Conditions: Asthma
Keywords: Asthma Bronchial Diseases Respiratory Tract Diseases Lung Diseases Obstructive Lung Diseases Respiratory Hypersensitivity Hypersensitivity Immune System Diseases Fevipiprant QAW039
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 604
Healthy volunteers: no

Brief summary:
The overall purpose of this study was to determine the efficacy of fevipiprant (150 mg and 450 mg once daily), compared with placebo, as add-on to standard-of-care asthma therapy, in terms of avoidance of corticosteroid use over 52 weeks.

Detailed description:
This was a randomized, multicenter, double-blind, double-dummy, placebo-controlled, parallel-group study to determine the ability of fevipiprant (QAW039) plus standard-of-care (SoC) compared with placebo plus SoC to reduce the use of systemic corticosteroids (SCS) in patients with severe asthma. The study included:

* a Screening period of up to 2 weeks to assess eligibility;
* a Run-in period of 4 or 10 weeks to evaluate maintenance of asthma control and to collect baseline safety data. The Run-in period was 4 weeks for patients coming with high-dose ICS/LABA (inhaled corticosteroids/long-acting beta-agonist) and 10 weeks for patients switching from mid-dose to high-dose ICS/LABA as per protocol during the run-in period;
* a Treatment period of 52 weeks. Upon completion of the Run-in period, all patients who met eligibility criteria were randomized to 1 of 3 treatment groups (fevipiprant 150 mg or 450 mg or placebo once daily) in a ratio 1:1:1. Randomized patients were stratified according to their peripheral blood eosinophil count (\< 250 cells/μl or ≥ 250 cells/μl);
* a Follow-up period of 2 weeks following the last dose of study drug to collect additional data for safety variables.

The main purpose of this study was to determine the efficacy of fevipiprant (150 mg and 450 mg once daily), compared with placebo, as add-on to GINA (Global Initiative for Asthma) treatment step 4 or 5 SoC asthma therapy in terms of avoidance of SCS use over 52 weeks in patients with inadequately controlled severe asthma and high eosinophil counts (eosinophil count at Visit 1 ≥250 cells/ μl) and in the overall patient population regardless of eosinophil counts.

On 16-Dec-2019 the sponsor decided to terminate study CQAW039A2323 earlier than the planned study completion. There were no safety findings with fevipiprant that contributed to this decision. The planned treatment period of 52 weeks was not completed by any patient; patients were treated for a median time of 14 weeks in each group and a maximum of up to 36 weeks.

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

Interventions: intervention 1: Placebo once daily intervention 2: QAW039 150 mg once daily intervention 3: QAW039 450 mg once daily
Intervention descriptions: intervention 1: Placebo to QAW039 once daily (one tablet blinded placebo to QAW039 150 mg and one tablet blinded placebo to QAW039 450 mg). intervention 2: QAW039 150 mg once daily (one tablet of blinded QAW039 150 mg to be given together with one tablet blinded placebo to QAW039 450 mg) intervention 3: QAW039 450 mg once daily (one tablet of blinded QAW039 450 mg to be given together with one tablet blinded placebo to QAW039 150 mg)

Protocol document:
Prot_001.pdf: 
Global Clinical Development - General Medicine
QAW039
Clinical Trial Protocol CQAW039A2323 / NCT03629249
A 52-week, multicenter, randomized, double-blind, double-
dummy, parallel-group, placebo-controlled study of 
fevipiprant once daily plus standard-of-care (SoC) for 
reduction of systemic corticosteroids (oral and parenteral) 
use in patients with severe asthma
Document type:
Amended Protocol Version
EUDRACT number:
2018-000212-25
Version number:
01 (Clean)
Clinical Trial Phase:
IV
Release date:
05-Dec-2018
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Development 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.................................................................................................................9
Amendment 1 ....................................................................................................................10
Protocol summary..............................................................................................................11
1
Introduction .......................................................................................................................15
1.1
Background............................................................................................................15
1.2
Purpose ..................................................................................................................17
2
Study objectives and endpoints .........................................................................................18
2.1
Objectives and related endpoints...........................................................................18
3
Investigational plan ...........................................................................................................19
3.1
Study design...........................................................................................................19
3.2
Rationale for study design .....................................................................................20
3.3
Rationale for dose/regimen, route of administration and duration of treatment....20
3.4
Rationale for choice of comparator .......................................................................21
3.5
Purpose and timing of interim analyses/design adaptations..................................22
3.6
Risks and benefits..................................................................................................22
4
Population..........................................................................................................................23
4.1
Inclusion criteria ....................................................................................................23
4.2
Exclusion criteria...................................................................................................24
5
Treatment...........................................................................................................................27
5.1
Study treatment......................................................................................................27
5.1.1
Investigational and control drugs..........................................................27
5.1.2
Additional treatment..............................................................................28
5.2
Treatment arms......................................................................................................28
5.3
Treatment assignment and randomization.............................................................28
5.4
Treatment blinding.................................................................................................29
5.5
Treating the patient................................................................................................30
5.5.1
Patient numbering .................................................................................30
5.5.2
Dispensing the study drug.....................................................................30
5.5.3
Handling of study and additional treatment..........................................30
5.5.4
Instructions for prescribing and taking study treatment........................31
5.5.5
Permitted dose adjustments and interruptions of study treatment ........32
5.5.6
Rescue medication ................................................................................33


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5.5.7
Concomitant medication .......................................................................34
5.5.8
Prohibited medication ...........................................................................35
5.5.9
Emergency breaking of assigned treatment code..................................36
5.6
Study completion and discontinuation...................................................................37
5.6.1
Study completion and post-study treatment..........................................37
5.6.2
Discontinuation of study treatment .......................................................37
5.6.3
Withdrawal of informed consent...........................................................38
5.6.4
Loss to follow-up ..................................................................................39
5.6.5
Early study termination by the sponsor.................................................39
6
Visit schedule and assessments .........................................................................................39
6.1
Information to be collected on screening failures..................................................44
6.2
Patient demographics/other baseline characteristics .............................................44
6.3
Treatment exposure and compliance .....................................................................45
6.4
Efficacy..................................................................................................................45
6.4.1
Systemic corticosteroids use .................................................................45
6.4.2
Health status (Patient Reported Outcomes) ..........................................45
6.4.3
eDiary....................................................................................................46
6.4.4
Worsening of asthma (and related eDiary alerts)..................................48
6.4.5
Biologic therapy administered during the treatment period..................48
6.4.6
Appropriateness of efficacy assessments..............................................48
6.5
Safety.....................................................................................................................48
6.5.1
Medical history and physical examination............................................49
6.5.2
Asthma Exacerbations...........................................................................49
6.5.3
Vital signs..............................................................................................50
6.5.4
Height and weight .................................................................................50
6.5.5
Laboratory evaluations..........................................................................50
6.5.6
Electrocardiogram (ECG) .....................................................................51
6.5.7
Pregnancy..............................................................................................52
6.5.8
Appropriateness of safety assessments .................................................52
6.6
Other assessments..................................................................................................52
6.6.1
Clinical Outcome Assessments (COAs) ...............................................52
52
6.6.3
Pharmacokinetics ..................................................................................53
6.6.4
Spirometry.............................................................................................53
6.6.5
Other biomarkers...................................................................................53
7
Safety monitoring..............................................................................................................53
............................53


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7.2
Serious adverse events...........................................................................................55
7.2.1
Definition of SAE .................................................................................55
7.2.2
SAE reporting........................................................................................56
7.3
Liver safety monitoring .........................................................................................56
7.4
Renal safety monitoring.........................................................................................57
7.5
Reporting of study treatment errors including misuse/abuse ................................57
7.6
Pregnancy reporting...............................................................................................58
7.7
Prospective suicidality assessment ........................................................................58
8
Data review and database management.............................................................................58
8.1
Site monitoring ......................................................................................................58
8.2
Data collection.......................................................................................................59
8.3
Database management and quality control............................................................59
8.4
Data Monitoring Committee..................................................................................60
8.5
Adjudication Committee........................................................................................60
9
Data analysis......................................................................................................................60
9.1
Analysis sets ..........................................................................................................60
9.2
Patient demographics and other baseline characteristics.......................................61
9.3
Treatments .............................................................................................................61
9.4
Analysis of the primary variable(s) .......................................................................61
9.4.1
Primary Variable(s)...............................................................................61
9.4.2
Statistical model, hypothesis, and method of analysis..........................61
9.4.3
Handling of missing values/censoring/discontinuations.......................64
9.4.4
Sensitivity analyses ...............................................................................64
9.5
Analysis of secondary variables ............................................................................64
9.5.1
Efficacy variables..................................................................................64
9.5.2
Safety variables .....................................................................................66
67
9.5.4
Pharmacokinetics ..................................................................................67
9.5.5
DNA......................................................................................................67
9.5.6
Biomarkers............................................................................................67
9.5.7
PK/PD ...................................................................................................67
9.7
Interim analyses.....................................................................................................67
9.8
Sample size calculation..........................................................................................68
10 Ethical considerations........................................................................................................70
10.1
Regulatory and ethical compliance........................................................................70
............................70


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10.3
Responsibilities of the investigator and IRB/IEC..................................................71
10.4
Publication of study protocol and results...............................................................71
10.5
Quality Control and Quality Assurance.................................................................71
11 Protocol adherence ............................................................................................................71
11.1
Protocol Amendments ...........................................................................................72
12 References .........................................................................................................................73
13 Appendix 1: Clinically notable laboratory values and vital signs.....................................76
14 Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.....................................................................................................................76
15 Appendix 3: Specific Renal Alert Criteria and Actions....................................................79
16 Appendix 4: List of idiosyncratic drug reactions (IDRs) for investigators.......................80
17 Appendix 5: Spirometry Guidance....................................................................................81
17.1
References for appendix ........................................................................................82
18 Appendix 6: Asthma Control Questionnaire (ACQ-5)......................................................84
19 Appendix 7: Asthma Quality of Life Questionnaire for 12 years and older 
(AQLQ+12).......................................................................................................................86
20 Appendix 8: Asthma Plan..................................................................................................91
21 Appendix 9: Estimated Equivalence of Inhaled Corticosteroids.......................................92
List of tables
Table 2-1
Objectives and related endpoints ..........................................................18
Table 5-1
Blinding levels ......................................................................................29
Table 5-2
Medications allowed under certain conditions......................................34
Table 5-3
Medications to be withheld prior to spirometry....................................35
Table 5-4
Prohibited medication ...........................................................................35
Table 6-1
Assessment Schedule ............................................................................41
Table 6-2
Daytime symptom diary scale questions...............................................47
Table 6-3
Nocturnal diary scale question..............................................................47
Table 7-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................58
Table 9-1
Frequency distribution of dose to display (non-normal) distribution 
of US Marketscan database...................................................................68
Table 9-2
Other scenario investigated for Fevipiprant single dose EOS 
greater or equal 250 cells/microliter .....................................................69
Table 14-1
Liver Event and Laboratory Trigger Definitions ..................................76
Table 14-2
Follow Up Requirements for Liver Events and Laboratory Triggers...76
Table 15-1
Specific Renal Alert Criteria and Actions.............................................79
Table 16-1
Definition of potential idiosyncratic drug reactions..............................80


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List of figures
Figure 3-1
Study design..........................................................................................19
Figure 9-1
Closed testing procedure for primary objectives ..................................63


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List of abbreviations
ACQ-5
Asthma Control Questionnaire
ACR
albumin-creatinine ratio
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AQLQ
Asthma Quality of Life Questionnaire
AST
aspartate aminotransferase
ATS
American Thoracic Society
AV
atrioventricular
b.i.d.
twice a day
BMI
body mass index
BTPS
body temperature and pressure saturated
BTS
British Thoracic Society
BUN
blood urea nitrogen
CFR
Code of Federal Regulation
CK
creatinine kinase
CK-MB
creatine kinase-muscle/brain
CMO&PS
Chief Medical Office and Patient Safety
COA
clinical outcome assessments
CPO
Country Pharma Organization
CRA
Clinical Research Associate
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CRTh2
chemoattractant receptor-homologous molecule expressed on T helper 2 cells
DMC
Data Monitoring Committee
DP2
Prostaglandin D2 receptor
DPI
dry-powder inhaler
EC
Ethics committee
ECG
Electrocardiogram
EDC
Electronic Data Capture
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EOS
eosinophil
EOT
End of Treatment
ERS
European Respiratory Society
EU
European Union
FAS
full analysis set
FEV1
Forced Expiratory Volume in 1 second
FVC
full volume capacity
GCP
Good Clinical Practice
GINA
Global Initiative for Asthma
HbA1c
Hemoglobin A1c
HCUP
Healthcare Cost and Utilization Project
HD
High Dose
HFA
Hydrofluoroalkanes 


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HRQOL
health related quality of life
i.v.
intravenous
ICH
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use
ICS
Inhaled corticosteroids
IEC
Independent Ethics Committee
IgE
Immunoglobulin E
IRB
Institutional Review Board
IRT
Interactive Response Technology
IVRS
Interactive voice response system
IWRS
Interactive web response system
LABA
Long-acting beta-agonist
LAMA
Long-acting muscarinic antagonist
LFT
Liver function test
LS
least square
LTRA
Leukotriene Receptor Antagonist
mcg
microgram
MedDRA
Medical dictionary for regulatory activities
mg
milligram(s)
OCS
Oral corticosteroids
p.o.
oral
PEF
peak expiratory flow
PGD2
Prostaglandin D2
QTc
corrected QT interval
RoW
Rest of World
SABA
Short-acting Beta-agonist
SAE
serious adverse event
sCR
serum creatinine
SCS
Systemic corticosteroids
SmPC
summary of product charateristics
SoC
Standard of Care
SOP
standard operating procedures
SUSAR
Suspected Unexpected Serious Adverse Reactions
TC
Telephone contact
TD
treatment discontinuation
TdP
Torsades de Pointes
Th2
T helper cells 2
UK
United Kingdom
ULN
upper limit of normal
US
United States of America
WHO
World Health Organization
µl
microliter


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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)
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 is synonymous with “investigational new drug” or 
“investigational medicinal product”.
Investigational 
treatment
All investigational drug(s) whose properties are being tested in the study as well as their 
associated treatment controls. This includes any placebos, any active controls, as well as 
approved drugs used outside of their indication/approved dosage or tested in a fixed 
combination. Investigational treatment generally does not include 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.
Period
A minor subdivision of the study timeline; divides phases into smaller functional segments 
such as screening, baseline, titration, washout, etc.
Personal Data
Subject information collected by the Investigator that is transferred to Novartis for the 
purpose of the clinical trial. This data includes subject identifier information, study 
information and biological samples.
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
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.
Subject
A trial participant (can be a healthy volunteer or a patient)
Subject number
A number assigned to each subject who enrolls in the study. When combined with the 
center number, a unique identifier is created for each subject in the study.
Variable
A measured value or assessed response that is determined in specific assessments and 
used in data analysis to evaluate the drug being tested in the study
Withdrawal of 
study consent
Withdrawal of consent from the study occurs only when a subject does not want to 
participate in the study any longer, and does not allow any further collection of personal 
data


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Amendment 1
Amendment rationale
This protocol is being amended based on health authority feedback. Based on this feedback the 
following changes have been implemented.

Modify in-clinic study visit frequencies to 8 weeks intervals after week 12, interspaced 
with telephone contacts.

Add additional collection of hematology, clinical chemistry and urinalysis in all in-clinic 
visits
In addition, clarifications has been included as well

correct abbreviations on the summary section

clarifications on treatment of patients after study end

misspells
Changes to the protocol
Updated visit schedule sequence between telephone contact (TC) and in-clinic visits. In-clinic 
visits (week 6, 12, 20, 28, 36, 44, 52) TC visits (week 16, 24, 32, 40, 48, 54)
Added additional hematology, clinical chemistry and urinalysis at all in-clinic visits on the visit 
schedule and assessments section 6
Corrected abbreviations in the summary section on the primary analysis portion.
Clarifications added on sections 5.5.6, 5.6.1 and table 6.1.


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Protocol summary
Protocol number
CQAW039A2323
Full Title
A 52-week, multicenter, randomized, double-blind, double-dummy, parallel-group, placebo-
controlled study of fevipiprant once daily plus standard-of-care (SoC) for reduction of 
systemic corticosteroids (oral and parenteral) use in patients with severe asthma
Brief title
SCS avoidance study in severe Asthma Patients
Sponsor and 
Clinical Phase
Novartis
3b
Investigation 
type
Drug
Study type
Interventional
Purpose and 
rationale
There is a correlation between Systemic Corticosteroids (SCS) use and Adverse Events 
(AEs). Sustained use of SCS is associated with significant side effects, including growth 
retardation in children, as well as osteoporosis, diabetes, cardiovascular adverse events, 
muscular weakness, skin atrophy and cataract. This translates in an advantage for AE 
avoidance for those patients that do not use any SCS. Alternative asthma therapies that 
reduce the need for SCS are urgently needed, especially if given orally, such as fevipiprant.
The overall purpose of this study is to determine the efficacy of fevipiprant (150 mg and 450 
mg once daily), compared with placebo, as add-on to GINA 2018 treatment step 4 or 5 
standard-of-care (SoC) asthma therapy, in terms of avoidance of SCS use over 52 weeks. 
This will be measured in patients with inadequately controlled severe asthma (Asthma 
Control Questionnaire score (ACQ-5) ≥ 1.5) and high eosinophil counts (eosinophil count at 
Screening Visit ≥ 250 cells/µl), and in the overall patient population regardless of eosinophil 
counts.
Primary 
Objective(s)

In patients with severe asthma and high eosinophil counts receiving flexible SoC 
asthma therapy, to demonstrate a reduction in the use of SCS with fevipiprant, 
compared with placebo.

In all patients with severe asthma receiving flexible SoC asthma therapy, to 
demonstrate a reduction in the use of SCS with fevipiprant , compared with placebo.
Secondary 
Objectives

To evaluate the effect of fevipiprant and flexible SoC asthma therapy, compared with 
placebo and flexible SoC asthma therapy in terms of proportion for patients with no 
SCS use from the overall population

To evaluate the effect of fevipiprant and flexible SoC asthma therapy, compared with
placebo and flexible SoC asthma therapy in terms of general safety / tolerability in the 
overall population

To evaluate the effect of fevipiprant and flexible SoC asthma therapy, compared with 
placebo and flexible SoC asthma therapy in terms of proportion of patients receiving 
continuous SCS during ≥ 30 days, at ≥ 7.5mg/day of prednisone/prednisolone (or 
equivalent) in the overall population

To evaluate the effect of fevipiprant and flexible SoC asthma therapy, compared with 
placebo and flexible SoC asthma therapy in terms of Asthma Related Quality of Life 
Questionnaire (AQLQ+12) in the overall population

To evaluate the efficacy fevipiprant and flexible SoC asthma therapy, compared with 
placebo and flexible SoC asthma therapy, with respect to change from baseline in 
Asthma Control Questionnaire (ACQ-5) in the overall population

To evaluate the effect of fevipiprant and flexible SoC asthma therapy, compared with 
placebo and flexible SoC asthma therapy in terms of time to first prescription of biologic 
therapy in the overall population

To evaluate the effect of fevipiprant and flexible SoC asthma therapy, compared with 
placebo and flexible SoC asthma therapy in terms of difference in daytime and 
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Study design
This study uses a randomized, multicenter, double-blind, double-dummy, placebo-
controlled, parallel-group study design. The study will include a Screening period of up to 2 
weeks to assess eligibility, a Run-in period of 4 (for high-dose ICS dose patients) or 10 (for 
mid-dose ICS patients) weeks to evaluate maintenance of asthma control and to collect 
baseline safety data, a Treatment period of 52 weeks and a Follow-up period of 2 weeks 
following the last dose of study drug to collect additional data for safety variables.
Population
The study population will consist of approximately 669 male and female patients with 
uncontrolled asthma aged 18 and above.
Key Inclusion 
criteria

Written informed consent must be obtained within 14 days prior to or at Screening Visit 
before any assessment is performed including any adjustment to asthma medication.

Male and female patients aged ≥ 18 years

Patients with a diagnosis of asthma for a period of at least 3 months prior to Screening 
Visit with current asthma severity step 4 or 5 (GINA 2018)

Currently on treatment with medium or high dose ICS/LABA +/- other controller (LAMA, 
LTRA or Theophylline as per GINA) for a minimum of 6 weeks prior to Screening Visit .

Demonstration of inadequate control of asthma based on an ACQ-5 score ≥ 1.5 at 
Screening Visit and Randomization Visit .

Documented history of at least 1 asthma exacerbation [(that required ≥ 3 consecutive 
days of oral corticosteroids or ≥ 1 dose of IM or IV corticosteroids or hospitalization 
(defined as an inpatient stay or > 24-hour stay in an observation area in the emergency 
room of other equivalent facility,)] within 1 year prior to enrolment

At screening, patients with FEV1 of ≤ 80% of the predicted normal value for the patient, 
after withholding bronchodilators at Screening Visit and beginning of Run-In Visit .

An increase of ≥ 12% and ≥ 200 ml in FEV1 approximately 10 to 15 minutes after 
administration of 400 mcg of salbutamol/albuterol prior to randomization (documented 
historical reversibility is accepted)
Key Exclusion 
criteria

Asthma exacerbation, within 6 weeks prior to enrolment (screening) that required SCS, 
hospitalization, or emergency room visit. Patients who experience an exacerbation 
between screening to end of run-in, prior randomization, to be considered failures and 
can be eligible for re-screening only once, 6 weeks after recovering from the 
exacerbation.

Chronic/ maintenance use of OCS for asthma (regular OCS use for over 6 months; 
continuously or intermittently) within the last year

Prior use of biologics (including but not limited to Omalizumab, Mepolizumab, 
Reslizumab, Dupilumab, Benralizumab etc., for asthma or any other indications) that 
has potential to interfere/ affect asthma disease progression, in the previous 6 months.

Any contra-indications to SCS use e.g. diabetes, narrow angle glaucoma, or any other 
as defined by the treating physician

Pregnant or nursing (lactating) women

Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using basic methods of contraception during 
dosing of investigational drug

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.

Patients requiring SCS use for conditions other than asthma (chronic or intermittent)

Patients with a known history of non-compliance to medication or who are unable or 
unwilling to complete an electronic patient diary or who are unable or unwilling to use 
Electronic Peak Flow with eDiary device or who are unable to demonstrate good 
eDiary compliance (defined as > 75% for eDiary compliance) during run-in.

Patients who have a clinically significant laboratory abnormality at the Run-in Visit 
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


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
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

Patients with serious co-morbidities including, but not limited to, neurodegenerative 
diseases, rheumatoid arthritis and other autoimmune diseases

Patients on > 20 mg of simvastatin, > 40 mg of atorvastatin, > 40 mg of pravastatin, or 
> 2 mg of pitavastatin. Statin doses less than or equal to these doses as well as other 
statins will be permitted during the study

Patients on any statin therapy with a CK level > 2 X ULN at Run-in Visit

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 Visit are also excluded
Study treatment

QAW039 150 mg and QAW039 450 mg once daily

placebos to QAW039 150 mg and QAW039 450 mg once daily
Efficacy 
assessments

Systemic Corticosteriods use

Health Status (PROs: AQLQ+12, ACQ-5)

Biologic therapy administered during the treatment period
Key safety 
assessments

Medical history and physical examination

Adverse events including serious adverse events

Asthma Exacerbations

Vital signs

ECG

Height and weight

Laboratory evaluations (Hematology, Blood chemistry including HbA1c, Urinalysis)

Pregnancy (female patients)

Serious asthma outcomes
Other 
assessments
None
Data analysis
Approximately 669 patients will be randomized in 1:1:1 ratio in either of the three arms 
Fevipiprant 450 mg dose, Fevipiprant 150 mg dose or placebo in addition to standard of 
care. The randomization will be stratified according to patients peripheral blood eosinophil 
count (< 250 cells/μl or ≥ 250 cells/μl).
Primary analysis:
The primary endpoint of the study is total systemic corticosteroid dose in mg 
prednisone/prednisolone or equivalent over 52 weeks of treatment. The primary endpoint will 
be analyzed in subpopulation of patients with eosinophil count ≥ 250 cells/µl and in overall 
population.
Demonstration of total systemic corticosteroid SCS dose used in mg over 52 weeks of 
treatment for subpopulation of patients with eosinophil count ≥ 250 cells/µl and in overall 
population will be evaluated using the following primary null hypothesis:

H01 450 eosinophil subgroup: the distribution of the total SCS dose (in mg) in Fevipiprant 
450 mg QD plus SoC is equivalent to the distribution of the total SCS dose (in mg) in 
placebo plus SoC in patients with eosinophil count ≥ 250 cells/µl

H02 150 eosinophil subgroup: the distribution of the total SCS dose (in mg) in 
Fevipiprant 150 mg QD plus SoC is equivalent to the distribution of the total SCS dose 
(in mg) in placebo plus SoC in patients with eosinophil count ≥ 250 cells/µl

H03 450 overall population: the distribution of the total SCS dose (in mg)in Fevipiprant 
450 mg QD plus SoC is equivalent to the distribution of the total SCS dose (in mg) in 
placebo plus SoC for the overall population


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
H04 150 overall population: the distribution of the total SCS dose (in mg)in Fevipiprant 
150 mg QD plus SoC is equivalent to the distribution of the total SCS dose (in mg) in 
placebo plus SoC for the overall population
The familywise type I error rate will be controlled at the two-sided 5% level across the primary 
null hypotheses using graphical approach.The total systemic corticosteroid dose in mg 
prednisone/prednisolone (or equivalent) over 52 weeks of treatment will be analyzed using 
the Wilcoxon-Mann-Whitney rank sum test (Van Elteren test). For overall population analysis 
will be stratified by randomization stratum – blood eosinophils levels (≥ 250 cells/µl and < 250 
cells/µl). For subgroup with blood eosinophils ≥ 250 cells/µl, analysis will not include 
stratification factor. The summary statistics for total SCS dose by treatment group will be 
provided. The total SCS dose data will be aggregated into monthly data for analysis. For the 
patients discontinuing treatment early, the total SCS dose for 52 weeks will be obtained as 
annualized SCS dose. For example if patient took 280 mg for 7 months then for 12 months 
patient will be taking 280*12/7 = 480mg total SCS dose. Efficacy data collected during the 
use of biologics will be set to missing, since use of biologics can confound efficacy data. After 
replacing SCS dose with missing, patient will not have data available for all 12 months, thus 
total SCS dose will be obtained as annualized dose. 
Secondary analysis:
The proportion of patients with free of SCS use over 52 weeks treatment will be summarized 
by treatment and analyzed using logistic regression in overall population. The model will 
include treatment and randomization strata as covariates.
The proportion of patients requiring ≥7.5mg systemic corticosteroid dose in mg 
prednisone/prednisolone (or equivalent) per day continuously for at least 30 days in 52 
weeks treatment period will be summarized by treatment and analyzed using logistic 
regression in overall population. The model will include treatment and randomization strata 
as covariates.
The AQLQ+12 and ACQ-5 score will be analyzed using a MMRM with an unstructured 
covariance structure with factors for treatment group, time and randomization stratum, as 
well as the baseline values as continuous linear covariates.
The time to first prescription of biologic therapy from first dose of study treatment received 
over 52 weeks of treatment will be summarized by treatment group. Between-treatment 
differences will be evaluated using cox regression model.
Change from baseline in each endpoint (daytime and nighttime symptom score) will be 
analyzed using mixed models repeated measures (MMRM) model with factors as treatment 
group, randomization strata, time interval, time interval by treatment group interaction and 
the associated baseline as continuous linear covariate.
Safety analysis will be based on safety set and analysis will be presented by treatment group. 
Safety summaries will be provided based on on-treatment data. The on-treatment period lasts 
from the date of first administration of study treatment to 14 days after the date of the last 
actual administration of any study treatment.
Key words
Efficacy and safety of QAW039, OCS avoidance, placebo-controlled, add-on to standard of 
care, flexible background therapy, uncontrolled severe asthma, female and male patient >= 
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1
Introduction
1.1
Background
Asthma presents a major global health burden. Despite existing therapies, there is still 
significant unmet medical need in asthma, with an estimated 300 million people affected 
worldwide. The World Health Organization (WHO) estimates that 15 million disability–
adjusted life years are lost annually due to asthma, representing 1% of the total global burden. 
It is estimated that asthma accounts for about 1 in every 250 deaths worldwide 
(Masoli et al 2004). Severe asthma is defined as asthma that requires treatment with high dose 
of inhaled corticosteroids (ICS) plus a second controller and/or systemic corticosteroids (SCS), 
including both oral (OCS) and injectable administration, to prevent it from becoming 
"uncontrolled" or that remains "uncontrolled" despite this therapy. Severe asthma is a 
heterogeneous condition consisting of multiple phenotypes (American Thoracic Society 2000).
In severe asthma, large cumulative doses of corticosteroids and, in particular, SCS are used to 
treat patients to maintain control. In a matched cohort study on patients suffering with severe 
asthma and receiving OCS or not, Zazzali at al. assessed an United States (US) commercial 
health care claims and found OCS use to be common: 60% of patients with asthma filled at 
least one OCS prescription over a 2-year period, (Zazzali et al 2015 ). Patients in the high-OCS 
group had a mean prednisone-equivalent dose exposure of 4592 mg during the 2 years-study 
period, compared with 0 mg for the no-OCS group. Moreover, according to data from the 
Healthcare Cost and Utilization Project (HCUP), corticosteroids were the most common cause 
of drug-related complications in 2004, accounting for 10% of all drug-related complications 
and 141,000 hospital stays in the US (Elixhauser A, HCUP Statistical Brief #29. April 2007). 
Although effective in patients with severe asthma, the use of SCS may be associated with 
serious systemic side effects such as osteoporosis, cataract, glaucoma, hypothalamic-pituitary-
adrenal axis suppression disorders (i.e. iatrogenic form of Cushing’s syndrome, adrenal 
insufficiency, and growth inhibition), myopathies (such as myalgia and muscle atrophy), 
psychiatric disorders, diabetes, hypertension and an increased risk of infection 
(Schäcke et al 2002).
Given the prevalent use of SCS in patients with severe asthma, it is important to characterize 
the adverse effects associated with SCS treatment in asthmatic patients to better understand the 
comparative risks. Hence, the review of several recent studies helps understand the range of 
toxicity presented by SCS:

In a recent analysis of the UK Optimum Patient Care Research Database (OPCRD) and 
British Thoracic Society (BTS) Difficult Asthma registry, most subjects (92%–93%) with 
severe asthma examined had at least one condition linked to systemic corticosteroid 
exposure, with significantly higher prevalence rates than in subjects with mild/moderate 
asthma and in subjects without asthma (Sweeney et al 2016).

In a retrospective study using administrative claims data from a subset of asthma patients 
from a U.S. large commercial database between 2003 and 2014, Dalal et al. found that 
patients continuously exposed for > 6 months with low (< 5 mg/day), medium (≥ 5-10 
mg/day) and high (> 10 mg/day) systemic corticosteroid exposure had a 1.36-fold, 2.28-
fold, and 2.42-fold risk, respectively, of developing bone- and muscle-related complications, 


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such as fractures, relative to patients without exposure to systemic corticosteroid 
(Dalal et al 2016).

De Vries et al. reported a significantly increased risk of developing fractures among 
obstructive airway disease patients exposed to an SCS compared to those never exposed. 
The total period of follow-up for each patient was taken as the time period from the first 
SCS prescription until the end of data collection for the UK General Practice Database. 
This total period of time was then divided into periods of current exposure and past 
exposure, with patients moving between current and past exposure. Each period of current 
exposure started with a SCS prescription and ended 3 months after the expected duration 
of SCS therapy. Depending on the type of fracture, they estimated a relative risk varying 
from 1.37 to 5.65 for patients with a cumulative dose of SCS between 1 gm and 5 gm, and 
from 3.00 to 10.61 for patients with a cumulative dose > 5 gm (De Vries et al 2007).

Lefebvre et al provided preliminary evidence that higher doses and continuous exposure to 
OCSs were associated with increased risk of AEs (Lefebvre et al 2015).

The published literature shows that there is a correlation between intermittent or short 
burst SCS use and AEs, and also a cumulative toxic effect of multiple bursts. In a 
retrospective cohort study of asthmatic patients 18 years and older in the 2000-2014 US 
MarketScan data set, subjects taking 4 or more OCS prescriptions within the year had 1.29 
times the odds of experiencing a new AE within the year. Each year of this kind of 
exposure resulted in 1.20 times the odds of having an AE per year. These patients had 
significantly greater odds of AEs for osteoporosis, hypertension, obesity, type 2 diabetes, 
gastrointestinal ulcers/bleeds, fractures, and cataracts (odds, 1.21-1.44 depending on the 
AE). This indicates a cumulative burden on SCS exposure. Exposure to 1 to 3 OCS 
prescriptions per year was also statistically significantly associated with the development 
of current and future AEs (Sullivan et al 2018). These studies showcase that intermittent 
or short bursts of OCS use increases the risk of the well-known side effects and 
comorbidities of SCS, and an additive effect of repeated doses. Hence, SCS-avoidance 
strategies, even of short-term bursts, are important to improve patient and populations 
well-being.
Prostaglandin D2 (PGD2) is one of the major prostanoid inflammatory mediators identified in 
asthma. The PGD2 type 2 receptor (DP2) usually mediates pre-inflammatory effects. 
Fevipiprant (QAW039) is a DP2 competitive antagonist in investigation in 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). Since these are the major effector 
cells and soluble factors driving airway inflammation in asthma, treatment with fevipiprant 
should result in a decrease in these parameters of airway inflammation as well as a clinical 
improvement in asthma, thus leading to a decrease of SCS therapy needs and a correlated 
decrease of the SCS-related AEs. In support of this premise are the results of Phase 2 studies of 
fevipiprant (Studies A2201, A2206, and A2208) in which fevipiprant demonstrated an 
improvement in lung function (i.e., forced expiratory volume in 1 second [FEV1]) in the overall 
population of patients with a range of asthma severities (Study A2206), an improvement in 
asthma control in patients with more severe asthma as defined by a baseline predicted FEV1 < 
70% (Study A2201) or in patients with a baseline Asthma Control Questionnaire-7 total score 
≥ 1.5 (Study A2208), and a 71% greater reduction from baseline in sputum eosinophils for 


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fevipiprant compared to placebo (geometric mean) in patients with severe asthma and sputum 
eosinophilia over 12 weeks of treatment.
The current SCS avoidance study (Study A2323) presents a novel concept: it will measure 
future total systemic corticosteroid use when fevipiprant is added to SoC, compared with 
placebo, in severe asthma patients (Global Initiative for Asthma [GINA] step 4 & 5) who are 
not on chronic or maintenance use of SCS (i.e. regular SCS use for over 6 months) within the 
last year prior to study enrollment. This is different to the approach of the OCS sparing studies, 
which measure reduction of OCS in patients already using chronic OCS at baseline. Considering 
that only a very small proportion of severe asthmatic patients (3.8%) use chronic OCS, and 
between 38% (US MarketScan database) and 59% (Bourdin et al 2018) of severe asthmatic 
patients receive bursts of SCS every year, we consider clinically and scientifically relevant to 
assess the use of fevipiprant to prevent or reduce the use of SCS in a real world setting where 
patient-individualized treatment is allowed along GINA guidelines step 4 and 5, allowing 
flexibility (step-up and step-down) of background control therapy and add-on other 
maintenance treatment options. The flexibility of the background therapy allows the 
investigator to increase or decrease doses of medications, or to add or remove medications in 
the background therapy based on the level of asthma control (see Section 5.5.5 ). The 
background therapy will be determined by the investigator however a standardized guidance 
will be provided as a support documentation.
1.2
Purpose
The overall purpose of this study is to determine the efficacy of fevipiprant (150 mg and 450 
mg once daily [OD]), compared with placebo, as add-on to GINA treatment step 4 or 5 standard-
of-care (SoC) asthma therapy, in terms of avoidance of SCS use over 52 weeks. This will be 
measured in patients with inadequately controlled severe asthma and high eosinophil counts 
(eosinophil count at Visit 1 ≥ 250 cells/ µl) and in the overall patient population regardless of 
eosinophil counts. This stepwise approach is in line with the fevipiprant LUSTER pivotal 
exacerbation studies (Studies A2307 and A2314). Inadequate control is defined as partly 
controlled or uncontrolled asthma (GINA 2018) with a value of Asthma Control Questionnaire 
score (ACQ-5) ≥ 1.5.


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2
Study objectives and endpoints
2.1
Objectives and related endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)
In patients with severe asthma and high eosinophil counts (≥ 
250 cells/μl) receiving flexible SoC asthma therapy, to 
demonstrate a reduction in the use of SCS with fevipiprant 
(150 mg or 450 mg once daily), compared with placebo
Total systemic corticosteroid dose in mg 
prednisone/prednisolone or equivalent over 52 
weeks of treatment
In all patients with severe asthma receiving flexible SoC 
asthma therapy, to demonstrate a reduction in the use of 
SCS with fevipiprant (150 mg or 450 mg once daily), 
compared with placebo
Total systemic corticosteroid dose in mg 
prednisone/prednisolone or equivalent over 52 
weeks of treatment
Secondary objective(s)
Endpoint(s) for secondary objective(s)
To evaluate the effect of fevipiprant 150 mg and 450 mg and 
flexible SoC asthma therapy, compared with placebo and 
flexible SoC asthma therapy in terms of difference in 
daytime and nighttime symptom scores
Change from baseline in daytime and nighttime 
symptom scores over 52 weeks of treatment by 
treatment group
To evaluate the efficacy fevipiprant 150 mg or 450 mg and 
flexible SoC asthma therapy, compared with placebo and
flexible SoC asthma therapy, with respect to change from 
baseline in Asthma Control Questionnaire (ACQ-5) in the 
overall population
Change from baseline in Asthma Control 
Questionnaire (ACQ-5) total score over 52 
weeks of treatment
To evaluate the effect of fevipiprant 150 mg and 450 mg and 
flexible SoC asthma therapy, compared with placebo and 
flexible SoC asthma therapy in terms of Asthma Related 
Quality of Life Questionnaire (AQLQ+12) in the overall 
population
Change from baseline in Asthma Related 
Quality of Life Questionnaire (AQLQ+12) total 
score over 52 weeks of treatment
To evaluate the effect of fevipiprant 150 mg and 450 mg and 
flexible SoC asthma therapy, compared with placebo and 
flexible SoC asthma therapy in terms of proportion of 
patients receiving continuous SCS during ≥ 30 days, at ≥ 
7.5mg/day of prednisolone or equivalent in the overall 
population
Proportion of patients requiring ≥ 7.5mg 
systemic corticosteroid dose in mg 
prednisone/prednisolone or equivalent per day
continuously for at least 30 days
To evaluate the safety and tolerability of fevipiprant 150 mg 
and 450 mg and flexible SoC asthma therapy, compared 
with placebo and flexible SoC asthma therapy in the overall 
population
Adverse events, ECG, vital signs and 
laboratory analysis over 52 weeks of treatment
To evaluate the effect of fevipiprant 150 mg and 450 mg and 
flexible SoC asthma therapy, compared with placebo and 
flexible SoC asthma therapy in terms of proportion for 
patients with no SCS use from the overall population
Proportion of patients with no SCS use over 52 
weeks of treatment
To evaluate the effect of fevipiprant 150 mg and 450 mg and 
flexible SoC asthma therapy, compared with placebo and 
flexible SoC asthma therapy in terms of time to first 
prescription of biologic therapy in the overall population
Time to first prescription of biologic therapy 
from first dose of study treatment received over 
52 weeks of treatment


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Objective(s)
Endpoint(s)
3
Investigational plan
3.1
Study design
This study uses a randomized, multicenter, double-blind, double-dummy, placebo-controlled, 
parallel-group study design to determine the ability of fevipiprant plus SoC compared with 
placebo plus SoC to reduce the use of SCS in patients with severe asthma. The study will 
include:

a Screening period of up to 2 weeks to assess eligibility;

a Run-in period of 4 or 10* weeks to evaluate maintenance of asthma control and to 
collect baseline safety data. Upon completion of the Run-in period, all patients who met 
eligibility criteria will be randomized to 1 of 3 treatment groups (Fevipiprant 150 mg or 
450 mg or placebo once daily) in a ratio 1:1:1. Randomized patients will be stratified 
according to their peripheral blood eosinophil count (< 250 cells/μl or ≥ 250 cells/μl);

a Treatment period of 52 weeks and

a Follow-up period of 2 weeks following the last dose of study drug to collect additional 
data for safety variables.
Approximately 669 patients will be randomized into this study. Please refer to Table 6-1 for 
clinical visit schedule and list of procedures to be conducted at each visit.
Figure 3-1
Study design


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* 4 weeks run-in for patients coming with high-dose ICS/LABA and 10 weeks for patients switching 
from mid-dose to high-dose ICS/LABA as per protocol during the run-in period.
The study will allow for flexible therapy, meaning that patients can be escalated or de-escalated 
on their SoC therapy or add any other controller (this is explained in more detail 
in Section 5.5.5 )
3.2
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 flexible SoC asthma therapy, compared with placebo plus flexible SoC asthma 
therapy, to reduce the use of SCS in patients with severe asthma and high eosinophil counts 
(eosinophil count at Visit 1 ≥ 250 cells/μl) as measured by total SCS use over 52 weeks. The 
study will also determine the ability of fevipiprant (150 mg and 450 mg OD) plus flexible SoC 
asthma therapy, compared with placebo plus flexible SoC asthma therapy, to reduce use of SCS 
use in the overall study population. The patient population will be described in more detail in 
the Section 4 below. The study will allow for flexible background therapy.
As mentioned previously, there is a correlation between SCS use and AEs. Sustained use of 
SCS is associated with significant side effects, including growth retardation in children, as well 
as osteoporosis, diabetes, cardiovascular adverse events, muscular weakness, skin atrophy and 
cataract (Schäcke et al 2002). This translates in an advantage for AE avoidance for those 
patients that do not use any SCS. Alternative asthma therapies that reduce the need for SCS are 
urgently needed, especially if given orally, such as fevipiprant. Unlike SCS, fevipiprant can 
target factors that contribute to asthma severity such as eosinophils.
Hence the primary endpoint of this study is comparing the total SCS use and expecting a lower 
SCS use especially for those patients who normally would receive high SCS doses. This should 
translate in lowering the toxicity. Most of the clinical importance would be based on the 
reduction of the percentage of patients who are the highest users. Given the mentioned 
correlation, they are the ones with the highest rate of AEs, so they would benefit the most.
The reduction in number of AEs would be especially relevant for those with predisposing 
conditions. Almost all patients with severe asthma (92%-93%) had at least one condition linked 
to systemic corticosteroid exposure, (Optimum Patient Care Research Database), so the vast 
majority of the population would fall into this category.
For yearly SCS usage, 30 days is considered the time threshold for high usage (Dalal et al 2016; 
Zazzali et al 2015 ). This encompasses both burst and chronic use.
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
Fevipiprant will be administered at doses of 150 mg and 450 mg once daily as oral film-coated 
tablets (FCTs) in this study.
A 450 mg once daily dose was selected for inclusion in the study based on the following:

At a dose of 450 mg once daily, > 98% receptor occupancy is expected for the entire 
dosing interval in a “typical patient” at steady state allowing inhibition of eosinophil 
migration over the entire treatment interval.


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
A 500 mg once daily dose of fevipiprant was efficacious on the endpoint of pre-dose 
FEV1 in a sub-set of patients with percent predicted FEV1 < 70% at baseline in Study 
[CQAW039A2201] (proof-of-concept study). A 450 mg total daily dose was also 
efficacious on the endpoint of pre-dose FEV1 in study [CQAW039A2206].

A total daily dose of 450 mg (225 mg twice daily) was evaluated in Study 
[CQAW039A2208] in patients with severe asthma as add-on to SoC asthma therapy. In 
this study, fevipiprant caused significant reduction of sputum eosinophilia in patients with 
severe eosinophilic asthma. The reduction in sputum eosinophils was comparable to that 
observed with the anti-IL5 antibodies, Mepolizumab (Pavord et al 2012) and Reslizumab 
(Castro et al 2011; Castro et al 2015). An association between reduction of eosinophilic 
airway inflammation and frequency of exacerbations has been reported in the literature 
(Haldar et al 2009; Pavord et al 2012; Wenzel et al 2013; Takaku et al 2013), suggesting 
fevipiprant may also cause a reduction in the frequency of asthma exacerbations in 
patients with severe refractory eosinophilic asthma.
The dose of 150 mg once daily was selected for inclusion in the study because it was the lowest 
dose of fevipiprant with “maximal efficacy” on the endpoint of FEV1 in a prior dose-ranging 
study (Study [CQAW039A2206]) in patients with moderate-to-severe asthma (GINA 2018
treatment steps 4 and 5) as add-on to low-dose ICS. This dose is ½ log lower than highest dose.
Since the fevipiprant dose of 150 mg was considered the optimal dose (i.e., lowest dose 
providing maximal efficacy) in a prior dose-ranging study, doses lower than 150 mg will not 
be included in this study
3.4
Rationale for choice of comparator
During the run-in period the background medication will be standardized and all patients will 
receive:
Salmeterol/fluticasone 50/500 μg b.i.d. delivered by DPI (dry-powder inhaler) marketed as 
Seretide® Accuhaler® or Seretide® Diskus®depending on the countries, +/- tiotropium or any 
Long-acting muscarinic antagonist (LAMA) approved for asthma and/or Leukotriene Receptor 
Antagonists (LTRAs).
During treatment period patients will be given fevipiprant or placebo as add on therapy in 
addition to the run-in treatment medications
The use of placebo will permit the assessment of reduction of incidence of total dose of systemic 
corticosteroids within 52 weeks in patients who are treated with fevipiprant and SoC, in 
comparison to those continuing solely on existing SoC asthma therapy. Additionally, the use of 
placebo will permit a controlled evaluation of the safety of fevipiprant in these patients.
This study does not include an active comparator since fevipiprant will be given as add-on 
therapy to standard of care asthma therapy in patients with severe asthma (GINA 2018 treatment 
steps 4 and 5).


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3.5
Purpose and timing of interim analyses/design adaptations
Flexible scenario
If the results of [CQAW039A2307]/[CQAW039A2314] studies are available before completion 
of recruitment of the CQAW039A2323 study, and in the case that an optimal dose of fevipiprant 
has been identified, the study team will decide whether to drop any fevipiprant dose or continue 
with current doses. There will not be an interim analysis for this study. Any change would be 
made based on external data and hence there would not be any alpha adjustment. At the decision 
point, the study team will assess the criterion below:

[CQAW039A2307]/[CQAW039A2314] results do not recommend one of the fevipiprant 
dose due to safety concerns / lack of efficacy: 

In CQAW039A2323 study, recruitment in the corresponding treatment arm will be 
stopped. To keep the blind the ongoing patients on this arm will be switched to the 
other fevipiprant dose at the next drug dispensing visit.

Final analysis will be based on comparison of selected fevipiprant arm and placebo 
arm at 5% significance level. The primary hypothesis will be tested first in the 
subgroup with blood eosinophils ≥ 250 cells/µl and then in the overall population for 
the selected fevipiprant dose.

Data collected on the non-optimal arm will be summarized but will not be used for 
statistical inference.

Any modifications in CQAW039A2323 study will be contingent upon number of patients 
recruited at the decision point.

At this decision point, CQAW039A2323 study data will not be unblinded to make a 
decision. The decision will be completely based on final results of 
[CQAW039A2307]/[CQAW039A2314] studies. Thus, there will not be any interim 
analysis performed for CQAW039A2323. This will control the type I error rate 
adequately.
Based on [CQAW039A2307]/[CQAW039A2314] results, one dose is selected for launch, and 
the decision is made that there is no need to compare the control arm with the dose not selected. 
Then the testing strategy will be to only perform the comparison between the control arm and 
the dose selected.
This flexible scenario strategy could reduce the total number of patients required to be enrolled 
in the study.
3.6
Risks and benefits
Fevipiprant is a potent and highly selective oral DP2 antagonist being developed as a potential 
therapy for patients with severe asthma. DP2 is a receptor for PGD2 which mediates the 
activation and migration of T helper 2 (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.
The overall clinical experience with fevipiprant includes 24 studies: 15 (nine in healthy 
volunteers and six in patients) have completed and 9 (five in patients and four in healthy 


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volunteers) are ongoing. The completed phase 2 studies consist of four in patients with asthma, 
one in patients with allergic rhinitis and one in patients with atopic dermatitis (Refer to the 
Investigator’s Brochure (IB) for information on the studies of fevipiprant). As of January 2018, 
over 2830 subjects have been exposed to fevipiprant in the clinical program.
Three Phase 2 studies in patients with asthma evaluated the effect of fevipiprant across the range 
of asthma severities (mild to severe). In these studies, fevipiprant demonstrated an effect on 
lung function (FEV1) in patients with moderate-to-severe asthma, and an improvement in 
quality of life scores and asthma control questionnaire scores in severe patients uncontrolled at 
baseline. In one study, fevipiprant also demonstrated a reduction in sputum eosinophils in 
patients with severe asthma.
The potential benefits of fevipiprant therapy need to be balanced against its potential risks. 
Potential side effects of fevipiprant include: increased heart rate, non-serious arrhythmia such 
as palpitations, headache, diarrhea, nausea, vomiting, nasopharyngitis, somnolence and 
dizziness. In humans, one major metabolite of fevipiprant has been identified which is formed 
by glucuronidation (acyl glucuronide) and partially binds to plasma proteins. In the literature, 
in vivo binding of acyl glucuronides to proteins has been reported to be associated with rare 
idiosyncratic drug reactions (IDRs), although a causal connection of protein adduction to IDRs 
remains uncertain (Regan et al 2010). There have been no IDRs observed with fevipiprant 
treatment in completed clinical trials as of January 2018. Taking fevipiprant at the doses used 
in this study with the cholesterol-lowering drug simvastatin has been shown to cause a small 
increase in the peak blood level of simvastatin.
The risk to patients in this trial will be minimized by compliance with the eligibility criteria and 
study procedures and close clinical monitoring.
Patients on doses of simvastatin > 20 mg, doses of atorvastatin >40 mg, doses of pravastatin 
>40 mg, or doses of pitavastatin > 2 mg per day (Elsby et al 2012; Deng et al 2008; 
Noé et al 2007; Kalliokoski and Niemi 2009), as well as patients on any statins with high 
creatine kinase (CK) levels (> 2 X ULN (upper limit of normal)) at screening will be excluded 
from the study. Patients on statin medication who are included in the study will have regular 
monitoring for relevant symptoms and be subject to discontinuation based on persistent myalgia 
and/or blood CK levels (Jacobson 2008). Cardiovascular risks will be monitored based on 
changes in vital signs, ECGs and biochemical parameters. Monitoring of liver function tests 
(LFT) and renal function will be conducted as described in Section 14 and Section 15, 
respectively, of this protocol. Surveillance of adverse events for identification of idiosyncratic 
drugs will be conducted.
Refer to the [QAW039 Investigator’s Brochure] for further information about risks and benefits.
4
Population
4.1
Inclusion criteria
Population eligible for inclusion in this study must fulfill all of the following criteria:
1. Signed informed consent must be obtained prior to participation in the study and before 
any assessment is performed including any adjustment to asthma medication.
2. Male and female patients aged ≥18 years


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3. Patients with a diagnosis of asthma for a period of at least 3 months prior to Screening 
Visit with current asthma severity step 4 or 5 (GINA 2018)
4. Currently on treatment with medium or high dose ICS/LABA +/- other controller (i.e. 
LAMA, LTRA etc. as per GINA) for a minimum of 6 weeks prior to Screening Visit .
5. At screening, patients with FEV1 of ≤80% of the predicted normal value for the patient, 
after withholding bronchodilators at Screening Visit and beginning of Run-In Visit .
6. An increase of ≥12% and ≥200 ml in FEV1 approximately 10 to 15 minutes after 
administration of 400 mcg of salbutamol/albuterol prior to randomization (documented 
historical reversibility is accepted). Spacer devices are not permitted during reversibility 
testing. All patients must perform a reversibility test at Screening Visit. If reversibility is 
not demonstrated at that visit, then documented evidence of reversibility that was 
performed according to ATS/ERS guidelines (ATS/ERS 2005) in the past 5 years is 
allowed. Where a patient is assessed as eligible based on historical evidence of 
reversibility, a copy of the original printed spirometry report with relevant spirometry 
tracings must be available as source documentation. If reversibility is not demonstrated at 
Screening Visit and documented evidence is not met, then the reversibility test may be 
repeated at Run-In Visit.
7. Demonstration of inadequate control of asthma based on an ACQ-5 score ≥1.5 at 
Screening Visit and Treatment Day 1 Visit.
8. Documented history of at least 1 asthma exacerbation [(that required ≥3 consecutive days 
of oral corticosteroids or ≥1 dose of IM or IV corticosteroids or hospitalization (defined 
as an inpatient stay or >24-hour stay in an observation area in the emergency room of 
other equivalent facility,)] within 1 year prior to enrolment
4.2
Exclusion criteria
Population fulfilling any of the following criteria are not eligible for inclusion in this study:
1. Asthma exacerbation, within 6 weeks prior to enrolment (screening) that required SCS, 
hospitalization, or emergency room visit. Patients who experience an exacerbation 
between screening to end of run-in, prior randomization, to be considered failures and can 
be eligible for re-screening only once, 6 weeks after recovering from the exacerbation.
2. Chronic/ maintenance use of OCS for asthma ( total OCS use days greater than 6 months; 
continuously or intermittently) within the last year
3. Prior use of biologics (including but not limited to Omalizumab, Mepolizumab, 
Reslizumab, Dupilumab, Benralizumab etc., for asthma or any other indications) that has 
potential to interfere/ affect asthma disease progression, in the previous 6 months from 
run-in period.
4. Any contra-indications of SCS use e.g. diabetes, narrow angle glaucoma, or any other as 
defined by the treating physician
5. Pregnant or nursing (lactating) women
6. 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:


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
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 United Kingdom: 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, local regulations apply and will be described in the ICF.
7. Use of other investigational drugs within 5 half-lives of enrollment, or [within 30 days], 
whichever is longer.
8. History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar 
chemical classes.
9. 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.
10. Patients who have smoked or inhaled any substance other than asthma medications within 
the 6 month period prior to Screening Visit , 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.)
11. Patients requiring SCS use for conditions other than asthma (chronic or intermittent)
12. Patients with a history of chronic lung disease other than asthma, including (but not 
limited to) chronic obstructive pulmonary disease, clinically significant 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, cystic fibrosis, and active tuberculosis


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13. Patients with history of alcohol or drug abuse within 12 months prior to Screening Visit .
14. Patients with a known history of non-compliance to medication or who are unable or 
unwilling to complete an electronic patient diary or who are unable or unwilling to use 
Electronic Peak Flow with eDiary device or who are unable to demonstrate good eDiary 
compliance (defined as >75% for eDiary compliance) during run-in.
15. Patients who have had a respiratory tract infection or asthma worsening within 4 weeks of 
Screening Visit. Patients who experience a respiratory tract infection or asthma worsening 
during screening may be re-screened after 4 weeks after recovery from their respiratory 
tract infection or asthma worsening
16. 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
17. Patients who have a clinically significant laboratory abnormality at the Run-in Visit 
laboratory test including (but not limited to):

Total white blood cell count <2500 cells/μL

AST or ALT>2.0 X ULN or total bilirubin >1.3 X ULN

Estimated Glomerular Filtration Rate (eGFR) by the Modification of Diet in Renal 
Disease (MDRD) equation or Bedside Schwartz equation <55 mL/minute/1.73 m2
18. Patients with serious co-morbidities including, but not limited to neurodegenerative 
diseases, rheumatoid arthritis and other autoimmune diseases
19. Patients receiving any medications in the classes listed in Table 5-4 should be excluded 
unless they meet the criteria as specified in Table 5-4
20. Patients receiving medications in the classes listed in Table 5-2 should be excluded unless 
the medication has been stabilized for the specified period and the stated conditions have 
been met
21. Patients who started immunotherapy or desensitization for allergies, within 3 months prior 
to Screening Visit, or where the maintenance dose is expected to change during the study
22. Inability to comply with all study requirements and demonstrate good medication 
compliance (>=80% compliance rate) during the run-in period
23. Patients with any medical or psychological condition that, in the investigators opinion, 
renders the patient unable to understand the nature, scope, and possible consequences of 
the study
24. Patients with a history of being unable to swallow tablets
25. Patients who have received methotrexate, gold salts, troleandomycin, cyclosporine, 
azathioprine, other immunomodulator or immumomodulatory drugs or any experimental 
anti-inflammatory therapies within 6 months of Run-in Visit
26. 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
27. Patients with a history of immunodeficiency disease or hepatitis B or hepatitis C
28. 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
29. Patients on any statin therapy with a CK level >2 X ULN at Run-in Visit


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30. Patients on rifampin, probenecid, ritonavir and valproic acid (i.e. medications blocking 
several pathways important for the elimination of QAW039 [broad range UGT inhibition 
and/or inhibition of OAT3, OATP1B3, MXR and P-gp]) 7 days prior to run-in visit.
31. No person directly associated with the administration of the study is allowed to participate 
as a study subject
32. No family member of the investigational study staff is allowed to participate in this study
33. History of lactose or milk sensitivity
34. 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 
Visit are also excluded
35. Patients with a history or current diagnosis of ECG abnormalities indicating significant 
risk of safety for patients participating in the study such as:

Concomitant clinically significant cardiac arrhythmias, e.g., sustained ventricular 
tachycardia, and clinically significant second or third degree atrioventricular (AV) 
block without a pacemaker.

History of familial long QT syndrome or known family history of Torsades de 
Pointes.
36. Patients with a resting QTcF (Fridericia) ≥450 msec (male) or ≥460 msec (female) at 
Screening Visit.
37. Use of agents with known risk of TdP unless it can be permanently discontinued for the 
duration of the study.
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
5
Treatment
5.1
Study treatment
5.1.1
Investigational and control drugs
The following investigational treatment will be supplied by Novartis to the study sites:

Name: QAW039

Formulation: tablet

Unit dose: 2 strengths: 150 mg and 450 mg

Name: placebos to QAW039 150 mg and QAW039 450 mg

Formulation: tablet

Unit dose: matching placebo to QAW039 150 mg, matching placebo to QAW039 450 mg
Please refer to the Investigator Brochure for composition of the QAW039 and placebo tablets.
The investigational treatment (tablets) will be supplied in bottles. The matching placebos for 
QAW039 will be identical in appearance to their active counterparts and will be identically 
packaged.


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5.1.2
Additional treatment
On the start of the run-in period all patients will be given standard of care treatment (SoC) to 
be taken daily for the duration of the study:

Open label salmeterol /fluticasone 50/500 μg b.i.d. (Seretide ® delivered as powder via 
Diskus®/Accuhaler® )
All patients will be provided with prednisone/prednisolone (or equivalent) tablets as the OCS 
for use during the study. Prednisone/prednisolone (or equivalent) will either be supplied to the 
investigator sites locally by Novartis or be provided by the study center and reimbursed by 
Novartis. The study patients will have a written asthma plan, provided by the Investigator, with 
instructions and information on how to self-manage their asthma daily, including taking 
medications appropriately and information on how to recognize and handle worsening asthma, 
and when, how, and who to contact in an emergency. The investigator should fill in the 
medication and dosage the patient should be taking during self-management. Adjustments and 
follow-up of the asthma worsening/exacerbation event can be managed either on the phone or 
during an unscheduled visit. Unscheduled visits can be necessary to evaluate the best treatment 
escalation for the patient’s current situation. This follows common medical practice, by which 
patients are prescribed OCS to be self-administered at home based on symptoms 
(Partridge 2004). The study patients will be instructed to make every effort to call the 
Investigator before taking the oral steroid and if not possible, as soon as they can, but not later 
than 48 hours after OCS intake has started.
All patients will be provided with Short-acting Beta-agonist (SABA) (salbutamol/albuterol) 
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 
locally by Novartis or be provided by the study center and reimbursed by Novartis.
5.2
Treatment arms
Patients will be assigned at randomization visit to one of the following 3 treatment arms in a 
ratio of 1:1:1

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. SoC asthma therapy will be taken as 
directed by the investigator.
5.3
Treatment assignment and 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 


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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 the 
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).
Randomization will be stratified by peripheral blood eosinophil counts at Run-in Visit (< 250 
cells/ml or ≥ 250 cells/ml).
The randomization scheme for subjects will be reviewed and approved by a member of the 
Randomization Group.
5.4
Treatment blinding
This study consists of a double-blind, double-dummy, randomized treatment period.
Subjects, investigator staff, persons performing the assessments, and data analysts will remain 
blind to the identity of the treatment from the time of randomization until database lock, using 
the following methods: (1) Randomization data are kept strictly confidential until the time of 
unblinding, and will not be accessible by anyone else involved in the study. (2) For each dose 
level of QAW039, the identity of the treatment will be concealed by the use of matching placebo 
identical in packaging, labeling, schedule of administration, appearance, taste, and odor to 
QAW039.
A double-dummy design is used because the identity of the study drug cannot be disguised, as 
the drug products are visibly different in size.
Unblinding will only occur in the case of patient emergencies (see Section 5.5.9) and at the 
conclusion of the study.
Table 5-1
Blinding levels
Role
Time or Event
Randomization 
list generated
Treatment allocation 
& dosing
Safety event (single 
subject unblinded)
Subjects/Patients
B
B
B
Site staff
B
B
B
Unblinded site staff (see text for 
details) 
B
B
B
Drug Supply and Randomization 
Office
UI
UI
UI
Unblinded sponsor staff (see text 
for details)
B
B
B
Statistician/statistical 
programmer/data analysts
B
B
B


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Role
Time or Event
Randomization 
list generated
Treatment allocation 
& dosing
Safety event (single 
subject unblinded)
Independent committees used for 
assessing interim results
NA
NA
NA
All other sponsor staff not 
identified above
B
B
B
B Remains blinded
NA Not applicable
UI Allowed to be unblinded on individual patient level
5.5
Treating the patient
Sponsor qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
5.5.1
Patient numbering
Each patient is uniquely identified by a Subject Number which is composed by the site number 
assigned by Novartis and a sequential number assigned by the investigator. Once assigned to a 
patient, the Subject Number will not be reused.
Upon signing the informed consent form, the patient is assigned the next sequential number by 
the investigator. The investigator or his/her staff will contact the IRT and provide the requested 
identifying information for the patient to register them into the IRT. The site must select the 
case report form (CRF) book with a matching Subject Number from the electronic data capture 
(EDC) system to enter data.
If the patient fails to be treated for any reason, the IRT must be notified within 2 days that the 
patient was not treated. The reason for not being treated will be entered on the Screening period 
Study Disposition CRF.
5.5.2
Dispensing the study drug
Each study site will be supplied with study drug in packaging of identical appearance.
The study drug packaging has a 2-part label. A unique medication number is printed on each 
part of this label which corresponds to one of the 3 treatment arms. Investigator staff will 
identify the study drug package(s) to dispense to the patient by contacting the IRT and obtaining 
the medication number(s). Immediately before dispensing the package to the patient, 
investigator staff will detach the outer part of the label from the packaging and affix it to the 
source document (Drug Label Form) for that patient’s unique subject number.
5.5.3
Handling of study and additional treatment
5.5.3.1
Handling of study treatment
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designees 
have access. Upon receipt, all study treatment must be stored according to the instructions 
specified on the labels. Clinical supplies are to be dispensed only in accordance with the 


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protocol. Technical complaints are to be reported to the respective Novartis Country 
Organization Quality Assurance.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the patient except for the medication number.
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Patients will be asked 
to return all unused study treatment and packaging at the end of the study or at the time of 
discontinuation of study treatment.
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site.
5.5.3.2
Handling of additional treatment
The following non-study treatment and rescue medication has to be monitored:

salmeterol /fluticasone 50/500 μg b.i.d. or 50/250 μg b.i.d via Diskus®/Accuhaler® used as 
SoC

prednisone/prednisolone (or equivalent) tablets (oral corticosteroids) used as rescue or 
preventive medication

SABA (such as salbutamol 100 mcg or albuterol 90 mcg)

tiotropium or "any LAMA approved for asthma"

LTRA (if started prior of study entry)
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.
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.
5.5.4
Instructions 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 


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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 eligible patients will start:
Salmeterol/fluticasone 50/500 μg b.i.d. delivered by DPI (dry-powder inhaler) is marketed as 
Seretide® Accuhaler® or Seretide® Diskus® depending on the countries +/- tiotropium (or 
any LAMA approved for asthma) and/or LTRAs.
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 after full recovery from the 
exacerbation.
At Randomization Visit, patients will be stratified according to their peripheral blood eosinophil 
counts at Run-In Visit (< 250 cells/ml or ≥ 250 cells/ml). Each randomized patient will then 
enter a 52-week treatment period where they will receive one of the following 3 treatments: (i) 
QAW039 150 mg once daily or (ii) QAW039 450 mg once daily or (iii) placebo once daily 
given on top of their individual background asthma treatment. All patients in this study will 
continue to receive their asthma medications as background treatment. The investigational 
treatment will be dispensed in medication packs (bottles) at dispensation visit during the 
treatment period to cover the treatment period between patient visits and to allow for late visits 
and other unforeseen events. All dosages prescribed and dispensed to the patient and all dose 
changes during the study must be recorded on the appropriate 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 6 ) 
and should be given at approximately the same time at each clinic visit. Between clinic visits, 
patients will take study medication once daily in the 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/databased in the IRT.
The investigator must promote compliance by instructing the patient to take the study treatment 
exactly as prescribed and by stating that compliance is necessary for the patient’s safety and the 
validity of the study. The patient must also be instructed to contact the investigator if he/she is 
unable for any reason to take the study treatment as prescribed.
5.5.5
Permitted dose adjustments and interruptions of study treatment
For patients who are unable to tolerate the protocol-specified dosing scheme, dose interruptions 
of investigational drug are permitted in order to keep the patient on study drug. The following 
guidelines must be followed:
Any interruption of study medication should be for the shortest time period possible. Any 
interruption of any duration must be recorded.
To reflect as near as possible the clinical practice setting in this trial, there is freedom to use 
flexible asthma background therapy, allowing to escalate (“step-up”) and de-escalate (“step-
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Stepping-up asthma treatment
As recommended by GINA guidelines (GINA 2018), the treating physician may “step-up” 
patient’s background medication and/or add-on maintenance treatment options if they remain 
uncontrolled or experience asthma exacerbations. Examples of background medication and add-
on other maintenance treatment options: tiotropium (or any LAMA approved for asthma), oral 
or injectable corticosteroids, biologic therapy (only those approved for asthma, not in 
investigation and according to SmPC and local regulations), among others. These medications 
should be used according to approved local labels.
Patients with “step-up” or add-on maintenance treatment(s) should continue on study treatment.
NOTE: LTRAs are not allowed as part of the stepping-up asthma treatment.
Stepping-down treatment when asthma is well controlled
As per GINA guidelines and as part of periodic reassessment of disease control the investigator 
should consider stepping down treatment once good asthma control has been achieved and 
maintained to find the minimum effective treatment that controls symptoms and exacerbations 
while minimizing side-effects (GINA 2018). The treating physician may “step-down” patient’s 
background medication according to GINA. The reduction of the dose of the ICS will be 
allowed after the investigator has withdrawn any other add-on medication such as OCS or 
tiotropium (or any LAMA approved for asthma).
GINA guidelines recommend choosing an appropriate time for step-down (no respiratory 
infection, patient not travelling) and document baseline status (symptom control and lung 
function), provide a written asthma action plan, monitor symptoms, and book a follow-up visit.
These changes must be recorded on the Prior and Concomitant Medications CRF.
5.5.6
Rescue medication
At Run-In Visit all patients will be provided with a SABA, (primary rescue medication such as 
salbutamol 100 mcg or albuterol 90 mcg) which they will be instructed to use throughout the 
study as rescue medication on an ‘as needed basis’. Patients will be advised that between visits 
they can take their rescue medication for symptoms of asthma. Rescue medication (i.e., SABAs) 
will either be supplied to the investigator sites locally by the Novartis CPO or provided by the 
study center and reimbursed by Novartis. Nebulized salbutamol/albuterol is not allowed as 
rescue medication and will not be supplied.
As part of their written asthma plan, patients will receive OCS (add on rescue medication such 
as prednisone/prednisolone (or equivalent) tablets) to use as instructed by the treating physician. 
There will be an asthma plan (given as a reference), which is described in Section 20 and that 
will be used to standardize the initial rescue treatment of the acute asthma exacerbation and/or 
symptoms. To standardize measurements, patients will be instructed not to use their rescue 
medication upon rising in the morning on days requiring spirometric assessments indicated in 
Table 6-1, unless absolutely necessary. If SABA medication is taken within 6 hours prior to 
spirometry at any of the scheduled visits, the visit should be rescheduled to the next possible 
day. However, if spirometry is performed within 6 hours of the use of rescue medication then 
this information will be recorded by the study site staff. Daily use of SABA medication (the 
number of puffs taken in the previous 12 hours) will be recorded (once in the morning and once 


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in the evening) by the patient on the eDiary as well as OCS intake. Unless clinically indicated, 
the type of rescue medication (i.e., SABA) a patient uses, the device used to deliver the 
medication (e.g. dry powder or HFA) and the way it is administered (e.g. with a spacer device) 
should not be adjusted.
5.5.7
Concomitant medication
The medications in Table 5-2 are only permitted under the circumstances given. This table is 
not considered all-inclusive. Medications should be assessed for adherence to the indication and 
other inclusion/exclusion criteria.
Table 5-3 indicates the wash-out periods for allowed asthma medications prior to spirometry 
assessments
The investigator must instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) administered 
after the patient was enrolled into the study must be recorded in the concomitant medications / 
significant non-drug therapies eCRF.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the investigator should contact the Novartis medical monitor before 
randomizing a patient or allowing a new medication to be started.
Table 5-2
Medications allowed under certain conditions
Class of medication
Conditions
Inhaled corticosteroids 
(ICS)
Medium or High dose* daily or equivalent. Used for at least 6 weeks prior to 
Screening Visit. Must be taken with LABA with or without a third therapy (LTRA 
or theophylline or LAMA) or with LABA/LAMA or with LABA/LTRA
Long-acting inhaled β2-
agonist (LABAs)
Permitted if used for at least 6 weeks prior to Screening Visit. Must be taken with 
medium - high dose* ICS
Fixed dose combinations 
of ICS and LABA (FDC)
Permitted at medium high dose if used at least 6 weeks prior to Screening
Leukotriene receptor 
antagonist (LTRAs)
Permitted if used for at least 6 weeks prior to Screening Visit. Must be taken with 
medium - high dose* ICS - New onset of LTRA during study is not allowed
Theophylline
Permitted if used at least 6 weeks prior to Screening Visit . Must be taken with 
medium - high dose* ICS
Long-acting muscarinic 
antagonists (LAMAs)
Permitted if used for at least 6 weeks prior to Screening Visit. Must be taken with 
medium - high dose* ICS
Maintenance oral 
corticosteroids for 
treatment of asthma
Less than 6 months during the previous year
Short-acting β2-agonist 
(SABAs)
Rescue medication to be taken as needed. Nebulized salbutamol/albuterol in not 
allowed as rescue medication, however can be taken if prescribed during 
exacerbation
Maintenance 
immunotherapy for 
allergies
Stable-dose for at least 3 months prior to screening and the dose remains stable 
throughout the study
Inactivated influenza 
vaccine pneumococcal 
vaccination or any other 
inactivated vaccine
Not administered within 48 hours prior to a study visit


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Class of medication
Conditions
Topical corticosteroids for 
treatment of eczema
Recommended doses and dosage regimens
Antihistamines (e.g., 
loratadine, cetirizine)
Stable dose for at least 1 month prior to Screening Visit and the 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 corticosteroids
Nasal or ophthalmological 
preparations of nedocromil
Nasal or ophthalmological 
preparations of 
antihistamines
*See GINA 2018 or Section 21 for definition of medium and high dose ICS
Table 5-3
Medications to be withheld prior to spirometry
Class of medication
Last dose prior to spirometry
Short-acting β2-agonists
≥ 6 hours
Long-acting β2-agonists (LABAs) given twice daily
≥ 12 hours
LABAs given once daily
≥ 24 hours
Fixed dose combinations of LABA and inhaled 
corticosteroid (ICS) given twice daily
≥ 12 hours
Long-acting muscarinic antagonists (LAMAs)
≥ 24 hours
5.5.8
Prohibited medication
Use of the treatments displayed in the below table is NOT allowed* according to the table below. 
Each concomitant drug must be individually assessed against all exclusion criteria and the tables 
below to see if it is allowed. If in doubt, the investigator should contact the Novartis medical 
monitor or designee before randomizing a patient or allowing a new medication to be started. 
This table is not considered all-inclusive. Medications should be assessed for adherence to the 
indication and other inclusion/exclusion criteria. These medications are also prohibited if 
administered for other indications.
Table 5-4
Prohibited medication
Medication
Prohibition period (Minimum cessation 
prior to start of run-in Visits)
Other investigational drugs
30 days or 5 half-lives, whichever is longer
Live attenuated vaccine
30 days
Other CR Th2 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


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Medication
Prohibition period (Minimum cessation 
prior to start of run-in Visits)
Simvastatin > 20 mg, atorvastatin > 40 
mg,pravastatin > 40 mg, or pitavastatin > 2 mg 
totaldaily dose
7 days
Rifampin, probenecid, ritonavir and valproic acid 
(i.e. medications blocking several pathways 
important for the elimination of QAW039 
(broadrange UGT inhibition and/or inhibition of 
OAT3, OATP1B3, MXR and P-gp)).
7 days
Methotrexate, gold salts, 
cyclosporine,troleandomycin, azathioprine, 
otherimmunomodulator drugs
6 months
Systemic (oral, intravenous, intramuscular) 
corticosteroids for non-asthma conditions
3 months
LTRAs
New onsets (during study duration)
*Biologics are allowed directly after randomization as part of the flexible therapy.
5.5.9
Emergency breaking of assigned treatment code
Emergency code breaks must only be undertaken when it is required to in order to treat the 
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 (if available)

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 un-blinding 
can be performed at any time.
Study drug must be discontinued after emergency unblinding. Study drug must also be 
discontinued for any patient whose treatment code has been inadvertently broken or for any 
other non-emergency reason.
Of note, the patient may continue in the study after discontinuing study drug.


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5.6
Study completion and discontinuation
5.6.1
Study completion and post-study treatment
A patient will be considered to have completed the study when the patient has completed the 
last visit planned in the protocol.
Study completion for a patient will occur after he/she has completed 52 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 52 weeks of treatment and the post-treatment 
follow-up visit.
Patients who have been screened when enrolment target has been met will be allowed to proceed 
onto study participation.
At the time of study completion or early termination, all patients will be placed on the 
appropriate asthma treatments as per the investigator judgement.
For all patients a safety follow-up visit should be conducted (e.g. by telephone) 14 days after 
last dose of study drug. The information to be collected at this follow up visit includes adverse 
events, 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.
5.6.2
Discontinuation of study treatment
Discontinuation of study treatment for a subject occurs when study treatment is stopped earlier 
than the protocol planned duration, and can be initiated by either the subject or the investigator.
The investigator must discontinue study treatment for a given subject if, he/she believes that 
continuation would negatively impact the subject's well-being.
Study treatment must be discontinued under the following circumstances:

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 14): 

Abnormal liver laboratory results requiring discontinuation – refer to 
Table 14-2 - Appendix 2;

If the investigator considers it appropriate after the confirmation of a liver safety 
monitoring signal: 


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
ALT or AST ≥ 2.5 x ULN and total bilirubin ≥ 1.5 x ULN (Section 14);

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 5.5.9;

Total white blood cell count < 1000 cells/µL;

If patients on statin therapy complain of persistent muscle pain without any obvious cause 
for greater than 3 days accompanied by increase in CK levels > 10 x ULN or persistent 
intolerable muscle pain regardless of the accompanying CK level;

If a patient develops a medical condition that requires consistent use of prohibited 
treatment as per Section 5.5.8 or if patient exhibits a behavior of non-compliance 
regarding prohibited medication.
If discontinuation of study treatment occurs, the 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 6-1).
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should 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, 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 patient's samples will still be used according to 
applicable laws.
The investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment.
5.6.3
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


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In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table.
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.
5.6.4
Loss 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
5.6.5
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. In taking the decision to terminate, 
Novartis will always consider the subject welfare and safety. Should early termination be 
necessary, subjects must be seen as soon as possible (provide instruction for contacting the 
subject, when the subject should stop taking drug, when the subject should come for a final 
visit) and treated as a prematurely withdrawn subject. The investigator may be informed of 
additional procedures to be followed in order to ensure that adequate consideration is given to 
the protection of the subject’s interests. The investigator or sponsor depending on the local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial.
6
Visit schedule and assessments
Visits must be scheduled to allow randomized study drug to be taken in the morning.


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Table 6-1 lists all of the assessments and indicates with an “x” when the visits are performed.
Patients must be seen for all visits on the designated day, or as close to it as possible. Missed or 
rescheduled visits should not lead to automatic discontinuation.
Patients, who discontinue study treatment before completing the study and will accept to remain 
in the study, will return for study visits as described in Section 5.6. If they fail to return for these 
assessments for unknown reasons, every effort should be made to contact them as specified in 
Section 5.6. At the very least, patients should be asked if they can be contacted by phone by 
study personnel at the date they would have been scheduled to end the follow up period (2 
weeks after premature drug discontinuation) to ask about surgery and procedures, SAEs, AEs 
and asthma exacerbations. The following assessments are scheduled to be performed in order 
as follows: Patient reported outcome (PRO) questionnaires (i.e. AQLQ and ACQ), ECG, Vital 
signs (pulse rate, body temperature and blood pressure), blood sample/urine samples, followed 
by spirometry.


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Table 6-1
Assessment Schedule
Period
Screening
Treatment
Post-Treatment 
Follow Up
Visit Name Screening
Run-In1,2
Treatment3
EOT or TD
Days -42 to -28 -28 to -1
1
1
42
84
112 140 168 196 224 252 280 308 336
364
378
Weeks
-6 to -4
-4 to -1
1
1
6
12
16
20
24
28
32
36
40
44
48
52
54
Telephone Contact
TC
TC
TC
TC
TC
TC
Informed consent
X
Inclusion / Exclusion criteria
X
X
X
Demography
X
Physical Examination
S
S
Medical history/current medical 
conditions4
X
X
X
Asthma exacerbation history
X
Surgeries and procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Smoking history
X
Prior medications
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Safety Follow up Call
S
Vital Signs
X
X
X
X
X
X
X
X
X
X
Body Height
X
Body Weight
X
X
X
Electrocardiogram (ECG)
X
X
Hematology
X
X
X
X
X
X
X
X
X
Blood sample for serum IgE level
X
HbA1C
X
X
Clinical Chemistry
X
X
X
X
X
X
X
X
X
Pregnancy Test (serum)
X
Urinalysis
X
X
X
X
X
X
X
X
X
Pregnancy Test (Urine)
S
S
S
S
S
S
S
S
 


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Period
Screening
Treatment
Post-Treatment 
Follow Up
Visit Name Screening
Run-In1,2
Treatment3
EOT or TD
Days -42 to -28 -28 to -1
1
1
42
84
112 140 168 196 224 252 280 308 336
364
378
Weeks
-6 to -4
-4 to -1
1
1
6
12
16
20
24
28
32
36
40
44
48
52
54
Contact IRT (IVRS/IWRS)
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
Randomization
S
Drug dispensation
S
S
S
S
S
S
Check IMP compliance
S
S
S
S
S
S
S
S
S
S
S
S
Study drug administration
Daily
Rescue medication dispense5
S
As Needed
Rescue medication review
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
Spirometry with Reversibility Test6
X
X
Spirometry
X
X
X
Asthma exacerbation7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serious Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Asthma Quality of Life Questionnaire
X
X
X
X
X
X
X
X
X
Asthma control questionnaire (ACQ-5)
X
X
X
X
X
X
X
X
X
eDiary Handout
S
eDiary training
S
S
S
eDiary/ePEF8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Check eDiary Compliance
S
S
S
S
S
S
S
S
S
S
S
S
S
S
Study completion information
X
 


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Period
Screening
Treatment
Post-Treatment 
Follow Up
Visit Name Screening
Run-In1,2
Treatment3
EOT or TD
Days -42 to -28 -28 to -1
1
1
42
84
112 140 168 196 224 252 280 308 336
364
378
Weeks
-6 to -4
-4 to -1
1
1
6
12
16
20
24
28
32
36
40
44
48
52
54
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 Patients experiencing an asthma exacerbation between screening to end of run-in, prior randomization, to be considered failures and can be eligible for re-screening 
only once, 6 weeks after recovering from the exacerbation
2 Patients switching from a mid-dose ICS to high dose (as per protocol) will require 6 additional weeks of run-in (total of 10 weeks of Run-In)   
3 Randomization Visit is at Day 1 
4 Including Protocol solicited events for Asthma
5 OCS and SABA
6 If reversibility is not met at Screening, historical reversibility will be assessed for inclusion, if not available a Run-in reversibility will be required.
7 In case of an asthma exacerbation, the patient should be encouraged by the site to contact it for advice. If necessary, an unscheduled visit to the site may be arranged.
8 eDiary will include Asthma Daily Symptoms questionnaire  
 


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6.1
Information to be collected on screening failures
All subjects who have signed informed consent but not randomized will have the disposition, 
demographics, inclusion/exclusion, informed consent, rescreening, withdrawal of consent (if 
subject withdrew consent) and serious adverse event (SAE) data collected. Adverse events that 
are not SAEs will be followed by the investigator or primary care physician and collected only 
in the source data.
All patients who have signed informed consent and have received high dose ICS/LABA 
medication, but discontinue prior to randomization (run-in failures) should have all data for the 
visits they attended and the summary pages (Adverse Event, Concomitant Medication, Dosage 
Administrative Record) completed. All adverse events occurring after informed consent is 
signed should be recorded on the Adverse Event CRF.
Investigators will have the discretion to record abnormal test findings on the medical history 
CRF whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature.
6.2
Patient demographics/other baseline characteristics
Patient demographic and baseline characteristic data to be collected on all patients include:

Age (calculated)

Sex

Race and ethnicity

Patients initials (where allowed by local legislation)

Height and Weight

BMI (calculated)

Baseline physical examination (not databases other than in the context of relevant medical 
history)

Vital signs

ECG

Date of diagnosis of asthma

Relevant medical history/ current medical condition present before signing the informed 
consent

Smoking history and status

Asthma Quality of Life (AQLQ+12)

Asthma Control (ACQ-5)

Blood eosinophil counts at Run-in Visit

Prior concomitant medication (Both asthma related and non-asthma related)

Pre and post-bronchodilator spirometry (run-in spirometry and reversibility testing)


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6.3
Treatment exposure and compliance
Study drug compliance will be assessed by the investigator and/or study personnel at designated 
visits by recording tablet counts from the previously dispensed bottles. This information must 
be captured in the source document at each visit. All study drug dispensed and returned must 
be recorded in the Drug Accountability Log. Where necessary, the Investigator will discuss 
compliance issues with the patient.
Start and end dates of only missed doses of study drug administered since the last dispensing 
visit will be recorded in the eCRFs (study drug dosage administration record summary page) at 
visits specified in the table of assessments (Table 6-1).
All doses of study drug taken at the clinic visits must be from the newly assigned medication 
bottles, except at EOT Visit when the medication returned by the patient should be used.
6.4
Efficacy
The following assessments of efficacy will be performed:

Systemic Corticosteroids use

Health Status (PROs: AQLQ+12, ACQ-5)

Biologic therapy administered during the treatment period
6.4.1
Systemic corticosteroids use
All patients will be provided with Oral Corticosteroids that can be used according to the asthma 
plan.
The total amount of daily OCS (number of tablets taken in the previous 12 hours) will be 
recorded morning and evening by the patient, in the eDiary/PEF
Investigators should instruct patients to record any OCS intake during the treatment period, on 
the eDiary/PEF device. At each study visit investigators and/or study personnel will count the 
number of OCS capsules taken (as part of the drug accountability), review OCS intake recorded 
on the eDiary by the patient, interview the patient on doses taken and enter it on the eCRF along 
with the start date, end date and the reason for the OCS intake.
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.
During certain circumstances (e.g. Hospitalization) patients might be taken injectable 
corticosteroids. This data will also be collected on the eCRF.
6.4.2
Health status (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 impact 
of uncontrolled asthma and the disease’s management: Asthma Quality of Life Questionnaire 
(AQLQ+12) and the shortened version of Asthma Control Questionnaire (ACQ-5).All PROs 


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should always be completed before any other assessments are performed to avoid influencing 
the responses. When occurring at the same visit they are to be completed in the following order: 
AQLQ+12 and ACQ-5.
6.4.2.1
Asthma Quality of Life Questionnaire (AQLQ+12)
The AQLQ+12 is a 32-item disease specific questionnaire designed to measure functional 
impairments that are most important to patients with asthma (the questionnaire is included in 
Section 19). It consists of 4 domains symptoms, emotions, exposure to environmental stimuli 
and activity limitation. Patients are asked to recall their experiences during the previous 2 weeks 
and to score each item on a 7-point scale (Juniper et al 1992, Juniper et al 1993, 
Juniper et al 2005b). The overall AQLQ score is the mean response to all 32 questions. 
Clinically important differences in scores between any two assessments have been determined 
by the authors of the AQLQ. Changes in scores of 0.5 to 1.0 are considered clinically 
meaningful; 1.0 to 1.5 as moderate and > 1.5 as marked clinically important differences for any 
individual domain or for the overall summary score ( Juniper et al 1994).
The AQLQ should be completed by the patient at the investigator's site as per the Assessment 
Schedule table (see Section 6).
6.4.2.2
Asthma Control Questionnaire (ACQ-5)
In this study, the ACQ-5 will be used to assess improvements in asthma symptom control. The 
original ACQ consists of 7 items: 5 items on symptom assessment, 1 item on rescue 
bronchodilator use, and 1 item on airway calibre (% FEV1 predicted). As the Spirometry 
assessments are performed centrally, the rescue bronchodilator use and % FEV1 predicted are 
not included in the version of ACQ chosen for this study.
The ACQ-5 will be self-administered at the clinic 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 2005a).
The ACQ-5 should be completed by the patient at the investigator's site as per the Assessment 
Schedule table (see Section 6).
6.4.3
eDiary
All patients will be provided with a patient electronic diary (referred to as eDiary/ePEF) to 
record daily asthma symptoms, peak flow, rescue medication (salbutamol/albuterol) and OCS 
use. Patients will be instructed to routinely complete the patient diary twice daily – at the same 
time each morning and each evening, approximately 12 hours apart. The eDiary/ePEF 
recordings are to be reviewed at the clinic visits as detailed in Table 6-1 until study completion. 
Sites and patients will receive appropriate training and guidance on the use of the eDiary device.
The study will use the asthma diary (Santanello et al 1997). The information detailed below 
will be collected in the eDiary/ePEF. Daytime asthma symptoms will be rated on a 0 to 6 scale 
and nocturnal asthma symptoms will be rated on a 0 to 3 scale


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6.4.3.1
Daily Symptom Scores
The asthma diary contains daytime and nocturnal asthma symptom questions as delineated 
below. The format of the electronically administered asthma diary may vary.
Symptom diary scale questions
Table 6-2
Daytime symptom diary scale questions
1) How often did you experience asthma symptoms today?
0
1
2
3
4
5
6
None of the 
time
All of the 
time
2) How much did your asthma symptoms bother you today?
0
1
2
3
4
5
6
Not at all 
bothered
Severely bot
hered
3) How much activity could you do today?
0
1
2
3
4
5
6
More than 
usual activity
Less than 
usual activity
4) How often did your asthma affect your activities today?
0
1
2
3
4
5
6
None of the 
time
All of the 
time
Table 6-3
Nocturnal diary scale question
1) Did you wake up with asthma symptoms?
This can be awakening in the middle of the night or on awakening in the morning
No
Once
More than once
Awake "all night"
6.4.3.2
Number of inhalations of Rescue Medication
The total number of inhalations used of rescue medication (number of puffs taken in the 
previous 12 hours) will be recorded morning and evening by the patient, in the eDiary/ePEF.
6.4.3.3
Peak expiratory flow (PEF)
PEF will be measured at consistent times for a patient, in the morning and evening each day 
during the study from Run-In to study completion. The measurements will be performed, using 
an eDiary/ePEF provided to the patients.
Patients should be encouraged to perform morning and evening PEF measurements BEFORE 
the use of any rescue medication, and patients will be asked to record if they have taken their 
SABA medication 6 hours prior to the peak flow assessment.
At each time point, the patient will be instructed to perform 3 consecutive maneuvers within 
approximately 10 minutes. These PEF values are captured in the eDiary /ePEF


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6.4.4
Worsening of asthma (and related eDiary alerts)
Asthma worsening criteria will be programmed into the eDiary/ePEF apart from criterion 4 
below.
The data captured in the eDiary/ePEF will be used to alert the patient and/or investigator to 
possible signs of worsening asthma.
The investigator should instruct the patient to contact the investigator if the patient 
develops one or more of the following asthma worsening criteria at any time during the 
trial from the run-in onwards. Patients may also receive an alert via their eDiary requesting 
them to contact their investigator:
1. An increase in SABA use on at least 2 of any 3 consecutive days exceeding the equivalent 
of 8 puffs/day (diary alert) *;
2. Nighttime awakenings requiring SABA use on at least 2 out of any 3 consecutive nights 
(diary alert)*;
3. <60% of PEF compared to baseline (diary alert)*; or
4. Urgent unscheduled clinic visit due to asthma-related deterioration.
*Note: The baseline for the run-in period is set the start of Run-in. The baseline during the 
treatment is set at the beginning of treatment (Day 1).
If patients develop any of the above criteria, the patient should notify the investigator and be 
evaluated by the investigator and treated as clinically appropriate. If any of these criteria are 
met while a patient is in the treatment or run-in periods of the study, they may be withdrawn if, 
in the opinion of the investigator, it is appropriate to do so.
Worsening of asthma symptoms may require unscheduled evaluation between visits. Study site 
personnel must be available to monitor and document the patient’s progress until the asthma 
worsening has resolved.
6.4.5
Biologic therapy administered during the treatment period
As part of the flexible therapy, investigators are allowed to prescribe biologics from 
randomization visit onwards. 
Given the delay to get access to the treatment in some countries, the date of prescription by the 
investigator should be recorded in addition to the start date and end date of the treatment. The 
dose, unit and reason for the treatment will also be collected.
6.4.6
Appropriateness of efficacy assessments
The measures described above are standard outcome measures in asthma studies.
6.5
Safety
The following safety assessments will be performed:

Medical history and physical examination

Adverse events including serious adverse events

Asthma Exacerbations


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
Height and weight

ECG

Laboratory evaluations (Hematology, Blood chemistry including HbA1c, Urinalysis)

Pregnancy (female patients); additional pregnancy testing might be performed if requested 
by local requirements

Serious asthma outcomes (asthma-related hospitalizations, intubations or deaths)
Spirometry will also be used to monitor the safety of patients during the study. Patients will be 
provided with an eDiary/ePEF. The data captured in the eDiary/ePEF will be used to alert the 
patient and/or investigator to possible signs of worsening of asthma.
A central laboratory will be used to analyze and report blood chemistry/hematology/urinalysis 
and urine chemistries.
A central ECG vendor will be used to collect, assess and report ECGs.
6.5.1
Medical history and physical examination
A complete physical examination will be performed at Screening Visits and EOT visit, or TD 
(if a patient discontinues investigational treatment but continues with study participation). It 
will include the examination of general appearance, skin, neck (including thyroid), eyes, ears, 
nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, vascular and neurological. 
If indicated based on medical history and/or symptoms, rectal, external genitalia, breast, and 
pelvic exams will be performed.
Information for all physical examinations must be included in the source documentation at the 
study site. Significant findings that are present prior to informed consent being granted must be 
included in the Relevant Medical History/Current Medical Conditions screen on the patient’s 
eCRF. Significant findings made after informed consent is given which meet the definition of 
an Adverse Event must be recorded on the Adverse Event screen of the patient’s eCRF.
6.5.2
Asthma Exacerbations
The following definitions of exacerbations are used in this study.
A mild asthma exacerbation is defined as one or more of the following:

Increase of asthma symptoms

An increase in SABA use on at least 2 of any 3 consecutive days exceeding the equivalent 
of 8 puffs/day (diary alert)

Nighttime awakenings requiring SABA use on at least 2 out of any 3 consecutive nights 
(diary alert)

<60% of PEF compared to baseline (diary alert)
A moderate asthma exacerbation is defined as treatment with ‘rescue’ systemic 
corticosteroids for greater than or equal to 3 days either as an outpatient or in emergency 
department visits (Emergency department visit less than or equal to 24 hours).


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A severe asthma exacerbation is defined as:

Treatment with ‘rescue’ systemic corticosteroids for greater than or equal to 3 days and 
hospitalization; or

Treatment with ‘rescue’ systemic corticosteroids for greater than or equal to 3 days and 
emergency department visit (greater than 24 hours*); or

Death due to asthma
*An emergency room visit greater than 24 hours is considered to be a hospitalization.
‘Rescue’ systemic corticosteroids are tablets, suspension, or injection, or an increase of a 
patient’s maintenance systemic corticosteroids of ≥2 fold (i.e., at least doubling of the 
maintenance dose of systemic corticosteroids). A single depo-injectable dose of corticosteroid 
will be considered the equivalent to a 3-day course of systemic steroids (Reddel et al 2009). 
Endotracheal intubations will be captured on the CRF.
Scheduled spirometry should not be performed during an exacerbation until it has completely 
resolved.
If patients experience an asthma attack/exacerbation requiring systemic corticosteroids, 
hospitalization, or emergency room visit during the screening period, they may be re-screened 
once with the re-screening of the patient occurring 6 weeks or more after recovery from the 
asthma exacerbation.
In case of an asthma exacerbation, the patient should be encouraged by the site to contact it for 
advice. If necessary, an unscheduled visit to the site may be arranged.
6.5.3
Vital signs
Vital signs will be performed at site visits specified in the table of assessments (Table 6-1). 
Measurements will include systolic and diastolic blood pressure, pulse rate, and body 
temperature.
6.5.4
Height and weight
Height in centimeters (cm) will be measured at the visits specified in the table of assessments 
(See Table 6-1).
Body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, but without shoes) will be 
measured at the visits specified in the table of assessments (See Table 6-1).
Body Mass Index (BMI) will be calculated as the weight in kg divided by the height in meters 
squared.
6.5.5
Laboratory evaluations
A central laboratory will be used for analysis of all specimens detailed in this section. Details 
on the collections, shipment of samples and reporting of results by the central laboratory are 
provided to investigators in the laboratory manual.
Details on clinically notable laboratory findings are defined in Section 13.


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6.5.5.1
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential, and 
platelet count will be measured according to the assessment schedule in Table 6-1. Other reflex 
testing will be performed as outlined in the laboratory manual.
6.5.5.2
Clinical chemistry
BUN/urea, creatinine, creatine kinase, total bilirubin, AST, ALT, alkaline phosphatase, gamma-
glutamyl transpeptidase, lactate dehydrogenase, sodium, potassium, chloride, calcium, 
magnesium, iron, bicarbonate, cholesterol, triglycerides, high-sensitivity C-reactive protein, 
phosphorus, total protein, albumin, glucose, uric acid, amylase, lipase, CK-MB and Troponin-
I (in response to CK results outside of the normal range), HbA1c (collected at start of Run-in 
Visit and EOT only) and immunoglobulins (total and specific IgE, as specified in the laboratory 
manual), will be measured according to the assessment schedule in Table 6-1. Other reflex 
testing will be performed as outlined in the laboratory manual.
If the total bilirubin concentration is increased 1.5 times and above the upper limit of normal 
range, the total bilirubin will differentiated into the direct and indirect reacting bilirubin.
All patients with laboratory tests containing clinically significant abnormalities should be 
followed until the values return to within the normal ranges or until a clinical explanation is 
identified, even after study medication has discontinued.
6.5.5.3
Urinalysis
Urine for urinalysis and urine chemistry will be collected according to the collection schedule 
in Table 6-1. All samples for urinalysis and urine chemistry will be sent to the central laboratory 
for analysis. The urinalysis evaluation by the central laboratory will include a urine dipstick for 
specific gravity, protein, glucose, leukocytes and blood and, if required, a microscopic 
examination. Urine chemistry and microscopic examination of the urine will be performed by 
the central laboratory as delineated in Section 15 “Specific Renal Alert Criteria and Actions” 
and in Section 7.4 “Renal Safety Monitoring” of this protocol. Other reflex testing will be 
performed as outlined in the laboratory manual.
6.5.6
Electrocardiogram (ECG)
ECGs will be measured according to the assessment schedule in Table 6-1. At Screening Visit, 
an ECG will be measured to test for eligibility for trial inclusion.
ECGs must be recorded according to the ECG investigator manual in the supine position to 
ensure a stable baseline. The preferred sequence of cardiovascular data collection during study 
visits is PRO collection first, followed by ECG, and then other study procedures. The Fridericia 
QT correction formula (QTcF) must be used for clinical decisions.
Single 12 lead ECGs are to be collected with ECG machines supplied by the core laboratory. 
Full details of all procedures relating to the ECG collection and reporting will be contained in 
an investigator manual to be provided to each investigator site.
The original trace will be sent electronically for central review directly from the ECG machine. 
Two ‘identical’ duplicate print-outs will be generated and kept at the investigator site as source 


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documentation and as back-up for submission to the central laboratory in case of problems with 
the electronic transmission. Each page of the ECG tracing must be labeled with study number 
(CQAW039A2323), subject initials (where this is allowed according to local regulations), 
subject number, date and time, and filed in the study site source documents.
For any ECGs with subject safety concerns, two additional ECGs must be performed to confirm 
the safety finding and copies forwarded to the central ECG laboratory for assessment. Clinically 
significant ECG findings prior to dosing with study drug must be discussed with the Novartis 
responsible person or designee.
Clinically significant abnormalities must be recorded on the relevant section of the medical 
history/Current medical conditions/AE CRF / e(CRF) page as appropriate.
In the event that the central cardiologist reports that an ECG is abnormal, then the investigator 
must comment as to whether the ECG abnormality is either clinically significant or clinically 
insignificant. If necessary a cardiologist may be consulted.
6.5.7
Pregnancy
All women of child bearing potential will have a serum pregnancy test at start of Run-In Visit 
and a urine pregnancy test at all site visits. No pregnancy testing will be performed when the 
visit is performed as a telephone call.
Pregnancy testing will begin at the visit a patient is first identified as being of child bearing 
potential.
In countries where monthly pregnancy testing is required for women of child-bearing potential 
by local laws or regulations, these patients will perform home urine pregnancy testing on the 
day of all telephone visits. These female patients will report the results of their home urine 
pregnancy test as “positive” or “negative” to study site staff as part of the telephone visit and 
the results will be recorded in source documents.
A positive urine pregnancy test requires immediate interruption of study medication until serum 
β-hCG is performed and found to be negative. If positive, the patient must be discontinued from 
the study treatment.
6.5.8
Appropriateness of safety assessments
The safety assessments selected are standard for this indication/patient population.
6.6
Other assessments
Not applicable
6.6.1
Clinical Outcome Assessments (COAs)
Please refer to Section 6.4.2


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6.6.3
Pharmacokinetics
Not applicable.
6.6.4
Spirometry
All clinic visits must occur in the morning. Please refer to Section 6 and Table 6-1 for full 
details of the scheduling of spirometry measurements. During the treatment period, the 
spirometry assessment should be done pre-dose.
Equipment for spirometry assessments will be provided to all study sites by a Central 
Spirometry vendor, and pre randomization measurements will be reviewed by trained 
spirometry overreaders at the central vendor. The final spirometry assessments for study 
qualification will be those provided by the spirometry overreaders of the central spirometry 
vendor.
Please refer to the Spirometry Guidance, in Section 17 , for full details on performing 
spirometry. Reversibility testing must be conducted in the morning
6.6.5
Other biomarkers
Not applicable.
7
Safety monitoring
7.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. 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 


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the subject during or between visits or through physical examination findings, laboratory test 
findings, or other assessments.
Adverse events must be recorded under the signs, symptoms or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 7.2.1)
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 7.2.1 for definition of SAE) and which 
seriousness criteria have been met
5. action taken regarding with study treatment
6. 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
7. its outcome i.e., its recovery status or whether it was fatal
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


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Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in subjects with 
the underlying disease. Alert ranges for laboratory and other test abnormalities are included in 
Section 13.
7.2
Serious adverse events
7.2.1
Definition of SAE
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the following 
criteria:

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:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition under study .

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

social reasons and respite care in the absence of any deterioration in the subject’s general 
condition

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant”. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse. (please refer to the ICH-
E2D Guidelines)
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.


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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.
7.2.2
SAE reporting
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days following the last administration of study 
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.
Any SAEs experienced after the 30 day period following the last administration of study 
treatment should only be reported to Novartis Safety if the investigator suspects a causal 
relationship to study treatment.
7.3
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 14-1 - Appendix 2 in Section 14 for complete definitions of liver 
laboratory triggers and liver events.


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Every liver event defined in Table 14-1 - 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 14-2 - 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.

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
7.4
Renal safety monitoring
The following two categories of abnormal renal laboratory values have to be considered during 
the course of the study:
Serum event:

Confirmed (after ≥24 hours) increase in serum creatinine (sCr) of ≥25% compared to 
baseline during normal hydration status
Urine event:

Albumin-creatinine ratio (ACR) ≥1g/g or ≥100 mg/mmol.

Protein-creatinine ratio (PCR ) ≥1g/g or ≥100 mg/mmol.
Every renal laboratory trigger or renal event as defined in Table 15-1 - Appendix 3 should be 
followed up by the investigator or designated personnel at the trial site as summarized in 
Section 15.
7.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (EMA definition)


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Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness.
Table 7-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dose 
Administration 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.
7.6
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 (CMO&PS). 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.
7.7
Prospective suicidality assessment
Not applicable
8
Data review and database management
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
8.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eCRFs) with the 


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investigators and their staff. During the study, Novartis employs several methods of ensuring 
protocol and GCP compliance and the quality/integrity of the sites’ data. The field monitor will 
visit the site to check the completeness of subject records, the accuracy of data capture / data 
entry, the adherence to the protocol and to Good Clinical Practice, the progress of enrollment, 
and to ensure that study treatment is being stored, dispensed, and accounted for according to 
specifications. Key study personnel must be available to assist the field monitor during these 
visits. Continuous remote monitoring of each site’s data may be performed by a centralized 
Novartis 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 to the filed 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.
8.2
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. Designated investigator site staff will not be given access to the EDC system until 
they have been trained. Automatic validation programs check for data discrepancies and, by 
generating appropriate error messages, allow the data to be confirmed or corrected before 
transfer of the data to the CRO working on behalf of Novartis. The Investigator must certify 
that the data entered into the Electronic Case Report Forms are complete and accurate. After 
database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site.
8.3
Database management and quality control
Novartis 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.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis.


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Spirometry readings will be processed centrally and the results will be sent electronically to 
Novartis.
ECG readings will be processed centrally and the results will be sent electronically to 
Novartis.Diary data will be entered into an electronic diary by the patient and patients will fill 
in their PRO data in a site-based tablet. The system will be supplied by a vendor(s), who will 
also manage the database. The database will be sent electronically to Novartis personnel.
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.
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/moved to restricted area to be accessed by independent 
programmer and statistician. Any changes to the database after that time can only be made 
after written agreement by Novartis development management.
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unblinded and made available for data analysis. Any 
changes to the database after that time can only be made after written agreement by Novartis 
Development management.
8.4
Data Monitoring Committee
Not required.
8.5
Adjudication Committee
Not required.
9
Data analysis
The analysis will be conducted on all subject data at the time the trial ends. Any data analysis 
carried out independently by the investigator should be submitted to Novartis before publication 
or presentation.
9.1
Analysis sets
The screened set (SCR) will include all patients who provided informed consent.


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The randomized set (RAN) will include all patients that were randomized. Data from these 
patients will be analyzed according to the treatment to which the patient was assigned at 
randomization.
The full analysis set (FAS) will include all randomized patients who received at least one dose 
of study drug. It was considered reasonable to limit the FAS to patients who took trial 
medication, because the decision on whether or not treatment is started will not be influenced 
by the treatment group assignment due to the effective treatment blinding procedures described 
in Section 5.4. Following the intent-to-treat principle, patients will be analyzed according to the 
treatment they were assigned to at randomization.
The safety set (SAF) will include all patients who received at least one dose of study drug. 
Patients will be analyzed according to the treatment they received.
The analysis of the primary objective will be performed on the FAS. The FAS will be used for 
the analysis of all other efficacy variables. The SAF will be used in the analysis of all safety 
variables.
9.2
Patient demographics and other baseline characteristics
Patient demographics and baseline characteristics measured before randomization will be 
summarized by treatment group for the FAS.
9.3
Treatments
The safety set will be used for the analysis below.
A data listing and a summary of the study drug administered will be provided.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system, by treatment group.
A listing and summary of rescue medications will be provided.
9.4
Analysis of the primary variable(s)
The primary analysis for this study will be conducted according to the intention to treat principle.
9.4.1
Primary Variable(s)
The primary endpoint for this study is total systemic corticosteroid dose in mg 
prednisone/prednisolone (or equivalent) over 52 weeks of treatment.
9.4.2
Statistical model, hypothesis, and method of analysis
The primary endpoint will be analyzed in subpopulation of patients with eosinophil count ≥ 250 
cells/µl and in overall population. The primary null hypotheses are:

H01 450 eosinophil subgroup: the distribution of the total systemic corticosteroid dose in mg 
prednisone/prednisolone (or equivalent) in Fevipiprant 450 mg QD plus SoC is equivalent 
to the distribution of the total systemic corticosteroid dose in mg prednisone/prednisolone 
(or equivalent) in placebo plus SoC in patients with eosinophil count ≥ 250 cells/µl


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
H02 150 eosinophil subgroup: the distribution of the total systemic corticosteroid dose in mg 
prednisone/prednisolone (or equivalent) in Fevipiprant 150 mg QD plus SoC is equivalent 
to the distribution of the total systemic corticosteroid dose in mg prednisone/prednisolone 
(or equivalent) in placebo plus SoC in patients with eosinophil count ≥ 250 cells/µl

H03 450 overall population: the distribution of the total systemic corticosteroid dose in mg 
prednisone/prednisolone (or equivalent) in Fevipiprant 450 mg QD plus SoC is equivalent 
to the distribution of the total systemic corticosteroid dose in mg prednisone/prednisolone 
(or equivalent) in placebo plus SoC for the overall population

H04 150 overall population: the distribution of the total systemic corticosteroid dose in mg 
prednisone/prednisolone (or equivalent) in Fevipiprant 150 mg QD plus SoC is equivalent 
to the distribution of the total systemic corticosteroid dose in mg prednisone/prednisolone 
(or equivalent) in placebo plus SoC for the overall population
The primary alternate hypotheses are:

HA1 450 eosinophil subgroup: the distribution of the total systemic corticosteroid dose in mg 
prednisone/prednisolone (or equivalent) in Fevipiprant 450 mg QD plus SoC is different 
to the distribution of the total systemic corticosteroid dose in mg prednisone/prednisolone 
(or equivalent) in placebo plus SoC in patients with eosinophil count ≥ 250 cells/µl

HA2 150 eosinophil subgroup: the distribution of the total systemic corticosteroid dose in mg 
prednisone/prednisolone (or equivalent) in Fevipiprant 150 mg QD plus SoC is different 
to the distribution of the total systemic corticosteroid dose in mg prednisone/prednisolone 
(or equivalent) in placebo plus SoC in patients with eosinophil count ≥ 250 cells/µl

HA3 450 overall population: the distribution of the total systemic corticosteroid dose in mg 
prednisone/prednisolone (or equivalent) in Fevipiprant 450 mg QD plus SoC is different 
to the distribution of the total systemic corticosteroid dose in mg prednisone/prednisolone 
(or equivalent) in placebo plus SoC for the overall population

HA4 150 overall population: the distribution of the total systemic corticosteroid dose in mg 
prednisone/prednisolone (or equivalent) in Fevipiprant 150 mg QD plus SoC is different 
to the distribution of the total systemic corticosteroid dose in mg prednisone/prednisolone 
(or equivalent) in placebo plus SoC for the overall population
Familywise type I error rate control
The familywise type I error rate will be controlled at the two-sided 5% level across the primary 
null hypotheses using graphical approach specified by Figure 9-1 (Bretz et al 2009).


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Figure 9-1
Closed testing procedure for primary objectives
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 subgroup 
with blood eosinophils ≥ 250 cells/μl for the 2 fevipiprant doses). Directed edges between the vertices 
specify how the local significance levels are propagated in case of significant results.
Initially, 50% of the alpha is assigned to each of the primary null hypotheses regarding the 
subgroup with blood eosinophils ≥ 250 cells/µl for the Fevipiprant 450 mg QD and Fevipiprant 
150 mg QD doses, respectively. Once this first primary null hypothesis for a dose has been 
rejected, the alpha will be distributed to the other null hypothesis regarding the overall 
population for the same dose. If the null hypothesis regarding the primary endpoint for the 
overall population is rejected for a dose, then alpha is reassigned to the primary null hypotheses 
regarding the subgroup with blood eosinophils ≥ 250 cells/µl for the other dose. Alpha will only 
be reassigned from the null hypotheses for a dose to the null hypotheses for the other dose once 
all null hypotheses for the dose to which the alpha was originally assigned have been rejected.
Statistical model for primary variable
The total systemic corticosteroid dose in mg prednisone/prednisolone (or equivalent) over 52 
weeks of treatment will be analyzed using the Wilcoxon-Mann-Whitney rank sum test (Van 
Elteren test). For overall population analysis will be stratified by randomization stratum – blood 
eosinophils levels (≥ 250 cells/µl and < 250 cells/µl). For subgroup with blood eosinophils ≥ 
250 cells/µl, analysis will not include stratification factor. The summary statistics for total SCS 
dose by treatment group will be provided.
The details and justification of primary as well as supplementary estimands are detailed in 
Estimand charter or statistical analysis plan (SAP).
The primary estimand will quantify the treatment effect based on on-treatment data. The total 
SCS dose data will be aggregated into monthly data for analysis. The primary estimand will 
account for different post-randomization events as follows:

Use of rescue medications: Efficacy data collected during use of rescue medication will be 
used for analysis.


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
Early discontinuation of study treatment (prior to completing 52 weeks of treatment 
period): For the patients discontinuing treatment early, the total SCS dose for 52 weeks 
will be obtained as annualized SCS dose. For example if patient took 280 mg for 7 months 
then for 12 months patient will be taking 280*12/7=480mg total SCS dose.

Use of biologics prior to discontinuation of treatment: Efficacy data collected during the 
use of biologics will be set to missing, since use of biologics can confound efficacy data. 
After replacing SCS dose with missing patient will not have data available for 12 months, 
thus total SCS dose will be obtained as annualized dose.
9.4.3
Handling of missing values/censoring/discontinuations
Some patients may discontinue early and may not complete the entire study duration. For the 
patients discontinuing treatment early, the total SCS dose for 52 weeks will be obtained as 
annualized SCS dose. For example if patient took 280 mg for 7 months then for 12 months 
patient will be taking 280*12/7=480mg total SCS dose. Efficacy data collected during the use 
of biologics will be set to missing, since use of biologics can confound efficacy data. After 
replacing SCS dose with missing, patient will not have data available for all 12 months, thus 
total SCS dose will be obtained as annualized dose.
9.4.4
Sensitivity analyses
The details on sensitivity analysis will be provided in SAP.
9.5
Analysis of secondary variables
9.5.1
Efficacy variables
Proportion of patients with no SCS use over 52 weeks of treatment
The proportion of patients with no SCS use over 52 weeks treatment will be summarized by 
treatment and analyzed using logistic regression in overall population. The model will include 
treatment and randomization strata as covariates. Estimates of the odds ratio between treatment 
groups will be displayed along with associated 95% confidence intervals and two-sided p-
values.
Proportion of patients requiring ≥ 7.5mg systemic corticosteroid dose in mg 
prednisone/prednisolone (or equivalent) per day continuously for at least 30 days 
The proportion of patients requiring ≥ 7.5mg systemic corticosteroid dose in mg 
prednisone/prednisolone (or equivalent) per day continuously for at least 30 days in 52 weeks 
treatment period will be summarized by treatment and analyzed using logistic regression in 
overall population. The model will include treatment and randomization strata as covariates. 
Estimates of the odds ratio between treatment groups will be displayed along with associated 
95% confidence intervals and two-sided p-values.
Asthma Quality of Life Questionnaire (AQLQ+12)
The 32 items in the AQLQ are divided into 4 domain- specific scores and a total score as 
follows:

Symptoms = Mean of Items 6,8,10,12,14,16,18,20,22,24,29,30 (12 items)


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
Activity limitation = Mean of Items 1,2,3,4,5,11,19,25,28,31,32 (11 items)

Emotional function = Mean of Items 7,13,15,21,27 (5 items)

Environmental stimuli = Mean of Items 9,17,23,26 (4 items)

Overall score = Mean of Items 1 to 32 (32 items)
Each item of the AQLQ is equally weighted and scored along a 7-point scale, where 1 indicates 
maximal impairment and 7 indicates no impairment. Thus, higher scores indicate better asthma-
related HRQOL. There is a mean score calculated for each of the four domains, as well as an 
overall quality of life score, which is the mean score of all 32 items. The resultant overall scores 
will be between 1 and 7. 
The developer suggests no more than 10% of missing data. This means no more than 3 missing 
responses for the overall score and no more than 1 missing response per domain. For the 
symptoms and activity domain scores, one missing value per domain is allowed. For the 
emotional function and environmental stimuli domain scores, no missing values are allowed. If 
these limits for missing questions are exceeded, the variable will be considered missing and 
imputation method will be detailed in statistical analysis plan.
The minimal important difference (MID), defined as “the smallest difference in score which 
patients perceive as beneficial and would mandate, in the absence of troublesome side effects 
and excessive cost, a change in the patient’s management,” of 0.5 has been established for this 
questionnaire as clinically significant (Juniper et al 1994).
The AQLQ score will be analyzed using a mixed model for repeated measures (MMRM) with 
an unstructured covariance structure with factors for treatment group, time and randomization 
stratum, as well as the baseline AQLQ as continuous linear covariates.
The null hypothesis will be tested for overall population for each dose group using this model 
versus two-sided alternative hypotheses. For each dose group the null hypothesis is that the 
treatment difference compared to placebo at the week 52 visit is equal to zero, while the 
alternative hypothesis is that the treatment difference to placebo at week 52 visit is not equal to 
zero.
Asthma Control Questionnaire (ACQ-5)
The ACQ measures asthma symptom control and consists of 7 items. It includes the 5 most 
important symptoms, 1 about rescue bronchodilator use and 1 about airway calibre (FEV1 % 
predicted pre-bronchodilator). Patients will be asked to recall their experiences during the past 
one week and to response items 1-6 (night-time waking, symptoms on waking, activity 
limitation, shortness of breath, wheeze, and rescue short-acting β2-agonist use) on a 7-point 
scale (0 – totally controlled, 6 – extremely poorly controlled). The ACQ-5 score calculated 
based on the 5 questions of the 5 most important symptoms. The 5 questions of the ACQ-5 are 
equally weighted. The ACQ-5 score is the mean of the responses to the 5 questions. The 
resultant score will be between 0 and 6.
A score of 1.5 at baseline indicates patients who entered the study had inadequately controlled 
asthma (Juniper et al 2006). In addition, the minimal important difference (MID) or smallest 
change that can be considered clinically important is 0.5.


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The ACQ-5 score will be analyzed using a MMRM with an unstructured covariance structure 
with factors for treatment group, time and randomization stratum, as well as the baseline ACQ-
5 as continuous linear covariates.
The null hypothesis will be tested for overall population for each dose group using this model 
versus two-sided alternative hypotheses. For each dose group the null hypothesis is that the 
treatment difference compared to placebo at the week 52 visit is equal to zero, while the 
alternative hypothesis is that the treatment difference to placebo at week 52 visit is not equal to 
zero.
Time to first prescription of biologic therapy from first dose of study treatment received 
over 52 weeks of treatment
The time to first prescription of biologic therapy from first dose of study treatment received 
over 52 weeks of treatment will be summarized by treatment group. Between-treatment 
differences will be evaluated using cox regression model.
Change from baseline in daytime and nighttime symptom scores in 52 weeks of treatment 
Change from baseline in each endpoint (daytime and nighttime symptom score) will be 
analyzed using mixed models repeated measures (MMRM) model with factors as treatment 
group, randomization strata, time interval, time interval by treatment group interaction and the 
associated baseline as continuous linear covariate. Estimates of the LS means between 
treatment groups will be displayed along with associated 95% confidence intervals and two-
sided p-values.
9.5.2
Safety variables
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group.
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs).
The on-treatment period lasts from the date of first administration of study treatment to 14 days 
after the date of the last actual administration of any study treatment.
Adverse events
All information obtained on adverse events will be displayed by treatment group and subject.
The number (and percentage) of subjects with treatment emergent adverse events (events started 
after the first dose of study medication or events present prior to start of double-blind treatment 
but increased in severity based on preferred term) will be summarized in the following ways:

by treatment, primary system organ class and preferred term.

by treatment, primary system organ class, preferred term and maximum severity.

by treatment, Standardized MedDRA Query (SMQ) and preferred term


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Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation and adverse events 
leading to dose adjustment.
The adverse events of special interest will be listed and summarized by treatment group.
A subject with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class.
Vital signs
All vital signs data will be listed by treatment group, subject, and visit and if ranges are available, 
abnormalities will be flagged. Summary statistics will be provided by treatment group.
12-lead ECG
All ECG data will be listed by treatment group, subject and visit, abnormalities will be flagged.
Summary statistics will be provided by treatment.
Clinical laboratory evaluations
All laboratory data will be listed by treatment group, subject, and visit and if normal ranges are 
available abnormalities will be flagged. Summary statistics will be provided by treatment group. 
Shift tables using the low/normal/high/ (low and high) classification will be used to compare 
baseline to the worst on-treatment value.
9.5.4
Pharmacokinetics
Not applicable.
9.5.5
DNA
Not applicable.
9.5.6
Biomarkers
Not applicable
9.5.7
PK/PD
Not applicable
9.7
Interim analyses
Not Applicable


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9.8
Sample size calculation
The historical data (US Marketscan database) shown in Table 9-1 indicates that the distribution 
of the total systemic corticosteroid dose in mg prednisone/prednisolone (or equivalent) across 
patients is not normal; rather the distribution is skewed; hence using a normal distribution 
assumption is not appropriate. In addition, the proportion of patients with 0 total systemic 
corticosteroid dose in mg prednisone/prednisolone (or equivalent) is quite high (>30%) 
therefore a transformation that could normalize the distribution is not feasible. As a 
consequence, a non-parametric method based on rank analysis will be used to analyze the 
primary end-point. The formula developed for the Wilcoxon-Mann-Whitney test adjusting for 
ties (Zhao et al 2008) has been used to estimate the sample size. A 1:1:1 randomization was 
used. There are four hypotheses to be tested for primary endpoint as stated in Section 9.4.2.
Table 9-1
Frequency distribution of dose to display (non-normal) distribution of 
US Marketscan database
HD ICS/LABA+LAMA
6 weeks
HD ICS/LABA+LTRA
6 weeks
HD ICS/LABA
6 weeks
Outcomes
n=1562
n=7409
n=18471
Dose Category 
(Count/%)
0 (0mg)
533
34.1%
2901
39.2%
8211
44.5%
1 (>0 - 50 mg)
5
0.3%
20
0.3%
46
0.2%
2 (>50 - 100 mg)
25
1.6%
90
1.2%
214
1.2%
3 (>100 - 150 mg)
107
6.9%
595
8.0%
1376
7.4%
4 (>150 - 200 mg)
62
4.0%
358
4.8%
904
4.9%
5 (>200 - 250 mg)
90
5.8%
335
4.5%
808
4.4%
6 (>250 - 300 mg)
50
3.2%
313
4.2%
789
4.3%
7 (>300 - 350 mg)
40
2.6%
184
2.5%
426
2.3%
8 (>350 - 400 mg)
47
3.0%
216
2.9%
608
3.3%
9 (>400 - 450 mg)
44
2.8%
219
3.0%
519
2.8%
10 (>450 - 500 mg)
34
2.2%
181
2.4%
396
2.1%
11 (>500 - 550 mg)
24
1.5%
141
1.9%
308
1.7%
12 (>550 - 600 mg)
39
2.5%
221
3.0%
479
2.6%
13 (>600 - 650 mg)
19
1.2%
99
1.3%
237
1.3%
14 (>650 - 700 mg)
16
1.0%
80
1.1%
214
1.2%
15 (>700 - 750 mg)
28
1.8%
103
1.4%
252
1.4%
16 (>750 mg)
399
25.5%
1353
18.3%
2684
14.5%
Table 9-2 represents the selected scenario for the null and alternative hypothesis and the sample 
size under a 90% power and an overall alpha two sided of 5%. As we have two doses to test, 
the alpha considered for the sample size is 2.5% two sided.
Under the assumptions specified above and scenarios described in Table 9-2, 134 patients per 
arm in the subpopulation with eosinophils count ≥ 250 cells/µl and 201 patients per arm in the 
overall population corresponding to a total sample size of 603 patients provide greater than 90% 
power for primary null hypotheses. Assuming 10% treatment discontinuation rate, a total of 
669 patients are needed.


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alpha 2.5% 
power 90%
0-
50mg/
year
>50-
150 
mg/
year
>150-
300 
mg/
year
>300-
450 
mg/
year
>450-
600 
mg/
year
>600 
mg/
year
High 
EoS
Full 
population
+10%
Placebo
42.7%
8.8%
13.5%
8.4%
6.6%
20.0%
-
-
-
Fevi
60.0%
15.0%
9.0%
3.0%
3.0%
10.0%
402
603
669
We have looked also at other possible distributions for both fevipiprant and placebo under a 
power of 80% or 90% and alpha 0.025 two sided.  Table 9-2 provides other scenarios for the 
placebo and the Fevi group. Even if we deviate from the original scenario, other possible 
distributions provide still good power.
Table 9-2
Other scenario investigated for Fevipiprant single dose EOS greater 
or equal 250 cells/microliter
alpha 
2.5% 
0-50mg 
/year
>50-150 
mg/year
>150-300 
mg/year
>300-450 
mg/year
>450-600 
mg/year
>600 
mg/year
Power 
under the 
assumption 
of 134 pts 
per arm
Placebo
0.0%
10.0%
25.0%
25.0%
15.0%
25.0%
-
Scenario 1 
Fevi
5.0%
25.0%
25.0%
20.0%
10.0%
15.0%
96%
alpha 
2.5% 
0-
50mg/year
>50-150 
mg/year
>150-300 
mg/year
>300-450 
mg/year
>450-600 
mg/year
>600 
mg/year
Placebo
20.0%
5.0%
20.0%
10.0%
15.0%
30.0%
-
Scenario 2 
Fevi
35.0%
20.0%
30.0%
5.0%
5.0%
5.0%
100%
alpha 
2.5% 
0-
50mg/year
>50-150 
mg/year
>150-300 
mg/year
>300-450 
mg/year
>450-600 
mg/year
>600 
mg/year
Placebo
42.7%
8.8%
13.5%
8.4%
6.6%
20.0%
-
Scenario 3 
Fevi
57.0%
18.0%
9.0%
3.0%
3.0%
10.0%
85%
Scenario 4 
Fevi
55.0%
14.0%
14.0%
5.0%
3.0%
9.0%
75%
alpha 
2.5% 
0-
50mg/year
>50-150 
mg/year
>150-300 
mg/year
>300-450 
mg/year
>450-600 
mg/year
>600 
mg/year
Placebo
0.0%
10.0%
25.0%
25.0%
15.0%
25.0%
-
Scenario 5 
Fevi
5.0%
25.0%
20.0%
20.0%
12.0%
18.0%
82%
Based on clinical judgment different scenarios are considered in the above table
The following formula to calculate the sample size has been used (Zhao et al 2008):
Where,
N is the total sample size for a 2 arm trial.


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t is the randomization ratio
pc are the % of patients in category c for the experiment arm
qc are the % of patients in category c for the control arm
D is number of categories
10
Ethical considerations
10.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21 ), and with the ethical 
principles laid down in the Declaration of Helsinki.
10.2
Informed consent procedures
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation), IRB/IEC-approved informed consent.
If applicable, in cases where the subject's representative(s) gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible given 
his/her understanding. If the subject is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document.
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the subject source documents.
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the subject 
informed consent and should be discussed with the subject during the study as needed. Any new 
information regarding the safety profile of the investigational drug that is identified between IB 
updates will be communicated as appropriate, for example, via an investigator notification or 
an aggregate safety finding. New information might require an update to the informed consent 
and then must be discussed with the subject.
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements.
A copy of the approved version of all consent forms must be provided to Novartis/sponsor after 
IRB/IEC approval.


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10.3
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures (e.g., 
advertisements) and any other written information to be provided to subjects. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made.
10.4
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.)
10.5
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.
11
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.


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Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented
11.1
Protocol Amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation.
Only amendments that are required for subject safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations.


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References
References are available upon request
ATS (2000). Proceedings of the ATS workshop on refractory asthma: current understanding, 
recommendations, and unanswered questions. American Thoracic Society. Am. J. Respir. 
Crit. Care Med. p. 2341-51.
ATS/ERS (2005) Recommendations for standardized procedures for the online and offline 
measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005. Am. J. 
Respir. Crit. Care Med; p. 912-30.
Bourdin A et al. (2018), abstr. CO01-4, actualisé Impact de l’asthme sévère en France: une 
étude à partir de l’échantillon généraliste de bénéficiaires”.
Bretz F, Maurer W, Brannath W, et al (2009) A graphical approach to sequentially rejective 
multiple test procedures. Stat Med; p. 586-604.
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.
Dalal AA, Duh MS, Gozalo L, et al (2016) Dose-Response Relationship Between Long-Term 
Systemic Corticosteroid Use and Related Complications in Patients with Severe Asthma. J 
Manag Care Spec Pharm p. 833-47.
De Vries F, Bracke M, Leufkens HG, et al (2007) Fracture risk with intermittent high-dose 
oral glucocorticoid therapy. Arthritis Rheum. p. 208-14.
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.
Global Initiative for Asthma (GINA) (2018) Global Strategy for Asthma Management and 
Prevention. Available from: http://www.ginasthma.org/. 
Haldar P, Brightling CE, Hargadon B, et al (2009) Mepolizumab and exacerbations of 
refractory eosinophilic asthma. N. Engl. J. Med. p. 973-84.
Jacobson TA (2008) Toward "pain-free" statin prescribing: clinical algorithm for diagnosis 
and management of myalgia. Mayo Clin. Proc. p. 687-700.


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Juniper EF, Bousquet J, Abetz L, et al (2006) Identifying 'well-controlled' and 'not well-
controlled' asthma using the Asthma Control Questionnaire. Respir Med p. 616-21.
Juniper EF, Guyatt GH, Epstein RS, et al (1992) Evaluation of impairment of health related 
quality of life in asthma: development of a questionnaire for use in clinical trials. Thorax p. 
76-83.
Juniper EF, Guyatt GH, Ferrie PJ, et al (1993) Measuring quality of life in asthma. Am. Rev. 
Respir. Dis. p. 832-8.
Juniper EF, Guyatt GH, Willan A, et al (1994) Determining a minimal important change in a 
disease-specific Quality of Life Questionnaire. J Clin Epidemiol p. 81-7.
Juniper EF, O'Byrne PM, Guyatt GH, et al (1999) Development and validation of a 
questionnaire to measure asthma control. Eur. Respir. J. p. 902-7.
Juniper EF, Svensson K, Mörk AC, et al (2005)a Measurement properties and interpretation 
of three shortened versions of the asthma control questionnaire. Respir Med p. 553-8.
Juniper EF, Svensson K, Mörk AC, et al (2005)b Modification of the asthma quality of life 
questionnaire (standardised) for patients 12 years and older. Health Qual Life Outcomes p. 58.
Kalliokoski A, Niemi M (2009) Impact of OATP transporters on pharmacokinetics. Br. J. 
Pharmacol. p. 693-705.
Lefebvre P, Duh MS, Lafeuille MH, et al (2015) Acute and chronic systemic corticosteroid-
related complications in patients with severe asthma. J. Allergy Clin. Immunol. p. 1488-1495.
Masoli M, Fabian D, Holt S, et al (2004) The global burden of asthma: executive summary of 
the GINA Dissemination Committee report. Allergy p. 469-78.
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.
Partridge MR (2004) Written asthma action plans. Thorax p. 87-8.
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.
Reddel HK, Taylor DR, Bateman ED, et al (2009) An official American Thoracic 
Society/European Respiratory Society statement: asthma control and exacerbations: 
standardizing endpoints for clinical asthma trials and clinical practice. Am. J. Respir. Crit. 
Care Med. p. 59-99.
Regan SL, Maggs JL, Hammond TG, et al (2010) Acyl glucuronides: the good, the bad and 
the ugly. Biopharm Drug Dispos p. 367-95.
Santanello NC, Barber BL, Reiss TF, et al (1997) Measurement characteristics of two asthma 
symptom diary scales for use in clinical trials. Eur. Respir. J. p. 646-51.
Schäcke H, Döcke WD, Asadullah K (2002) Mechanisms involved in the side effects of 
glucocorticoids. Pharmacol. Ther. p. 23-43.


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Sullivan PW, Ghushchyan VH, Globe G, et al (2018) Oral corticosteroid exposure and 
adverse effects in asthmatic patients. J. Allergy Clin. Immunol. p. 110-116.e7.
Sweeney J, Patterson CC, Menzies-Gow A, et al (2016) Comorbidity in severe asthma 
requiring systemic corticosteroid therapy: cross-sectional data from the Optimum Patient Care 
Research Database and the British Thoracic Difficult Asthma Registry. Thorax p. 339-46.
Takaku Y, Soma T, Nishihara F, et al (2013) Omalizumab attenuates airway inflammation 
and interleukin-5 production by mononuclear cells in patients with severe allergic asthma. Int. 
Arch. Allergy Immunol. p. 107-17.
Wenzel S, Ford L, Pearlman D, et al (2013) Dupilumab in persistent asthma with elevated 
eosinophil levels. N. Engl. J. Med. p. 2455-66.
Zazzali JL, Broder MS, Omachi TA, et al (2015) Risk of corticosteroid-related adverse events 
in asthma patients with high oral corticosteroid use. Allergy Asthma Proc p. 268-74.
Zhao YD, Rahardja D, Qu Y (2008) Sample size calculation for the Wilcoxon-Mann-Whitney 
test adjusting for ties. Stat Med p. 462-8.


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13
Appendix 1: Clinically notable laboratory values and vital 
signs
The central laboratory will flag laboratory values falling outside of the normal ranges on the 
central laboratory reports. Investigators are responsible for reviewing these abnormal values for 
clinical significance, signing the laboratory reports to indicate their review, and reporting values 
considered clinically significant in the appropriate electronic case report form (eCRF).
Any clinically significant abnormal laboratory value should be evaluated and followed-up by 
the investigator until normal or a cause for the abnormality is determined.
See Section 14 for specific liver event and laboratory test trigger definitions and follow-up 
requirements. See Section 15 for specific renal alert criteria and actions.
For electrocardiograms (ECGs), a notable QTc value is defined as a QTcF (Fridericia) interval 
of ≥450 msec for males or ≥460 msec for females – all such ECGs will be flagged by the Central 
contract research organization (CRO) and require assessment for clinical relevance and 
continuance of the patient by the Investigator.
14
Appendix 2: Liver event and Laboratory trigger Definitions 
and Follow-up Requirements
Table 14-1
Liver Event and Laboratory Trigger Definitions
Definition/ threshold
LIVER 
LABORATORY 
TRIGGERS

3 x ULN < ALT / AST ≤ 5 x ULN

1.5 x ULN < TBL ≤ 2 x ULN
LIVER EVENTS

ALT or AST > 5 × ULN

ALP > 2 × ULN (in the absence of known bone pathology)

TBL > 2 × ULN (in the absence of known Gilbert syndrome)

ALT or AST > 3 × ULN and INR > 1.5

Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and TBL > 2 × ULN 
[mainly conjugated fraction] without notable increase in ALP to > 2 × ULN)

Any clinical event of jaundice (or equivalent term)

ALT or AST > 3 × ULN accompanied by (general) malaise, fatigue, abdominal pain, 
nausea, or vomiting, or rash with eosinophilia

Any adverse event potentially indicative of a liver toxicity*
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-related 
conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver neoplasms TBL (total 
bilirubin), ULN (upper limit of normal).
Table 14-2
Follow Up Requirements for Liver Events and Laboratory Triggers
Criteria
Actions required
Follow-up monitoring
Potential Hy’s Law case[a]

Discontinue the study treatment 
immediately

Hospitalize, if clinically appropriate

Establish causality

Record the AE and contributing 
factors (e.g., conmeds, med hx, 
lab) in the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolution[c] (frequency 
at investigator discretion)


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Criteria
Actions required
Follow-up monitoring
ALT or AST
> 8 × ULN

Discontinue the study treatment 
immediately

Hospitalize if clinically appropriate

Establish causality

Record the AE and contributing 
factors (e.g., conmeds, med hx, 
lab) in the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolution[c] (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 GGT until resolution[c] (frequency 
at investigator discretion)
> 5 to ≤ 8 × ULN

Repeat LFT within 48 hours

If elevation persists, continue 
follow-up monitoring

If elevation persists for more than 2 
weeks, discontinue the study drug

Establish causality

Record the AE and contributing 
factors (e.g., conmeds, med hx, 
lab) in the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolution[c] (frequency 
at investigator discretion)
> 3 × ULN accompanied by 
symptoms[b]

Discontinue the study treatment 
immediately

Hospitalize if clinically appropriate

Establish causality

Record the AE and contributing 
factors (e.g., conmeds, med hx, 
lab) in the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolution[c] (frequency 
at investigator discretion)
> 3 to ≤ 5 × ULN (patient is 
asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate 
close observation of the patient
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolution[c] (frequency 
at investigator discretion)
ALP (isolated)
> 2 × ULN (in the absence 
of known bone pathology)

Repeat LFT within 48 hours

If elevation persists, establish 
causality

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 GGT until resolution[c] (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
Investigator discretion
 


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Criteria
Actions required
Follow-up monitoring

If elevation is confirmed, initiate 
close observation of the patient
Monitor LFT within 1 to 4 weeks or at 
next visit
Jaundice

Discontinue the study treatment 
immediately

Hospitalize the patient

Establish causality

Record the AE and contributing 
factors (e.g., conmeds, med hx, 
lab) in the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolution[c] (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.
ULN (upper limit of normal), ALT (alanine aminotransferase), AST (aspartate aminotransferase), TBL (total 
bilirubin), ALP (alkaline phosphatase), INR (international normalized ratio), PT (prothrombin time), Alb 
(albumin), LFT (lung function test), CRF (case report form).


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15
Appendix 3: Specific Renal Alert Criteria and Actions
Table 15-1
Specific Renal Alert Criteria and Actions
Serum Event
Serum creatinine increase 25% – 49% compared 
to baseline
Confirm 25% increase after 24-48h
Follow up within 2-5 days
Acute Kidney Injury: Serum creatinine increase 
≥50% compared to baseline
Follow up within 24-48h if possible
Consider study treatment interruption
Consider patient hospitalization /specialized treatment
Urine Event
Albumin-creatinine ratio (ACR) ≥1g/g or ≥100 
mg/mmol;
Protein-creatinine ratio (PCR )≥1 g/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
Appendix 4: List of idiosyncratic drug reactions (IDRs) for 
investigators
Table 16-1
Definition of potential idiosyncratic drug reactions
Type of reaction
Possible events diagnoses and signs/symptoms
Anaphylaxis
Anaphylactic/anaphylactoid reactions
Angioedema: diagnosis and/or signs and 
symptoms
Angioedema, site specific angioedema urticaria, 
anisarca/generalized edema urticaria
Severe skin reactions
Acute generalised exanthematous pustulosis, Cutaneous 
vasculitis, Drug reaction with eosinophilia and systemic 
symptoms (DRESS), Epidermal necrosis, Toxic skin 
eruption , Oculomucocutaneous syndrome, Skin necrosis, 
Stevens-Johnson syndrome (SJS), Toxic epidermal 
necrolysis (TENS)
Agranulocytosis and other cytopenic events
Agranulocytosis, aplastic anemia, pancytopenia
Other hypersensitivity reactions
Other suspected hypersensitivity to suspected drug
Liver reactions
Any event that qualifies as a liver laboratory trigger or event 
as defined in Appendix 2
While this list is intended as a guide to the investigator, other potential IDRs may arise.


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17
Appendix 5: Spirometry Guidance
Equipment
Spirometers must meet the specifications and performance criteria recommended in the 
American Thoracic Society (ATS)/European Respiratory Society (ERS) Standardization of 
Spirometry[1] . Spirometers must have the capacity to print forced vital capacity (FVC) tracings. 
All spirometry values should be reported at body temperature and pressure saturated (BTPS) 
by the method established by the manufacturer.
Calibration
The spirometer should be calibrated every morning before any spirometric measurements for 
the study are performed. Calibration reports should be printed and stored as source data at the 
site.
Preparing the test subject
On study days when spirometry will be performed, patients should refrain from the following:

Coffee, tea, chocolate, cola and other caffeine-containing beverages and foods and ice-
cold beverages for 4 hours prior to spirometry

Alcohol for 4 hours prior to spirometry

Strenuous activity for 12 hours prior to spirometry

Exposure to environmental smoke, dust or areas with strong odors
Every effort should be made to assure consistent testing conditions throughout the study. A 
seated position with nose clips is recommended to reduce risks related to dizziness or syncope. 
When possible, spirometry should be conducted by the same technician using the same 
spirometer. To minimize the effects of diurnal variation on lung function, spirometry visits 
should start at approximately the same time of day at each visit.
Performing Spirometry
The subject’s age, height and gender will be entered into the spirometer. It is important that the 
height is measured accurately at the study site. Spirometry, an effort-dependent test, requires 
careful instruction and cooperation of the subject. The technician should ensure a good seal 
around the mouthpiece, and confirm that the subject’s posture is correct. The subject should be 
instructed to perform a maximal inspiration, followed by maximum forced expiration until no 
more air can be exhaled or for at least 6 seconds. Expiration must be rapid with exertion of 
maximal effort. The results of spirometry should meet the ATS/ERS criteria for acceptability 
and repeatability. Acceptability criteria should be applied before repeatability is determined.
Number of trials
A minimum of 3 acceptable forced vital capacity (FVC) maneuvers should be performed. If a 
subject is unable to perform a single acceptable maneuver after 8 attempts, testing may be 
discontinued.
Acceptability
An acceptable maneuver has the following characteristics:

No hesitation or false start;


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
A rapid start;

No cough, especially during the first second of the maneuver;

No glottic closure or obstruction by tongue or dentures;

No early termination of exhalation (minimum exhalation time of 6 seconds is 
recommended and no volume change for at least 1 second) or the subject cannot continue 
to exhale further.
Overall acceptability will be determined by expert over-read by spirometry vendor.
Repeatability
The 2 largest forced expiratory volume in 1 second (FEV1) values from 3 acceptable maneuvers 
should not vary by more than 0.150 L.
If patient does not meet the repeatability or acceptability criteria during the screening period, 
patient may be rescreened once or allow one spirometry retest.
Recording of data
The greatest FEV1 and FVC from any of the acceptable curves are recorded. (The greatest 
FEV1 and FVC may not necessarily result from the same acceptable curve).
Predicted normal
For all patients, this study will utilize the global lung function 2012 equations (GLI2012) 
published by Quanjer et al 2012[2] or Japanese Respiratory Society[3] .
Reversibility
All reversibility evaluations should follow the recommendations of the ATS/ERS Task force: 
Standardization of Lung Function Testing[1] . A pre-bronchodilator spirometry assessment 
should be performed after withholding of specified medications as specified in Table 5-3
“Medications to be withheld prior to spirometry”.
Administer 400µg of salbutamol/albuterol (or equivalent) following the completion of the pre-
bronchodilator 
assessment. Spacers 
will 
be allowed for 
the 
administration of 
salbutamol/albuterol (or equivalent) for reversibility testing. Post-bronchodilator spirometry 
assessment is then performed approximately 10 to 15 minutes after administration of the 
salbutamol/albuterol.
Reversibility is calculated as:
100 x FEV1 (post-bronchodilator) – FEV1 (pre-bronchodilator)
/ FEV1 (pre-bronchodilator)
Patients will be considered reversible if an increase of at least 12% (and 200 mL) is 
demonstrated after administration of the salbutamol/albuterol.
17.1
References for appendix
1Miller MR et al (2005) Standardization of Lung Function Testing. Eur Resp J; 26:153-161.
2Quanjer PH, Stanojevic S, Cole TJ, Baur X, L Hall GL, et al (2012) Multi-ethnic reference 
values for spirometry for the 3-95 yr age range: the global lung function 2012 equations. Report 


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of the Global Lung Function Initiative (GLI), ERS Task Force to establish improved Lung 
Function Reference Values. Eur Resp J; 40:1324-1343.
3Kubota, Kobayashi, Quanjer PH, et al (2014) Reference values for spirometry, including vital 
capacity, in Japanese adults calculated with the LMS method and compared with previous 
values. Clinical Pulmonary Functions Committee of the Japanese Respiratory Society. 
Respiratory Investigations; 242-250.


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18
Appendix 6: Asthma Control Questionnaire (ACQ-5)


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19
Appendix 7: Asthma Quality of Life Questionnaire for 12 
years and older (AQLQ+12)


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20
Appendix 8: Asthma Plan
An asthma plan should be completed for each patient and given to the patient to manage their 
asthma symptoms. The medicines taken should be written including dose strength.


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21
Appendix 9: Estimated Equivalence of Inhaled 
Corticosteroids
From the Global Strategy for Asthma Management and Prevention 2018, © Global Initiative 
for Asthma (GINA) all rights reserved. Available from http://www.ginasthma.org.
For the purposes of calculating total daily dose for the study, if the table has the medication 
dose listed by DPI, but not MDI, then use the DPI classification as a reference and vice versa 
(i.e., if the table has the medication dose listed by MDI, but not DPI, then use the MDI 
classification). For ICS/LABA combination ICS/LABA products, the highest approved 
maintenance dose in the local country will meet this ICS criterion

SAP_000.pdf: 
Clinical Development
QAW039/Fevipiprant
CQAW039A2323 / NCT03629249
A 52-week, multicenter, randomized, double-blind, double-
dummy, parallel-group, placebo-controlled study of 
fevipiprant once daily plus standard-of-care (SoC) for 
reduction of systemic corticosteroids (oral and parenteral) 
use in patients with severe asthma
Statistical Analysis Plan (SAP)
Author:
Trial Statistician, 
Document type:
SAP Documentation
Document status:
Final 1.1
Release date:
20-Apr-2020
Number of pages:
38
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis  


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Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
30-
Nov-
2018
Prior 
to 
DB 
lock
Creation of 
final 
version
N/A - First version
NA
20-
Apr-
2020
Prior 
to 
DB 
lock
Early 
termination 
of the study
 
 
Section 1.2
20-
Apr-
2020
Prior 
to 
DB 
lock
Early 
termination 
of the study
Removed all statistical analyses for 
secondary endpoints and changed to 
descriptive only
Section 2.7, 5.1, 
5.2
20-
Apr-
2020
Prior 
to 
DB 
lock
Early 
termination 
of the study
Adjusted text in General Definitions and 
Baseline Characteristics.
Section 2.1
20-
Apr-
2020
Prior 
to 
DB 
lock
Early 
termination 
of the study
Removed all subgroup analyses
Section 2.2.1
20-
Apr-
2020
Prior 
to 
DB 
lock
Early 
termination 
of the study
Removed compliance to study treatment
Section 
2.4.1, 
2.4.1.2
20-
Apr-
2020
Prior 
to 
DB 
lock
Early 
termination 
of the study
Added definition of categories for 
cumulative duration of exposure
Section 2.4.1.1
20-
Apr-
2020
Prior 
to 
DB 
lock
Early 
termination 
of the study
Removed all supportive analyses
Section 2.5.4
20-
Apr-
2020
Prior 
to 
DB 
lock
Early 
termination 
of the study
Follow-up of deaths changed to last drug 
intake +7 days, changed follow-up of 
laboratory data to +7 days of last drug 
Section 
2.8.2, 
2.8.3, 
Section 
2.8.3.3


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Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
intake, newly occurring worsening of 
notable lab values removed 
20-
Apr-
2020
Prior 
to 
DB 
lock
Early
termination 
of the study
Conversion of OCS to prednisolon 
equivalent added
Section 5.2
20-
Apr-
2020
Prior 
to 
DB 
lock
Early 
termination 
of the study
Definition of statistical analyses models 
not used anymore removed
Section 5


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Table of contents
Table of contents .................................................................................................................4
List of abbreviations............................................................................................................6
1
Introduction .........................................................................................................................7
1.1
Study design.............................................................................................................7
1.2
Study objectives and endpoints ...............................................................................8
2
Statistical methods...............................................................................................................9
2.1
Data analysis general information ...........................................................................9
2.1.1
General definitions................................................................................10
2.2
Analysis sets ..........................................................................................................15
2.2.1
Subgroup of interest ..............................................................................16
2.3
Patient disposition, demographics and other baseline characteristics ...................16
2.3.1
Patient disposition.................................................................................16
2.3.2
Protocol Deviations...............................................................................16
2.3.3
Analysis sets..........................................................................................16
2.3.4
Demographics and baseline characteristics...........................................16
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................17
2.4.1
Study treatment / compliance................................................................17
2.4.2
Prior, concomitant and post therapies...................................................18
2.5
Analysis of the primary objective..........................................................................18
2.5.1
Primary endpoint...................................................................................18
2.5.2
Statistical hypothesis, model, and method of analysis..........................18
2.5.3
Handling of missing values/censoring/discontinuations.......................21
2.6
Analysis of the key secondary objective ...............................................................21
2.7
Analysis of secondary efficacy objective(s)..........................................................21
2.7.1
Secondary endpoints .............................................................................21
2.7.2
Statistical hypothesis, model, and method of analysis..........................23
2.7.3
Handling of missing values/censoring/discontinuations.......................23
2.8
Safety analyses.......................................................................................................23
2.8.1
Adverse events (AEs)............................................................................24
2.8.2
Deaths....................................................................................................25
2.8.3
Laboratory data .....................................................................................25
2.8.4
Other safety data ...................................................................................26
2.9
Pharmacokinetic endpoints....................................................................................28
2.10
PD and PK/PD analyses.........................................................................................28
2.11
Patient-reported outcomes .....................................................................................29


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2.12
Biomarkers.............................................................................................................29
2.13
Other Exploratory analyses....................................................................................29
2.14
Interim analysis......................................................................................................29
3
Sample size calculation .....................................................................................................29
4
Change to protocol specified analyses ..............................................................................31
5
Appendix ...........................................................................................................................31
5.1
Imputation rules.....................................................................................................31
5.1.1
Study drug.............................................................................................31
5.1.2
AE date imputation ...............................................................................32
5.1.3
Prior and Concomitant medication date imputation..............................33
5.2
Conversion of OCS to prednisolon equivalent......................................................35
5.3
AEs coding/grading ...............................................................................................35
5.4
Laboratory parameters derivations ........................................................................35
5.5
Statistical models...................................................................................................37
5.5.1
Primary analysis....................................................................................37
5.6
Rule of exclusion criteria of analysis sets..............................................................37
6
Reference...........................................................................................................................38


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List of abbreviations
AE
Adverse event
CSR
Clinical Study report
FAS
Full Analysis Set
eCRF
Electronic Case Report Form
MedDRA
Medical Dictionary for Drug Regulatory Affairs
o.d.
Once Daily
PK
Pharmacokinetics
PRO
Patient-reported Outcomes
qd
Qua’que di’e / once a day
QoL
Quality of Life
RAP
Report and Analysis Process
SAP
Statistical Analysis Plan
SCS
Systemic Corticosteroids
SOC
System Organ Class
SoC
Standard of Care
TFLs
Tables, Figures, Listings
WHO
World Health Organization


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1
Introduction
This statistical analysis plan (SAP) describes all planned analyses for the Clinical Study Report 
(CSR) of study QAW039A2323, a 52-week phase IIIb, multicenter, randomized, double-blind, 
double-dummy, parallel-group, placebo-controlled study of fevipiprant once daily plus 
standard-of-care (SoC) for reduction of systemic corticosteroids (oral and parenteral) use in 
patients with severe asthma.
The content of this SAP is based on protocol QAW039A2323 version 01.
Data will be analyzed by Novartis or a contracted contract research organization (CRO)
according to the data analysis section 9 of the study protocol which is available in Appendix 
16.1.1 of the CSR. Important information is given in the following sections and details will be 
provided, as applicable, in Appendix 16.1.9 of the CSR.
1.1
Study design
This study uses a randomized, multicenter, double-blind, double-dummy, placebo-controlled, 
parallel-group study design to determine the ability of fevipiprant plus SoC compared with 
placebo plus SoC to reduce the use of systemic corticosteroids (SCS) in patients with severe 
asthma. The study will include:

a Screening period of up to 2 weeks to assess eligibility;

a Run-in period of 4 or 10 weeks to evaluate maintenance of asthma control and to 
collect baseline safety data. Upon completion of the Run-in period, all patients who met 
eligibility criteria will be randomized to 1 of 3 treatment groups (Fevipiprant 150 mg or 
Fevipiprant 450 mg or placebo once daily) in a ratio 1:1:1. Randomized patients will be 
stratified according to their peripheral blood eosinophil count (< 250 cells/μl or ≥ 250 
cells/μl). Patients coming with high-dose ICS/LABA will have 4 weeks of run-in period 
and 10 weeks of run in period will be allowed for patients switching from mid-dose 
to high-dose ICS/LABA as per protocol;

a Treatment period of 52 weeks and;

a Follow-up period of 2 weeks following the last dose of study drug to collect additional 
data for safety variables.


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The study will allow for flexible therapy, meaning that patients can be escalated or de-escalated 
on their SoC therapy or add any other controller.
Study completion for a patient will occur after he/she has completed 52 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 52 weeks of treatment and the post- treatment 
follow-up visit.
Approximately 669 patients will be randomized in the study.
The primary analysis will be conducted upon study completion. 
There is no interim analysis planned for this study. 
1.2
Study objectives and endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

In patients with severe asthma and high 
eosinophil counts (≥ 250 cells/μl) receiving 
flexible SoC asthma therapy, to demonstrate a 
reduction in the use of SCS with fevipiprant (150 
mg or 450 mg once daily), compared with 
placebo

Total systemic corticosteroid dose in mg 
prednisone/prednisolone or equivalent 
over 52 weeks of treatment

In all patients with severe asthma receiving 
flexible SoC asthma therapy, to demonstrate a 
reduction in the use of SCS with fevipiprant (150 
mg or 450 mg once daily), compared with 
placebo

Total systemic corticosteroid dose in mg 
prednisone/prednisolone or equivalent 
over 52 weeks of treatment
Secondary objective(s)
Endpoint(s) for secondary objective(s)


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
To evaluate the effect of fevipiprant 150 mg and 
450 mg and flexible SoC asthma therapy, 
compared with placebo and flexible SoC asthma 
therapy in terms of difference in daytime and 
nightime symptom scores

Change from baseline in daytime and 
nightime symptom scores over 52 weeks 
of treatment by treatement group

To evaluate the efficacy fevipiprant 150 mg or 
450 mg and flexible SoC asthma therapy, 
compared with placebo and flexible SoC asthma 
therapy, with respect to change from baseline in 
Asthma Control Questionnaire (ACQ-5) in the 
overall population

Change from baseline in Asthma Control 
Questionnaire (ACQ-5) total score over 
52 weeks of treatment

To evaluate the effect of fevipiprant 150 mg and 
450 mg and flexible SoC asthma therapy, 
compared with placebo and flexible SoC asthma 
therapy in terms of Asthma Related Quality of 
Life Questionnaire (AQLQ+12) in the overall 
population

Change from baseline in Asthma 
Related Quality of Life Questionnaire 
(AQLQ+12) total score over 52 weeks of 
treatment

To evaluate the effect of fevipiprant 150 mg and 
450 mg and flexible SoC asthma therapy, 
compared with placebo and flexible SoC asthma 
therapy in terms of proportion of patients 
receiving continuous SCS during ≥ 30 days, at ≥ 
7.5mg/day of prednisolone or equivalent in the 
overall population

Proportion of patients requiring ≥ 7.5mg 
systemic corticosteroid dose in mg 
prednisone/prednisolone or equivalent 
per day continuously for at least 30 days

To evaluate the safety and tolerability of 
fevipiprant 150 mg and 450 mg and flexible SoC 
asthma therapy, compared with placebo and 
flexible SoC asthma therapy in the overall 
population

Adverse events, ECG, vital signs and 
laboratory analysis over 52 weeks of 
treatment

To evaluate the effect of fevipiprant 150 mg and 
450 mg and flexible SoC asthma therapy, 
compared with placebo and flexible SoC asthma 
therapy in terms of proportion for patients with 
no SCS use from the overall population

Proportion of patients with no SCS use 
over 52 weeks of treatment

To evaluate the effect of fevipiprant 150 mg and 
450 mg and flexible SoC asthma therapy, 
compared with placebo and flexible SoC asthma 
therapy in terms of time to first prescription of 
biologic therapy in the overall population

Time to first prescription of biologic 
therapy from first dose of study 
treatment received over 52 weeks of 
treatment
2
Statistical methods
2.1
Data analysis general information
The final efficacy analysis will be performed by Novartis or a designated CRO. The most recent 
version of SAS or R software will be used to perform all data analyses and to generate tables, 
figures and listings.
Data included in the analysis
The analysis cut-off date for the primary analysis of study data will be established after all 
randomized patients have completed 52 weeks of treatment or have discontinued study, or study 


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terminatde by sponsor. All statistical analyses will be performed using all data collected in the 
database up to the data cutoff date. All data with an assessment date or event 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.
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
descriptive statistics (i.e. mean, standard deviation, median, minimum, and maximum) by
treatment group.
2.1.1
General definitions
Study drug
For this double blind trial, study treatment refers to QAW039 150 mg, QAW039 450 mg or 
placebo as assigned to a patient at randomization. 
Date of first administration study treatment 
The date of first administration of study treatment is derived as the first date when a nonzero 
dose of study treatment was administered as per the Dosage Administration CRF. The date of 
first administration of study treatment will also be referred as start of study treatment.
Date of last administration of study treatment 
The date of last administration of study treatment is defined as the last date when a nonzero 
dose of study treatment was administered as per Dose Administration  (e)CRF.
Study day
The study day, describes the day of the event or assessment date, relative to the reference start 
date. The date of first dose of study medication is defined as Day 1 and the day before the first 
dose of study medication is defined as Day -1.
The study day is calculated as:


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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., SCS use, eDiary, patient 
reported outcomes (PRO) (AQLQ and ACQ) and biologic therapy administered during the 
treatment period) 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.
Time unit
A year length is defined as 365.25 days. 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.  If duration is reported in 
years, duration in days will be divided by 365.25.
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 eDiary, PRO, biologic 
therapy.  
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.
Patients coming with medium dose of SoC will have 10 weeks of run-in period. For those 
patients the last 4 weeks of run-in period will be used for baseline calulcations in and effort to 
standarize the groups with the patients coming with high dose of SoC (4 weeks of run-in period)
Parameter
Baseline Assessment
Details
Vital Signs
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 


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set to missing without 
imputation.
Height and Weight
Baseline 
height 
and 
weight is defined as the 
last 
available 
measurement taken prior 
to first dose of study 
drug.  Missing baseline 
values 
will 
not 
be 
imputed.
ECG
Baseline 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. For baseline 
ECG interpretation, there 
will 
only 
be 
one 
assessment at each time-
point, and, hence, this 
will be used as the 
baseline 
ECG 
interpretation (screening 
value 
if 
present, 
otherwise the last value 
prior to the first dose).
ECG is collected as 
single 12 lead ECG, not 
as a triplet.
Laboratory data
Baseline 
hematology, 
biochemistry 
and 
urinalysis are defined as 
the 
last 
scheduled 
assessment taken prior to 
first dose of study drug on 
Day 1. If the pre-dose 
measurement on Day 1 is 
missing (or was not 
confirmed to be pre-


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dose), then the last value 
prior to the first dose will
be used. Otherwise, the 
baseline laboratory data 
will be set to missing.
AQLQ+12
Baseline 
AQLQ+12
score 
is 
defined 
as 
AQLQ+12
score 
obtained on Day 1. If the 
AQLQ+12 score on Day 
1 is missing then the last 
available 
AQLQ+12
score prior to Day 1 will 
be used. If the AQLQ+12 
score is missing on Day 1 
and on all visits before 
Day 1, the respective 
baseline value will be set 
to missing.
AQLQ assessments are 
taken during run-in and 
day 1.
ACQ-5
Baseline ACQ-5 score is 
defined as ACQ-5 scores 
obtained on Day 1. If the 
ACQ-5 score on Day 1 is 
missing then the last 
available ACQ-5 score 
prior to Day 1 will be 
used. If the ACQ-5 score 
is missing on Day 1 and 
on all visits before Day 1, 
the respective baseline 
value
will be set to 
missing.
ACQ assessments are 
taken during screening 
and on day 1.
e-Diary daytime and night time 
asthma symptoms
For e-diary data (daytime 
and night time asthma 
symptoms) 
which 
are 
collected daily, the mean 
score for the baseline is 
calculated from Visit 101 
to 
Day 
1) 
will 
be 
considered as the baseline 
mean score. The non-
missing data within that 
interval will be used to 
calculate the mean value 
Note that the morning 
assessment for Day 1 
counts 
towards 
the 
baseline (as a part of 
run-in). However, the 
evening assessment for 
Day 1 counts as the 
treatment period (not as 
a part of run-in).


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as long as there are at 
least 75% days in the 
period with non-missing 
e-diary data. Since these 
measurements 
are 
collected at both morning 
and evening at Day 1, the 
morning assessment for 
Day 1 counts towards the 
baseline (as a part of run-
in) while the evening 
assessment counts as the 
treatment period.
Post-baseline measurement
Post baseline measurements are defined as those assessments after the start of study treatment.  
Change from baseline
When change from baseline is of interest, the following formula will be used for each scheduled 
visit and time-point where baseline and post-baseline values are both available:
Change from baseline = post-baseline value – baseline value; and
If baseline or post-baseline values are missing, then the change from baseline will be missing.
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 (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.


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Visit remapping and assessment windows
If a scheduled visit did not occur, then the data from the treatment discontinuation or study 
discontinuation visit may be used as the data from the scheduled visit. This is done 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.
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 
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 include all patients who provided informed consent.
The randomized set (RAN) will include all patients that were randomized. Data from these
patients will be analyzed according to the treatment to which the patient was assigned at 
randomization. 
The full analysis set (FAS) will include all randomized patients who received at least one dose 
of study treatment. It was considered reasonable to limit the FAS to patients who took study 
treatment, because the decision on whether or not treatment is started will not be influenced by 
the treatment group assignment due to the effective treatment blinding procedures described in 
protocol Section 5.4. Following the intent-to-treat principle, patients will be analyzed according 
to the treatment they were assigned to at randomization. 
The safety set (SAF) will include all patients who received at least one dose of study treatment. 
Patients will be analyzed according to the treatment they received. 
The analysis of the primary objective 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.
If an incorrect randomization stratum is inadvertently selected for a patient by the investigator 
in the IRT, patients will still be included in all analyses. The corrected stratum information as 
per the CRF data will be used in any analysis models.


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2.2.1
Subgroup of interest
NA
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 RAN 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 

Primary reason for study treatment phase discontinuation

Number (%) of patients who have discontinued the study

Reasons for discontinuation from the study
Patient randomization numbers and whether they completed or discontinued from the study will 
be listed, with date of last dose and primary reason for discontinuation, including the unblinding 
date if applicable.
2.3.2
Protocol Deviations
The number of subjects with protocol deviations will be tabulated by category and deviation for 
the RAN. Protocol deviations will be listed with date and study day of occurrence and deviation.  
2.3.3
Analysis sets
The number of subjects included in each analysis set will be tabulated. Reasons for exclusions 
from analysis sets will be tabulated for RAN. Patient exclusion from analysis sets will be listed 
for all patients with reasons for exclusion (including protocol deviations).
2.3.4
Demographics and baseline characteristics
Demographics and baseline characteristics will be summarized by treatment group using the 
FAS set. Summaries will include age, gender, race, ethnicity, height, weight, BMI, pre- and 
post-bronchodilator FEV1, percent predicted FEV1, FEV1 reversibility, duration of asthma, 
number of asthma exacerbations in prior year, smoking history (never/former), number of pack 
years, baseline ACQ-5, baseline AQLQ+12 and Peripheral blood eosinophils. 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.


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Blood eosinophil counts will also be summarized for the SCR. The baseline blood eosinophil 
will be considered as the eosinophil value at Visit 1. If the value at Visit 1 is missing then the 
baseline value will be considered as the first assessment after Visit 1 and prior to first dose of 
study medication, unless there is no value before randomization, in which situation, it will be 
missing.
Background asthma therapy will be categorized into GINA steps and will be summarized at 
baseline.
No statistical analyses will be provided for baseline comparability among the treatment groups.
Derivation of the demographics and baseline characteristics

BMI is calculated as: BMI (kg/m2) = Weight (kg) / [Height (m) * Height (m)]

Duration of asthma is calculated from the date of asthma first diagnosed recorded on the 
eCRF until the 1st visit. If the date is missing in day and/or month, it will be imputed as 
follows. If the year is before the first visit, the missing days will be imputed as the first of 
the month and the missing months will be imputed as July. If the year is the current year of 
the first visit, the missing days will be imputed as the first of the month and the missing 
months will be imputed as January.
Medical history
Medical history will be coded with the Medical Dictionary for Regulatory Activities 
terminology (MedDRA) using the most recent version at the time of database lock. 
History/conditions as well as protocol solicited events for asthma will be summarized for the 
FAS set by primary system organ class and preferred term. Verbatim recorded 
history/conditions will be listed together with the coded terms, date of diagnosis/surgery and 
whether the problem was ongoing at start of the study.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
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 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. 
2.4.1.1
Duration of exposure
Duration of exposure to a treatment will be calculated as the number of days between the first 
dose date and the last dose date exposed to that treatment over the specified period (expressed 
as: Duration of exposure (weeks)= (Date of last known dose of study drug – Date of first dose 
of study drug + 1)/7). The duration of exposure will be summarized by treatment group for the 
safety set as a continuous variable with the standard descriptive statistics. 


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In addition, the duration of exposure and cumulative exposure will be summarized as a 
categorical variable classified into ≤ 4 weeks, > 4 – 12 weeks, > 12 – 20 weeks, > 20 – 28 
weeks, > 28 – 36 weeks, > 36 – 44 weeks, > 44 weeks or ≥ 4 weeks, ≥ 12 weeks, ≥ 20 weeks, 
≥ 28 weeks, ≥ 36 weeks, ≥ 44 weeks, ≥ 52 weeks, respectively.
Dose administration data will be listed for patients in the SAF.
2.4.1.2
Compliance
NA
2.4.2
Prior, concomitant and post therapies
Medications started and stopped prior to study drug and taken concomitantly will be 
summarized by treatment group in separate tables in the SAF. The medication will be classified 
into “prior”, “concomitant” 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 therapies will be recorded and summarized separately for asthma related 
medications and other medications.Concomitant therapies will be recorded and summarized
separately for asthma related medications and other medications. Concomitant asthma related 
medications will be summarized by pre-defined category. Concomitant medications not related 
to asthma will be summarized by pharmacological (ATC) class and preferred term. More than 
one ATC class per medication is possible and the medication will be reported under all 
applicable classes.
Short acting beta2 agonist (SABA) rescue medication usage (mean number of puffs) during the 
screening/run-in period will be summarized. Patients taking prohibited concomitant 
medications will be noted in the summary of protocol deviations.
All summaries will be by treatment group on the Safety Set.
2.5
Analysis of the primary objective
2.5.1
Primary endpoint
The primary endpoint for this study is total systemic corticosteroid dose in mg 
prednisone/prednisolone (or equivalent) over 52 weeks of treatment. The primary endpoint is 
analysed using FAS.
2.5.2
Statistical hypothesis, model, and method of analysis
The primary endpoint will be analyzed in subpopulation of patients with eosinophil count ≥ 250 
cells/µl and in overall population. The primary null hypotheses are:

H01 450 eosinophil subgroup: the distribution of the total systemic corticosteroid dose in mg 
prednisone/prednisolone (or equivalent) in Fevipiprant 450 mg QD plus SoC is equivalent 


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to the distribution of the total systemic corticosteroid dose in mg prednisone/prednisolone 
(or equivalent) in placebo plus SoC in patients with eosinophil count ≥ 250 cells/µl

H02 150 eosinophil subgroup: the distribution of the total systemic corticosteroid dose in mg 
prednisone/prednisolone (or equivalent) in Fevipiprant 150 mg QD plus SoC is equivalent 
to the distribution of the total systemic corticosteroid dose in mg prednisone/prednisolone 
(or equivalent) in placebo plus SoC in patients with eosinophil count ≥ 250 cells/µl

H03 450 overall population: the distribution of the total systemic corticosteroid dose in mg 
prednisone/prednisolone (or equivalent) in Fevipiprant 450 mg QD plus SoC is equivalent 
to the distribution of the total systemic corticosteroid dose in mg prednisone/prednisolone 
(or equivalent) in placebo plus SoC for the overall population

H04 150 overall population: the distribution of the total systemic corticosteroid dose in mg 
prednisone/prednisolone (or equivalent) in Fevipiprant 150 mg QD plus SoC is equivalent 
to the distribution of the total systemic corticosteroid dose in mg prednisone/prednisolone 
(or equivalent) in placebo plus SoC for the overall population
The primary alternate hypotheses are:

HA1 450 eosinophil subgroup: the distribution of the total systemic corticosteroid dose in mg 
prednisone/prednisolone (or equivalent) in Fevipiprant 450 mg QD plus SoC is different 
to the distribution of the total systemic corticosteroid dose in mg prednisone/prednisolone 
(or equivalent) in placebo plus SoC in patients with eosinophil count ≥ 250 cells/µl

HA2 150 eosinophil subgroup: the distribution of the total systemic corticosteroid dose in mg 
prednisone/prednisolone (or equivalent) in Fevipiprant 150 mg QD plus SoC is different 
to the distribution of the total systemic corticosteroid dose in mg prednisone/prednisolone 
(or equivalent) in placebo plus SoC in patients with eosinophil count ≥ 250 cells/µl

HA3 450 overall population: the distribution of the total systemic corticosteroid dose in mg 
prednisone/prednisolone (or equivalent) in Fevipiprant 450 mg QD plus SoC is different 
to the distribution of the total systemic corticosteroid dose in mg prednisone/prednisolone 
(or equivalent) in placebo plus SoC for the overall population

HA4 150 overall population: the distribution of the total systemic corticosteroid dose in mg 
prednisone/prednisolone (or equivalent) in Fevipiprant 150 mg QD plus SoC is different 
to the distribution of the total systemic corticosteroid dose in mg prednisone/prednisolone 
(or equivalent) in placebo plus SoC for the overall population
Familywise type I error rate control
The familywise type I error rate will be controlled at the two-sided 5% level across the primary 
null hypotheses using graphical approach specified by Figure 2-1 (Bretz et al 2009).


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Figure 2-1
Closed testing procedure for primary objectives
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 subgroup with blood eosinophils ≥ 250 cells/μl for the 2 fevipiprant doses). 
Directed edges between the vertices specify how the local significance levels are propagated in 
case of significant results.
Initially, 50% of the alpha is assigned to each of the primary null hypotheses regarding the 
subgroup with blood eosinophils ≥ 250 cells/µl for the Fevipiprant 450 mg QD and Fevipiprant 
150 mg QD doses, respectively. Once this first primary null hypothesis for a dose has been 
rejected, the alpha will be distributed to the other null hypothesis regarding the overall 
population for the same dose. If the null hypothesis regarding the primary endpoint for the 
overall population is rejected for a dose, then alpha is reassigned to the primary null hypotheses 
regarding the subgroup with blood eosinophils ≥ 250 cells/µl for the other dose. Alpha will only 
be reassigned from the null hypotheses for a dose to the null hypotheses for the other dose once 
all null hypotheses for the dose to which the alpha was originally assigned have been rejected.
Statistical model for primary variable
The total systemic corticosteroid dose in mg prednisone/prednisolone (or equivalent) over 52 
weeks of treatment will be analyzed using the Wilcoxon-Mann-Whitney rank sum test (Van 
Elteren test). For overall population analysis will be stratified by randomization stratum – blood 
eosinophils levels (≥ 250 cells/µl and < 250 cells/µl). For subgroup with blood eosinophils ≥ 
250 cells/µl, analysis will not include stratification factor. The summary statistics for total SCS 
dose by treatment group will be provided.
The primary estimand will quantify the treatment effect based on on-treatment data. The total 
SCS dose data will be aggregated into monthly data for analysis. The primary estimand will 
account for different post-randomization events as follows:

Use of rescue medications: Efficacy data collected during use of rescue medication will be 
used for analysis.


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
Early discontinuation of study drug (prior to completing 52 weeks of treatment period): 
For the patients discontinuing study drug early, the total SCS dose for 52 weeks will be 
obtained as annualized SCS dose. For example if patient took 280 mg for 7 months then 
for 12 months patient will be taking 280*12/7=480mg total SCS dose.

Use of biologics prior to discontinuation of treatment: Efficacy data collected during the 
use of biologics will be set to missing, since use of biologics can confound efficacy data. 
Biologics are usually taken for long period of time. Thus, after replacing SCS dose with 
missing, patient will not have data available for remaining duartion of the study. The total 
SCS dose will be obtained as annualized dose as explained above.
2.5.3
Handling of missing values/censoring/discontinuations
Some patients may discontinue early and may not complete the entire study duration. For the 
patients discontinuing treatment early, the total SCS dose for 52 weeks will be obtained as 
annualized SCS dose. For example if patient took 280 mg for 7 months then for 12 months 
patient will be taking 280*12/7=480mg total SCS dose. Efficacy data collected during the use 
of biologics will be set to missing, since use of biologics can confound efficacy data. After 
replacing SCS dose with missing, patient will not have data available for all 12 months, thus 
total SCS dose will be obtained as annualized dose.

2.6
Analysis of the key secondary objective
There is no key secondary objective. 
2.7
Analysis of secondary efficacy objective(s)
2.7.1
Secondary endpoints
2.7.1.1
Proportion of patients with no SCS use over 52 weeks of treatment or 
during on-treatment period
The proportion of patients with no SCS use in individually observed on-treatment time will be 
presented. Patients will be considered as non-responders if patient takes SCS dose in observed 
period of treatment. 
2.7.1.2
Proportion of patients requiring ≥ 7.5mg systemic corticosteroid dose 
in mg prednisone/prednisolone (or equivalent) per day continuously 
for at least 30 days
This is a composite endpoint where patients requiring ≥ 7.5mg systemic corticosteroid dose in 
mg prednisone/prednisolone (or equivalent) per day continuously for at least 30 days in 52 
weeks treatment period or during on-treatment period are considered as responders. Patients 
will be considered as non-responders if patient do not satisfy either of the conditions.


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2.7.1.3
Summary of Change from baseline in Asthma Related Quality of Life 
Questionnaire (AQLQ+12) total score during on-treatment period
The 32 items in the AQLQ+12 are divided into 4 domain-specific scores and a total score as 
follows: 

Symptoms = Mean of Items 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 29, 30 (12 items) 

Activity limitation  = Mean of Items 1, 2, 3, 4, 5, 11, 19, 25, 28, 31, 32 (11 items) 

Emotional function  = Mean of Items 7, 13, 15, 21, 27 (5 items) 

Environmental Stimuli = Mean of Items 9, 17, 23, 26 (4 items) 

Overall Score = Mean of Items 1 to 32 (32 items) 
Each item of the AQLQ+12 is equally weighted and scored along a 7-point scale, where 1 
indicates maximal impairment and 7 indicates no impairment. Thus, higher scores indicate 
better asthma-related HRQOL (Health-Related Quality of Life). There is a mean score 
calculated for each of the four domains, as well as an overall quality-of-life score, which is the 
mean score of all 32 items. The resultant overall scores will be between 1 and 7.
The developer suggests no more than 10% of missing data. This means no more than 3 missing 
responses for the overall score and no more than 1 missing response per domain.  For the 
symptoms and activity domain scores, one missing value per domain is allowed.  For the 
emotional function and environmental stimuli domain scores, no missing values are allowed. If 
these limits for missing questions are exceeded, the variable will be considered missing and will 
be imputed as described in Section 2.7.3.
The minimal important difference (MID), defined as “the smallest difference in score which 
patients perceive as beneficial and would mandate, in the absence of troublesome side effects 
and excessive cost, a change in the patient’s management,” of 0.5 has been established for this 
questionnaire as clinically significant (Juniper, et al 1994).
2.7.1.4
Summary of change from baseline of Asthma Control Questionnaire 
(ACQ-5) total score during on-treatment period
In this study, the ACQ-5 will be used to assess improvements in asthma symptom control. The 
original ACQ consists of 7 items: 5 items on symptom assessment, 1 item on rescue 
bronchodilator use, and 1 item on airway calibre (% FEV1 predicted). As the Spirometry 
assessments are performed centrally, the rescue bronchodilator use and % FEV1 predicted are 
not included in the version of ACQ chosen for this study. 
The ACQ-5 will be self-administered at the clinic 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 2005a). 
A score of 1.5 at baseline indicates patients who entered the study had inadequately controlled 
asthma (Juniper et al 2006). In addition, the minimal important difference (MID) or smallest 
change that can be considered clinically important is 0.5.


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2.7.1.5
Proportion of patients with prescription of biologic treatment 
The proportion of patients with any prescription of biologic therapy  during the on-treatment 
period will be presented. Events which occur during on-treatment period will be included. 
2.7.1.6
Summary of change from baseline of daytime and nighttime symptom 
scores by 4-week intervals during on-treatment period
The daytime and night time symptom scores will be collected using validated electronic patient 
diary. Scoring of measures: A range of response categories for each question from 0 to 6 (0 –
totally controlled, 6 – extremely poorly controlled) is used in the daytime asthma symptom 
scale. Response categories ranging from 0 (indicating no awakening with asthma symptoms) to 
3 (indicating awake all night) are used in the nocturnal diary scale. Daily daytime symptom 
scores will be computed as the average of the avaiable scores on four questions on the daytime 
symptom scale.
The mean daytime asthma symptom scores/nighttime symptom score will be calculated for each 
patient for each 4 week visit interval and over on-treatment period. The average score for each 
time interval is defined as the sum of daily scores (based on all the available questions) divided 
by the number of days where ediary records have been made on nighttime/daytime score for 
that visit interval. The non-missing data within each 4 week interval in treatment period will be 
used to calculate the mean value, as long as there are at least 14 days with non-missing e-diary 
data (based on all the available questions) in a 4-week period. Otherwise, the value will be set 
as missing.
2.7.2
Statistical hypothesis, model, and method of analysis
The analysis of all secondary endpoints will be based on on-treatment data (that is from first 
dose of study treatment till last dose of study treatment + 1). 
The proportion of patients with no SCS use during on-treatment will be summarized by 
treatment. groups.
The proportion of patients requiring ≥ 7.5mg systemic corticosteroid dose in mg 
prednisone/prednisolone (or equivalent) per day continuously for at least 30 days within the on-
treatment period will be summarized by treatment in overall population. 
AQLQ+12, ACQ-5 and change from baseline in daytime and nighttime score will be 
summarized by treatment for all visits. All the summaries will be based on observed on-
treatment data and non-imputed data.
2.7.3
Handling of missing values/censoring/discontinuations
No imputation will be done for secondary endpoints.
2.8
Safety analyses
All safety data will be summarized for the safety set. Safety summaries will be primarily based 
on on-treatment data with selected tables also presented for all data after the first intake of study 
drug, while all safety data will be listed. 


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2.8.1
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 7 days 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 the first intake 
of study drug will be classified as prior adverse events and not included in tabulations of 
treatment emergent adverse events.
The number and percentage of patients who reported 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 treatment group. If a patient reported more 
than one AE with the same preferred term, the AE will be counted only once. If a patient 
reported more than one AE within the same primary system organ class, the patient will be 
counted only once at the system organ class level.
In addition, the most frequent AEs will be presented by preferred term in descending order of 
frequency in the QAW039 150 mg once daily treatment group.
2.8.1.1
Adverse events of special interest / grouping of AEs
The number and percentage of patients with 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 
SMQ (when applicable) and preferred term. The Compound Case Retrieval Strategy (CRS) will 
be used to determine the MedDRA search criteria to be used to identify events of special interest.
2.8.1.2
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


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
more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.
2.8.2
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 + 7 day will be included in summary 
tables. Additionally all deaths after first dose of study drug will be tabulated by treatment group.
2.8.3
Laboratory data
Laboratory data consist of hematology, biochemistry and urinalysis measurements.
Laboratory data measured after first intake of study drug and until 7 days after last intake of 
study drug are regarded as on-treatment data. Laboratory data measured more than 7 days
after last intake of study drug are regarded as post-treatment data and will not be summarized. 
All data will be listed with abnormal values flagged.
2.8.3.1
Summary of absolute values
For all continuous laboratory parameters, the worst post-baseline values (including values from 
post-baseline unscheduled and premature discontinuation visits), will be summarized with 
standard descriptive statistics by parameter and treatment group. 
The direction of interest for worst post-baseline for selected hematology and biochemistry 
parameters is tabulated in Table 6.3.1. For continuous urinalysis parameters, the direction of 
interest is always High.
For categorical laboratory parameters and categorical urinalysis parameters, a frequency table 
of results will be produced by laboratory parameter and treatment. Worst post-baseline on-
treatment values (including values from post-baseline unscheduled and premature 
discontinuation visits) will also be included.
For summary tables and figures on laboratory parameters considering values, which are lower 
or greater than the limit of quantification, the following approach will be taken. For values 
which are flagged as lower than the lower limit of quantification, the values presented in 
summary tables should be multiplied by 0.5 and for values which are flagged as greater than 
upper limit of quantification as 1.5, the values presented in summary tables should be multiplied 
by 1.5.


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2.8.3.2
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.
2.8.3.3
Notable values
For selected laboratory parameters, abnormalities occurring at any time-point over the on-
treatment period, considering all post-baseline data from scheduled, unscheduled and premature 
discontinuation visits will be summarized. 
The criteria for clinically notable values are presented in Table 6.3.2.
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. This is 
necessary because BUN is Urea Nitrogen, not Urea and there are two nitrogens in each urea 
molecule. The factor of 0.357 converts BUN in mg/dL to Urea in mmol/L.
Listings of patients with notable laboratory values will be provided by laboratory parameter, 
treatment group, and patient number.
Additionally, box plot of change from baseline will be presented over time for ALT, AST, 
ALT/AST ratio, total bilirubin, creatinine, albumin, urine albumin, urine protein, urine 
albumin/creatinine ratio (ACR), urine protein/creatinine ratio (PCR). 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.
2.8.4
Other safety data
2.8.4.1
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.


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Clinically relevant values

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
QTc (msec)
≥450 (male)
QTc (msec)
≥460 (female)
QTc (msec)
> 500 (both) 
Change from baseline
QTc
< 30 
QTc
30 – 60
QTc
> 60
Clinically notable values

A summary table will also be produced for number and percentage of subjects with 
notable QT and QTcF intervals (irrespective of the time point) using the following 
categories:
a. any treatment emergent (new) QTcF 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
Patients with notable post-baseline ECG values will be listed.
2.8.4.2
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 drug and until 7 days after the last intake of study drug are regarded as on-


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treatment data. Vital signs data measured more than 7 days after last intake of study drug are 
regarded as post-treatment data and will not be summarized. All data will be included in the 
analyses regardless of rescue medication use.
The following analyses will be performed by treatment group:

absolute on-treatment values and change from baseline summarized by parameter, and 
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: 
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 value considering newly occurring or worsening cases
Systolic blood pressure (mmHg)
< 75
> 200
Diastolic blood pressure (mmHg)
< 40
> 115
Pulse rate (bpm)
< 40
> 130
Notable change from baseline
Systolic blood pressure (mmHg)
≤ 90 and decrease from 
baseline by ≥ 20 
≥ 180 and increase from 
baseline by ≥ 20
Diastolic blood pressure (mmHg)
≤ 50 and decrease from 
baseline by ≥ 15
≥ 105 and increase from 
baseline by ≥ 15
Pulse rate (bpm)
≤ 50 and decrease from 
baseline by ≥ 15
≥ 120 and increase from 
baseline by ≥ 15
Weight (kg)
Decrease ≥ 7% from 
baseline
Increase ≥ 7% from 
baseline
2.9
Pharmacokinetic endpoints
Not applicable.
2.10
PD and PK/PD analyses
Not applicable.


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2.11
Patient-reported outcomes
PROs such as AQLQ+12 and ACQ-5 will be analysed as part of secondary endpoints. 
2.12
Biomarkers
Not applicable.
2.13
Other Exploratory analyses
NA
2.14
Interim analysis
Not applicable.
3
Sample size calculation
The historical data (US Marketscan database) shown in Table 3.1 indicates that the distribution 
of the total systemic corticosteroid dose in mg prednisone/prednisolone (or equivalent) across 
patients is not normal; rather the distribution is skewed; hence using a normal distribution
assumption is not appropriate. In addition, the proportion of patients with 0 total systemic 
corticosteroid dose in mg prednisone/prednisolone (or equivalent) is quite high (>30%) 
therefore a transformation that could normalize the distribution is not feasible. As a 
consequence, a non-parametric method based on rank analysis will be used to analyze the 
primary end-point. The formula developed for the Wilcoxon-Mann-Whitney test adjusting for 
ties (Zhao et al 2008) has been used to estimate the sample size. A 1:1:1 randomization was 
used. There are four hypotheses to be tested for primary endpoint as stated in Section xxx.
Table 3.1
Frequency distribution of dose to display (non-normal) distribution of 
US Marketscan database
HD ICS/LABA+LAMA
6 weeks
HD ICS/LABA+LTRA
6 weeks
HD ICS/LABA
6 weeks
Outcomes
n=1562
n=7409
n=18471
Dose Category (Count/%)
0 (0mg)
533
34.1%
2901
39.2%
8211
44.5%
1 (>0 - 50 mg)
5
0.3%
20
0.3%
46
0.2%
2 (>50 - 100 mg)
25
1.6%
90
1.2%
214
1.2%
3 (>100 - 150 mg)
107
6.9%
595
8.0%
1376
7.4%
4 (>150 - 200 mg)
62
4.0%
358
4.8%
904
4.9%
5 (>200 - 250 mg)
90
5.8%
335
4.5%
808
4.4%
6 (>250 - 300 mg)
50
3.2%
313
4.2%
789
4.3%
7 (>300 - 350 mg)
40
2.6%
184
2.5%
426
2.3%
8 (>350 - 400 mg)
47
3.0%
216
2.9%
608
3.3%
9 (>400 - 450 mg)
44
2.8%
219
3.0%
519
2.8%
10 (>450 - 500 mg)
34
2.2%
181
2.4%
396
2.1%
11 (>500 - 550 mg)
24
1.5%
141
1.9%
308
1.7%
12 (>550 - 600 mg)
39
2.5%
221
3.0%
479
2.6%


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13 (>600 - 650 mg)
19
1.2%
99
1.3%
237
1.3%
14 (>650 - 700 mg)
16
1.0%
80
1.1%
214
1.2%
15 (>700 - 750 mg)
28
1.8%
103
1.4%
252
1.4%
16 (>750 mg)
399
25.5%
1353
18.3%
2684
14.5%
table_9_2Table 3.2 represents the selected scenario for the null and alternative hypothesis and 
the sample size under a 90% power and an overall alpha two sided of 5%. As we have two doses 
to test, the alpha considered for the sample size is 2.5% two sided.
Under the assumptions specified above and scenarios described in Table 3.2, 134 patients per 
arm in the subpopulation with eosinophils count ≥ 250 cells/µl and 201 patients per arm in the 
overall population corresponding to a total sample size of 603 patients provide greater than 90% 
power for primary null hypotheses. Assuming 10% treatment discontinuation rate, a total of 
669 patients are needed.
Table 3.2
Fevipiprant single dose EOS≥ 250 cells/µl
alpha 
2.5% 
power 
90%
0-
50mg/ye
ar
>50-
150 
mg/yea
r
>150-
300 
mg/yea
r
>300-
450 
mg/yea
r
>450-
600 
mg/yea
r
>600 
mg/yea
r
Hig
h 
EoS
Full 
populatio
n
+10
%
Placeb
o
42.7%
8.8%
13.5%
8.4%
6.6%
20.0%
-
-
-
Fevi
60.0%
15.0%
9.0%
3.0%
3.0%
10.0%
402
603
669
We have looked also at other possible distributions for both fevipiprant and placebo under a 
power of 80% or 90% and alpha 0.025 two sided. table_9_3Table 3.3 provides other scenarios 
for the placebo and the Fevi group. Even if we deviate from the original scenario, other possible 
distributions provide still good power.
Table 3-3
Other scenario investigated for Fevipiprant single dose EOS≥ 250 
cells/µl
alpha 
2.5% 
0-50mg 
/year
>50-150 
mg/year
>150-
300 
mg/year
>300-
450 
mg/year
>450-
600 
mg/year
>600 
mg/year
Power under 
the 
assumption of 
134 pts per 
arm
Placebo
0.0%
10.0%
25.0%
25.0%
15.0%
25.0%
-
Scenario 
1 Fevi
5.0%
25.0%
25.0%
20.0%
10.0%
15.0%
96%
alpha 
2.5% 
0-
50mg/year
>50-150 
mg/year
>150-
300 
mg/year
>300-
450 
mg/year
>450-
600 
mg/year
>600 
mg/year
Placebo
20.0%
5.0%
20.0%
10.0%
15.0%
30.0%
-
Scenario 
2 Fevi
35.0%
20.0%
30.0%
5.0%
5.0%
5.0%
100%


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alpha 
2.5% 
0-
50mg/year
>50-150 
mg/year
>150-
300 
mg/year
>300-
450 
mg/year
>450-
600 
mg/year
>600 
mg/year
Placebo
42.7%
8.8%
13.5%
8.4%
6.6%
20.0%
-
Scenario 
3 Fevi
57.0%
18.0%
9.0%
3.0%
3.0%
10.0%
85%
Scenario 
4 Fevi
55.0%
14.0%
14.0%
5.0%
3.0%
9.0%
75%
alpha 
2.5% 
0-
50mg/year
>50-150 
mg/year
>150-
300 
mg/year
>300-
450 
mg/year
>450-
600 
mg/year
>600 
mg/year
Placebo
0.0%
10.0%
25.0%
25.0%
15.0%
25.0%
-
Scenario 
5 Fevi
5.0%
25.0%
20.0%
20.0%
12.0%
18.0%
82%
Based on clinical judgment different scenarios are considered in the above table
The following formula to calculate the sample size has been used (Zhao et al 2008):
Where
N is the total sample size for a 2 arm trial.
t is the randomization ratio
pc are the % of patients in category c for the experiment arm
qc are the % of patients in category c for the control arm
D is number of categories
4
Change to protocol specified analyses
The primary endpoint will be analyzed as specified in the protocol for the CSR and is detailed 
in this SAP. As the study is treminated early by sponsor, most of the patients don’t have 
sufficient follow up and most of the data will not be matured enough do the analysis as defined 
in the protocol, due to that all secondary endpoints will be analyzed descriptively. 
NA
5
Appendix
5.1
Imputation rules
5.1.1
Study drug
Missing/partial start date or end date of study drug will not be imputed.


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5.1.2
AE date imputation
5.1.2.1
AE end date imputation
Rules for imputing AE end dates are stated below. Date of last contact in the study has been 
defined as in Section 2.1.1. 
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.
5.1.2.2
AE start date imputation
Rules for imputing the AE start date:
The following table explains the notation used in the logic matrix. Please note that missing 
start dates will not be imputed.
Day
Month
Year
Partial Adverse Event Start Date
Not used
MON
YYYY
Treatment Start Date 
Not used
TRTM
TRTY
The following matrix explains the logic behind the imputation. 
MON
MISSING
MON < TRTM
MON = TRTM
MON > TRTM
YYYY
MISSING
( 1 )
No convention
( 1 )
No convention
( 1 )
No convention
( 1 )
No convention
YYYY < TRTY
( 2.a )
Before Treatment 
Start
( 2.b )
Before Treatment 
Start
( 2.b )
Before Treatment 
Start
( 2.b )
Before Treatment 
Start
YYYY = TRTY
( 4.a )
Uncertain
( 4.b )
Before Treatment 
Start
( 4.c )
Uncertain
( 4.c )
After Treatment Start
YYYY > TRTY
( 3.a )
After Treatment Start
( 3.b )
After Treatment Start
( 3.b )
After Treatment Start
( 3.b )
After Treatment Start
Before imputing AE start date, find the AE start reference date. 
1. If the imputed AE end date is complete and the imputed AE end date < treatment start date 
then AE start reference date = min(informed consent date, earliest visit date).
2. Else AE start reference date = treatment start date
Impute AE start date -


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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.
5.1.3
Prior and Concomitant medication date imputation
5.1.3.1
Concomitant medication end date imputation
Rules for imputing the CM end date are stated below. Date of last contact in the study has been 
defined as in Section 2.1.1. Concomitant medication end dates will not be imputed for ongoing 
records.
1. If CM end day is missing and CM month/year are non-missing then impute CM day as 
the minimum of  date of last contact and the last day of the month.
2. If CM end day/month are missing and CM year is non-missing then impute CM day as 
the minimum of  date of last contact and the end of the year (31DECYYYY).
3. If CM day/month/year is missing then use the date of last contact + 1 day as the imputed 
CM end date. 
4. If imputed CM end date is less than the CM start date, use the CM start date as the 
imputed CM end date.


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5.1.3.2
Concomitant medication start date imputation
Rules for imputing the CM start date:
The following table explains the notation used in the logic matrix. Please note that missing start 
dates will not be imputed.
Day
Month
Year
Partial CMD Start Date
Not used
MON
YYYY
Treatment Start Date
Not used
TRTM
TRTY
The following matrix explains the logic behind the imputation.
MON
MISSING
MON < TRTM
MON = TRTM
MON > TRTM
YYYY
MISSING
( 1 )
Uncertain
( 1 )
Uncertain
( 1 )
Uncertain
( 1 )
Uncertain
YYYY < TRTY
( 2.a ) 
Before Treatment Start
( 2.b )
Before Treatment Start
( 2.b )
Before Treatment Start
( 2.b )
Before Treatment Start
YYYY = TRTY
( 4.a )
Uncertain
( 4.b )
Before Treatment Start
( 4.a )
Uncertain
( 4.c )
After Treatment Start
YYYY > TRTY
( 3.a )
After Treatment Start
( 3.b )
After Treatment Start
( 3.b )
After Treatment Start
( 3.b )
After Treatment Start
1. If the CM start date year value is missing, the imputed CM start date is set to one day 
prior to treatment start date. 
2. If the CM start date year value is less than the treatment start date year value, the CM 
started before treatment.  Therefore:
a.
If the CM month is missing, the imputed CM start date is set to the mid-year 
point (01JulYYYY).
b. Else if the CM month is not missing, the imputed CM start date is set to the mid-
month point (15MONYYYY).
3. If the CM start date year value is greater than the treatment start date year value, the CM 
started after treatment. Therefore:
a.
If the CM month is missing, the imputed CM start date is set to the year start 
point (01JanYYYY).
b. Else if the CM month is not missing, the imputed CM start date is set to the 
month start point (01MONYYYY).
4. If the CM start date year value is equal to the treatment start date year value:
a.
And the CM month is missing or the CM month is equal to the treatment start 
date month, then the imputed CM start date is set to one day prior treatment start 
date.
b. Else if the CM month is less than the treatment start date month, the imputed 
CM start date is set to the mid-month point (15MONYYYY).


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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
Conversion of OCS to prednisolon equivalent
Prednisone 5 mg is comparable to 
Drug
Dose
Conversion factor
Deflazacort
6 mg
0.83
Triamcinolone
4 mg
1.25
Dexamethasone
0.75 mg
6.67
Methylprednisolone
4 mg
1.25
Prednisolone
5 mg
1
Betamethasone
0.75 mg
6.67
Prednisone
5 mg
1
Hydrocortisone
20 mg
0.25
Fluocortolone
5 mg
1
Meprednisone
4 mg
1.25
5.3
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.
5.4
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 6.3.1
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 6.3.2
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
Urinalysis
Dipstick blood
≥2+
Dipstick glucose
≥2+
Dipstick leukocytes
≥2+
Dipstick protein
≥2+
v = volume, ULN = upper limit of normal 
5.5
Statistical models
5.5.1
Primary analysis
A Van Elteren test will be used to analyze the ranked data with stratifications. The SAS 
procedure PROC FREQ will be used for this analysis. The test can be done by defining a 
stratified, three-way table and using the CMH and SCORES=MODRIDIT options. In the 
TABLE statement, the variable(s) defining the strata appear first, followed by the treatment 
variable and finally the response variable.
5.6
Rule of exclusion criteria of analysis sets 
The following protocol deviations will lead to exclusion of patients from the RAN, FAS, SCR 
or safety set:
PD 
Identifier
‘PD Description’ for Reporting
CP_Exclude from analysis set
INCL01A
Did not sign informed consent
Exclude from all analysis sets


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INCL01B
Written Informed Consent obtained after 
date of a study assessment
All concerned assessments excluded 
from SCR
TRT01
Received study drug but not randomized
Exclude from RAN, FAS and SAF (also 
evaluate on case by case basis)
TRT02
Randomized but no study drug given
Patient did not receive a study drug 
then exclude from FAS and SAF; 
otherwise do not exclude from any 
population set
TRT04
Double blind study drug taken prior to 
baseline FEV1 assessment
Do not consider FEV1 baseline value 
for analysis
WITH01
Patient not withdrawn from the study even 
after Withdrawal of informed consent.
Include data up to withdrawal of 
consent in all analysis sets
WITH07
Blind broken and study drug not stopped
Data before unblinding can be used for 
efficacy ; otherwise use all data for 
safety
6
Reference
Bretz F, Maurer W, Brannath W et al. (2009) A graphical approach to sequentially rejective
multiple test procedures. Statistics in Medicine; 28(4): 586-604.
Juniper EF, Guyatt GH, Willan A, et al (1994) Determining a minimal important change in a
disease-specific Quality of Life Questionnaire. J Clin Epidemiol p. 81-7.
Juniper EF, O'Byrne PM, Guyatt GH, et al (1999) Development and validation of a
questionnaire to measure asthma control. Eur. Respir. J. p. 902-7.
Juniper EF, Svensson K, Mörk AC, et al (2005)a Measurement properties and interpretation
of three shortened versions of the asthma control questionnaire. Respir Med p. 553-8.
Juniper EF, Bousquet J, Abetz L et al., GOAL Committee (2006) Identifying ‘well-controlled’
and ‘not well-controlled’ asthma using the Asthma Control Questionnaire. Respir Med; 100:
616- 621.
Zhao YD (2006) Sample size estimation for the van Elteren test—a stratified Wilcoxon–Mann–
Whitney test. Statistics in Medicine; 25:2675–2687
Zhao YD, Rahardja D, Qu Y (2008) Sample size calculation for the Wilcoxon-Mann-Whitney 
test adjusting for ties. Stat Med p. 462-468.