured by 
the University of Pennsylvania Smell 
Identification Test (UPSIT) with fevipiprant (150 
mg or 450 mg once daily), compared with 
placebo.

Increase (in terms of change from baseline to 
week 16) in Smell score for fevipiprant (150 mg 
or 450 mg once daily, separately) as compared to 
placebo.

To evaluate the effect on symptoms as measured 
by the Nasal Congestion Score (NCS) with 

Reduction (in terms of change from baseline to 
week 16) in NCS for fevipiprant (150 mg or 450 


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Objective(s)
Endpoint(s)
fevipiprant (150 mg or 450 mg once daily), 
compared with placebo.
mg once daily, separately) as compared to 
placebo.
3
Study design
This is a Phase 3b, Proof-of-concept study with a randomized, multicenter, double-blind, 
placebo-controlled, parallel-group study design to determine the ability of fevipiprant plus SoC 
compared to placebo plus SoC to reduce the size of NPs. The study will include: Screening 
period of two weeks to assess eligibility; Run-in period of 4 weeks where patients will utilize 
mometasone furoate spray (200 µg once daily, administered as two 50 µg actuations into each 
nostril); Treatment period of 16 weeks (with visits held every month for study procedures); and 
a Follow-up period of two weeks following the last dose of study drug to collect additional data 
for safety variables. Patients will continue to use the mometasone furoate SoC throughout the 
Treatment period. Approximately 93 patients will be enrolled into this study. Please refer to 
Table 8-1 for the clinical visit schedule and the details of procedures to be performed at each 
visit.
Figure 3-1
Study Schematic
4
Rationale
4.1
Rationale for study design
The overall purpose of this study is to determine the ability of fevipiprant (150 mg and 450 mg 
once daily) plus SoC (mometasone furoate 200 µg daily), compared with placebo plus SoC, to 
reduce the size of nasal polyps during a 16 week Treatment period, assessed by nasal endoscopy 


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with central reading. The study will also determine if fevipiprant (150 mg and 450 mg once 
daily) plus SoC, compared with placebo plus SoC, can reduce symptoms and improve quality 
of life and smell, assessed via patient-reported outcomes (PROs) and the UPSIT.
4.1.1
Rationale for choice of background therapy
Mometasone furoate is the standard of care for nasal polyposis as per British society for allergy 
and clinical immunology (BSACI) treatment guidelines and will be utilized throughout the 
study, from the start of Run-in until the completion of treatment.
4.2
Rationale for dose/regimen and duration of treatment
QAW039 will be administered at doses of 150 mg and 450 mg once daily as oral film-coated 
tablets (FCTs) in this study. These doses have been selected for the ongoing asthma trials and 
are based on the following rationale:
The 450 mg once daily dose was selected because at a dose of 450 mg once daily, > 98% 
receptor occupancy is expected at steady state allowing inhibition of eosinophil migration over 
the entire treatment interval. Meanwhile in Study [CQAW039A2208], QAW039 caused 
significant reduction of sputum eosinophils in patients with severe eosinophilic asthma. The 
reduction in sputum eosinophils was comparable to that observed with the anti-IL5 antibodies, 
mepolizumab (Pavord et al 2012) and reslizumab (Castro et al 2011, Castro et al 2015).
A lower dose of 150 mg once daily was selected because it was the lowest dose of QAW039 
with “maximal efficacy” on the endpoint of FEV1 in a prior dose-ranging study (Study 
[CQAW039A2206]) in patients with moderate-to-severe asthma (GINA treatment steps 4 and 
5) as add-on to low-dose ICS. This dose is ½ log lower than the highest dose.
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
All patients in this study will receive mometasone furoate nasal spray (MFS) as SoC treatment 
with QAW039 or placebo administered as an add-on therapy. Patients currently using nasal 
corticosteroid drops or lavage will transfer on to MFS at the start of the Run-in period.
The use of placebo will permit the assessment of a reduction in nasal polyp score (NPS) along 
with improvement in symptoms, quality of life (QoL) and smell for patients treated with 
QAW039, in comparison to those on placebo, who will be on the nasal polyposis SoC therapy 
only. Additionally, the use of placebo will permit a controlled evaluation of the safety of 
QAW039.
This study does not include an active comparator since QAW039 will be given as an add-on 
therapy to standard of care therapy in patients with a NPS ≥ 4.
4.4
Purpose and timing of interim analyses/design adaptations
Not applicable as no interim analysis will be performed on this study.


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4.5
Risks and benefits

QAW039 is a potent and highly selective oral DP2 receptor antagonist being developed as 
a potential therapy treatment for patients with severe asthma. DP2 is a receptor for PGD2,
which mediates the activation and migration of Th2 cells and eosinophils, some of the key 
inflammatory cell types in asthma. Recruitment of these cells into the lung is partly 
responsible for the intermittent airway obstruction, which leads to wheezing and shortness 
of breath characteristic of asthma.

QAW039 is at least 300-fold selective for the DP2 receptor compared to other available 
prostanoid receptors and to cyclooxygenase-1 and cyclooxygenase-2, and it has been 
demonstrated to be a potent in-vitro inhibitor of human whole blood eosinophil 
activation and induction of Th2 cytokines. After oral dosing in rats, QAW039 inhibited 
pulmonary eosinophilia induced by the PGD2 metabolite DK-PGD2.

The potential benefits of QAW039 therapy need to be balanced against its potential risks. 
The risk to patients in this study will be minimized by compliance with the 
inclusion/exclusion criteria and close clinical monitoring. All patients will remain on the 
background SoC asthma therapy they were taking at screening throughout the study.

Women of child-bearing potential and sexually active males will be informed that taking 
the study treatment may involve unknown risks to the fetus if pregnancy were to occur 
during the study, and agree that in order to participate in the study they must adhere to the 
contraception requirements outlined in the exclusion criteria. If there is any question that 
the patient will not reliably comply, they should not be entered or continue in the study.

The overall clinical experience with QAW039 includes 12 studies: 10 (6 in healthy 
volunteers and 4 in patients) have completed and 2 (in patients) are ongoing. The 
completed phase 2 studies consist of 3 in patients with asthma and 1 in patients with 
allergic rhinitis. The ongoing Phase 2 studies include one study in patients with asthma 
([CQAW039A2214]) and 1 study in patients with atopic dermatitis ([CQAW039X2201]).

QAW039 has been well tolerated in populations studied to date at total daily doses up to 
500 mg given for up to 12 weeks. In the 10 completed studies, 16 patients reported 17 
SAEs, no deaths due to SAEs were reported, and 5 discontinuations due to SAEs were 
reported. Of the 16 patients reporting SAEs, 12 patients reported 13 events, 2 patients 
reported 2 events and 2 patients reported 2 events in the QAW039, placebo, and 
montelukast treatment groups, respectively. There were no SAEs with a suspected causal 
relationship to QAW039. There have been no adverse events of idiopathic drug reactions.

Cardiovascular risks: Transient, increases in heart rate were observed in a cardiovascular 
safety pharmacology study in dogs. These changes were not associated with any 
significant alterations in blood pressure, ECG interval duration, morphology or rhythm or 
any structural changes in cardiac tissues. No cardiac findings have been identified in the 
healthy volunteer and patient studies completed to date apart from an observed imbalance 
in the frequency of post-randomization cardiac adverse events in study 
[CQAW039A2206] with a higher incidence in the QAW039 treatment group (1.7%) 
compared with either placebo (0.7%) or montelukast (0%) treated patients. The cardiac 
events comprised a number of different non-serious arrhythmias and one serious adverse 
event of pericarditis not suspected to be related to study drug by the Investigator. Three of 
the events in the QAW039 treatment groups occurred during the washout period and 


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resolved on treatment. Based on the inability to identify discernable trends with QAW039 
dose, regimen, time-of-onset, patient age and gender, concomitant medication, event type 
and following detail ECG review, it was considered that these were most probably 
coincidental events without a causal association to study drug. A formal QTc study has not 
been completed for QAW039. Monitoring for changes in vital signs, ECGs and 
biochemical parameters will be conducted.

Liver toxicity: Dose-dependent increases in liver weights with concomitant hepatocellular 
hypertrophy were the primary findings during 2- and 13-week toxicity studies in mice. 
These changes were considered to be a species-specific adaptive metabolic response with 
no relevance for humans. Liver toxicity findings have not been identified in the healthy 
volunteer and patient studies completed to date. Monitoring of liver function tests (LFTs) 
will be conducted as described in Section 16.2 of this protocol.

Potential risk of idiosyncratic drug reactions CCN362 is an acylglucuronide metabolite of 
QAW039 and its potential to covalently bind to plasma proteins, such as albumin, was 
demonstrated in the human ADME (Absorption, distribution, metabolism, excretion) 
study of QAW039 ([CQAW039A2104]). In the literature, in vivo binding of acyl 
glucuronides to proteins has been reported to be associated with rare idiosyncratic drug 
reactions (IDRs), although a causal connection of protein adduction to IDRs remains 
uncertain (Regan et al 2010). There have been no IDRs observed with QAW039 treatment 
in completed clinical trials. Surveillance of adverse events for identification of IDRs will 
be conducted.

Drug-drug interactions: QAW039 and CCN362 did not show any relevant inhibition or 
induction of the cytochrome P450 isoenzymes or inhibition of ubiquitous efflux 
transporters. The most potent in-vitro inhibition by QAW039 was found for OATP1B1, 
but clinically only a small impact was observed at 450 mg/day (~2-fold increase in Cmax 
of simvastatin acid and rosuvastatin without change in AUC). Based on these data, as well 
as recommendations in the simvastatin label, simvastatin doses of > 20 mg per day should 
not be co-administered with QAW039; no relevant impact on the disposition of other co-
medications are expected with QAW039 dosed up to 450 mg/day. Patients on doses of 
simvastatin > 20 mg, doses of atorvastatin > 40 mg, doses of pravastatin > 40mg, or doses 
of pitavastatin > 2 mg per day (Elsby et al 2012, Deng et al 2008, Noé et al 2007, and 
Kalliokoski and Niemi 2009), as well as patients on any statins with high CK levels (> 2 X 
upper limit of normal (ULN)) at screening (Visit 1) will be excluded from the study. 
Furthermore, patients on statin medication who are included in the study will have regular 
monitoring for relevant symptoms and be subject to discontinuation based on persistent 
myalgia and blood CK levels (Jacobson 2008).

Overall, the safety profile of QAW039 has been favorable across studies. Three Phase 2 
studies in patients with asthma demonstrated the effect of QAW039 across the range of 
asthma severities (mild to severe). For detailed information on the studies described 
below, please refer to the Investigator's Brochure (IB).


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5
Population
The study population will consist of approximately 93 male and female patients aged 18 and 
above, diagnosed with nasal polyposis with polyps size ≥ 4 (nasal polyp score, assessed by nasal 
endoscopy) with a minimum score of 2 in each nostril; and a concomitant diagnosis of asthma.
5.1
Inclusion criteria
Subjects eligible for inclusion in this study must meet all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed.
2. Patients aged ≥ 18 years with a diagnosis of nasal polyposis with polyp size score ≥ 4 and 
a minimum score of 2 in each nostril, measured by nasal endoscopy at screening and prior 
to randomization on Run-in/Treatment Day 1 (to ensure no reduction in NPS following the 
use of the mometasone furoate SoC therapy).
3. Patients with a concomitant diagnosis of asthma for a period of at least 6 months prior to 
screening.
4. Have been on a stable asthma treatment regimen of at least inhaled corticosteroids (any 
dose), alone for at least 6 months prior to Screening or ICS for 6 months prior to screening 
with any other required, inhaled asthma medication (LABA, LAMA) added at least 6 
weeks prior to Screening.
5.2
Exclusion criteria
Subjects meeting any of the following criteria are not eligible for inclusion in this study.
1. Asthma exacerbation, within 6 weeks prior to screening that required systemic 
corticosteroids, hospitalization, or emergency room visit. When patients experience an 
exacerbation between screening and the end of the 4-week Run-in period, and prior to 
randomization, they will be considered screen failures and can be eligible for re-screening 
only once the required 6 weeks post exacerbation window has passed.
2. Chronic/maintenance use of oral corticosteroids (OCS) or systemic corticosteroids (SCS) 
defined as any continuous use of OCS/SCS for a period of 1 month or more within 1 year 
of Screening.
3. Patients who, in the judgement of the Investigator, have a clinically significant ECG 
abnormality such as, but not limited to, sustained ventricular tachycardia or clinically 
significant second or third degree AV block without a pacemaker.
4. Patients with a history of familial long QT syndrome or known family history of Torsades 
de Pointes.
5. Patients with a resting QTcF (Fridericia) ≥ 450 msec (males) or ≥ 460 msec (females) at 
screening.
6. Use of biologics (omalizumab, mepolizumab, reslisumab, dupilumab, benralizumab etc., 
for asthma or any other indications) that has potential to interfere/affect asthma or NP 
disease progression, within 6 months of the start of the Run-in period.
7. Use of medication for sino-nasal symptoms (antibiotics with or without OCS) within 30 
days of Screening or during the Run-in period.


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8. Use of tetracycline (e.g. doxycycline) or macrolide antibiotics specifically within the 8 
weeks prior to the start of the Run-in period due to the influence they have on Nasal 
Polyps.
9. Any contra-indications to inhaled or nasal steroids e.g. narrow angle glaucoma, or any 
other as decided by the Investigator.
10. Pregnant or nursing (lactating) women
11. 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 
investigational drug. Basic contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking 
investigational drug. In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow-up hormone level assessment

Male sterilization (at least 6 months prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject

Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps). For UK: with spermicidal foam/gel/film/cream/ vaginal 
suppository

Use of oral, (estrogen and progesterone), 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 or placement of an intrauterine device (IUD) or intrauterine system 
(IUS)
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking investigational drug.
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total 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.
If local regulations deviate from the contraception methods listed above to prevent 
pregnancy, then local regulations apply and will be described in the informed consent 
form. 
12. Use of other investigational drugs within 5 half-lives of enrollment, or within 30 days until 
the expected pharmacodynamic effect has returned to baseline, whichever is longer.
13. History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar 
chemical classes.


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14. 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.
15. Patients who are unable to follow instructions to complete the study, either because of 
mental or physical conditions.
16. Patients with a terminal disease, or conditions that may impede the timely completion of 
the study as decided by the investigator.
17. Patients with a diagnosis of Cystic Fibrosis
18. History of nasal surgery (including polypectomy) within 6 months prior to screening. 
19. History of sinus or nasal surgery modifying the structure of the nose such that assessment 
of NPS via nasal endoscopy is not possible. 
20. Patients with a diagnosis of ciliary dyskinesia
21. Patients with allergic fungal sinusitis as diagnosed from previous surgery or from CT 
scan.
22. Patients with ACQ-5 ≥ 1.5 at Screening
23. Uncontrolled epistaxis requiring surgical or procedural intervention, including nasal 
packing, within 2 months of screening
24. Concomitant conditions that interfere with evaluation of the primary endpoint:

Marked nasal septal deviation occluding one or both nostrils

Ongoing rhinitis medicamentosa

Acute sinusitis, nasal infection or upper respiratory tract infection during run-in 
period.
25. Initiation of or change in immunotherapy or aspirin desensitization for allergies within 3 
months prior to Screening or during the Run-in period.
26. Patients receiving any medications in the classes listed in Table 6-2 should be excluded 
unless they meet the criteria as specified in Table 6-2.
27. Patients on >20 mg of simvastatin, > 40 mg of atorvastatin, >40 mg of pravastatin, or >2 
mg of pitavastatin 7 days prior to run-in visit. Statin doses less than or equal to these doses 
as well as other statins will be permitted during the study
28. Patients on any statin therapy with a CK level >2 X ULN at Screening Visit
29. Patients receiving any medications in the classes listed in Table 6-1 should be excluded 
unless the medication has been stabilized for the specified period and the stated conditions 
have been met
30. Patients receiving any medications or other agents known to prolong the QT interval. 
31. 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.
32. Patients with a history of chronic lung disease other than asthma, including (but not 
limited to) chronic obstructive pulmonary disease, bronchiectasis, (non-clinically 
significant bronchiectasis may be allowed provided recent [within 3 months prior to 
Screening Visit] CT scan proof is available), sarcoidosis, interstitial lung disease, and 
tuberculosis.


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33. Patients with uncontrolled diabetes having an HbA1c test result ≥8% at the Screening 
Visit laboratory test.
34. Patients who have a clinically significant laboratory abnormality at the 
Screening laboratory test including (but not limited to):
• Total white blood cell count <2500 cells/µL 
• AST or ALT>2.0 X ULN or total bilirubin >1.3 X ULN 
• Estimated Glomerular Filtration Rate (eGFR) by the Modification of Diet in Renal 
Disease (MDRD) equation or Bedside Schwartz equation <55 mL/minute/1.73 m2
35. Patients who, in the judgement of the investigator, have a clinically significant condition 
such as (but not limited to) unstable ischemic heart disease, NYHA Class III/IV left 
ventricular failure, arrhythmia, uncontrolled hypertension, cerebrovascular disease, 
neurodegenerative diseases, or other neurological disease, uncontrolled hypo- and 
hyperthyroidism and other autoimmune diseases, hypokalemia, hyperadrenergic state, or 
ophthalmologic disorder or patients with a medical condition that might compromise 
patient safety or compliance, interfere with evaluation, or preclude completion of the 
study.
36. Patients who have smoked or inhaled any substance other than asthma medications within 
the 6 month period prior to Screening, or who have a smoking history of greater than 10 
pack years (Note:10 pack years = 1 pack /day x 10 yrs., or ½ pack/day x 20 yrs.).
37. Patients with a history of myocardial infarction within 12 months of Screening.
38. Patients with serious co-morbidities including, but not limited to, neurodegenerative 
diseases, rheumatoid arthritis and other autoimmune diseases.
39. Patients with a history of alcohol or drug abuse within 12 months prior to Screening.
40. Patients with a weight <30 kg.
41. Patients with a known history of non-compliance to medication. 
42. Patients with a history of being unable to swallow tablets. 
43. 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.
44. Patients with a history of immunodeficiency disease or hepatitis B or hepatitis C.
45. No person directly associated with the administration of the study is allowed to participate 
as a study subject.
46. No family member of the investigational study staff is allowed to participate in this study.
47. History of lactose or milk sensitivity.
48. Patients with a history of conditions other than asthma that could result in elevated 
eosinophils (e.g., hypereosinophilic syndromes, Churg-Strauss Syndrome, eosinophilic 
esophagitis). Patients with known parasitic infestation within 6 months prior to Screening 
are also excluded.
49. Patients requiring SCS use for conditions other than asthma (chronic or intermittent) or 
nasal polyposis.
No additional exclusions may be applied by the Investigator, in order to ensure that the study 
population will be representative of all eligible subjects


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6
Treatment
6.1
Study treatment
6.1.1
Investigational and control drugs
The following investigational treatment will be supplied by Novartis to the study sites:

Name: fevipiprant (labeled as QAW039)

Formulation: tablet

Unit dose: 2 strengths: 150 mg and 450 mg
Please refer to the Investigator’s Brochure for composition of the fevipiprant tablets.

Name: fevipiprant placebo

Formulation: tablet

Unit dose: matching placebo to fevipiprant 150 mg, matching placebo to fevipiprant 450 
mg
Please refer to the Investigator’s Brochure for composition of the placebo tablets.
The investigational treatment (tablets) will be supplied in bottles. The matching placebos for 
fevipiprant will be identical in appearance to their active counterparts and will be identically 
packaged.
6.1.2
Additional study treatments
At the start of the Run-in period, all patients will be provided with mometasone furoate 
nasal spray (no specific brand required) as the SoC for use during the study. This will either be 
supplied to the Investigator sites by Novartis or sourced locally and reimbursed by Novartis. 
All patients will remain on their current asthma treatment for the duration of the study (with the 
exception of LTRAs, which should be discontinued prior to patients entering the Run-in period). 
Patients 
will 
also 
be 
provided 
with 
short-acting 
β2-agonists 
(SABAs), 
(salbutamol/albuterol/other SABA) which they will be instructed to use throughout the study as 
rescue medication to treat asthma symptoms on an ‘as needed basis’. SABAs will either be 
supplied to the Investigator sites by Novartis or sourced locally and reimbursed by Novartis.
Should patients develop any sino-nasal exacerbations during the course of the study, the treating 
physician should follow their normal treatment regimen with systemic corticosteroids and/or 
antibiotics.
6.1.3
Treatment arms/group
Subjects will be assigned at the randomization visit to one of the following 3 treatment arms in 
a ratio of 1:1:1.
During the Run-in period, all patients will receive the NP SoC treatment only - Mometasone 
Furoate 200 µg once daily, administered as two 50 µg actuations into each nostril.
For the treatment period, patients will be assigned to one of three treatment arms as follows in 
a 1:1:1 ratio:


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
QAW039 150 mg once daily (one tablet of blinded QAW039 at 150 mg dosage strength to 
be given together with one tablet blinded placebo to QAW039 450 mg).

QAW039 450 mg once daily (one tablet of blinded QAW039 at 450 mg dosage strength to 
be given together with one tablet blinded placebo to QAW039 150 mg).

Placebo to QAW039 once daily (one tablet blinded placebo to QAW039 150 mg and one 
tablet blinded placebo to QAW039 450 mg).
Patients will be instructed to take their investigational treatment (QAW039 or placebo) once 
daily in the morning without regard to time of food intake.
6.1.4
Treatment duration
The planned duration of the study treatment period is 16 weeks from the point of randomization. 
Subjects will take their assigned study treatments along with the NP SoC which will be supplied 
to patients at the start of the Run-in period. The patients will administer the SoC only, during 
the Run-in period and then administer both the SoC and the study treatment, during the 16-week 
Treatment period.
6.2
Other treatment(s)
All 
patients 
will 
be 
provided 
with 
short-acting 
β2-agonists 
(SABAs) 
(salbutamol/albuterol/other SABA) which they will be instructed to use throughout the study as 
rescue medication on an ‘as needed basis.’
6.2.1
Concomitant therapy
All medications, procedures and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the subject was enrolled into the study must be recorded 
on the appropriate Case Report Forms (CRFs). The medications in Table 6-1 are only permitted 
under the circumstances given and this table is not considered all-inclusive.
Each concomitant drug must be individually assessed for adherence to the indication and against 
all exclusion criteria/prohibited medication. If in doubt the Investigator should contact the 
Novartis/sponsor medical monitor before randomizing a subject or allowing a new medication 
to be started. If the subject is already enrolled, contact Novartis/sponsor to determine if the 
subject should continue participation in the study.
Table 6-1
Medications allowed under certain conditions
Class of medication
Conditions
Short-acting β2-agonist (SABA)
Rescue medication to be taken as needed
SCS for treatment of symptoms of asthma or NP
One treatment of up to 5 consecutive days allowed during 
the study. SCS should not be administered within the 2 
weeks prior to nasal endoscopy
Maintenance Immunotherapy for allergies
Stable dose for at least 3 months prior to Screening and 
the dose remains stable throughout the study
Inactivated influenza vaccine, pneumococcal 
vaccine or any other inactivated vaccine
Not administered with 48 hour prior to a study visit
Topical corticosteroids for treatment of eczema
Recommended doses and dosage regimens


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Class of medication
Conditions
Antihistamines (e.g. loratadine, cetirizine)
Stable for at least 1 month prior to Screening visit and 
dose remains stable throughout the study
Nasal anticholinergic
Treatment regimen has been stable for at least 1 month 
prior to Screening visit. In the case of as needed use, 
providing an established pattern of use, has been 
documented
Nasal or ophthalmological preparations of 
nedocromil
Nasal or ophthalmological preparations of 
antihistamines
6.2.2
Prohibited medication
Use of the treatments displayed in the below table is NOT allowed after screening. Each 
concomitant drug must be individually assessed against all exclusion criteria and the tables 
below to see if it is allowed. If in doubt, the Investigator should contact the Novartis medical 
monitor or designee before randomizing a patient or allowing a new medication to be started. 
This table is not considered all-inclusive. Medications should be assessed for adherence to the 
indication and other inclusion/exclusion criteria. These medications are also prohibited if 
administered for other indications.
Table 6-2
Prohibited Medication
Medication
Prohibition period (Minimum cessation prior to Run-in)
Other investigational drugs
30 days or 5 half-lives, whichever is longer
Oral and Nasal Decongestants (more than 3 weeks 
total use)
30 days
Live attenuated vaccine
30 days
Simvastatin > 20 mg, atorvastatin > 40 mg, 
pravastatin > 40 mg, or pitavastatin > 2 mg total 
daily dose
7 days
Other DP2 antagonists (e.g., ramatroban)
7 days or 5 half-lives whichever is longer
Short-acting anticholinergics
8 hours
Fixed combinations of short-acting β2 agonists and 
short-acting anticholinergics
8 hours
Systemic mast cell stabilizers (e.g.,cromoglycate, 
nedocromil, ketotifen)
7 days
Monoclonal antibodies, investigational or approved, 
for the treatment of asthma (e.g., omalizumab)
6 months
Nasal corticosteroids in the form of drops, sprays 
that are administered via devices (e.g. OptiNose 
device or stents) or lavage
8 weeks
Tetracyclic or macrolide antibiotics
8 weeks
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 immuno-
modulator drugs or immuno-modulatory monoclonal 
antibodies
6 months
Systemic (oral, intravenous, intramuscular) 
corticosteroids for non-asthma conditions
3 months


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Medication
Prohibition period (Minimum cessation prior to Run-in)
Leukotriene receptor antagonists (LTRA)
Stopped at beginning of Run-in period
6.2.3
Rescue medication
At the start of the Run-in period, 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 could take 
their rescue medication for symptoms of asthma. Rescue medication (i.e., SABAs) will either 
be supplied to the Investigator sites locally by the Novartis country pharma organization (CPO) 
or sourced locally and reimbursed by Novartis. Nebulized salbutamol/albuterol is not allowed 
as rescue medication and will not be supplied.
Should patients develop any sino-nasal exacerbations during the course of the study, the treating 
physician should follow their normal treatment regimen with systemic corticosteroids and/or 
antibiotics. Short term oral or nasal decongestants may also be utilised as a rescue therapy 
however the assessment of NPS must not be performed within 3 days of their use. 
Use of rescue medication must be recorded on the concomitant medications in the CRF.
6.3
Subject numbering, treatment assignment, randomization
6.3.1
Subject numbering
Each subject is identified in the study by a Subject Number (Subject No.), that is assigned when 
the patient is first enrolled for screening and is retained as the primary identifier for the subject 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential subject 
number suffixed to it, so that each subject is numbered uniquely across the entire database. 
Upon signing the informed consent form, the patient is assigned to the next sequential Subject 
No. available.
6.3.2
Treatment assignment, randomization
At randomization visit, all eligible subjects will be randomized via Interactive Response 
Technology (IRT) to one of the treatment arms. The Investigator or his/her delegate will contact 
the IRT after confirming that the patient fulfills all the inclusion/exclusion criteria. The IRT 
will assign a randomization number to the patient, which will be used to link the patient to a 
treatment arm and will specify unique medication numbers for the first packages 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 subjects and Investigator staff. A patient 
randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of patient numbers to randomization numbers. These randomization 
numbers are linked to the different treatment arms, which in turn are linked to medication 
numbers. A separate medication list will be produced by or under the responsibility of Novartis 
Global Clinical Supplies using a validated system that automates the random assignment of 
medication numbers to packs containing the investigational drug(s).


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The randomization scheme for subjects will be reviewed and approved by a member of the 
Randomization Group.
6.4
Treatment blinding
Subjects, Investigator staff, persons performing the assessments, and clinical trial team (CTT) 
will remain blind to the identity of the treatment from the time of randomization until database 
lock, using the following methods: (1) Randomization data are kept strictly confidential until 
the time of unblinding, and will not be accessible by anyone else involved in the study, (2) the 
identity of the treatments will be concealed by the use of study treatment that are all identical 
in packaging, labeling, schedule of administration, appearance, taste and odor.
A double-dummy design is used because the identity of the study treatment cannot be disguised, 
as the drug products are visibly different.
Unblinding will occur in the case of subject emergencies and at the conclusion of the study.
Table 6-3
Blinding and unblinding plan
Time or Event
Role
Randomization list 
generated
Treatment allocation 
& dosing
Safety event (single 
subject unblinded)
Subjects
B
B
B
Site staff
B
B
B
Unblinded site staff e.g. pharmacy 
staff (specify)
B
B
B
Drug Supply and Randomization 
Office
UI
UI
UI
Unblinded Pharmacovigilance 
sponsor staff
UI
UI
UI
Statistician/statistical programmer/ 
data analysts (e.g. biomarker, PK)
B
B
B
Independent committees used for 
assessing interim results, if 
required (e.g. DMC)
NA
NA
NA
All other sponsor staff not 
identified above (trial team, project 
team, management & decision 
boards, support functions)
B
B
B
Key:
UI: Allowed to be unblinded on individual subject level
B: Remains blinded
NA: Not applicable to this study
6.5
Dose escalation and dose modification
Investigational or other study treatment dose adjustments and/or interruptions are not permitted 
and should any such changes in dosing regimen occur during the study then the patients will be 
excluded unless highlighted as a rescue therapy within other sections of the protocol.


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6.5.1
Dose modifications
For subjects who do not tolerate the protocol-specified dosing schedule, dose interruptions 
and/or reductions are not permitted and the patients will be withdrawn from the study. 
6.5.2
Follow-up for toxicities
Not applicable.
6.6
Additional treatment guidance
6.6.1
Treatment compliance
The Investigator must promote compliance by instructing the subject to take the study treatment 
exactly as prescribed and by stating that compliance is necessary for the subject's safety and the 
validity of the study. The subject must also be instructed to contact the Investigator if he/she is 
unable, for any reason, to take the study treatment as prescribed.
Compliance will be assessed by the Investigator and/or study personnel at each visit using pill 
counts and information provided by the subject. This information should be captured in the 
source document at each visit. All study treatment dispensed and returned must be recorded in 
the Drug Accountability Log.
All doses of study drug taken at the clinic visits must be from the newly assigned medication 
bottles, except at the end of treatment (EOT) visit when the medication returned by the 
patient should be used.
6.6.2
Emergency breaking of assigned treatment code
Emergency code breaks must only be undertaken when it is required to in order to treat the 
subject safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study subject who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
Investigator contacts the system to break a treatment code for a subject, he/she must provide 
the requested subject identifying information and confirm the necessity to break the treatment 
code for the subject. The Investigator will then receive details of the investigational drug 
treatment for the specified subject and a fax or email confirming this information. The system 
will automatically inform the Novartis monitor for the site and the study team that the code has 
been broken.
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

name

subject number
In addition, oral and written information to the subject must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that unblinding 


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can be performed at any time. Following any emergency breaking of the blind, the subject will 
be withdrawn from the study.
6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section.
Investigator staff will identify the study medication kits to dispense to the subject by contacting 
the IRT and obtaining the medication number(s). The study medication has a 2-part label (base 
plus tear-off label), immediately before dispensing the medication kit to the subject, site 
personnel will detach the outer part of the label from the packaging and affix it to the source 
document.
6.7.1
Handling of study treatment and additional treatment
6.7.1.1
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 CPO Quality 
Assurance.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the patient except for the medication number.
The Investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Patients/subjects will 
be asked to return all unused study treatment and packaging at the end of the study or at the 
time of discontinuation of study treatment.
At the conclusion of the study, and as appropriate during the course of the study, the Investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the Investigator 
folder at each site.
6.7.1.2
Handling of additional treatment
The following non-study treatment has to be monitored specifically:

Mometasone furoate 200 µg used as SoC

SABA (such as salbutamol 100 µg)
The non-investigational treatment must be received by a designated person at the study site, 
handled and stored safely and properly, and kept in a secured location to which only the 
Investigator and designees have access. Clinical supplies are to be dispensed only in accordance 
with the protocol.


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The Investigator must maintain an accurate record of the shipment and dispensing of the non-
investigational 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 non-study treatments and packaging at the end of the 
study or at the time of discontinuation from the study.
6.7.2
Instruction for prescribing and taking study treatment
Study treatment will be double-blind, double-dummy, and placebo-controlled during the 
treatment period. QAW039 will be supplied as tablets. Since the tablets for QAW039 150 mg 
and QAW039 450 mg are not identical, treatment will be double-dummy and patients will take 
2 tablets of study medication (one tablet of blinded QAW039 at 150 mg dosage strength to be 
given together with one tablet blinded placebo to QAW039 450 mg or one tablet of blinded 
QAW039 at 450 mg dosage strength to be given together with one tablet blinded placebo to 
QAW039 150 mg or one tablet blinded placebo to QAW039 150 mg and one tablet blinded 
placebo to QAW039 450 mg) once daily as described below.
During the Run-in period, all patients will start treatment with mometasone furoate 200 µg daily, 
administered as 2 50 µg into each nostril, in the morning. Patients will continue to use their 
standard asthma therapy, as needed.
If a patient experiences an asthma exacerbation during the Run-in period, the patient is 
considered Run-in failure and can be re-screened only once 6 weeks have passed after full 
recovery from the exacerbation.
At the Randomization Visit (Treatment Day 1) patients will be randomized to receive one of 
the three study treatments:

QAW039 150 mg once daily

QAW039 450 mg once daily

placebo once daily
The treatment period will continue for a period of 16-weeks and patients will continue to take 
the mometasone furoate SoC in addition to the study treatments, during the treatment period. 
The investigational treatment will be dispensed in medication packs (bottles) at each clinic visit 
during the treatment epoch with enough medication supplied to cover the period between patient 
visits and to allow for late visits and other unforeseen events. All dosages prescribed and 
dispensed to the patient must be recorded in the appropriate section of the CRF.
At clinic visits, patients will receive a witnessed dose of study medication. These in-clinic 
witnessed doses will be given after the completion of all pre-dose assessments (see Section 8) 
and should be given at approximately the same time at each clinic visit. Between clinic visits, 
patients will take study medication once daily in the morning. Patients will be instructed to take 
their study medication at approximately the same time each morning.
All kits of study treatment assigned by the IRT will be recorded in the IRT system.
The Investigator must promote compliance by instructing the patient to take the study treatment 
exactly as prescribed and by stating that compliance is necessary for the patient’s safety and the 
validity of the study. The patient must also be instructed to contact the Investigator if he/she is 
unable for any reason to take the study treatment as prescribed.


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7
Informed consent procedures
Eligible patients/subjects may only be included in the study after providing signed (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. In 
cases where the patient’s representative gives consent, the patient must be informed about the 
study to the extent possible given his/her understanding. If the patient is capable of doing so, 
he/she must indicate assent by personally signing and dating the informed consent document or 
a separate assent form. Informed consent must be obtained before conducting any study-specific 
procedures (e.g. all of the procedures described in the protocol). The process of obtaining 
informed consent must be documented in the patient source documents.
Novartis will provide to Investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guideline and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
Investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC approval.
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirement for the duration of 
the study. If there is any question that the patient will not reliably comply, they must not be 
entered in the study.
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the subject 
informed consent and should be discussed with the subject during the study as needed. Any new 
information regarding the safety profile of the investigational drug that is identified between IB 
updates will be communicated as appropriate, for example, via an Investigator notification or 
an aggregate safety finding. New information might require an update to the informed consent 
and then must be discussed with the subject.
Subjects might be asked to complete an optional questionnaire to provide feedback on their 
clinical trial experience.
8
Visit schedule and assessments
Assessment schedule lists all of the assessments and indicates with an “X” or an "S", the visits 
when they are performed. All data obtained from these assessments must be supported in the 
patient’s source documentation with those events marked by an "X" being captured in the 
CRF/Clinical Database and those marked with an "S" will be captured in source documentation 
only.
Patients should be seen for all visits/assessments as outlined in the assessment schedule or as 
close to the designated day/time as possible. Missed or rescheduled visits should not lead to 
automatic discontinuation. Patients who prematurely discontinue the study for any reason 
should be scheduled for a visit as soon as possible, at which time all of the assessments listed 
for the final visit will be performed. At this final visit, all dispensed investigational product 
should be reconciled, and the adverse event and concomitant medications recorded on the CRF.


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Table 8-1
Assessment Schedule
Period
Screening
Treatment
Visit Name
Screening
Run-in1
Treatment
EOT or 
TD
Follow-up
Days
-42 to -28
-28 to -1
1
1
28
56
84
112
124
Weeks
-6 to -4
-4 to -1
1
1
4
8
12
16
18
Informed consent
X
Inclusion / Exclusion criteria
X
X
X
Demography
X
Physical Examination
S
S
Medical history/current medical 
conditions
X
Surgeries and Procedures
X
Prior medications
X
Safety Follow up Call
S
ACQ-5
X
Vital Signs
X
X
X
X
X
X
X
Body Height
X
Electrocardiogram (ECG)
X
X
X
Body Weight
X
Pregnancy Test (serum)
X
Pregnancy Test (Urine)
S
S
S
S
S
Hematology
X
X
X
X
HbA1C
X
X
Clinical Chemistry
X
X
X
X
Urinalysis
X
X
Check IMP Compliance
S
S
S
S
Contact IRT (IVRS/IWRS)
S
S
S
S
S
S
S
S
Randomization
S


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Period
Screening
Treatment
Visit Name
Screening
Run-in1
Treatment
EOT or 
TD
Follow-up
Days
-42 to -28
-28 to -1
1
1
28
56
84
112
124
Weeks
-6 to -4
-4 to -1
1
1
4
8
12
16
18
Study Drug Dispensation
S
S
S
S
Study drug administration
Daily
SoC/Rescue Medication Dispense
S
S
S
S
S
S
Adverse Events
X
X
X
X
X
X
X
X
Serious Adverse Events
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
Liver Event Monitoring2
X
X
X
X
X
X
X
X
X
Renal Event Monitoring3
X
X
X
X
X
X
X
X
X
Nasal Endoscopy4
X
X
X
X
Nasal Congestion Score 
Questionnaire
X
X
X
X
X
X
X
QoL Questionnaire (SNOT-22)
X
X
X
X
X
X
X
Smell Assessment (UPSIT)
X
X
X
X
X
X
X
Study completion information
X
X Assessment to be recorded in the clinical database or received electronically from a vendor
S Assessment to be recorded in the source documentation only
1 Assessments at Run-in Day 1 will be performed prior to Randomization. Run-in Day 1 and the Treatment Day 1 visit will take place on the same day if the patient is 
randomized
2 Please refer to protocol Section 10.2.1
3 Please refer to protocol Section 10.2.2
4 Nasal polyp score will be determined by central reading. 
5
 
6 For patient familiarization with device only. 


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8.1
Screening
Patients will be scheduled to attend for the screening visit within 14 days of the scheduled start 
of the Run-in period. It is permissible to re-screen a patient if he/she fails the initial screening; 
however, each case must be discussed and agreed with Novartis on a case-by-case basis.
8.1.1
Information to be collected on screening failures
Subjects who signed an informed consent form and subsequently found to be ineligible prior to 
randomization will be considered a screen failure. The reason for screen failure should be 
recorded on the appropriate Case Report Form. The demographic information, informed 
consent, and Inclusion/Exclusion pages must also be completed for screen failure subjects. No 
other data will be entered into the clinical database for subjects who are screen failures, unless 
the subject experienced a serious adverse event during the screening phase (see SAE Reporting 
Section, Section 10.1.3 for reporting details). If the subject fails to be randomized, the IRT must 
be notified within 2 days of the screen fail that the subject was not randomized.
Subjects who are randomized and fail to start treatment, e.g. subjects randomized in error, will 
be considered an early terminator. The reason for early termination should be recorded on the 
appropriate Case Report Form.
8.2
Subject demographics/other baseline characteristics
Patient demographic and baseline characteristic data to be collected on all patients include:

Date of birth (where allowed by local legislation)

Age (calculated)

Sex

Race and ethnicity

Patients initials (where allowed by local legislation)

Height and Weight

BMI (calculated)

Baseline physical examination (not databased other than in the context of relevant medical 
history)

Vital signs

Date of diagnosis of asthma

Relevant medical history/ current medical condition present before signing the informed 
consent

Asthma Control (ACQ-5)

Prior concomitant medication (Both asthma/NP related and non-asthma/NP related)
8.3
Efficacy
The following assessments of efficacy will be performed:

Nasal Polyp Score

Patient-reported Outcomes (NCS and SNOT-22)


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
Smell (UPSIT)
8.3.1
Nasal Polyp Score
The nasal polyp score is assessed four times during the study by nasal endoscopy. The initial 
assessment will be performed at screening to assess the patient’s eligibility on the study. 
Patients will be deemed eligible with a NPS ≥ 4 with a minimum score of at least 2 in one nostril, 
determined by central reading at screening and prior to randomization, using the following scale 
(Gevaert et al 2013):
Table 8-2
Nasal Polyp Scale
Polyp Score
Polyp Size
0
No polyps
1
Small polyps in the middle meatus not reaching below the inferior border of the 
middle turbinate
2
Polyps reaching below the lower border of the middle turbinate
3
Large polyps reaching the lower border of the inferior turbinate or polyps medial to 
the middle turbinate
4
Large polyps causing complete obstruction of the inferior nasal cavity
NPS will be re-assessed at Treatment Day 1 to both re-confirm eligibility for the study but also 
for a baseline measurement. The central reading result must be received for the baseline 
assessment, prior to randomization. At the 8 and 16-week treatment visits, NPS will again be 
re-assessed for efficacy. The readings from the endoscopies performed will be uploaded for 
central reading for NPS determination.
The nasal endoscopy may be performed on a different day from the other study procedures as 
long as this is performed within approximately 5 days of the original scheduled visit.
Note that the nasal endoscopy procedure should not be performed within 3 days of any 
concomitant use of oral or nasal decongestants.
8.3.2
Patient Reported Outcomes
A patient reported outcome (PRO) is any report of the status of a patient’s health condition that 
comes directly from the patient, without interpretation of the patient’s response by a clinician 
or anyone else. Patient reported outcomes may provide quantitative information for patients 
regarding the ‘impact on daily life’, which is of key importance, for patients and their physicians 
and also for health technology assessments. In this study, two PROs are used to assess the 
improvement in symptoms (nasal congestion score) and quality of life (SNOT-22). All PROs 
should be completed prior to any other assessments (especially the nasal endoscopy) to avoid 
any influence on the responses.
8.3.2.1
Symptoms (Nasal Congestion Score)
The nasal congestion score is assessed via a questionnaire where the patients are asked "Is your 
nose blocked?" with responses ranging from 0 = not at all, to 3=severe. The test is performed 
within the clinic at the visits outlined in Table 8-1 on a tablet computer and the questionnaire is 
outlined in Section 16.4.


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8.3.2.2
Quality of Life (SNOT-22)
For this study, the SNOT-22 questionnaire (listed in Section 16.5) will be used to assess any 
improvement in the patients quality of life. The questionnaire consists of 22 questions relating 
to various quality of life indicators and answers are scored from 0 (no problem) to 5 (problem 
as bad as it can be) with questions relating to the patients experience in the previous 2 weeks.
The test will be self-administered by the patient via a tablet computer at the clinic visits outlined 
in Table 8-1 and takes only a few minutes to complete. The final outcome is a total score from 
0 to 110.
8.3.3
Smell (UPSIT)
For this study, any change in the patients sense of smell will be assessed using the University 
of Pennsylvania Smell Identification Test. The test comprises of a kit which will be supplied to 
sites. The test includes 4 workbooks, each of which contains 10 microencapsulated (scratch and 
sniff) odors with forced choice responses accompanying each test item. The sites will also be 
supplied with the relevant instruction manual and scoring key.
The test is administered at the clinic visits and usually takes 10-15 minutes to complete. The 
result is a score out of 40 and this will be captured within the Clinical Database by the site 
personnel.
8.3.4
Appropriateness of efficacy assessments
The efficacy assessments outlined above are deemed to be sufficient for the objectives of the 
study.
8.4
Safety
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed.
For details on AE collection and reporting, refer to AE section.
Table 8-3
Physical Assessments
Assessment
Specification
Physical 
examination
A complete physical examination will include the examination of general appearance, 
skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, 
lymph nodes, extremities, vascular, and neurological. If indicated based on medical 
history and/or symptoms, rectal, external genitalia, breast, and pelvic exams will be 
performed.
Information for all physical examinations must be included in the source documentation at 
the study site. Clinically relevant findings that are present prior to signing informed 
consent must be recorded on the appropriate CRF that captures medical history. 
Significant findings made after first administration of investigational drug which meet the 
definition of an Adverse Event must be recorded as an adverse event.


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Assessment
Specification
Vital signs
Vital signs include blood pressure and pulse measurements. After the subject has been 
sitting for five minutes, with back supported and both feet placed on the floor, systolic and 
diastolic blood pressure will be measured three times using an automated validated 
device, e.g. OMRON, with an appropriately sized cuff. The repeat sitting measurements 
will be made at 1 - 2 minute intervals and the mean of the three measurements will be 
used. In case the cuff sizes available are not large enough for the subject's arm 
circumference, a sphygmomanometer with an appropriately sized cuff may be used.
Height and 
weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg) in indoor 
clothing, but without shoes) will be measured.
8.4.1
Laboratory evaluations
Samples for safety will be collected as per the assessment schedule in Table 8-1 . A central 
laboratory will be used for analysis of all specimens detailed in this section. Details on the 
collections, shipment of samples and reporting of results by the central laboratory are provided 
to Investigators in the laboratory manual.
Details on clinically notable laboratory findings are defined in Section 16.1 .
Table 8-4
Laboratory Assessments
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, MCH, MCHC, MCV, Platelets, Red blood cells, White blood 
cells, Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, 
Other).
Clinical Chemistry
Albumin, Alkaline phosphatase, ALT , AST , Gamma-glutamyl-transferase (GGT),
Lactate dehydrogenase (LDH), Calcium, Magnesium, Phosphorus, Chloride, Sodium, 
Potassium, Creatinine, Creatine kinase, CK-MB and Troponin I (in response to CK 
results outside of the normal range), HbA1c (collected at Screening visit and EOT 
only), Direct Bilirubin, Total Bilirubin, Total Cholesterol, Total Protein, Triglycerides, 
Blood Urea Nitrogen (BUN) or Urea, Uric Acid, Amylase, Lipase, Glucose.
Urinalysis
Microscopic Panel (Red Blood Cells, White Blood Cells, Casts, Crystals, Bacteria, 
Epithelial cells) - if required.
Macroscopic Panel (Dipstick) (Color, Bilirubin, Blood, Glucose, Ketones, Leukocytes 
esterase, Nitrite, pH, Protein, Specific Gravity, Urobilinogen)
Urine chemistry and microscopic examination of the urine will be performed by the 
central laboratory as delineated in Section 10.2.2 "Renal Safety Monitoring" 
and Section 16.3 "Specific Renal Alert Criteria and Actions and Event Follow-up"
Coagulation
International normalized ratio (INR), activated partial thromboplastin time (APTT)
Pregnancy Test
Serum / Urine pregnancy test
8.4.2
Electrocardiogram (ECG)
ECGs will be measured according to the assessment schedule in Table 8-1. ECGs must be 
recorded after 10 minutes rest in the supine position to ensure a stable baseline. The preferred 
sequence of cardiovascular data collection during study visits is ECG collection first, followed 
by vital signs. The Fridericia QT correction formula (QTcF) should be used for clinical 
decisions.
Single 12-lead ECGs will be collected using the sites own ECG machines and key parameters 
and the original trace available within the source data.


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For any ECGs with subject safety concerns, two additional ECGs must be performed to confirm 
the safety finding. A monitoring or review process should be in place for clinically significant 
ECG findings throughout the study and especially at baseline before administration of study 
treatment. Clinically significant abnormalities must be recorded on the CRF as either medical 
history/current medical conditions or adverse events as appropriate.
Any identifier details must be redacted e.g subject initials, date of birth.
8.4.3
Pregnancy
All pre-menopausal women who are not surgically sterile will have serum/urine pregnancy 
testing. Additional pregnancy testing might be performed if requested by local requirements.
8.4.4
Appropriateness of safety measurements
The safety assessments selected are standard for this indication/patient population.
8.5
Additional assessments
8.5.1
Clinical Outcome Assessments (COAs)
COAs are utilised on this study for assessment of study eligibility and also as part of the 
secondary study objectives. Those COAs related to the study objectives and efficacy are 
documented in protocol Section 8.3.2.
The remaining COAs used on this study are documented as follows.
8.5.1.1
Asthma Control Questionnaire (ACQ-5)
In this study the ACQ-5 will be used as Exclusion criterion at screening in order to identify 
those subjects who are currently symptomatic and who may exacerbate during the Run-in or 
treatment periods.
The ACQ-5 will be self-administered at the clinic during the screening visit and it 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 and therefore between 0 (totally controlled) and 6 (severely uncontrolled) 
(Juniper et al 1999; Juniper et al 2005) (Section 16.6).


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9
Study discontinuation and completion
9.1
Discontinuation
9.1.1
Discontinuation of study treatment
Discontinuation of study treatment for a patient occurs when study drug is stopped earlier than 
the protocol planned duration, and can be initiated by either the patient or the Investigator.
The Investigator must discontinue study treatment for a given patient if, on balance, he/she 
believes that continuation would negatively impact the risk/benefit of trial participation.
Study treatment must be discontinued under the following circumstances:

Withdrawal of informed consent (and the Investigator must prematurely withdraw the 
patient from the study);

Pregnancy;

Female subjects non-compliant with the chosen effective method of contraception during 
the study: The Investigator must provide appropriate advice on the continued use of 
effective contraception for at least one week (at least 5 half-lives of QAW039) after study 
drug discontinuation and follow up with the subject as appropriate at least to the end of 
this period;

Any protocol deviation that results in a significant risk to the patient’s safety;

Liver laboratory test abnormality / event (see Section 16.2 ): 

Abnormal liver laboratory results requiring discontinuation – refer 
to Table 16-1 - Section 16.2 ;

If the Investigator considers it appropriate after the confirmation of a liver safety 
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
ALT or AST ≥ 5xULN, or

ALT or AST ≥ 2.5xULN and total bilirubin (TBL) ≥ 1.5xULN ( Section 16.2 );

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 treatment for a patient for any reason; please refer 
to Section 6.6.2 ;

Total white blood cell count < 1000 cells/µL;

Patient requires SCS/OCS use for a period of more than 5 consecutive days during the 
study. Any OCS/SCS use in addition to this allowed 5 days of treatment will result in 
withdrawal;

If patients on statin therapy complain of persistent muscle pain without any obvious cause
for greater than 3 days, accompanied by an increase in CK levels >10xULN or persistent 
intolerable muscle pain, regardless of the accompanying CK level;

If a patient undergoes nasal surgery, including but not limited to the following: treatment 
of nasal polyposis, septal deviation correction, turbinectomy, para-nasal sinus drainage, 
nasal plastic surgery, hypophysis tumor nasal approach.

If a patient develops a medical condition, that requires consistent use of prohibited 
treatment as per Section 6.2.2 or if patient exhibits a behavior of non-compliance 
regarding prohibited medication.
If discontinuation of study treatment occurs, the Investigator should make a reasonable effort 
to understand the primary reason for the subject’s premature discontinuation of study treatment 
and record this information.
Subjects who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see withdraw of informed consent section,). Where possible, they should return 
for the assessments indicated in the Assessment schedule ( Table 8-1 ).
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should to be collected at clinic visits or via telephone visits:

new/concomitant treatments including OCS use

adverse events/Serious Adverse Events
If they fail to return for these assessments for unknown reasons, every effort (e.g. telephone, e-
mail or letter) should be made to contact the subject/pre-designated contact as specified in the 
lost to follow-up section. This contact should preferably be done according to the study visit 
schedule.
If the patient cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the patient, or with a person pre-designated by the patient. This telephone 
contact should preferably be done according to the study visit schedule. The information 
already collected during the study including your samples will still be used according to 
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The Investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment.
9.1.2
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject:

Does not want to participate in the study anymore, and

Does not allow further collection of personal data
In this situation, the Investigator should make a reasonable effort (e.g. telephone, e-mail or letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table.
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject’s samples until their time of withdrawal) according to applicable 
law.
For US: All biological samples not yet analyzed at the time of withdrawal may still be used for 
further testing/analysis in accordance with the terms of this protocol and of the informed consent 
form.
For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to applicable 
legal requirements.
9.1.3
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the Investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A subject should not be considered as lost to follow-up until due 
diligence has been completed or until the end of the study.
9.1.4
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. In taking the decision to terminate, 
Novartis will always consider the patient welfare and safety. Should early termination be 
necessary, patients must be seen as soon as possible (provide instruction for contacting the 


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patient, when the patient should stop taking drug, when the patient should come for a final visit) 
and treated as a prematurely withdrawn patient. The Investigator may be informed of additional 
procedures to be followed in order to ensure that adequate consideration is given to the 
protection of the patient’s interests. The Investigator or sponsor depending on the local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial.
9.2
Study completion and post-study treatment
A patient will be considered to have completed the study when the patient has completed the 
last visit planned in the protocol. Study completion for a patient will occur after he/she has 
completed 16-weeks of treatment (through the follow-up visit) or they have prematurely 
withdrawn. Completion of the study will be when all randomized patients have completed 16 
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.
For all patients a safety follow-up visit should be conducted (e.g. by telephone) 14 days after 
last visit (Week 16). The information to be collected at this follow up visit includes adverse 
events, concomitant medications and SAEs.
When the patient has completed all scheduled study assessments or prematurely withdrawn 
from the study, the Investigator must contact the IRT to record the patient completion 
/discontinuation and complete applicable eCRF .
10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign (including abnormal laboratory findings), symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The Investigator has the responsibility for managing the safety of individual subject and 
identifying adverse events.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of adverse events must be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject during or between visits or through physical examination findings, laboratory test 
findings, or other assessments.


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Adverse events must be recorded under the signs, symptoms or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2):
1. the severity grade

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities
2. its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘not suspected’. The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single subject.
3. its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported.
4. whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met
5. action taken regarding with study treatment
6. its outcome i.e., its recovery status or whether it was fatal
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

Dose not changed

Dose Reduced/increased

Drug interrupted/withdrawn
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the subject.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms.
Adverse event monitoring should be continued for at least 14 days (or 5 half-lives or end of 
study visit, whichever is longer) following the last dose of study treatment
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator Brochure (IB).
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms

they are considered clinically significant

they require therapy
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 


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baseline or the previous visit, or values which are considered to be non-typical in subjects with 
the underlying disease. Alert ranges for laboratory and other test abnormalities are included in 
Section 16.1.
10.1.2
Serious adverse events
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the following 
criteria:

fatal

life-threatening
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines).

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:
1. routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition under study 
2. 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
3. social reasons and respite care in the absence of any deterioration in the subject’s general 
condition
4. treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life-threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant”. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines).
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred.


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10.1.3
SAE reporting
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days following the last administration of study 
treatment must be reported to Novartis safety within 24 hours of learning of its occurrence. 
Detailed instructions regarding the submission process and requirements are to be found in the 
Investigator folder provided to each site.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the Investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a Chief Medical Office and 
Patient Safety Department associate may urgently require further information from the 
Investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all Investigators involved in any study with the same study treatment 
that this SAE has been reported.
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries.
10.1.4
Pregnancy reporting
To ensure subject safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
Pregnancy should be recorded and reported by the Investigator to the Novartis Chief Medical 
Office and Patient Safety. Pregnancy follow-up should be recorded on the same form and should 
include an assessment of the possible relationship to the study treatment any pregnancy outcome. 
Any SAE experienced during pregnancy must be reported.
10.1.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.


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Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dose 
Administration Record 
(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
For more information on AE and SAE definition and reporting requirements, please see the, 
respective sections.
10.2
Additional Safety Monitoring
10.2.1
Liver safety monitoring
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study (irrespective of whether classified/reported as AE/SAE):

Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter

Liver events, which will require close observation, follow-up monitoring and contributing 
factors are recorded on the appropriate CRFs
Please refer to Table 16-1 - Appendix 2 in Section 16 for complete definitions of liver 
laboratory triggers and liver events.
Every liver event defined in Section 16.1- Appendix 2 should be followed up by the 
Investigator or designated personnel at the trial site, as summarized below. Additional details 
on actions required in case of liver events are outlined in Table 16-2 - Appendix 2. Repeat liver 
function test (LFT) to confirm elevation.

These liver chemistry repeats will be performed using the central laboratory. If results will 
not be available from the central laboratory, then the repeats can also be performed at a 
local laboratory to monitor the safety of the subject. If a liver event is subsequently 
reported, any local liver chemistry tests previously conducted that are associated with this 
event should have results recorded on the appropriate CRF.

If the initial elevation is confirmed, close observation of the subject will be initiated, 
including consideration of treatment interruption if deemed appropriate.


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
Discontinuation of the investigational drug (refer to the Discontinuation of study treatment 
section), if appropriate

Hospitalization of the subject if appropriate

Causality assessment of the liver event

Thorough follow-up of the liver event should include

These investigations can include based on Investigator’s discretion: serology tests, 
imaging and pathology assessments, hepatologist’s consultancy; obtaining more detailed 
history of symptoms and prior or concurrent diseases, history of concomitant drug use, 
exclusion of underlying liver disease
All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF
10.2.2
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.

Protein-creatinine ratio (PCR ) ≥1g/g or ≥100 mg/mmol.
Every renal laboratory trigger or renal event as defined in Table 16-3 - Appendix 3 should be 
followed up by the investigator or designated personnel at the trial site as summarized 
in Section 16 .
11
Data Collection and Database management
11.1
Data collection
Designated Investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to US CFR 21 Part 11 
requirements. Investigator site staff will not be given access to the electronic data capture (EDC) 
system until they have been trained. Automatic validation programs check for data 
discrepancies in the eCRFs, allow modification and/or verification of the entered data by the 
Investigator staff. The Investigator/designee is responsible for assuring that the data entered 
into the eCRF is complete, accurate and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered is complete and accurate.
After final database lock, the Investigator will receive copies of the subject data for archiving 
at the investigational site.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.


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11.2
Database management and quality control
Novartis personnel will review the data entered by investigational staff for completeness and 
accuracy. Electronic data queries stating the nature of the problem and requesting clarification 
will be created for discrepancies and missing values and sent to the investigational site via the 
EDC system. Designated Investigator site staff are required to respond promptly to queries and 
to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Randomization codes and data about all study treatment(s) dispensed to the subject and all 
dosage changes will be tracked using an Interactive Response Technology (IRT). The system 
will be supplied by a vendor, who will also manage the database. The data will be sent 
electronically to Novartis at specific timelines.
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of Novartis.
Laboratory samples will be processed by a central lab and the results will be provided 
electronically to Novartis.
The PROs will be recorded on site by patients on tablet computers and the database from the 
vendor will be provided electronically to Novartis. The videos of the nasal endoscopies will be 
provided to the vendor (either by upload to a cloud server or postage of encrypted USB drives) 
for central reading. Videos will be read by two independent reviewers to assign the nasal polyp 
score with a third adjudicating reader making the decision on NPS should the original two 
readers not agree during their assessment.
 
 
 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
available for data analysis. Any changes to the database after that time can only be made after 
written agreement by Novartis development management.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an Investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eCRFs) with the 
Investigators and their staff. During the study, Novartis employs several methods of ensuring 
protocol and GCP compliance and the quality/integrity of the sites’ data. The field monitor will 
visit the site to check the completeness of subject records, the accuracy of data capture / data 
entry, the adherence to the protocol and to Good Clinical Practice, the progress of enrollment, 
and to ensure that study treatment is being stored, dispensed, and accounted for according to 
specifications. Key study personnel must be available to assist the field monitor during these 


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visits. Continuous remote monitoring of each site’s data may be performed by a centralized 
Novartis CRA organization. Additionally, a central analytics organization may analyze data & 
identify risks & trends for site operational parameters, and provide reports to Novartis clinical 
teams to assist with trial oversight.
The Investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject’s file. The Investigator must also keep the original informed consent form signed by the 
subject (a signed copy is given to the subject).
The Investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
subjects will be disclosed.
12
Data analysis and statistical methods
The primary efficacy and safety analyses will be conducted at the time the trial ends. All data 
captured in the study up to the end of study will be analyzed and reported.
Any data analysis carried out independently by the Investigator should be submitted to Novartis 
before publication or presentation.
12.1
Analysis sets
The Full Analysis Set (FAS) will be comprised of all randomized patients who meet both of 
the following criteria: 

Received at least one dose of study treatment 

Have a baseline NPS score ≥ 4 as measured by the central reader. 
According to the intent to treat principle, subjects will be analyzed according to the treatment 
they have been assigned to at the randomization. However, if patients received study 
treatment without being randomized into the study they will be excluded from the FAS. 
The Safety Analysis Set (SAF) includes all subjects who received at least one dose of study 
treatment. Subjects will be analyzed according to the study treatment received, where treatment 
received is defined as the randomized/assigned treatment if the patient took at least one dose of 
that treatment or the first treatment received if the randomized/assigned treatment was never 
received.
The analysis of the primary objectives will be performed on the FAS. 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.


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12.2
Subject demographics and other baseline characteristics
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment group for the FAS.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation (SD), median, minimum, and maximum will be presented. For selected 
parameters, 25th and 75th percentiles will also be presented.
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term, by treatment group.
12.3
Treatments
The Safety Analysis Set will in general be used for the analyses of treatments. Categorical data 
will be summarized as frequencies and percentages. For continuous data, mean, standard 
deviation, median, 25th and 75th percentiles, minimum, and maximum will be presented.
The duration of exposure (expressed in weeks), the dose intensity (computed as the ratio of 
actual cumulative dose received and actual duration of exposure) and the relative dose intensity 
(computed as the ratio of dose intensity and planned dose intensity) will be summarized by 
means of descriptive statistics.
The number of patients with dose adjustments (reductions, interruption, or permanent 
discontinuation) and the corresponding reasons will be summarized for the study treatment. 
Compliance with study medication over the course of the entire study will be summarized as 
the percentage of days with study medication intake during the period from first intake to last 
intake.
All fevipiprant dosing data will be listed.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system in the Safety Analysis Set.
Concomitant nasal polyp related medications will be summarized by pre-defined category.
12.4
Analysis of the primary endpoint(s)
The primary aim of the study is to evaluate a change in nasal polyp size with fevipiprant (150 
mg or 450 mg once daily, separately) as compared to placebo. This will be evaluated by using 
the nasal polyp score (NPS) which is assessed by nasal endoscopy and determined by central 
reading. The total NPS is recorded as the sum of the right and left nostril scores with a range of 
0 to 8 . A decrease in the NPS is considered a favorable outcome.
The analysis of the primary endpoint will be conducted according to the intention to treat 
principle using FAS population.


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12.4.1
Definition of primary endpoint(s)
The primary endpoint for this study is the mean change in terms of reduction in polyp size as 
measured by the nasal polyp score (NPS) from baseline to week 16, for patients treated with 
fevipiprant (150 mg or 450 mg once daily, separately) as compared to placebo.
12.4.2
Statistical model, hypothesis, and method of analysis
The primary endpoint for this study is the efficacy in terms of change from baseline in the nasal 
polyp score of fevipiprant 450 mg plus SoC and fevipiprant 150 mg plus SoC over placebo plus 
SoC. The primary null hypotheses are:

H0 450 : the reduction in the polyp size at 16 weeks from the baseline as measured by the 
NPS in fevipiprant 450 mg QD plus the SoC is less than or equal to the reduction in the 
polyp size as measured by the NPS in placebo plus the SoC for the population.

H0 150: the reduction in the polyp size at 16 weeks from the baseline as measured by the 
NPS in fevipiprant 150 mg QD plus the SoC is less than or equal to the reduction in the 
polyp size as measured by the NPS in placebo plus the SoC for the population.
The primary alternative hypotheses are:

HA 450 : the reduction in the polyp size at 16 weeks from the baseline as measured by the 
NPS in fevipiprant 450 mg QD plus the SoC is greater than the reduction of the polyp size 
as measured by the NPS in placebo plus the SoC for the population

HA 150: the reduction in the polyp size at 16 weeks from the baseline as measured by the 
NPS in fevipiprant 150 mg QD plus the SoC is greater than the reduction of the polyp size 
as measured by the NPS in placebo plus the SoC for the population
Familywise Type I error rate control
The familywise type I error rate will be controlled at a 1-sided 2.5% level across the primary 
null hypothesis using graphical approach specified by Figure 12-1 (Bretz et al 2011). The 
Dunnett test will be used to test H0 450 and H0 150
Figure 12-1
Representation of Approach to Test Hypotheses


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Vertices with associated weights denote the individual null hypotheses and their local 
significance levels (initially the alpha is split 50%:50% across the primary null hypotheses 
regarding the two dose levels. Directed edges between the vertices specify how the local 
significance levels are propagated in case of significant results.
Statistical model for primary variable
The primary efficacy endpoint is mean change in nasal polyp score from baseline to Week 16.
Baseline NPS is defined as the last measurement performed before the first dose of study drug. 
The absolute change from baseline NPS values will be defined as the NPS at the timepoint 
minus the NPS at baseline.
The primary efficacy variable will be analyzed using a mixed model repeated measures 
(MMRM) approach (fevipiprant 450 mg plus SoC and fevipiprant 150 mg plus SoC). The model 
will include change from baseline to follow-up timepoints every 4 weeks through week 16 as 
response variables, fixed-effects factors for treatment, visit, treatment × visit interaction, nasal 
polyp score baseline value, and baseline × visit interaction. An unstructured correlation 
structure will be assumed for the repeated measures within patients. Parameters will be 
estimated using the restricted maximum likelihood method with the Newton- Raphson 
algorithm. The least square mean change in nasal polyp score from baseline to week 16 
alongside with 95% confidence interval and the P-value corresponding to the least square mean 
difference will be presented. The change in the least square mean will also be plotted against 
the visits to look at the general trend of the values across the visits.
The absolute change from baseline in NPS will be summarized by treatment arm and timepoint
12.4.3
Handling of missing values/censoring/discontinuations
Despite all attempts to ensure complete follow-up for all patients, some patients may not be 
followed for nasal polyp size for the whole planned study duration of 16 weeks. The primary 
analysis will be done using a Mixed Model Repeated Measures (MMRM) approach. Under the 
assumption that the missing values are missing at random (MAR), this provides asymptotically 
unbiased and consistent estimates of the treatment effects.
12.4.4
Sensitivity and Supportive analyses
Sensitivity Analysis 1: A responder analysis of patients achieving a reduction of at least 1 in 
the Nasal Polyp score would be performed using a logistic regression, including terms for 
treatment, visits and interaction between treatment and visit. 
Sensitivity Analysis 2: The primary efficacy endpoint will be evaluated using the MMRM 
approach after imputing the Nasal Polyp Scores following surgery, only for patients who are 
considered as study withdrawals due to undergoing surgical procedures, by using the last 
observation carried forward (LOCF) technique. All other missing values will be imputed under 
the MAR approach within the MMRM model.
Sensitivity Analysis 3: The primary efficacy endpoint will be evaluated using the MMRM 
approach after imputing the Nasal Polyp Scores following surgery only for patients who are 
considered as study withdrawals due to undergoing surgical procedures, by using the worst 


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observed score for that patient. All other missing values will be imputed under the MAR 
approach within the MMRM model.
12.5
Analysis of secondary endpoints
The secondary objectives include:
To evaluate the effect of symptoms as measured by the nasal congestion score with 
fevipiprant (150 mg or 450 mg once daily, separately) as compared to placebo, in terms of 
reduction in NCS from baseline to week 16.
Nasal congestion is defined as the objective restriction of the nasal cavity airflow caused by 
mucosal pathology and or by mucosal secretions when anatomical variations have been 
excluded. The nasal congestion score is calculated based on the responses from the patients in 
Question 1 from the nasal congestion questionnaire outlined in Section 16.4. The questionnaire 
has four questions relating to the symptoms of nasal obstruction with each question having four 
categories ranging from 0-3, where the scores relate to the degree of severity as follows:

0 = Not at all

1 = Mild

2 = Moderate

3 = Severe
The score however is calculated based on the response to the first question in the questionnaire.
The change in Nasal Congestion Score (NCS) will be analyzed using an MMRM model with 
visit, treatment, interaction between visit and treatment and the baseline average NCS as 
covariates. The least square mean change in Nasal Congestion Score from baseline to week 16 
alongside with 95% confidence interval and the P-value corresponding to the least square mean 
difference will be presented.
To evaluate the effect on quality of life as measured by the sino-nasal outcome test (SNOT-
22) with fevipiprant (150 mg or 450 mg once daily, separately) , compared to placebo, in 
terms of increase in QoL score from baseline to Week 16.
SNOT-22 measures the quality of life in patients facing nasal obstructions (Section 16.5). There 
are 22 items available on the questionnaire. Each item in the questionnaire are followed by five 
options to choose from:

0 = No problem

1 = Very Mild Problem

2 = Mild or slight Problem

3= Moderate problem

4 = Severe Problem

5 = Problem as bad as it can be.
The scores for each of the items are added to get a total out of 110, with 110 being the worst 
signifier of quality of life. Also the questionnaire has the option for the patient to select the five 
most important items affecting their health which are analyzed separately to give a rating across 
the patients The treatment group difference in terms of change from baseline at Week 16 in 


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SNOT-22 will be estimated using an MMRM model with change from baseline as the response 
variable, adjusted for visits (Week 4, 8, 12 and 16), treatment, interaction between visit and 
treatment and baseline SNOT-22.
The least square mean change in SNOT-22 Score from baseline to week 16 alongside with 95% 
confidence interval and the P-value corresponding to the least square mean difference will be 
presented.
To evaluate the effect on smell as measured by the university of Pennsylvania smell 
identification test (UPSIT) with fevipiprant (150 mg or 450 mg, once daily) ,compared to 
placebo, in terms of increase in smell score from baseline to Week 16.
The university of Pennsylvania smell identification test (UPSIT) is a test for smell identification 
to test an individuals olfactory response. The test is a measure of an individual's ability to detect 
odor. It consists of 4 workbooks of 10 questions, giving a total of 40 questions. On each page, 
there is a different "scratch and sniff" strip which are embedded with a microencapsulated 
odorant. There is also a four choice multiple choice question on each page. The scents are 
released using a pencil. After each scent is released, the patient smells the level and detects the 
odor from the four choices. There is an answer column on the back of the test booklet, and the 
test is scored out of 40 items. The score is compared to scores in a normative database from 
4000 normal individuals, this tells the level of absolute smell function. The score also indicates 
how the patient does in accordance to their age group and gender. The maximum score 
achievable on the scale is 40.
The treatment group difference in terms of change from baseline at Week 16 in UPSIT will be 
estimated using an MMRM model with change from baseline as the response variable, adjusted 
for visits (week 4, 8, 12 and 16), treatment, interaction between visit and treatment and baseline 
UPSIT. The least square mean change in UPSIT Score from baseline to week 16 alongside with 
95% confidence interval and the P-value corresponding to the least square mean difference will 
be presented.
To evaluate the general safety and tolerability of fevipiprant (150 mg and 450 mg, 
separately) as compared to placebo.
Safety and tolerability assessments were based on the incidence of adverse events and serious 
adverse events, as well as vital signs, clinical laboratory evaluation, and 12-lead 
electrocardiogram findings.
12.5.1
Safety Variables
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group. Safety summaries will be primarily based on on-treatment data with selected 
tables also presented for the all data after the first intake of study drug, while all databased 
safety data will be listed. The on-treatment period lasts from the date of first administration of 
study treatment to 30 days after the date of the last actual administration of any study treatment.
Adverse events
Adverse events starting on or after the time of first intake of study drug and until the 30 days 
after the last 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 first intake 


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of the study drug will be classified as a prior adverse event 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 and preferred,

overall by system organ class, preferred term and maximum severity,

suspected drug related 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.
Serious adverse events, non-serious adverse events, adverse events requiring dose adjustment 
or study-drug interruption adverse events requiring additional therapy during the on-treatment 
period will be summarized.
The adverse events of special interest (AESI) will be listed and summarized by treatment group.
Vital signs
All vital signs data will be listed by treatment group, On-treatment notable vital signs 
abnormalities will be summarized by treatment group.
12-lead ECG
The notable ECG abnormalities will be summarized for following ECG variables,QT interval, 
RR interval, PR interval, QRS duration, heart rate, and Friedericia’s QTc. 
Clinical laboratory evaluations
All laboratory data will be listed with abnormal values flagged.
All laboratory parameter values will be classified into one of the four mutually exclusive groups 
(low, normal, high, and low + high).
For selected laboratory parameters, the number and percentage of patients with newly occurring 
or worsening on-treatment laboratory abnormalities meeting the clinically notable will be 
summarized by laboratory parameter at any time-point over the treatment period, considering 
all post-baseline data from scheduled, unscheduled and premature discontinuation visits. 
Patients with any newly occurring or worsening on-treatment value meeting the clinically 
notable criteria will be counted under the applicable criteria.
12.7
Interim analyses
No formal interim analysis will be performed in this trial.


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12.8
Sample size calculation
12.8.1
Primary endpoint(s)
Based on clinical judgement a mean reduction of 1.5 in polyp score (as measured by the 
NPS) can be expected with fevipiprant (450 mg and 150 mg) and SoC as compared to Placebo 
and SoC. Considering this factor, the sample size was calculated under an 80% power and 1.25% 
one sided alpha for comparison of each of the two dose levels of fevipiprant and SoC with 
placebo and SoC. A 10% dropout rate is considered as appropriate with reference to prior 
studies (omalizumab study by Gevaert et al 2013 and dupilumab study by Bachert et al 2016). 
From prior literature standard deviation of 1.8 is considered as appropriate for the change of 
score from baseline at 16 weeks in Nasal Polyp Score.
The sample size calculation was performed using the software PASS 2008 using inequality tests 
using difference of two independent means with equal variance.
The randomization will be performed in a 1:1:1 ratio for the two separate doses level of 
fevipiprant (450 mg and 150 mg) and the placebo arm. Under these assumptions (effect size = 
1.5, equal SD = 1.8,power = 80% for each arm individually, one-sided alpha = 0.0125 and 
dropout = 10%), the total sample size yielded was 93 with 31 patients in each arm.
The sample size provides a power of 80% for each comparison but since we will be testing 
correlated hypothesis using a Dunnet's test, this is a lower bound on the power. The real power 
is expected to be higher if in at least one of the 2 dosages i.e. fevipiprant 150 mg or fevipiprant 
450 mg, the standardized effect size (in other words, keeping the assumption of an SD of 1.8 in 
each group) is equal to the clinically significant value of 1.5 and there is some treatment benefit 
in the other groups as well. However, if the effect size is equal to 1.5 in both of the groups, the 
power will be substantially higher i.e. around 93%
13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki.
13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the Investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures (e.g., 
advertisements) and any other written information to be provided to subjects. Prior to study 
start, the Investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to 
Novartis monitors, auditors, Novartis Quality Assurance representatives, designated agents of 
Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site 


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is requested by a regulatory authority, the Investigator must inform Novartis immediately that 
this request has been made.
13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defines as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.) .
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial Investigator 
meetings
13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures (SOPs) as well as applicable global/local GCP regulations and ICH 
Guidelines.
Audits of Investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes
14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an Investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the Investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
Investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented.


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14.1
Protocol Amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis health authorities where required, and the IRB/IEC prior to 
implementation.
Only amendments that are required for subject safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the Investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations.


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15
References
References are available upon request
Bachert C, Mannent L, Naclerio RM, et al (2016) Effect of Subcutaneous Dupilumab on 
Nasal Polyp Burden in Patients With Chronic Sinusitis and Nasal Polyposis: A Randomized 
Clinical Trial. JAMA p. 469-79.
Bretz F, Posch M, Glimm E, et al (2011) Graphical approaches for multiple comparison 
procedures using weighted Bonferroni, Simes, or parametric tests. Biom J p. 894-913.
Castro M, Mathur S, Hargreave F, et al (2011) Reslizumab for poorly controlled, eosinophilic 
asthma: a randomized, placebo-controlled study. Am. J. Respir. Crit. Care Med. p. 1125-32.
Castro M, Zangrilli J, Wechsler ME, et al (2015) Reslizumab for inadequately controlled 
asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-
blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med p. 355-66.
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. p. 2056-60.
Deng JW, Song IS, Shin HJ, et al (2008) The effect of SLCO1B1*15 on the disposition of 
pravastatin and pitavastatin is substrate dependent: the contribution of transporting activity 
changes by SLCO1B1*15. Pharmacogenet. Genomics p. 424-33.
Elsby R, Hilgendorf C, 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. Ther. p. 584-98.
Gevaert P, Calus L, Van Zele T, et al (2013) Omalizumab is effective in allergic and 
nonallergic patients with nasal polyps and asthma. J. Allergy Clin. Immunol. p. 110-6.e1.
Jacobson TA (2008) Toward "pain-free" statin prescribing: clinical algorithm for diagnosis 
and management of myalgia. Mayo Clin. Proc. p. 687-700.
Juniper EF, O'Byrne PM, Guyatt GH, et al. 1999. Development and validation of a 
questionnaire to measure asthma control. Eur. Respir. J.. 14(4):902-7.
Juniper EF, Svensson K, Mörk AC, et al (2005) Measurement properties and interpretation of 
three shortened versions of the asthma control questionnaire. Respir Med p. 553-8.
Kalliokoski A, Niemi M (2009) Impact of OATP transporters on pharmacokinetics. Br. J. 
Pharmacol. p. 693-705.
Larsen K The clinical relationship of nasal polyps to asthma. Allergy Asthma Proc p. 243-9.
Mjösberg JM, Trifari S, Crellin NK, et al (2011) Human IL-25- and IL-33-responsive type 2 
innate lymphoid cells are defined by expression of CRTH2 and CD161. Nat. Immunol. p. 
1055-62.
Newton JR, Ah-See KW (2008) A review of nasal polyposis. Ther Clin Risk Manag p. 507-
12.


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Noé 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. p. 1308-14.
Orlandi RR, Kingdom TT, Hwang PH, et al (2016) International Consensus Statement on 
Allergy and Rhinology: Rhinosinusitis. Int Forum Allergy Rhinol p. S22-209.
Pavord ID, Korn S, Howarth P, et al (2012) Mepolizumab for severe eosinophilic asthma 
(DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet p. 651-9.
Pérez-Novo CA, Holtappels G, Vinall SL, et al (2010) CRTH2 mediates the activation of 
human Th2 cells in response to PGD(2) released from IgE/anti-IgE treated nasal polyp tissue. 
Allergy p. 304-10.
 
Regan SL, Maggs JL, Hammond TG, et al (2010) Acyl glucuronides: the good, the bad and 
the ugly. Biopharm Drug Dispos p. 367-95.
Shaw JL, Ashoori F, Fakhri S, et al Increased percentage of mast cells within sinonasal 
mucosa of chronic rhinosinusitis with nasal polyp patients independent of atopy. Int Forum 
Allergy Rhinol p. 233-40.
Yamamoto M, Okano M, Fujiwara T, et al (2009) Expression and characterization of PGD2 
receptors in chronic rhinosinusitis: modulation of DP and CRTH2 by PGD2. Int. Arch. 
Allergy Immunol. p. 127-36.


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16
Appendices
16.1
Appendix 1: Clinically notable laboratory values and vital signs
The central laboratory will flag laboratory values falling outside of the normal ranges on the 
central laboratory reports. Investigators are responsible for reviewing these abnormal values for 
clinical significance, signing the laboratory reports to indicate their review, and reporting values 
considered clinically significant in the appropriate 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 Section 16.2 for specific liver event and laboratory test trigger definitions and follow-
up requirements. See Section 16.3 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 ECGs will be assessed locally at site and 
with assessment of clinical relevance and continuance of the patient being confirmed by the 
Investigator.


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


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Criteria
Actions required
Follow-up monitoring
> 3 × ULN accompanied by 
symptomsb

Discontinue the study treatment immediately

Hospitalize if clinically appropriate

Establish causality

Record the AE and contributing factors (e.g., 
conmeds, med hx, lab) in the appropriate CRF
ALT, AST, TBL, Alb, 
PT/INR, ALP and γGT 
until resolutionc
(frequency at Investigator 
discretion)
> 3 to ≤ 5 × ULN (patient is 
asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate close 
observation of the patient
Investigator discretion
Monitor LFT within 1 to 4 
weeks
ALP (isolated)
> 2 × ULN (in the absence 
of known bone pathology)

Repeat LFT within 48 hours

If elevation persists, establish causality

Record the AE and contributing factors (e.g., 
conmeds, med hx, lab) in the appropriate CRF
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit
TBL (isolated)
> 2 × ULN (in the absence 
of known Gilbert 
syndrome)

Repeat LFT within 48 hours

If elevation persists, discontinue the study drug 
immediately

Hospitalize if clinically appropriate

Establish causality

Record the AE and contributing factors (e.g., 
conmeds, med hx, lab) in the appropriate CRF
ALT, AST, TBL, Alb, 
PT/INR, ALP and 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

Record the AE and contributing factors (e.g., 
conmeds, med hx, lab) in the appropriate 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

Record the AE and contributing factors (e.g., 
conmeds, med hx, lab) in the appropriate CRF
Investigator discretion
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN b(General) 
malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia cResolution is defined as an 
outcome of one of the following: (1) return to baseline values, (2) stable values at three subsequent monitoring 
visits at least 2 weeks apart, (3) remain at elevated level after a maximum of 6 months, (4) liver transplantation, 
and (5) death.


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16.3
Appendix 3: Specific Renal Alert Criteria and Actions and Event 
Follow-up
Table 16-3
Specific Renal Alert Criteria and Actions
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.


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16.4
Appendix 4: Nasal Congestion Score Questionnaire
Figure 16-1
Nasal Congestion Score


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16.5
Appendix 5: SNOT-22 Questionnaire
Figure 16-2
SNOT-22 Questionnaire


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16.6
Appendix 6: ACQ-5 Questionnaire
Figure 16-3
Asthma Control Questionnaire - 5 - Page 1


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Figure 16-4
Asthma Control Questionnaire - 5 - Page 2


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16.7
Appendix 7: Nasal Endoscopy
Nasal Endoscope will be performed at the clinic using either a flexible fiber optic endoscope or 
a rigid endoscope. Polyps will be evaluated using the following scale:
Polyp Score
Polyp Size
0
No polyps
1
Small polyps in the middle meatus not reaching below the inferior border of the middle 
turbinate
2
Polyps reaching below the lower border of the middle turbinate
3
Large polyps reaching the lower border of the inferior turbinate or polyps medial to the middle
turbinate
4
Large polyps causing complete obstruction of the inferior nasal cavity
Note: Scoring system is used to evaluate polyp size in each nasal passage by means of video 
nasal endoscopy. Nasal polyp score is the sum of unilateral polyp scores for each nasal 
passage.The scoring is modified to accommodate patients who have had a middle turbinectomy, 
such that the polyp must reach the top of the inferior turbinate to be graded as Score 2.
If the patient has polyps between the middle turbinate and septum meaning that polyps are 
coming from posterior ethmoid cells, one point was added, but not if the polyp scale was already 
confirmed. The grade of polyps in each nasal cavity of all patients will be taken into account in 
the results.
A video of each endoscopy will be recorded and initially saved locally within the clinical site. 
For endoscopy procedures performed at screening, the initial assessment of eligibility will be 
performed locally by the Investigator with the video files then uploaded for assessment of the 
NPS and confirmation of eligibility by central reading. This should be confirmed before the 
patient enters the run-in period. The endoscopy will be assessed at the end of the run-in with 
baseline NPS assigned locally by the Investigator. Should the Investigator deem the patient 
eligible for randomization then the baseline video will be uploaded for central reading 
assessment. The final result from the central readers must be received to re-confirm eligibility, 
prior to randomization. Upon confirmation of eligibility, the endoscopy assessments from 
Treatment Day 1 onwards, will also be uploaded to the vendors cloud based system for central 
reading assessment of the NPS. Should this upload not be possible due to local restrictions or 
logistics, the endoscopy video will be posted to the vendor on an encrypted USB drive. The 
vendor will utilize two independent experts who will each review the video and assign a score 
for NPS for that patient at the specific timepoint. Should there not be an agreement between the 
two reviewers, a third review will act as adjudicator and will make the final decision on the 
NPS.
Full training on the use of the vendors cloud based system will be provided.

SAP_000.pdf: 
Clinical Development
QAW039/Fevipiprant
QAW039A2322 / NCT03681093
A multicenter, randomized, double-blind, parallel-group, 
placebo-controlled study of fevipiprant once daily plus 
standard-of-care (SoC) for assessment of the efficacy in 
reduction of nasal polyp size in patients with nasal 
polyposis and concomitant asthma 
Statistical Analysis Plan (SAP)
Author:
Trial Statistician, 
; 
Document type:
SAP Documentation
Document status:
Amendment 2
Release date:
20-07-2020
Number of pages:
333
Property of Novartis
For business use only


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SAP
CQAW039A2322
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
01-
03-
2019
Prior 
to 
DB 
lock
Creation of 
final 
version
N/A - First version
NA
20-
04-
2020
Prior 
to 
DB 
lock
Amendment 
1
A sensitivity analysis added for UPSIT 
instrument to exclude patients from few 
sites (Documented in DHP),because the 
site peronnelfilled up this questionnaire
by pencil instead pen. 
Section 2.7.1.3
20-
07-
2020
Prior 
to 
DB 
lock
Amendment 
2
Definition of full analysis set updated. 
Protocol deviation related to nasal 
endoscopy added.
Section 
2.2 
, 
Section  5.5
.


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SAP
CQAW039A2322
Table of contents
Table of contents .................................................................................................................3
List of abbreviations............................................................................................................5
1
Introduction .........................................................................................................................6
1.1
Study design.............................................................................................................6
1.2
Study objectives and endpoints ...............................................................................7
2
Statistical methods...............................................................................................................8
2.1
Data analysis general information ...........................................................................8
2.1.3    General definitions.......................................................................................9
2.1.3.1    Study drug.................................................................................................9
2.1.3.2    Date of first administration of study drug.................................................9
2.1.3.3    Date of last administration of Study Drug................................................9
2.1.3.4    Study Day .................................................................................................9
2.1.3.5    Time unit.................................................................................................10
2.1.3.6    Baseline...................................................................................................10
2.1.3.7   Post-baseline measurement......................................................................10
2.1.3.8    Change from baseline .............................................................................10
2.1.3.9    On-treatment assessment/event and observation periods .......................11
2.1.3.10    Visit remapping and assessment windows ...........................................11
2.1.3.11    Last contact date ...................................................................................11
2.2
Analysis sets ..........................................................................................................12
2.2.1
Subgroup of interest ..............................................................................12
2.3
Patient disposition, demographics and other baseline characteristics ...................12
2.3.1
Patient disposition.................................................................................12
2.3.2
Protocol Deviations...............................................................................13
2.3.3
Analysis sets..........................................................................................13
2.3.4
Demographics and baseline characteristics...........................................13
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................14
2.4.1
Study treatment / compliance................................................................14
2.4.2
Prior, concomitant and post therapies...................................................14
2.5
Analysis of the primary objective..........................................................................15
2.5.1
Primary endpoint...................................................................................15
2.5.2
Statistical hypothesis, model, and method of analysis..........................15
2.5.3
Handling of missing values/censoring/discontinuations.......................17
2.5.4
Supportive analyses...............................................................................17
2.6
Analysis of the key secondary objective ...............................................................17


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2.6.1
Key secondary endpoint........................................................................18
2.6.2
Statistical hypothesis, model, and method of analysis..........................18
2.6.3
Handling of missing values/censoring/discontinuations.......................18
2.7
Analysis of secondary efficacy objective(s)..........................................................18
2.7.1
Secondary endpoints .............................................................................18
2.7.2
Statistical hypothesis, model, and method of analysis..........................19
2.7.3
Handling of missing values/censoring/discontinuations.......................19
2.7.4
To evaluate the general safety and tolerability of fevipiprant (150 
mg and 450 mg, separately) as compared to placebo............................19
2.7.5
Adverse events (AEs)............................................................................20
2.7.6
Deaths....................................................................................................21
2.7.7
Laboratory data .....................................................................................21
2.8
Other safety data....................................................................................................22
2.9
Pharmacokinetic endpoints....................................................................................24
2.10
PD and PK/PD analyses.........................................................................................24
2.11
Patient-reported outcomes .....................................................................................25
2.12
Biomarkers.............................................................................................................25
25
2.14
Interim analysis......................................................................................................25
3
Sample size calculation .....................................................................................................25
4
Change to protocol specified analyses ..............................................................................25
5
Appendix ...........................................................................................................................26
5.1
Imputation rules.....................................................................................................26
5.1.1
AE date imputation ...............................................................................26
5.1.2
Concomitant medication date imputation .............................................27
5.2
AEs coding/grading ...............................................................................................29
5.3
Laboratory parameters derivations ........................................................................29
5.4
Statistical models...................................................................................................31
5.4.1
Primary analysis....................................................................................31
5.4.2
Key secondary analysis.........................................................................32
5.5
Rule of exclusion criteria of analysis sets..............................................................32
6
Reference...........................................................................................................................33


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List of abbreviations
AE
Adverse event
ATC
Anatomical Therapeutic Classification
AUC
Area Under the Curve
bid
bis in diem/twice a day
CM
Concomitant Medication
CSR
Clinical Study report
CTC
Common Toxicity Criteria
DMC
Data Monitoring Committee 
FAS
Full Analysis Set
eCRF
Electronic Case Report Form
IVR
Interactive Voice Response
IWR
Interactive Web Response
MedDRA
Medical Dictionary for Drug Regulatory Affairs
NPS
Nasal Polyp Score
NCI
National Cancer Institute
o.d.
Once Daily
OS
Overall Survival
PFS
Progression-Free Survival
PK
Pharmacokinetics
PPS
Per-Protocol Set
PRO
Patient-reported Outcomes
qd
Qua’que di’e / once a day
QoL
Quality of Life
RAP
Report and Analysis Process
SAP
SoC
Statistical Analysis Plan
Standard of Care
SOC
System Organ Class
TFLs
Tables, Figures, Listings
UPSIT
University of Pennsylvania Smell Identification Test
WHO
World Health Organization


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1
Introduction
The statistical analysis plan (SAP) describes all planned analyses for the Clinical Study Report 
(CSR) of study QAW039A2322, a phase IIIB, 16 week multicenter, randomized, double-blind, 
parallel-group, placebo-controlled study of fevipiprant once daily plus standard-of-care (SoC) 
for assessment of the efficacy in reduction of nasal polyp size in patients with nasal polyposis 
and concomitant asthma
The content of this SAP is based on the protocol of QAW039A2322 version v03.
The purpose of the statistical analysis plan is to describe the implementation of the statistical 
analysis planned in section 12 of the study protocol. Data will be analyzed by Novartis
according to the data analysis section 12 of the protocol which is available in Appendix16.1.1 
of the CSR. Important information is given in the following sections and the details will be 
provided, as applicable, in Appendix 16.1.9 of the CSR. 
1.1
Study design
This study uses a randomized, multicenter, double-blind, placebo-controlled, parallel-group 
study design to determine the ability of fevipiprant plus SoC compared to placebo plus SoC to  
reduce the size of Nasal Polyps in patients with asthma. 
The study will include a Screening period of 2 weeks to assess eligibility followed by run-in 
period of 4 weeks where the patients will utilize Mometasone Furoate spray (200µg once daily 
administered as two 50µg actuations into each nostril) for baseline assessments treatment. The 
patients would then enter a treatment period of 16 weeks (with visits held every months for 
study procedures) and a follow-up period of 2 weeks following the last dose of study drug to 
collect additional data for safety variables. 
The study will follow a 1:1:1 central randomization in each of the three arms (450 µg 
Fevipiprant+SoC , 150 µg Fevipiprant+SoC and Placebo)
The primary analysis will be performed after all patients have completed 16 weeks of study 
treatment or have discontinued early.


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CQAW039A2322
Approximately 93 patients will be enrolled into this study.
No formal interim analyses would be performed. 
1.2
Study objectives and endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

To compare the reduction in nasal polyps score 
(NPS, assessed by Nasal Endoscopy with 
central reading) after 16 weeks of treatment with 
fevipiprant + SoC (150mg or 450mg once daily, 
separately) versus placebo + SoC in patients 
with nasal polyps with a NPS ≥4.
,

Reduction (in terms of change from 
baseline to week 16) in the  Nasal Polyp 
Score, for fevipiprant (150mg or 450mg 
once daily, separately ) as compared to  
placebo
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To evaluate the effect on symptoms as 
measured by the Nasal Congestion Score (NCS) 
with fevipiprant (150mg or 450mg once daily), 
compared with placebo.

Reduction (in terms of change from 
baseline to week 16) in NCS for 
fevipiprant (150mg or 450mg once daily, 
separately) as compared to placebo. 

To evaluate the effect on Quality of Life as 
measured by the Sino-Nasal Outcome Test 
(SNOT 22) with fevipiprant (150mg or 450mg 
once daily), compared with placebo. 

Increase (in terms of change from 
baseline to week 16) in SNOT 22 for 
fevipiprant (150mg or 450mg once daily, 
separately) as compared to  placebo. 

To evaluate the effect on Smell as measured by 
the University of Pennsylvania Smell 
Identification Test (UPSIT) with fevipiprant 
(150mg or 450mg once daily), compared with 
placebo.

Increase (in terms of change from 
baseline to week 16) in UPSIT for 
fevipiprant (150mg or 450mg once daily, 
separately) as compared to placebo. 


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SAP
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
To evaluate the general safety and tolerability of 
fevipiprant (150 mg and 450 mg, separately) as 
compared to placebo.

Adverse events, ECG, vital signs and 
laboratory analysis following 16 weeks 
of treatment.
2
Statistical methods
This section contains information that will be used to draft CSR Section 9.7 on statistical 
analysis.
2.1
Data analysis general information
The final analysis will be performed by Novartis or a designated CRO. The most recent version 
of SAS and R software available in the statistical programming environment will be used for 
the analysis. There are no formal interim analysis to be performed. 
2.1.1   Data included in the analysis
The analysis cut off date is defined as the date of last patient last visit during the 2 week follow-
up period post the 16 weeks treatment period. The entire data collected up to the cut off date 
would be used under the scope of the analysis defined in the subsequent sections. All data with 
an assessment date or even start date (e.g. vital sign assessment date or start date of an adverse 
event ) prior to or on the cut off date will be included in the analysis. Any data collected beyond
the cut-off date will not be included in the analysis and will not be used for any derivations. 
All events with start date before or on the cut-off date and end date after the cut-off date will be 
reported as ‘continuing at the cut-off date’. The same rule will be applied to events starting 
before or on the cut-off date and not having documented end date. This approach applies, in 
particular, to adverse event and concomitant medication reports. For these events, the end date 
will not be imputed and therefore will not appear in the listings
2.1.2  General analysis conventions
Pooling of center: Unless specified otherwise, data from all study centers will be pooled for 
the analysis. Due to expected small size of centers, no center effect will be assessed. 
Qualitative data (e.g., gender, race, etc.) will be summarized by means of contingency tables
by treatment group; a missing category will be included as applicable. Percentages will be
calculated using the number of patients in the relevant population or subgroup as the
denominator.
Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate


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descriptive statistics (i.e. mean, standard deviation, median, minimum, and maximum) by
treatment group.
2.1.3    General definitions
2.1.3.1    Study drug
In this document, ‘study treatment’ or ‘study drug’ will be used to refer to investigational 
therapy assigned to a patient. Specifically, for this double-blind trial,study treatment refers to 
QAW039 150 mg, QAW039 450 mg or placebo as assigned to a patient at randomization.
2.1.3.2    Date of first administration of study drug
The ‘date of first administration of the study drug’ is derived as the first date when a non zero 
dose of study drug is administered as per the Dosage Administration (e)CRF. The date of first 
administration of study treatment will also be referred as start of study treatment.
2.1.3.3    Date of last administration of Study Drug
The ‘date of last administration of the study drug’ is derived as the last date when a non zero 
dose of study drug is administered as per the Dosage Administration (e)CRF.
2.1.3.4    Study Day
The study day, describes the day of the event or assessment date, relative to the reference start 
date.. The date of first administration of the study drug is defined as Day 1 and the day before 
the first administration of the study drug is defined as Day -1. 
Therefore, for a particular date, study day will be calculated as follows :
The date of the event (visit date, onset date of an event, assessment date etc.) − 
reference start date + 1 if event is on or after the reference start date;
The date of the event (visit date, onset date of an event, assessment date etc.) − 
reference start date if event precedes the reference start date.
The reference start date for safety assessments (e.g. adverse events, laboratory abnormality
occurrence, vital sign measurements, dose interruption etc.) is the start of study treatment.
The reference start date for all other, non-safety assessments (i.e., eDiary, patient reported 
outcomes (PRO)) is the date of randomization.
The study day will be displayed in the data listings. If an event starts before the reference start 
date, the study day displayed on the listing will be negative.


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2.1.3.5    Time unit
A month length is 30.4375 days (365.25/12). If duration is reported in months, duration in days 
will be divided by 30.4375.  
2.1.3.6    Baseline
For efficacy evaluations, the last non-missing assessment, including unscheduled assessments 
on or before the date of randomization is taken as “baseline” value or “baseline” assessment. In 
the context of baseline definition, the efficacy evaluations also include PRO and performance 
status.  
For safety evaluations, the last available assessment on or before the date of start of study 
treatment is taken as ‘‘baseline” assessment.
If patients have no value as defined above, the baseline result will be missing.

Vital signs include body temperature, pulse rate and systolic and diastolic blood pressures.
Baseline vital signs are defined as the last available assessment taken pre-dose on Day 1. 
If this assessment is missing or not confirmed to be pre-dose, the last value prior to the 
first dose will be used for baseline. Otherwise, the vital sign baseline will be set to missing 
without imputation. 
Baseline height and weight are defined as the last measurements taken prior to first dose 
of study treatment. Missing baseline values will not be imputed.  

Baseline electrocardiogram (ECG) is defined as the last scheduled assessment taken prior 
to the first dose of study drug on screening. If the value on screening is missing (or not 
confirmed to be pre-dose), then the last value prior to the first dose will be used for 
baseline. Otherwise, the ECG baseline will be set to missing without imputation. Missing 
ECG baseline values will not be imputed.

Laboratory data include hematology and biochemistry. Baseline hematology and 
biochemistry are defined as the last available assessment taken prior to first dose of study 
treatment on Day 1. If the pre-dose measurement on Day 1 is missing (or was not 
confirmed to be pre-dose), then the last value prior to the first dose will be used. 
Otherwise, the baseline laboratory data will be set to missing. Missing laboratory baseline 
values will not be imputed. 
2.1.3.7   Post-baseline measurement

Post baseline measurements are defined as those assessments after the start of study 
treatment.  
2.1.3.8    Change from baseline

When change from baseline is of interest, the following formula will be used for each 
scheduled visit and time-point where baseline and post-baseline values are both available:

Change from baseline = post-baseline value – baseline value; and


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
If baseline or post-baseline values are missing, then the change from baseline will be
missing.
2.1.3.9    On-treatment assessment/event and observation periods
The overall observation period will be divided into three mutually exclusive segments: 
1. pre-treatment period: from day of patient’s informed consent to the day before first 
administration of study treatment
2. on-treatment period: from date of first administration of study treatment to  date of last 
actual administration of any study treatment +1 day (including start and stop date)
3. post-treatment period: starting at day 1 after last administration of study treatment.
Safety summaries (tables, figures) include data from the pre-treatment period (to display the 
baseline status e.g. for ECG) and the on-treatment period. Data from the post-treatment period 
with the exception of deaths should not be included unless requested from Health Authorities 
or external committees.
In particular, summary tables for adverse events (AEs) will summarize only on-treatment events,
with a start date during the on-treatment period, the so-called treatment-emergent AEs.  
However, all safety data (including those from the post-treatment period) will be listed and 
those collected during the pre-treatment and post-treatment period are to be flagged.
2.1.3.10    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.
2.1.3.11    Last contact date
The maximum of the date of last visit, date of last epoch completion, date of withdrawal of 
consent would be the date of last contact for the patient participating in the study.
The last contact date is defined as the latest complete date from the above list or the cut-off date 
whichever comes first. The cut-off date will not be used for last contact date, unless the patient 
was seen or contacted on that date. No date post cut-off date will be used. Completely 


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imputed dates (e.g. the analysis cut-off date programmatically imputed to replace the missing
end date of a dose administration record) will not be used to derive the last contact date.
2.2
Analysis sets
The Screened Set (SCR) will consist of all patients who provided infirmed consent 
The Full Analysis Set (FAS) will be comprised of all randomized patients who meet both of
the following criteria:

Received at least one dose of study treatment

Have a baseline NPS score ≥ 4 as measured by the central reader.
According to the intent to treat principle, subjects will be analyzed according to the treatment
they have been assigned to at the randomization. However, if patients received study
treatment without being randomized into the study they will be excluded from the FAS.
The Safety Set (SAF) includes all subjects who received at least one dose of study treatment. 
Subjects will be analyzed according to the study treatment received, where treatment received 
is defined as the randomized/assigned treatment if the patient took at least one dose of that 
treatment or if the patient recieved more than one treatment, then the patient would be analyzed 
according to the randomized treatment. 
The analysis of the primary objectives will be performed on the FAS. 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.
2.2.1
Subgroup of interest
No subgroups are defined in this study.
2.3
Patient disposition, demographics and other baseline 
characteristics
2.3.1
Patient disposition
The following summaries will be provided overall and by treatment group: % based on the total 
number of FAS patients:

Number of screened patients 

Number (%) of patients who were randomized 

Number (%) of patients who were randomized but not treated.

Number (%) of patients who were treated

Number (%) of patients who discontinued the study treatment phase


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
Primary reason for study treatment phase discontinuation

Number (%) of patients who have discontinued the study 

Reasons for discontinuation from the study.
Patient randomization numbers whether they completed or discontinued from the study will be 
listed, with date of last dose and primary reson for discontinuation, including the unblinding 
date if applicable.
2.3.2
Protocol Deviations
The number of subjects with protocol deviations will be tabulated by category and deviation for 
the FAS. Protocol deviations will be listed with date and study day of occurence and deviation. 
2.3.3
Analysis sets
The number of subjects included in each analysis set will be tabulated . Reasons for exclusion 
from the analysis sets will be tabulated for FAS. Patient exclusion from analysis sets will be 
listed for all patients with reason for exclusion (including protocol deviations)
2.3.4
Demographics and baseline characteristics 
Demographics and baseline characteristics will be summarized by treatment group using the 
FAS set. Summaries would include age, gender, race, ethnicity , heigh, weight , BMI and 
baseline ACQ-5.  Continuous variables will be summarized using 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.
Derivation of BMI : 

BMI is calculated as : BMI (kg/m2) = weight (kg) /[Height(m) *Height (m)]
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 nasal polyposis 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.


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2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
Since the study has a double dummy design, each patient will be dispensed two bottles of study 
medication at the dispensing visits. Bottle 1 has study medication corresponding to 150 mg 
QAW039 or placebo and Bottle 2 has study medication corresponding to 450 mg QAW039 or 
placebo. Exposure and compliance will be presented on the SAF. Exposure will be presented 
for each treatment while compliance will be presented by treatment arm for each of the bottles 
separately. 
The SAF will be used for the analyses of treatments.Categorical variables will be summarized 
as frequencies and percentages. For continuous data , mean , standard deviation , median , 25th
and 75th percentiles, minimum and maximum will be presented. 
2.4.1.1       Duration of exposure
Duration of exposure to a study drug 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 (weeks) = (Date of last known dose of study drug – Date of first dose 
of study drug + 1)/7). 
In addition, the duration of exposure will be summarized as a categorical variable classified into 
≤ 4 weeks, > 4 – 8 weeks, > 8 – 12 weeks and > 12 weeks. 
Dose administration data will be listed for patients in the SAF.
Patients in the randomized set who received any wrong study medications will be listed. These 
patients will be identified using the information recorded on the DAR page of the eCRF. If there 
is a record with reason = dispensing error, then the pack number will be used to identify whether 
or not the patient received the wrong study drug.
The number of patients with dose adjustments (interruption, or permanent discontinuation) and 
the corresponding reasons will be summarized for the study treatment . 
2.4.1.2       Compliance
Compliance with study medication over the course of the entire study will be summarized 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 non-zero study 
treatment intake/(Day of last Treatment – Day1 +1).
Compliance will be categorized as <80% , 80-100%, >100% , and summarized by treatment 
arm for each of the pills separately based of the safety set. 
2.4.2
Prior, concomitant and post therapies
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 


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Chemical (ATC) classification system in the Safety Analysis Set. More than one ATC class per 
medication is possible and the medication will be reported under all applicable classes.
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” based on the start/end dates.
Prior: Any medication with a start date before Day 1.
Concomitant: Any medication with end date on or after Day 1 or ongoing at the end of trial or
missing end date and start date before the end of the Treatment Epoch.
Medications can be considered both prior and concomitant.
Concomitant nasal polyp related medications will be summarized 
All summaries will be by treatment group on the Safety Set.
2.5
Analysis of the primary objective
2.5.1
Primary endpoint
The primary analysis of this study will be conducted according to the intention to treat principle 
and will be based on the FAS.
The primary population considered here are patients with nasal polyps with a Nasal Polyp Score
(NPS) >4 (minimum of 2 per nostril) and a concommitant diagnosis of ashtma.
The primary aim of the study is to evaluate a change in nasal polyp size with fevipiprant 
(150 mg or 450 mg once daily, separately) as compared to placebo. This will be evaluated by 
using the NPS assessed by nasal endoscopy. The total NPS is recorded as the sum of the right 
and left nostril scores with a range of 0 to 8 . A decrease in the NPS is considered a favorable 
outcome.
The primary endpoint for this study is the mean change in terms of reduction in polyp size as 
measured by the nasal polyp score (NPS) from baseline to week 16, for patients treated with 
fevipiprant (150 mg or 450 mg once daily, separately) as compared to placebo.
2.5.2
Statistical hypothesis, model, and method of analysis
The primary null hypotheses are:

H0 450 : the reduction in the polyp size at 16 weeks from the baseline as measured by the
NPS in fevipiprant 450 mg QD plus the SoC is less than or equal to the reduction in the
polyp size as measured by the NPS in placebo plus the SoC for the population.

H0 150: the reduction in the polyp size at 16 weeks from the baseline as measured by the
NPS in fevipiprant 150 mg QD plus the SoC is less than or equal to the reduction in the
polyp size as measured by the NPS in placebo plus the SoC for the population.
The primary alternative hypotheses are:


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
HA 450 : the reduction in the polyp size at 16 weeks from the baseline as measured by the
NPS in fevipiprant 450 mg QD plus the SoC is greater than the reduction of the polyp 
size as measured by the NPS in placebo plus the SoC for the population

HA 150: the reduction in the polyp size at 16 weeks from the baseline as measured by the
NPS in fevipiprant 150 mg QD plus the SoC is greater than the reduction of the polyp 
size as measured by the NPS in placebo plus the SoC for the population
Familywise Type I error rate control
The familywise type I error rate will be controlled at a 1-sided 2.5% level across the primary 
null hypothesis using graphical approach specified by Figure 2-1 (Bretz et al 2011). The 
Dunnett test will be used to test H0 450 and H0 150
Figure 2-1 Representation of Approach to Test Hypothesis
Vertices with associated weights denote the individual null hypotheses and their local 
significance levels (initially the alpha is split 50%:50% across the primary null hypotheses 
regarding the two dose levels. Directed edges between the vertices specify how the local 
significance levels are propagated in case of significant results.
Statistical model for primary variable
The primary efficacy endpoint is mean change in nasal polyp score from baseline to Week 16. 
Baseline NPS is defined as the last measurement performed on or before the date of 
randomization. The absolute change from baseline NPS values will be defined as the NPS at 
the timepoint minus the NPS at baseline.
The primary efficacy variable will be analyzed using a mixed model repeated measures 
(MMRM) approach (fevipiprant 450 mg plus SoC and fevipiprant 150 mg plus SoC). The model 
will include change from baseline to follow-up timepoints every 8 weeks through week 16 as 
response variables, fixed-effects factors for treatment, visit, treatment × visit interaction, nasal 


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polyp score baseline value, and baseline × visit interaction. An unstructured correlation 
structure will be assumed for the repeated measures within patients. Parameters will be 
estimated using the restricted maximum likelihood method with the Newton- Raphson 
algorithm. The least square mean change in nasal polyp score from baseline to week 16 
alongside with 95% confidence interval and the P-value corresponding to the least square mean 
difference will be presented. The change in the least square mean will also be plotted by visit.
The change from baseline in NPS will be summarized by treatment arm and timepoint
2.5.3
Handling of missing values/censoring/discontinuations
Despite all attempts to ensure complete follow-up for all patients, some patients may not be 
followed for nasal polyp size for the whole planned study duration of 16 weeks. The primary 
analysis will be done using a Mixed Model Repeated Measures (MMRM) approach. Under the 
assumption that the missing values are missing at random (MAR), this provides asymptotically 
unbiased and consistent estimates of the treatment effects.
2.5.4
Supportive analyses
Sensitivity Analysis 1: A responder analysis of patients achieving a reduction of at least 1 in 
the Nasal Polyp score would be performed using a logistic regression, including covariates for 
treatment, visits and interaction between treatment and visit. 
If the data suggests a logistic regression model is not the most appropriate for a responder 
analysis (possible reasons may include majority of a particular response) we will use additional 
analysis methods such as Cochran Mantel Haeszel test for the relative proportion of responders 
in each treatment arm and check whether there is a significant difference among them.
Sensitivity Analysis 2: The primary efficacy endpoint will be evaluated using the MMRM 
approach after imputing the Nasal Polyp Scores following surgery, only for patients who are 
considered as study withdrawals due to undergoing surgical procedures, by using the last 
observation carried forward (LOCF) technique. All other missing values will be imputed under 
the MAR approach within the MMRM model.
Sensitivity Analysis 3: The primary efficacy endpoint will be evaluated using the MMRM 
approach after imputing the Nasal Polyp Scores following surgery only for patients who are 
considered as study withdrawals due to undergoing surgical procedures, by using the worst 
observed score for that patient. All other missing values will be imputed under the MAR 
approach within the MMRM model.
2.6
Analysis of the key secondary objective
There are no key secondary endpoints defined.


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2.6.1
Key secondary endpoint
2.6.2
Statistical hypothesis, model, and method of analysis
2.6.3
Handling of missing values/censoring/discontinuations
2.7
Analysis of secondary efficacy objective(s)
2.7.1
Secondary endpoints
2.7.1.1 To evaluate the effect of symptoms as measured by the 
nasalcongestion score with fevipiprant (150 mg or 450 mg once daily, 
separately) as compared to placebo, in terms of reduction in NCS from 
baseline to week 16.
Nasal congestion is defined as the objective restriction of the nasal cavity airflow caused by 
mucosal pathology and or by mucosal secretions when anatomical variations have been 
excluded. The nasal congestion score is calculated based on the responses from the patients in 
Question 1 from the nasal congestion questionnaire. The questionnaire has four questions 
relating to the symptoms of nasal obstruction with each question having four categories ranging 
from 0-3, where the scores relate to the degree of severity as follows:

0 = Not at all

1 = Mild

2 = Moderate

3=Severe
The score however is calculated based on the response to the first question in the questionnaire.
2.7.1.2
To evaluate the effect on quality of life as measured by the sino-nasal 
outcome test (SNOT- 22) with fevipiprant (150 mg or 450 mg once 
daily, separately) , compared to placebo, in terms of increase in QoL 
score from baseline to Week 16.
SNOT-22 measures the quality of life in patients facing nasal obstructions (Section 16.5). There 
are 22 items available on the questionnaire. Each item in the questionnaire are followed by five
options to choose from:

0 = No problem

1 = Very Mild Problem

2= Mild or slight problem

3= Moderate problem

4= Severe Problem

5 = Problem as bad as it can be.


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The scores for each of the items are added to get a total out of 110, with 110 being the worst 
signifier of quality of life. The treatment group difference in terms of change from baseline at 
Week 16 in
2.7.1.3 To evaluate the effect on smell as measured by the university of 
Pennsylvania smell identification test (UPSIT) with fevipiprant (150 mg 
or 450 mg, once daily) ,compared to placebo, in terms of increase in 
smell score from baseline to Week 16.
The university of Pennsylvania smell identification test (UPSIT) is a test for smell identification 
to test an individuals olfactory response. The test is a measure of an individual's ability to detect 
odor. It consists of 4 workbooks of 10 questions, giving a total of 40 questions. On each page, 
there is a different "scratch and sniff" strip which are embedded with a microencapsulated 
odorant. There is also a four choice multiple choice question on each page. The scents are 
released using a pencil. After each scent is released, the patient smells the level and detects the 
odor from the four choices. There is an answer column on the back of the test booklet, and the 
test is scored out of 40 items. The score also indicates how the patient does in accordance to 
their age group and gender. The maximum score achievable on the scale is 40.
A sensitivity analysis would be performed excluding the patients from the sites for whom the 
UPSIT instrument was completed with pencil. This information would be recorded in the Data 
Handling Plan document.
2.7.2
Statistical hypothesis, model, and method of analysis
The treatment group difference in terms of change from baseline at Week 16 in UPSIT, SNOT 
22 and Nasal Congestion Score  will be estimated using an MMRM model with change from 
baseline as the response variable, and will be analysed similarly to the primary endpoint with 
appropriate baseline measurement .The least square mean change in scores for each of the 
questionnaires from baseline to week 16 alongside with 95% confidence interval and the P-
value corresponding to the least square mean difference will be presented . 
2.7.3
Handling of missing values/censoring/discontinuations
Despite all attempts to ensure complete follow-up for all patients, some patients may not be 
followed for nasal polyp size for the whole planned study duration of 16 weeks. The primary 
analysis will be done using a Mixed Model Repeated Measures (MMRM) approach. Under 
the assumption that the missing values are missing at random (MAR), this provides 
asymptotically unbiased and consistent estimates of the treatment effects.Safety analyses
2.7.4
To evaluate the general safety and tolerability of fevipiprant (150 mg 
and 450 mg, separately) as compared to placebo.
Safety and tolerability assessments would be based on the incidence of adverse events and 
serious adverse events, as well as vital signs, clinical laboratory evaluation, and 12-lead 
electrocardiogram findings.


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For all safety analyses , the safety set will be used. All listings and tables will be presented by 
treatment group. Safety summaries will be primarily based on on-treatment data with selected 
tables also presented for all data after the first intake of study drug, while all databased safety 
data will be listed. The on-treatment period lasts from the date of first administration of study 
treatment to 1 day after the date of the last actual administration of any study treatment.
2.7.5
Adverse events (AEs)
.
Adverse events after informed consent including asthma exacerbations will be listed. 
Adverse events starting on or after the day of the first intake of study drug and until the day 
after the last intake of study drug will be classified as treatment emergent adverse events. 
Adverse events that started during the study after informed consent and before the day of thefirst 
intake of study drug will be classified as prior adverse events and not included in tabulations of 
treatment emergent adverse events.
The number and percentage of patients who reported 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

Serious adverse events
Unless otherwise specified, primary system organ classes will be sorted alphabetically and, 
within each primary system organ class, the preferred terms will be sorted in descending order 
of frequency in the QAW039 150 mg once daily and QAW039  450 mg once daily treatment 
group. If a patient reported more than one AE with the same preferred term, the AE will be 
counted only once. If a patient reported more than one AE within the same primary system 
organ class, the patient will be counted only once at the system organ class level. In addition, 
the most frequent AEs will be presented by preferred term in descending order of frequency in 
the QAW039 150 mg QAW039 450 mg once daily treatment group.
Serious adverse events will also be summarized.
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.
All adverse events and related preferred terms and system organ class will be categorised using 
latest MedDRA version avilable at the time of data analysis.
2.7.5.1
Adverse events of special interest / grouping of AEs
The number and percentage of patients and treatment emergent adverse events of special 
interest will be summarized for each type of event with a break-down for each type of event by 


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SMQ(when applicable) and preferrred term. The Compound Case Retrieval Strategy (CRS) will 
be used to determine the MeDRA search criteria to be used to identify events of special interest.
2.7.5.2
Adverse events reporting for safety disclosure
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 
treatment emergent serious adverse events and SAEs suspected to be related to study drug 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 drug 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 drug / 
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 drug and SAEs 
irrespective of study drug relationship will be provided by SOC and PT.
2.7.6
Deaths
A summary of deaths will be presented by primary system organ class, preferred term, and 
treatment groups regardless of study drug relationship. 
All the deaths in the clinical database incuding those occurring during screening will be listed, 
but only those between the first treatment and the last dose + 1 day will be included in summary 
tables. Additionally all deaths after first dose of study treatment will be tabulated by treatment 
group.
2.7.7
Laboratory data
Laboratory data consist of hematology and biochemistry measurements. Laboratory data 
measured after first intake of study drug and until the day after last intake of study drug are 
regarded as on-treatment data. Laboratory data measured more than 1 day after last intake of 
study drug are regarded as post-treatment data and will not be summarized. All data will be 
listed with abnormal values flagged.
2.7.7.1
Summary of change from baseline 
For continuous laboratory parameters, the on-treatment change from baseline to the worst post-
baseline values (including values from post-baseline unscheduled and premature 
discontinuation visits) will be summarized by laboratory parameter and treatment group with 
standard descriptive statistics.


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2.7.7.2
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 also have a worse post-baseline value. For patients 
with a missing baseline value, any post-baseline notable value will be considered as newly 
occurring. 
The criteria for clinically notable values are presented in Table 5.3.2.
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. 
Listings of patients with notable laboratory values will be provided by laboratory parameter, 
treatment group, and patient number.
Additionally, box plot of change from baseline will be presented over time for ALT, AST, 
ALT/AST ratio, total bilirubin, creatinine, albumin,. ACR value will be considered missing if 
either the albumin or the creatinine values are missing. Similarly, PCR will be considered 
missing if either the protein or the creatinine values are missing.
2.8
Other safety data
2.8.1       ECG and cardiac imaging data
ECG measurements include heart rate, QT interval, RR interval, PR interval, QRS duration, and 
Fridericia’s QTc (calculated as QTcF = QT / 3√RR (in seconds), where 3√denotes the cube 
root). 
ECG data measured more than 1 day 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.
Clinically relevant values


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
The number and percentage of patients with newly occurring or worsening clinical relevant 
QTcF values (see Table 2.8.1) summarized at any time on treatment considering all post-
baseline data from scheduled, unscheduled and premature discontinuation visits.
Table 2.8.1 Clinically relevant criteria for QTcF (Fridericia's formula)
ECG parameter (unit)
Clinically relevant range
Value considering newly occurring or worsening cases
QTcF (msec)
≥450 (male)
QTcF (msec)
≥460 (female)
QTcF (msec)
> 500 (both) 
Change from baseline
QTcF
< 30 
QTcF
30 – 60
QTcF
> 60
Clinically notable values

A summary table will also be produced for number and percentage of subjects with 
notable QT and QTcF intervals (irrespective of the time point) using the following 
categories:
a. any treatment emergent (new) QTcF or QT interval ≥450 ms – 480 ms, > 480 ms –
500 ms or > 500 ms
b. QTcF or QT increase from baseline of ≥ 30 ms –  < 60 ms, ≥ 60 ms
c. QTcF and QT increase from baseline of ≥ 30 ms plus QTcF interval ≥450 ms, > 480 
ms or > 500 ms
d. QTcF increase from baseline of ≥ 60 ms plus QTcF interval ≥450 ms, > 480 ms or > 
500 ms

The number and percentage of subjects with noteworthy PR, QRS and HR interval 
changes will be reported using the below categories:
a. New PR > 200 ms to <= 220 ms; and > 220 ms 
b. New QRS > 110 ms to <= 120 ms; and > 120 ms
c. PR increase > 25% to a value > 200 ms 
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
2.8.2   Vital signs
Vital signs measurements include systolic and diastolic blood pressure (SBP and DBP), pulse 
rate, temperature, height and body weight. Vital signs data taken on or after the time of the first 
intake of study treatment and until the day after the last intake of study drug are regarded as on-
treatment data. Vital signs data measured more than 1 day after last intake of study drug are 


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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:

the number and percentage of patients with newly occurring or worsening notable vital signs 
on-treatment values (see Table 2.8.2 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 at the baseline and the 
week 16 visits : 
1. Pulse rate:  < 40 bpm, 40 – 90 bpm, and > 90 bpm
2. Systolic blood pressure: < 90 mm Hg, 90 – 140 mm Hg, and > 140 mm Hg
3. Diastolic blood pressure: < 50 mm Hg, 50 – 90 mm Hg, and > 90 mm Hg.
The same approach as for notable laboratory values will be used to define a newly occurring 
notable vital sign value and a worsening notable vital sign value.
A listing of all patients with notable vital sign values and changes will be provided. 
Table 2.8.2
Clinical notable criteria for vital signs 
Vital sign parameter (unit)
Lower bound of clinically 
notable range
Upper bound of clinically 
notable range
Notable values
Systolic blood pressure (mmHg)
< 75
> 200
Diastolic blood pressure (mmHg)
< 40
> 115
Pulse rate (bpm)
< 40
> 130
Notable change from baseline
Systolic blood pressure (mmHg)
≤ 90 and decrease from 
baseline by ≥ 20 
≥ 180 and increase from 
baseline by ≥ 20
Diastolic blood pressure (mmHg)
≤ 50 and decrease from 
baseline by ≥ 15
≥ 105 and increase from 
baseline by ≥ 15
Pulse rate (bpm)
≤ 50 and decrease from 
baseline by ≥ 15
≥ 120 and increase from 
baseline by ≥ 15
Weight (kg)
Decrease ≥ 7% from 
baseline
Increase ≥ 7% from 
baseline
2.9
Pharmacokinetic endpoints
Not Applicable
2.10
PD and PK/PD analyses
Not Applicable.


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2.11
Patient-reported outcomes
Nasal Congestion Score, SNOT 22 and UPSIT are the Patient reported outcomes questionnaires 
that we would be collecting in this study. Endpoints related to these questionnaires and analysis 
method described in section 2.7.1.
2.12
Biomarkers
Not Applicable 
2.14
Interim analysis
No interim analysis is planned.
3
Sample size calculation
Based on clinical judgement a mean reduction of 1.5 in polyp score (as measured by the NPS) 
can be expected with fevipiprant (450 mg and 150 mg) and SoC as compared to Placebo and 
SoC. Considering this factor, the sample size was calculated under an 80% power and 1.25% 
one sided alpha for comparison of each of the two dose levels of fevipiprant and SoC with 
placebo and SoC. A 10% dropout rate is considered as appropriate with reference to prior 
studies (omalizumab study by Gevaert et al 2013 and dupilumab study by Bachert et al 2016). 
From prior literature standard deviation of 1.8 is considered as appropriate for the change of 
score from baseline at 16 weeks in Nasal Polyp Score.
The sample size calculation was performed using the software PASS 2008 using inequality tests 
using difference of two independent means with equal variance. 
The randomization will be performed in a 1:1:1 ratio for the two separate doses level of 
fevipiprant (450 mg and 150 mg) and the placebo arm. Under these assumptions (effect size = 
1.5, equal SD = 1.8,power = 80% for each arm individually, one-sided alpha = 0.0125 and 
dropout = 10%), the total sample size yielded was 93 with 31 patients in each arm. The sample 
size provides a power of 80% for each comparison but since we will be testing correlated 
hypothesis using a Dunnet's test, this is a lower bound on the power. The real power is expected 
to be higher if in at least one of the 2 dosages i.e. fevipiprant 150 mg or fevipiprant 450 mg, the 
standardized effect size (in other words, keeping the assumption of an SD of 1.8 in each group) 
is equal to the clinically significant value of 1.5 and there is some treatment benefit in the other 
groups as well. However, if the effect size is equal to 1.5 in both of the groups, the power will 
be substantially higher i.e. around 93%.
4
Change to protocol specified analyses
Not Applicable 


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5
Appendix
5.1
Imputation rules
5.1.1
AE date imputation
Rules for imputing AE end dates are stated below. Date of last contact in the study has been 
defined as in Section 2.1.3.11. 
1.If the AE end date month is missing, the imputed end date should be set to the earliest of the 
(date of last contact, 31DECYYYY, date of death).
2. If the AE end date day is missing, the imputed end date should be set to the earliest of the      
(date of last contact, last day of the month, date of death).
3. If AE year is missing or AE is ongoing, the end date will not be imputed.
5.1.1.1
AE start date imputation
Rules for imputing the AE start date:
The following table explains the notation used in the logic matrix. Please note that missing 
start dates will not be imputed.
Day
Month
Year
Partial Adverse Event 
Start Date
Not Used
MON
YYYY
Treatment Start Date
Not Used
TRTM
TRTY
The following matrix explains the logic behind the imputation.
MON
MISSING
MON < TRTM
MON = TRTM
MON > TRTM
YYYY
MISSING
(1)
No Convention
(1)
No Convention
(1)
No Convention
(1)
No Convention
YYYY < TRTY
(2.a)
Before Treatment 
Start
(2.b)
Before Treatment 
Start
(2.b)
Before Treatment 
Start
(2.b)
Before Treatment 
Start
YYYY = TRTY
(4.a)
Uncertain
(4.b)
Before Treatment 
Start
(4.c)
Uncertain
(4.c)
After Treatment 
Start
YYYY > TRTY
(3.a)
After Treatment 
Start
(3.b)
After Treatment 
Start
(3.b)
After Treatment 
Start
(3.b)
After Treatment 
Start


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Before imputing AE start date, find the AE start reference date.
1. If the imputed AE end date is complete and the imputed AE end date < treatment start date 
then AE start reference date = min(informed consent date, earliest visit date).
2. Else AE start reference date = treatment start date
Impute AE start date -
1. If the AE start date year value is missing, the date uncertainty is too high to impute a 
rational     date. Therefore, if the AE year value is missing, the imputed AE start date is 
set to NULL.
2. If the AE start date year value is less than the treatment start date year value, the AE 
started before treatment. Therefore:
a.
If AE month is missing, the imputed AE start date is set to the mid-year point 
(01JulYYYY).
b.   Else if AE month is not missing, the imputed AE start date is set to the mid-
month point (15MONYYYY).
3. If the AE start date year value is greater than the treatment start date year value, the AE 
started after treatment. Therefore:
a.
If the AE month is missing, the imputed AE start date is set to the year start 
point (01JanYYYY).
b. Else if the AE month is not missing, the imputed AE start date is set to the 
later of (month start point (01MONYYYY), AE start reference date + 1 day).
4.   If the AE start date year value is equal to the treatment start date year value:
a. And the AE month is missing the imputed AE start date is set to the AE reference start    
date + 1 day.
b. Else if the AE month is less than the treatment start month, the imputed AE start date is 
set to the mid-month point (15MONYYYY).
c. Else if the AE month is equal to the treatment start date month or greater than the 
treatment start date month, the imputed AE start date is set to the later of (month start point 
(01MONYYYY), AE start reference date + 1 day).
If complete imputed AE end date is available and the imputed AE start date is greater than 
the imputed AE end date, then imputed AE start date should be set to the imputed AE end 
date.
5.1.2
Concomitant medication date imputation
5.1.2.1
Concomitant medication end date imputation
Rules for imputing the CM end date are stated below. Date of last contact in the study has been
defined as in Section 2.1.3.10. Concomitant medication end dates will not be imputed for 
ongoing records.


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1. If CM end day is missing and CM month/year are non-missing then impute CM day as 
the minimum of date of last contact and the last day of the month.
2. If CM end day/month are missing and CM year is non-missing then impute CM day as 
the minimum of date of last contact and the end of the year (31DECYYYY).
3. If CM day/month/year is missing then use the date of last contact + 1 day as the imputed 
CM end date.
4. If imputed CM end date is less than the CM start date, use the CM start date as the 
imputed CM end date.
5.1.2.2
Concomitant medication start date imputation
Rules for imputing the CM start date:
The following table explains the notation used in the logic matrix. Please note that missing 
start dates will not be imputed.
Day
Month
Year
Partial CMD Start Date
Not Used
MON
YYYY
Treatment Start Date
Not Used
TRTM
TRTY
The follwoing matrix explains the logic behind the imputation.
MON
MISSING
MON < TRTM
MON = TRTM
MON > TRTM
YYYY
MISSING
(1)
Uncertain
(1)
Uncertain
(1)
Uncertain
(1)
Uncertain
YYYY < TRTY
(2.a)
Before Treatment 
Start
(2.b)
Before Treatment 
Start
(2.b)
Before Treatment 
Start
(2.b)
Before Treatment 
Start
YYYY = TRTY
(4.a)
Uncertain
(4.b)
Before Treatment 
Start
(4.a)
Uncertain
(4.c)
After Treatment 
Start
YYYY > TRTY
(3.a)
After Treatment 
Start
(3.b)
After Treatment 
Start
(3.b)
After Treatment 
Start
(3.b)
After Treatment 
Start
1. If the CM start date year value is missing, the imputed CM start date is set to one day
prior to treatment start date.
2. If the CM start date year value is less than the treatment start date year value, the CM
started before treatment. Therefore:
a.
If the CM month is missing, the imputed CM start date is set to the mid-year point 
(01JulYYYY).


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b. Else if the CM month is not missing, the imputed CM start date is set to the 
midmonth point (15MONYYYY).
3. If the CM start date year value is greater than the treatment start date year value, the CM 
started after treatment. Therefore:
a.
If the CM month is missing, the imputed CM start date is set to the year start point 
(01JanYYYY).
b. Else if the CM month is not missing, the imputed CM start date is set to the month 
start point (01MONYYYY).
      4. If the CM start date year value is equal to the treatment start date year value:
a.
And the CM month is missing or the CM month is equal to the treatment start date 
month, then the imputed CM start date is set to one day prior treatment start date.
b. Else if the CM month is less than the treatment start date month, the imputed CM 
start date is set to the mid-month point (15MONYYYY).
c.
Else if the CM month is greater than the treatment start date month, the imputed CM 
start date is set to the month start point (01MONYYYY).
If complete imputed CM end date is available and the imputed CM start date is greater than the 
(imputed) CM end date, then imputed CM start date should be set to the (imputed) CM end date.
5.2
AEs coding/grading
The MedDRA version which will be available at the time of database lock, will be used for the 
coding purpose of the adverse events. 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.
5.3
Laboratory parameters derivations
The following table shows the criteria for clinically notable laboratory values. Not all 
parameters have notable criteria defined.


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Table 5.3.1
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 5.3.2
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 12-17
     Male 18-65
     Male >=66
     Female 12-65
     Female >=66
0.34
0.37
0.34
0.32
0.31


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Laboratory parameter (unit)
Bound for notably low
values
Bound for notably high 
values
Hemoglobin (g/L)
    Male 12-17
    Male >=18
    Female
100
110
95
Thrombocytes (x10E9/L
75 
700
WBC’s (x109/L)
2.8
16.0
Chemistry
Alkaline Phosphatase (IU/L)
-
3xULN
Total Bilirubin (µmol/L)
-
34.2
Creatinine (µmol/L)
176.8
Potassium (mmol/L)
3
6
Glucose (mmol/L)
2.78
9.99
ALT/SGPT (U/L)
-
3 x ULN
AST/SGOT (U/L)
-
3 x ULN
BUN/ Urea (mmol/L)
9.99
Sodium (mmol/L)
125
160
Gamma GT (U/L)
3 x ULN
CPK (IU/L)
4 x ULN
5.4
Statistical models
5.4.1
Primary analysis
The primary endpoint for this study is the efficacy in terms of change from baseline in the nasal 
polyp score of fevipiprant 450 mg plus SoC and fevipiprant 150 mg plus SoC over placebo plus 
SoC. 
The following mixed model with repeated measures will be used for changes from baseline in 
the Nasal Polyp Score :
Change from baseline = intercept + treatment + visit + treatment * visit + NPS baseline value 
+ NPS baseline value * visit + error
The random effect in the mixed model will be represented by the use of an unstructured 
covariance matrix for the within patient variability. 
The SAS procedure MIXED will be used with the follwing code :
proc mixed data=...order=internal;
  **include schedule assessments/visits only;
  where avisitn in (201,208,216);
  class trt avisitn;
  model chg= trt avisitn trt*avisitn base base*avisitn /ddfm=kr;
  repeated avisitn/subject=usubjid type=un;
  lsmeans trt*avisitn/ cl diff;


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  adjust=DUNNET;
  run; 
where chg          = change from baseline
           trt            = treatment (QAW 450 mg + SoC , QAW 150 mg +SoC , Placebo+SoC)
           avisitn     = visit ( include scheduled visit and assesments only) 
           base         = baseline Nasal Polyp Score 
          usubjid    = unique subject identifier 
Appropriate baseline values and visits will be included for each of the endpoints i.e. Nasal 
Congestion Score, SNOT-22 score and the UPSIT smell test score.
The default estimation method for the covariance parameters will be used, which is the 
restricted maximum likelyhood.
Results will be presented with least square means and standard errors (SE) for treatment effects 
and least square mean, SE, associated two sided 95% confidence interval , a two sided p-value 
for treatment contrast QAW-Placebo at each visit. 
If the analysis fails to converge with an unstructured covariance matrix, either a compound 
symmetry (first choice) or the first order auto regressive (AR1) (second choice) covariance 
structure will be used. 
5.4.2
Key secondary analysis
There are no key secondary endpoints for this study. 
5.5
Rule of exclusion criteria of analysis sets 
The following protocol deviations will lead to exclusion of patients from FAS, SCR or 
safety set :
PD Identifier
‘PD
Description’ 
for 
reporting
CP_Exclude from analysis 
sets
INCL01A
Did  not sign informed 
consent 
Exclude from all analysis sets 
INCL01B
Written informed consent 
obtained after date of a study 
assessment 
All concerned assessments 
removed from SCR
TRT01
Received study drug but not 
randomized 
Exclude from FAS and SAF 
(also evaluate on a case by 
case basis)
TRT02
Randomized but no study 
drug given
Patient did not recieve a 
study drug; then exclude 


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from 
FAS 
and 
SAF; 
otherwise do not exclude 
from any population set 
EXCL19
History of sinus or nasal 
surgery 
modifying 
the 
structure if the nose such that 
assessment of NPS via nasal 
endoscopy is not possible.
Exclude from all analysis sets
INCL02B
No current diagnosis of nasal 
polyposis
Exclude from all analysis sets 
INCL02C
Diagnosis of nasal polyposis 
with polyp size score is less 
than 4 and a less than 2 score 
in each nostril, measured by 
nasal endoscopy at SCR and 
prior to randomization on 
Treatment Day 1.
Exclude from Full analysis 
set.
6
Reference
Bachert et al .(2016) Effect of Subcutaneous Dupilumab on Nasal Poly Burden in Patients With 
Chronic Sinusitis and Nasal Polyposis. A Randomized Clinical Trial . Journal of the American 
Medical Association ; Volume 315, Number 5 : 469-479 
Bretz F, Maurer W, Brannath W et al. (2009) A graphical approach to sequentially rejective 
multiple test procedure. Statistics in Medicine; 28(4) : 586-604
Bretz F, Tamhane A , Dmitrienko A , Multiple Testing Problems in Pharmaceutical Statistics 
(2010)  : CRC Press
Gaveart et al (2011) Mepolizumab, a humanized anti- IL-5 mAb, as a treatment option for 
severe nasal polyposis . Journal of Allergy and Clinical Immunology ; Volume 128 , Number 
5 : 989-995
Niloofar Ramezani , Analyzing Corelated Data in SAS® , Paper 1251-2017 , SAS Institute Inc.