Clinical trial NCT03650400
Conditions: Asthma
Keywords: Fevipiprant, GINA 2018, Pediatrics
Sponsor: Novartis Pharmaceuticals
Start date: 2019-05-01; Completion date: 2020-01-22
Enrollment: 11 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study was to assess the pharmacokinetics (PK) of fevipiprant (QAW039) delivered as a chewable tablet (CT) in pediatric asthma subjects aged 6 to \< 12 years with asthma. The results of this study will support the identification of a fevipiprant dose for subsequent pediatric efficacy studies aiming to provide an exposure similar to that of the to-be marketed adult/adolescent dose. In addition, the first data on safety and tolerability of fevipiprant in this age group was obtained.

Detailed description:
The purpose of this study was to assess the pharmacokinetics (PK) of fevipiprant delivered as a chewable tablet (CT) in pediatric asthma subjects aged 6 to \< 12 years. The results of this study would have supported the identification of a fevipiprant dose for subsequent pediatric efficacy studies aiming to provide an exposure similar to that of the to-be marketed adult/adolescent dose. Based on evaluation of the fevipiprant asthma development program in the recently completed studies (CQAW039A2307/ CQAW039A2314) in the adult population (the analyses of these studies did not meet the clinically relevant threshold for reduction in rate of moderate-to-severe exacerbation compared to placebo over a 52-week treatment period for either of the doses \[i.e. 150 mg/ 450 mg\]), Novartis decided to discontinue this study (CQAW039B2201).

Arms: arm 1: QAW039 75 mg Chewable tablet arm 2: QAW039 375 mg Chewable tablet
Interventions: intervention 1: Fevipiprant
Intervention descriptions: intervention 1: Chewable tablet

Protocol documents:
Prot_001.pdf: 
Novartis Research and Development
QAW039
Clinical Trial Protocol CQAW039B2201 / NCT03650400
A multicenter, open-label, 8 day treatment study to assess 
the pharmacokinetics, safety and tolerability of fevipiprant 
delivered via a once daily chewable tablet in children aged 
6 to <12 years with asthma
Document type:
Amended Protocol Version
EUDRACT number:
2018-003920-35
Version number:
01 (Clean)
Clinical Trial Phase:
II
Release date:
13-Feb-2019
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template version 1.0 dated 01-Dec-2017


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................5
List of abbreviations............................................................................................................6
Glossary of terms.................................................................................................................8
Amendment 1 ....................................................................................................................10
Protocol summary..............................................................................................................12
1
Introduction .......................................................................................................................14
1.1
Background............................................................................................................14
1.2
Purpose ..................................................................................................................15
2
Objectives and endpoints...................................................................................................15
3
Study design ......................................................................................................................16
4
Rationale............................................................................................................................20
4.1
Rationale for study design .....................................................................................20
4.1.1
Rationale for choice of background therapy.........................................20
4.2
Rationale for dose/regimen and duration of treatment ..........................................20
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................21
4.4
Purpose and timing of interim analyses/design adaptations..................................21
4.5
Risks and benefits..................................................................................................22
5
Population..........................................................................................................................23
5.1
Inclusion criteria ....................................................................................................23
5.2
Exclusion criteria...................................................................................................24
6
Treatment...........................................................................................................................25
6.1
Study treatment......................................................................................................25
6.1.1
Investigational and control drugs..........................................................25
6.1.2
Additional study treatments ..................................................................25
6.1.3
Treatment arms/group ...........................................................................26
6.1.4
Treatment duration................................................................................26
6.2
Other treatment(s)..................................................................................................26
6.2.1
Concomitant therapy.............................................................................26
6.2.2
Prohibited medication ...........................................................................27
6.2.3
Rescue medication ................................................................................27
6.3
Subject numbering, treatment assignment, randomization....................................27
6.3.1
Subject numbering ................................................................................27
6.3.2
Treatment assignment, randomization ..................................................27


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6.4
Treatment blinding.................................................................................................28
6.5
Dose escalation and dose modification..................................................................28
6.5.1
Dose modifications................................................................................28
6.5.2
Follow-up for toxicities.........................................................................28
6.6
Additional treatment guidance...............................................................................28
6.6.1
Treatment compliance...........................................................................28
6.6.2
Emergency breaking of assigned treatment code..................................28
6.7
Preparation and dispensation.................................................................................29
6.7.1
Handling of study treatment and additional treatment..........................29
6.7.2
Instruction for prescribing and taking study treatment .........................29
7
Informed consent procedures ............................................................................................30
8
Visit schedule and assessments .........................................................................................30
8.1
Screening ...............................................................................................................35
8.1.1
Information to be collected on screening failures.................................35
8.2
Subject demographics/other baseline characteristics.............................................35
8.3
Efficacy..................................................................................................................35
8.3.1
Appropriateness of efficacy assessments..............................................35
8.4
Safety.....................................................................................................................35
8.4.1
Laboratory evaluations..........................................................................36
8.4.2
Electrocardiogram (ECG) .....................................................................37
8.4.3
Pregnancy and assessments of fertility .................................................37
8.4.4
Asthma Exacerbation ............................................................................37
8.5
Additional assessments..........................................................................................38
8.5.1
Pharmacokinetics ..................................................................................38
9
Study discontinuation and completion ..............................................................................38
9.1
Discontinuation......................................................................................................38
9.1.1
Discontinuation of study treatment .......................................................38
9.1.2
Withdrawal of informed consent...........................................................39
9.1.3
Lost to follow-up...................................................................................40
9.1.4
Early study termination by the sponsor.................................................40
9.2
Study completion and post-study treatment ..........................................................40
10 Safety monitoring and reporting........................................................................................41
10.1
Definition of adverse events and reporting requirements......................................41
10.1.1
Adverse events ......................................................................................41
10.1.2
Serious adverse events ..........................................................................42
10.1.3
SAE reporting........................................................................................43
10.1.4
Pregnancy reporting ..............................................................................44


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10.1.5
Reporting of study treatment errors including misuse/abuse................44
10.2
Additional Safety Monitoring................................................................................45
10.2.1
Liver safety monitoring.........................................................................45
11 Data Collection and Database management......................................................................46
11.1
Data collection.......................................................................................................46
11.2
Database management and quality control............................................................46
11.3
Site monitoring ......................................................................................................47
12 Data analysis and statistical methods ................................................................................47
12.1
Analysis sets ..........................................................................................................47
12.2
Subject demographics and other baseline characteristics......................................48
12.3
Treatments .............................................................................................................48
12.4
Analysis of the primary endpoint(s) ......................................................................48
12.4.1
Definition of primary endpoint(s).........................................................48
12.4.2
Statistical model, hypothesis, and method of analysis..........................48
12.4.3
Handling of missing values/censoring/discontinuations.......................49
12.4.4
Sensitivity and Supportive analyses......................................................49
12.5
Analysis of secondary endpoints ...........................................................................49
12.5.1
Safety endpoints....................................................................................49
12.5.2
Pharmacokinetics ..................................................................................50
12.6
Interim analyses.....................................................................................................50
12.7
Sample size calculation..........................................................................................51
12.7.1
Primary endpoint(s)...............................................................................51
13 Ethical considerations and administrative procedures ......................................................52
13.1
Regulatory and ethical compliance........................................................................52
13.2
Responsibilities of the investigator and IRB/IEC..................................................53
13.3
Publication of study protocol and results...............................................................53
13.4
Quality Control and Quality Assurance.................................................................53
14 Protocol adherence ............................................................................................................53
14.1
Protocol Amendments ...........................................................................................54
15 References .........................................................................................................................55
16 Appendices ........................................................................................................................56
16.1
Appendix 1: Clinically notable laboratory values and vital signs .........................56
16.2
Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.........................................................................................................56
16.3
Appendix 3: Blood Volume Table.........................................................................58
16.4
Appendix 4: Pharmacokinetic/Vital signs/ECG/Lab assessment timed 
schedule (End of treatment)...................................................................................59


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16.5
Appendix 5: Definition of pharmacokinetic parameters .......................................59
16.6
Appendix 6: List of idiosyncratic drug reactions (IDRs) for investigators ...........60
List of tables
Table 2-1
Objectives and related endpoints ..........................................................15
Table 6-1
Fevipiprant (QAW039).........................................................................25
Table 6-2
Medications allowed under certain conditions......................................26
Table 6-3
Prohibited medications..........................................................................27
Table 6-4
Dose and treatment schedule.................................................................29
Table 8-1
Assessment Schedule ............................................................................32
Table 8-2
Physical assessments.............................................................................36
Table 8-3
Laboratory Assessments........................................................................36
Table 10-1
Guidance for capturing the study treatment errors including
misuse/abuse .........................................................................................45
Table 16-1
Liver Event and Laboratory Trigger Definitions ..................................56
Table 16-2
Follow-Up Requirements for Liver Events and Laboratory Triggers...56
Table 16-3
Blood volume........................................................................................58
Table 16-4
PK urine sample....................................................................................58
Table 16-5
PK/VS/ECG/Lab assessment schedule (EOT)......................................59
Table 16-6
Pharmacokinetic parameters .................................................................59
Table 16-7
Definition of potential idiosyncratic drug reactions..............................60
List of figures
Figure 3-1
Study Design .........................................................................................16


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List of abbreviations
AD
atopic dermatitis
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the curve
AUC0-24
area under the drug concentration-time curve from 0 to 24 hours
BMI
body mass index
BP
blood pressure
BUN
blood urea nitrogen
CFR
Code of Federal Regulation
CI
confidence interval
CL/F
oral clearance
CLr
renal clearance
Cmax
maximum plasma concentration
Cmin
minimum plasma concentration
CMO&PS
Chief Medical Office and Patient Safety
CO 
country organization
CRA
Clinical Research Associate
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CRTh2
Chemoattractant Receptor-homologous molecule expressed on Th2 cells (also called DP2)
CSR
Clinical Study Report
CT
chewable tablet
CTT
Clinical Trial Team
CV
coefficient of variation
DAR
drug administration record
DBP
diastolic blood pressure
DDE
direct data entry
DP2
Prostaglandin D2 receptor 2 (also called CRTh2)
EC
Ethics committee
ECG
Electrocardiogram
eCRFs
Electronic Case Report Forms
EDC
Electronic Data Capture
EOT
end of treatment
EPR-3
Expert Panel Report 3
eSource 
electronic source
EU
European Union
FCT
film-coated tablet
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GGT
gamma-glutamyl-transferase
GINA
Global Initiative for Asthma
h
hour
IA
Interim Analysis


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IB
Investigator's Brochure
ICF
Inform Consent Form
ICH
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use
ICS
Inhaled corticosteroids
IEC
Independent Ethics Committee
IL
Interleukin
ILC2
Type 2 innate lymphoid cells
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
Intrauterine Device
IUS
Intrauterine System
LABA
Long-acting β-agonists
LAMA
Long-acting muscarinic antagonists
LLOQ
lower limit of quantification
LTRAs
Leukotriene receptor-antagonists
MedDRA
Medical Dictionary for Regulatory Activities
NORA®
Network Oriented Research Assistant
o.d.
once a day
PGD2
Prostaglandin D2
PIP
pediatric investigation plan
PK
pharmacokinetic(s)
PopPK
A population pharmacokinetics
PT/INR
Prothrombin ratio and international normalized
QMS
Quality Management System
QTc
QT interval
QTcF
Fridericia QT correction formula
RDC
Remote Data Capture
RoW
rest of world
SABAs
Short-acting β-agonists
SAEs
serious adverse event(s)
SAMA
Short-acting-muscarinic-antagonists
SBP
systolic blood pressure
SD
Standard Deviation
SoC
standard-of-care
ss
steady state
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBL
total bilirubin
TD
treatment discontinuation
Th2
Type 2 helper T cells
Tmax
time of maximum plasma concentration
VS
vital signs
WHO
World Health Organization


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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
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)
End of Treatment
A visit that may occur after 3 consecutive days of dosing in subjects where study drug 
compliance is a concern
Enrollment
Point/time of subject entry into the study at which informed consent must be obtained (i.e.
prior to starting any of the procedures described in the protocol)
Epoch
Interval of time in the planned conduct of a study. An epoch is associated with a purpose 
(e.g. screening, randomization, treatment, follow-up), which applies across all arms of a 
study.
Investigational 
drug
The study drug whose properties are being tested in the study; this definition is consistent 
with US CFR 21 Section 312.3 and 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.
Medication pack 
number
A unique identifier on the label of each drug package in studies that dispense study 
treatment 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 completion
Point/time at which the subject came in for a final evaluation visit or when study drug was 
discontinued whichever is later.
Study drug 
discontinuation
Point/time when subject permanently stops taking study drug for any reason; may or may 
not also be the point/time of premature subject withdrawal.
Study treatment
Any drug administered to the study participants as part of the required study procedures; 
includes investigational drug (s), control(s) or non-investigational medicinal product(s)
Study treatment 
discontinuation
When the subject permanently stops taking study treatment prior to the defined study 
treatment completion date
Subject
An individual who has consented to participate in this study. The term Subject may be 
used to describe either a healthy volunteer or a patient.
Subject number
A unique number assigned to each subject upon signing the informed consent. This 
number is the definitive, unique identifier for the subject and should be used to identify the 
subject throughout the study for all data collected, sample labels, etc.
Variable
A measured value or assessed response that is determined in specific assessments and 
used in data analysis to evaluate the drug being tested in the study


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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
Changes to the protocol
The described changes in the aforementioned amendment rationale are implemented throughout 
the protocol in the sections noted.
The opportunity was also taken to:

Updated Section 2 Objectives and endpoints to clarify that steady state could be achieved 
after four days of consecutive dosing. 

Updated Section 3 Study design to include the addition of a light breakfast about 30 
minutes prior to dosing during the clinic/home visit; confirmation light breakfast was 
given; Figure 3-1 clarified treatment period day 1 to steady state. 

Clarified process on how the chewable tablet should be administered in the following 
order: banana/yogurt, chewable tablet, followed by banana/yogurt 

Clarified end of treatment visit may occur from Day 4 to 8, after 3 consecutive days of 
dosing have been confirmed

Added additional guidance around the time of dosing for the End of Treatment (EOT) 
Visit

Updated Section 4.2 Rationale for dose/regimen and duration of treatment based on 
previous trial data, 

clarified preliminary food effect assessment was conducted using capsules;

removed reference sentence no major effect of food on fevipiprant pharmacokinetic(s) 
(PK) is expected, dosing in this study can happen independent of meals; 

added a light breakfast should be provided on all study days

Updated Section 5 Population to include flexible window in regards to EOT Visit

Updated Section 5.2 Exclusion criteria to include exclusionary criteria which states 
“subject is unable to ingest banana and/or yogurt”. 

Updated Section 6.1.4 Treatment duration due to the EOT Visit being able to occur on 
Day 4 to 8.

Updated Section 6.2.2 , Table 6-3 prohibited medications to include cyclosporine and 
modified omalizumab language to be consistent with phase 3 clinical trials

Updated Section 6.3.2Treatment assignment, randomization, added language for remote 
visit enrollment 

Updated Section 6.7.2 Instructions for prescribing and taking study treatment


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
Updated Section 8 Visit schedule and assessments based on changes to treatment duration 
and steady state occurring after four consecutive days of dosing 

Updated Table 8-1 to include footnote referencing a light breakfast and remote visits

Updated Section 8.1.1, removed collecting AEs for screen failures; added AEs that are 
not SAEs will be collected in source data

Updated Section 12.3 Treatment based on steady state being achieved after four 
consecutive days of dosing 

Updated Section 12.4.2 Statistical model, hypothesis, and method of analysis due to EOT 
Visit occurring on Day 4 to 8

Updated Section 12.5.2 clarified Pharmacokinetics based on steady state 

Updated Section 12.7.1 Primary endpoint(s), updated in terms of exposure i.e. mean 
AUC0-24h,ss dose lower/higher than 225 mg

Updated Section 3, Section 6.3.2, Section 8 to allow flexibility for optional remote home 
visits 

Updated Table 16-3, revised footnotes to define EOT and last dose

Updated Table 16-4, included footnote referencing treatment timing
IRB Section
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval, a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Protocol summary
Protocol number
CQAW039B2201
Full Title
A multicenter, open-label, 8 day treatment study to assess the pharmacokinetics, safety 
and tolerability of fevipiprant delivered via a once daily chewable tablet in children aged 
6 to < 12 years with asthma
Brief title
Pharmacokinetics, safety and tolerability of fevipiprant delivered via a once daily 
chewable tablet in children aged 6 to < 12 years with asthma 
Sponsor and 
Clinical Phase
Novartis Phase II
Investigation type
Fevipiprant Chewable Tablet (CT)
Study type
Interventional
Purpose and 
rationale
The purpose of this study is to assess the pharmacokinetics (PK) of fevipiprant 
(QAW039) delivered as a chewable tablet (CT) in pediatric asthma subjects aged 6 to < 
12 years. The results of this study will support the identification of a fevipiprant dose for 
subsequent pediatric efficacy studies aiming to provide an exposure similar to that of 
the to-be marketed adult/adolescent dose. In addition, the first data on safety and 
tolerability of fevipiprant in this age group will be obtained.
Primary 
Objective(s) 
To determine the key pharmacokinetic parameters of fevipiprant at steady state (ss), 
after at least four consecutive days of dosing))
Secondary 
Objectives
Objective 1: To evaluate additional pharmacokinetic parameters of fevipiprant at steady 
state 
Objective 2: To evaluate the pharmacokinetics of CCN362, the major metabolite of 
fevipiprant at steady state 
Objective 3: To evaluate the urinary excretion of fevipiprant and CCN362 at steady state 
Objective 4: To evaluate the safety and tolerability of fevipiprant over treatment period
Study design
This is a multicenter, open-label, study to assess the pharmacokinetics, safety, and 
tolerability of fevipiprant CT in children aged 6 to < 12 years with asthma. The study 
includes a 4-8 day, open-label treatment period in which subjects receive fevipiprant CT 
once daily in addition to their rescue medication (e.g. short-acting β-agonists [SABAs]) 
and standard-of-care (SoC) asthma therapy (inhaled corticosteroids [ICS] with or 
without an additional controller therapy). There will be 2 treatment dose cohorts studied 
(fevipiprant 75 mg once daily and one higher dose selected based on PK obtained at 75 
mg/day, [e.g. 150, 225, 300, or 375 mg once daily]) Within each dose cohort, subjects 
will be stratified approximately 1:1 ratio into 2 age groups: ages 6 to < 9 years and ages 
9 to < 12 years.
Population
At least 12 but not more than 24 male or female children. Within each dose cohort, 
subjects will be stratified approximately 1:1 ratio into 2 age groups: ages 6 to < 9 years 
and ages 9 to < 12 years.
Key Inclusion 
criteria
1.
Male and female children ≥ 6 years and <12 years
2.
Written informed consent by parent(s)/legal guardian(s) for the pediatric patient and 
assent by the pediatric patient (depending on local requirements) must be obtained 
before any study-specific assessment is performed.
3.
Confirmed/documented diagnosis of asthma, as defined by national or international 
asthma guidelines for at least 6 months prior to study enrollment.
4.
Subjects using asthma rescue medication (e.g. SABA) without asthma controller 
therapy or subjects receiving daily treatment with a stable dose ICS (with or without 
additional controller such as long-acting β-agonists [LABA], long-acting muscarinic 
antagonists [LAMA]) for at least 4 weeks prior to Treatment visit (Day 1).
5.
Subjects must be able to attend study visits as per Study Visit Assessment 
Schedule (Section 8) which includes 8 to 9 hours in the clinic/home on the day of 
End of Treatment Visit and have blood draws as scheduled in the study.


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6.
Parents/ legal guardian must be willing and able to attend study visits and assist 
the child with the procedures outlined in the protocol (e.g. compliance with taking 
study medication and completing the diary).
Key Exclusion 
criteria
1.
Use of other investigational drugs within 5 half-lives of enrollment, or [within 30 
days (for small molecules) /until the expected pharmacodynamic effect has 
returned to baseline (for biologics)], whichever is longer.
2.
Subject is unable to ingest banana and/or yogurt.
3.
History of hypersensitivity to any of the study drugs or its excipients or to drugs of 
similar chemical classes.
4.
History of chronic lung disease other than asthma such as and not limited to, 
sarcoidosis interstitial lung disease, cystic fibrosis, mycobacterial or other infection 
(including active tuberculosis or atypical mycobacterial disease).
5.
History of active bacterial, viral or fungal infection within 6 weeks of Treatment Visit 
(Day 1).
6.
Subjects who, in the opinion of the investigator, are not able to be compliant with 
study treatment or who have any medical or mental disorder, situation, or diagnosis 
which could interfere with the proper completion of the protocol requirements or 
risk the subject’s safety while participating in the study.
Study treatment
Fevipiprant 75 mg CT
Fevipiprant 150, 225, 300 or 375 mg CT or at a different dose
Efficacy 
assessments
Not applicable
Pharmacokinetic 
assessments
Blood and urine collection at steady state to determine PK parameters of fevipiprant 
and its major metabolite CCN362
Key safety 
assessments

Medical history and physical examination including oropharyngeal examination

Vital signs

Hematology, blood chemistry, urine dipsticks

Electrocardiogram (ECG)

Adverse events (AEs) including asthma exacerbations, worsening asthma, and 
serious adverse events (SAEs)
Data analysis
For all analysis sets, subjects will be analyzed according to the study treatment(s) 
received.
The safety analysis set will include all subjects that received any study drug.
The PK analysis set will include all subjects with at least one available valid (i.e. not
flagged for exclusion) PK concentration measurement, who received any study drug and 
with no protocol deviations that impact PK data.
PK parameters will be analyzed by standard non-compartmental analysis and 
summarized by cohort through descriptive summary statistics (including mean, SD, CV% 
mean, Geometric mean, CV% geometric mean, median, minimum and maximum). 
Additionally, CL/F will also be summarized across cohorts.
Key words
Fevipiprant, GINA 2018, Pediatrics


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1
Introduction
1.1
Background
Asthma is affecting approximately 300 million people of all ages worldwide. Dramatic 
increases in the prevalence of asthma have occurred over the past two decades in Westernized 
countries (Fanta 2009, Wilson et al 2006) and more recently in less-developed nations 
(Pearce et al 2007, Fanta 2009). Asthma is a common childhood chronic disease 
(Bastain et al 2011) and its prevalence has increased especially among children over the past 
20 years (GINA 2018). Asthma currently affects nearly 6 million or 8.8% of all children less 
than 15 years of age in the United States (Ward et al 2015), with data showing that the incidence 
and prevalence of asthma is increasing more rapidly in children than that in adults, particularly 
in children under 15 years (Masoli et al 2004). Although the exact prevalence of severe asthma 
in children is unknown, it tends to be rare in the setting of good medication access and 
compliance and likely affects less than 5% (or approximately 300,000) of all asthmatic children 
in the US (Coverstone et al 2015).
Although most children with asthma (i.e., up to 95%) derive clinical benefit from daily 
administration of low-to-medium-dose inhaled corticosteroid (ICS) therapy, (National Asthma 
Education and Prevention Panel. Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis 
and Management of Asthma-Summary Report 2007) nearly half of these children experience at 
least 1 episode of poor asthma control per year despite the prescription of asthma controller 
therapy (Ward et al 2015).
Consequently, there remains an unmet need for well tolerated, easily administered, cost-
effective anti-inflammatory therapies with the capability to improve the asthma control by 
reducing asthma exacerbations, particularly for those children with severe asthma who appear 
to be at greatest risk for recurrent asthma exacerbations.
Novartis is developing fevipiprant which is a selective, orally-administered, reversible, 
competitive antagonist at the prostaglandin D2 receptor 2 (also called CRTh2 or DP2) with no 
affinity for the DP receptor, which also blocks prostaglandin (PGD2)-mediated eosinophil 
activation in whole blood as well as release of Interleukin (IL)-5 and IL-13 cytokines from type 
2 helper T cells (Th2) (Sykes et al 2016). Blockade of the actions of PGD2 and its DP2 active 
metabolites acting at the DP2 receptor on these cell types, together with type 2 innate lymphoid 
cells (ILC2) (Xue et al 2014), will enable suppression of the key inflammatory pathways in 
asthma and is expected to reduce disease progression.
Although there are no published data on DP2 antagonist’s efficacy in pediatric populations 
below the age of 12, fevipiprant has the potential to be of significant benefit over therapeutic 
alternatives based on clinical data to date in the adult population.
The pediatric development in children will be initiated by conducting this Phase II study 
(B2201) investigating the pharmacokinetics (PK), safety and tolerability of fevipiprant in 6 to 
less the 12 year old children with asthma. The expression of DP2 across a broad age range was 
assessed in study [CQAW039B2104]
to complement the information about the 
pharmacokinetics for the dose selection in this age group. Fevipiprant is cleared via 
glucuronidation by several uridine diphosphate glucuronosyltransferases as well as renal 
excretion and possibly biliary excretion. Only one major metabolite is formed: the acyl 


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glucuronide CCN362, which is not pharmacologically active. It is generally assumed that most 
drug clearance pathways are mature in children 2 years and older (Holford et al 2013). Since a 
number of enzymes and transporters contribute to the clearance of fevipiprant, a strong 
sensitivity of PK to any specific slowly maturing clearance pathway in children of 6 years and 
older is not expected for fevipiprant.
1.2
Purpose
The purpose of this study is to assess the pharmacokinetics (PK) of fevipiprant (QAW039) 
delivered as a chewable tablet (CT) in pediatric asthma subjects aged 6 to < 12 years. The results 
of this study will support the identification of a fevipiprant dose for subsequent pediatric 
efficacy studies aiming to provide an exposure similar to that of the to-be marketed 
adult/adolescent dose. In addition, the first data on safety and tolerability of fevipiprant in this 
age group will be obtained.
2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

To determine the key pharmacokinetic 
parameters of fevipiprant at steady state (ss), 
after at least four consecutive days of dosing))

Area under the curve (AUC0-24h,ss), maximum 
plasma concentration (Cmax,ss), and oral 
clearance (CL/F)
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To evaluate additional pharmacokinetic 
parameters of fevipiprant at steady state

Tmax,ss, Cmin,ss, (CL/F)/kg of fevipiprant

To evaluate the pharmacokinetics of CCN362, 
the major metabolite of fevipiprant at steady state

Cmax,ss, time of maximum plasma concentration 
(Tmax,ss), AUC0-24h,ss, minimum plasma 
concentration (Cmin,ss) of CCN362

To evaluate the urinary excretion of fevipiprant 
and CCN362 at steady state

CLr, amount and fraction of dose excreted over 
the PK collection interval 

To evaluate the safety & tolerability of fevipiprant 
over treatment period

Safety laboratory values (including peripheral 
blood eosinophils), vital signs, electrocardiogram 
(ECG), adverse events


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3
Study design
This is a multicenter, open-label, study to assess the pharmacokinetics, safety, and tolerability 
of fevipiprant CT in children aged 6 to < 12 years with asthma. The study includes a 4-8 day, 
open-label treatment period in which subjects receive fevipiprant CT once daily (o.d.) in 
addition to their rescue medication (e.g. short-acting β-agonists [SABAs]) and potentially 
standard-of-care (SoC) asthma therapy (inhaled corticosteroids [ICS] with or without an 
additional controller therapy). There will be 2 treatment dose cohorts studied (fevipiprant 75 
mg o.d. and one higher dose selected based on PK obtained at 75 mg/day, [e.g. 150, 225, 300, 
or 375 mg once daily]). Within each dose cohort, subjects will be stratified approximately 1:1 
ratio into 2 age groups: ages 6 to < 9 years and ages 9 to < 12 years.
The study will include the following:

A Screening period of up to 14 days;

A Treatment period of 4-8 days for each dose cohort (8 days of treatment is preferred); 
and

A Follow-up period of 30 days
Figure 3-1
Study Design
IA-interim analysis, o.d.-once daily


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In Cohort (A), 6 subjects (3 subjects from each of the 2 age strata) will be dosed with fevipiprant 
75 mg CT o.d. in the morning. After 6 subjects have completed the treatment period, an interim 
analysis (IA) will be performed. Exposure results and variability of the PK as measured by 
AUC0-24, steady state (ss) will be used to determine:

*whether dosing in Cohort B will be at 225 mg CT o.d. or at a different dose (e.g. 150, 
300 or 375 mg); and

the number of subjects for Cohort B.
See Section 12.6 for the complete details of the IA.
This study may be conducted using the decentralized remote study model, using a telemedicine 
technology for interactions between the investigator/study staff and study subjects. Network 
Oriented Research Assistant, or NORA® is the software interface that connects participants to 
their investigators and study teams. Additionally, mobile study personnel will visit sumjects’ 
homes to complete the designated study procedures, such as the collection of lab samples. 
A description of the study by period follows below.
Screening Period (Screening to Treatment Visit)
Within 14 days prior to treatment visit or at Screening Visit, written informed consent from the 
parent(s)/legal guardian(s), and subject assent (if applicable), will be obtained before any study-
related assessments or procedures are performed. The subject’s participation in the trial must 
be documented in the subject’s medical record and all study related evaluations performed at 
each visit must be clearly documented in source documentation and on electronic case report 
forms (eCRFs).
Study sites should check the interactive response technology (IRT) for subject age cohort 
availability before Screening Visit begins. If the subject qualifies, Screening Visit can proceed 
with the documentation of demographic data, the assessment of study inclusion/exclusion 
criteria, and past/current medical history. The subject can then be entered into the IRT system 
to continue screening. 
Once IRT has confirmed subject participation, physical and laboratory assessments may be 
performed ( Section 8.4 ). At this visit, subjects will be instructed to withhold any prohibited 
medication as applicable ( Table 6-3 ) prior to Treatment Visit (Day 1). The window between 
Screening Visit and Treatment Visit Day 1 (Screening Period) is up to 14 days.
Throughout the study (from Screening Visit through Follow-up period), subjects will continue 
to receive their rescue medication (e.g. SABA) and potentially SoC asthma therapy which could 
be ICS with or without additional controller medication. Leukotriene receptor-antagonists 
(LTRAs) must be stopped at Screening Visit and in that case ICS should be initiated or up-
titrated to the next higher dose as per investigator’s judgement; this change of treatment should 
be allowed to stabilize during the 14 days Screening Period. LTRAs treatment can be continued 
after End of Treatment (EOT) as per investigators decision.
Rescue medication such as SABAs will not be provided in this study, but may be prescribed by 
the investigator and used as needed.


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Treatment period Day 1 to Day 4-8 (Treatment Visit to End of Treatment Visit) 
Eligible subjects meeting all inclusion and exclusion criteria will enter the 4-8-day Treatment 
Period of the respective cohort.
Treatment Visit (Day 1)
On Treatment Visit (Day 1), qualifying subjects should have scheduled visit in the morning. 
Prior to the performance of Treatment Visit (Day 1) clinical evaluations, the investigator will 
re-assess inclusion/exclusion criteria, adverse events (AEs) serious adverse events (SAEs), 
Screening Visit laboratory results and the ECG interpretation. If eligible to continue, subjects 
will have procedures performed as outlined in Table 8-1 , and entered into the IRT system to 
obtain treatment pack assignment. For remote visits IRT entry into the system will occur prior 
to home visit.
Subjects will then receive a witnessed dose of fevipiprant CT. Depending on the assigned cohort, 
the subjects will receive 1 or more CTs. A light breakfast (e.g. average sized serving of cereal, 
milk, banana, and/or yogurt) should be provided about 30 minutes prior to dosing during the 
clinic/remote visit. Subjects will be instructed to chew small piece of banana/yogurt followed 
immediately by CT(s) and then followed with an additional piece of banana/yogurt. 
Subjects will be encouraged to drink some water thereafter. Time of dosing and confirmation 
that a light breakfast was given will be recorded on the patient diary card. Subjects will remain 
in the clinic/remote visit for at least 2 hours for observation after the witnessed dose of 
fevipiprant. For remote visits the nurse will remain in the home for 2 hour observation.
At this visit, subjects and parent(s)/guardian(s) will be instructed to:

Give a light breakfast about 30 minutes prior to administration of study drug at the 
approximate same time each morning of Treatment Day 2 through 1 day prior to EOT.

CT(s) administration should be done in the following order: chew small piece of 
banana/yogurt followed immediately by CT(s) and then followed with an additional piece 
of banana/yogurt. 
Subjects will be encouraged to drink some water thereafter.

Record the actual time of dosing and confirmation that a light breakfast was given on the 
patient diary card each day.

Dosing 1 day prior to EOT should ideally happen approximately 23 h before the planned 
arrival at the clinic/remote visit on Day 4 to 8 (End of Treatment Visit).

Withhold study drug the morning of EOT Visit. Study drug will be administered by study 
site staff/remote nurse in the clinic/home.
Prior to leaving the clinic/home, parent(s)/legal guardian(s) will be dispensed study drug for 
home administration during the Treatment Period, a study diary card to record time of dosing, 
and will make an appointment to return to the clinic on EOT Day.
End of Treatment Visit (Day 4 to 8)
The End of Treatment Visit can only occur after 3 consecutive days of dosing (i.e., as early as 
Day 4 of dosing).
At the EOT Visit Day, subjects should not take the study drug at home, and arrive at the site or 
planned remote visit in the morning. Study drug will be taken in the clinic/home, and PK 


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sampling will occur over 8 hours; the subject and parent/guardian will need to be available to 
remain in the clinic/home for about 8 to 9 hours.
The scheduling and timing of EOT Visit should ensure dosing of study drug in the clinic/home 
takes place about 24 ± 2 hours after the last dose of study drug taken at home. On the day prior 
to EOT, visit study personnel should remind the subject and parent/guardian in a phone call to 
take study medication at the right time in relation to the scheduled EOT visit. Additionally, PK 
sampling requires confirmation that study drug was taken for 3 consecutive days prior to EOT 
Visit. This information must be confirmed by study personnel/remote nurse at EOT Visit by the 
review of the subject's daily dosing diary. If study personnel/remote nurse cannot confirm that 
study drug was taken by the subject on 3 consecutive days prior to EOT Visit, the EOT Visit can 
be rescheduled for +1 to 2 days later. In cases where the subject cannot make the scheduled 
EOT Visit or has mistakenly taken the study drug at home on the Day of EOT Visit, the Visit 
can be re-scheduled to the next available clinic/home day.
At the start of the EOT Visit, eligibility to proceed with PK assessments will be confirmed and 
subjects will receive a light breakfast (e.g. average sized serving of cereal, milk, banana, and/or 
yogurt) at the study site about 30 minutes prior to dosing. Prior to dosing subjects should be 
encouraged to empty their bladder in the rest room (not collected for urine PK sampling, but 
can be used for urine dipstick) in order to get a clear pool of urine post dosing, used for urine 
PK sampling. Subjects will be administered the final dose of study drug by study staff within
approximately 30 minutes after completion of breakfast. Subjects will be instructed to chew 
small piece of banana/yogurt followed immediately by CT(s) and then followed with an 
additional piece of banana/yogurt. Subjects will be encouraged to drink some water 
thereafter. The procedures associated with EOT Visit (including the placement of an indwelling 
catheter with local anesthetic for blood draws) will be performed in the clinic/home as outlined 
in Table 8-1 . Section 16.4 outlines the PK and vital sign (VS) timing of assessments noting 
that at time points where multiple procedures occur; the following order is recommended: VS, 
e.g. PK sampling, laboratory blood draws.
The time of dosing for witnessed dose of fevipiprant CT will be recorded in the eCRF. 
Throughout the visit, subjects should be encouraged to drink water in order to allow urine 
production for urine collection.
Blood for PK sampling may be drawn via intermittent venous punctures with topical anesthetic 
or via the placement of an indwelling catheter with local anesthetic. PK sampling will be 
obtained as close as feasible to planned times with the actual times of blood draws recorded in 
source and on the eCRF.
In addition to breakfast, subjects may have food during their time at the clinic/home, but it is 
recommended that they wait at least 3 hours after dosing to eat.
To avoid the need for an overnight stay at the clinical site, the pre-dose drug concentration 
values obtained on EOT Visit will also be used as the 24-hour post-dose drug concentration 
value to calculate AUC0-24,ss. For this reason it is important to have approximately 24 h 
between the last at home dose and the witnessed dose in the clinic at the EOT Visit. 
Upon completion of all EOT Visit study assessments, at the investigator’s discretion, the subject 
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Follow-up Period (Phone call to Parent/Gurdian)
Following the treatment period or discontinuation (last dose of study drug), a follow-up period 
of 30 days, investigational drug free, will assess any safety-related adverse events.
4
Rationale
4.1
Rationale for study design
This is an open-label study with an 8 day preferred treatment period to assess pharmacokinetics 
and safety of 2 different doses levels of fevipiprant CT. The 2 dose cohorts (A and B) will be 
studied consecutively, to allow to assess low dose data before escalating to a higher dose level 
in this first study in children of 6 to < 12 years. After cohort A an interim analysis will decide 
the fevipiprant dose and number of subjects tested in cohort B. By this a sufficiently good 
definition of the primary pharmacokinetic endpoint and an adequate exposure in the high dose 
group is supported. As the primary objective of the study is a pharmacokinetic assessment, the 
open-label design is considered appropriate. A population pharmacokinetics (PopPK) modeling 
approach will be used to integrate data from this study with adult and adolescent PK data to 
support the pediatric Phase III dose selection. The PK sampling in this study (i.e. from pre-dose 
to 8 h post dose at steady state) is adequate to inform the PopPK model. This is the first 
fevipiprant study in this age range and final dose selection requires the data obtained in this 
study. Therefore, pediatric Phase III dose level may not be identical to one of the dose levels 
tested in this study. However, the flexility in selecting the high dose based on 75 mg/day data 
will allow an appropriate range to be covered.
4.1.1
Rationale for choice of background therapy
Subjects will continue to receive their rescue medication (e.g. SABA) and potentially SoC 
asthma therapy throughout the study (from Screening Visit through Follow-up period). Since 
the purpose of the study is to assess PK, safety and tolerability of fevipiprant CT there is no 
need to alter the background medication (with exemption of LTRAs which could potentially 
interfere with the PK analyses of fevipiprant).
4.2
Rationale for dose/regimen and duration of treatment
The ongoing Phase III program in asthma tests the dose levels of 150 and 450 mg/day once 
daily in adults and adolescents down to age 12. Dose levels for Phase III studies in subjects < 
12 years of age are planned to be selected to provide systemic fevipiprant exposure similar to 
that of dose level finally selected for treatment of adults and adolescents (either 150 or 450 
mg/day). 
Since the adult dose of fevipiprant is once daily, a once daily regimen for fevipiprant will also 
be used in this initial trial to obtain pharmacokinetic exposure of fevipiprant in subjects aged 6 
to <12 years. It is known that in adults, steady state exposure is reached within 4 days of once 
daily dosing with little (~ 1.3 fold) accumulation. Based on adult data a similar duration of 
dosing to obtain steady state information in subjects 6 to <12 years is also planned. 
Pharmacokinetic sampling at steady state in 6 to <12 years old subjects can occur as early as 4 
days after dosing as long as study personnel can confirm that study drug was taken by the subject 


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on 3 consecutive days prior to End of Treatment Visit. In order to introduce flexibility in the 
protocol a visit window is included, which allows the pharmacokinetic sampling at steady state 
to occur anywhere from 4-8 days after dosing. In case study personnel cannot confirm that study 
drug was taken by the subject on 3 consecutive days prior to EOT Visit (which can occur 
anywhere from Day 4-8), the EOT Visit can be rescheduled for +1 to 2 days later. In addition, 
this duration will allow the first and last doses of study medication requiring visits at the 
hospital/clinic to occur during the weekend or on a designated day in the week most convenient 
to the family.
Based on the current understanding of the dose-effect and dose-safety relationship, it is assumed 
that children aged 6 to < 12 years can be treated by 1 fixed dose level. The dose levels of 75 mg 
and potentially 225 mg selected for this study are expected to provide an exposure in children 
aged 6 to < 12 years which is comparable to the 150 mg and 450 mg dose levels in adults. The 
dose levels were derived by weight-based allometric scaling, also considering physiologically-
based PK modeling results. The bioavailability of the CT used in this study relative to the film-
coated tablet (FCT) used in adults and adolescents was assessed in adults and was close to one 
(~ 1.18). If the exposure at 75 mg/day is relevantly lower or higher than expected, the dose level 
in the high dose group will be adjusted accordingly considering available dose strength of CTs 
(e.g. to 150 mg (2*75 mg) or 300 mg (225 + 75 mg)).
In a preliminary food effect assessment with capsules, food had no clinically relevant impact 
on the PK of fevipiprant: a delay in median Tmax from 2 to 2.5 h was observed with a high fat 
meal and based on the point estimate Cmax was 7% reduced. Fevipiprant is dosed independent 
of meals in Phase III studies in asthma. Although no major effect of food on fevipriprant PK is 
expected, a light breakfast should be provided before dosing on all study days to standardize 
food effects across the study population and, hence, minimize any potential effect of meal 
conditions on PK variability as well as to support the well-being of children during blood 
collection.
Fevipiprant has a good safety profile in populations studied to date at total daily doses up to 
500 mg/day given for durations of up to 12 weeks and at doses of 1800 mg/day administered 
for a duration of up to 1 week; the maximal tolerated dose of fevipiprant in humans has not 
been identified thus far.
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
The study does not include a placebo control as this would not be considered ethical in this 
population of pediatric asthma subjects and is not required to support the primary 
pharmacokinetic endpoint.
4.4
Purpose and timing of interim analyses/design adaptations
A planned interim analysis will be conducted to support decision making when 6 subjects (3 
subjects from each of the 2 age strata) receiving the 75 mg dose level complete the treatment
and provide the planned PK and safety data. At interim analysis, safety, as well as mean and 
variability of PK data of the 75 mg dose level will be assessed to have the right dose and number 
of subjects for the higher dose at the second stage.


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For detailed information, please refer to Section 12.7. Once PK data from 6 children are 
available, an interim analysis will be performed using non-compartmental methods and based 
on protocol times (e.g. preliminary PK data).
Additional interim analysis may be conducted when at least 6 subjects on high dose will 
complete the treatment (in case where sample size on high dose is adjusted to be more than 6 
after first interim analysis) and the sample size of high dose can be refined based on emerging 
PK data.
The flexibility to adapt the sample size and dose of the high dose cohort based on mean and 
variability of PK data at the low dose will ensure that the primary endpoint of this study is met 
supporting pediatric dose selection for Phase III. The Phase III dose selection will apply 
population PK methodology and combined analysis with PK data from other age strata. The 
non-compartmental analysis performed in this study is considered adequate to ensure 
sufficiently good definition of key PK properties to inform the population PK model.
4.5
Risks and benefits
Fevipiprant is a potent and highly selective oral DP2 (also referred to as CRTh2) receptor 
antagonist being developed as a potential therapy treatment for subjects with severe asthma. 
DP2 is a receptor for PGD2 which mediates the activation and migration of Th2 cells and 
eosinophils, some of the key inflammatory cell types in asthma. Recruitment of these cells into 
the lung is partly responsible for the intermittent airway obstruction which leads to wheezing 
and shortness of breath characteristic of asthma.
Fevipiprant is at least 300-fold selective for the DP2 receptor compared to other available 
prostanoid receptors and to cyclooxygenase-1 and cyclooxygenase-2, and it has been 
demonstrated to be a potent in vitro inhibitor of human whole blood eosinophil activation and 
induction of Th2 cytokines. After oral dosing in rats, QAW039 inhibited pulmonary 
eosinophilia induced by the PGD2 metabolite DK-PGD2.
The potential benefits of QAW039 therapy need to be balanced against its potential risks. The 
risk to subjects in this study will be minimized by compliance with the inclusion/exclusion 
criteria and close clinical monitoring. All subjects will remain on the background SoC asthma 
therapy they were taking at screening throughout the study, with exemption of LTRAs (LTRAs 
have to be stopped but in that case ICS can be initiated or dosed higher in case the subject was 
already on ICS). Furthermore, subjects will be instructed how to react to worsening of asthma 
symptoms so subjects can be managed appropriately.
Appropriate eligibility criteria and specific dose-limiting toxicity definitions, as well as specific 
dose modification and stopping rules, are included in this protocol.
All assessments in this trial are relatively small and part of regular medical assessments in this 
subject population. Procedural risks are related to blood sampling for safety and PK labratory 
analyses: puncturing of the veins can cause discomfort, pain, hematoma or in rare cases lead to 
an infection.
The overall clinical experience with fevipiprant includes 24 studies: 15 (nine in healthy 
volunteers and six in patients) have completed and nine (five in asthma subjects, 2 in healthy 
volunteers and 2 in subjects with renal or hepatic impairment) are ongoing. The completed 
Phase II studies consist of four in subjects with asthma, one in subjects with allergic rhinitis and 


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one in subjects with atopic dermatitis (AD). Five Phase III studies ( [CQAW039A2307], 
[CQAW039A2314], [CQAW039A2315], [CQAW039A2316] and [CQAW039A2317]) in 
asthma and four Phase I studies in healthy volunteers ( [CQAW039A2114]
and 
[CQAW039A2120]
</intref>) 
and 
subjects 
with 
renal 
or 
hepatic 
impairment 
( [CQAW039A2107] and  [CQAW039A2108]) are ongoing. For detailed information on the 15 
completed studies, please refer to Section 5 and Section 5.2.1.2 of the [Investigator's Brochure 
(IB)].
As of January 2018, over 2830 subjects have been exposed to fevipiprant in the clinical program. 
In the completed and ongoing studies of fevipiprant, approximately 2835 subjects (420 healthy 
volunteers and 2415 subjects with asthma, allergic rhinitis, or atopic dermatitis) received 
fevipiprant, approximately 1045 subjects received placebo, and approximately 420 received 
other 
treatments 
(rosuvastatin, 
simvastatin, 
montelukast, 
fluticasone, 
or 
probenecid). Fevipiprant has been well tolerated in populations studied to date at total daily 
doses up to 500 mg given for durations of up to 12 weeks and at a total daily dose up to 1800 
mg for a duration of up to 1 week. In the four completed studies in the asthma program, 21 
subjects reported 21 serious adverse events (SAEs), no deaths due to SAEs were reported, and 
seven discontinuations due to SAEs were reported. Of the 21 subjects reporting SAEs, 15 
subjects reported 15 events, five subjects reported five events, and one subject reported one 
event in the fevipiprant, placebo, and montelukast treatment groups, respectively. In the one 
study completed in the atopic dermatitis program, five subjects (one on fevipiprant and four on 
placebo) experienced a total of 6 SAEs (one in the fevipiprant group in the follow-up period, 
and 5 in the placebo group with 3 of them occurring during the treatment period). There were 
no SAEs in either program (including fatal events) with a suspected causal relationship to 
fevipiprant. There have been no adverse events (AEs) of idiosyncratic drug reactions.
Overall, the safety profile of fevipiprant has been favorable across studies.
5
Population

At least 12 but not more than 24 male and female children ≥6 years and <12 years 
diagnosed with asthma.

Six subjects will be included in Cohort A and 6 to18 subjects in Cohort B.

It is anticipated that approximately 20 subjects will need to be screened in order to include 
12 subjects into the treatment period (screen failure rate ~40%). After the interim analysis, 
additional subjects may need to be recruited so that total number of subjects completing 
treatment is maximum 24, in this case approximately 40 subjects will need to be screened.

It is intended that 12 to 24 patients will complete the study. Dropouts, non-completers and 
patients who are not eligible for PK assessment at EOT (e.g. because they did not take 
study drug for 3 consecutive days prior to EOT Visit) will be replaced.
Subjects will be stratified approximately 1:1 ratio into 2 age groups; 6 to < 9 years and 9 to < 
12 years to ensure approximately equal allocation of subjects throughout the whole age range 
being studied.
5.1
Inclusion criteria
Subjects eligible for inclusion in this study must meet all of the following criteria:


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1. Male and female children ≥ 6 years and <12 years.
2. Written informed consent by parent(s)/legal guardian(s) for the pediatric patient and assent 
by the pediatric patient (depending on local requirements) must be obtained before any 
study-specific assessment is performed.
3. Confirmed/documented diagnosis of asthma, as defined by national or international 
asthma guidelines for at least 6 months prior to study enrollment.
4. Subjects using asthma rescue medication (e.g. SABA) without asthma controller therapy 
or patients receiving daily treatment with a stable dose ICS (with or without additional 
controller such as long-acting β-agonists (LABA), long-acting muscarinic antagonists 
(LAMA)) for at least 4 weeks prior to Treatment Visit (Day 1).
5. Subjects must be able to attend study visits as per Study Visit Assessment Schedule 
(Section 8) which includes 8 to 9 hours in the clinic/home on the day of End of Treatment 
Visit and have blood draws as scheduled in the study.
6. Parents/legal guardian must be willing and able to attend study visits and assist the child 
with the procedures outlined in the protocol (e.g. compliance with taking study medication 
and completing the diary).
5.2
Exclusion criteria
Subjects meeting any of the following criteria are not eligible for inclusion in this study.
1. Use of other investigational drugs within 5 half-lives of enrollment, or (within 30 days (for 
small molecules)/until the expected pharmacodynamic effect has returned to baseline (for 
biologics)), whichever is longer.
2. Subject is unable to ingest banana and/or yogurt
3. History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar 
chemical classes.
4. History of chronic lung disease other than asthma such as and not limited to, sarcoidosis 
interstitial lung disease, cystic fibrosis, mycobacterial or other infection (including active 
tuberculosis or atypical mycobacterial disease).
5. History of active bacterial, viral or fungal infection within 6 weeks of Treatment Visit 
(Day 1).
6. Subjects who, in the opinion of the investigator, are not able to be compliant with study 
treatment or who have any medical or mental disorder, situation, or diagnosis, which 
could interfere with the proper completion of the protocol requirements or risk the 
subject’s safety while participating in the study.
7. Parent/guardian who, in the opinion of the investigator, has a history of psychiatric 
disease, intellectual deficiency, substance abuse, or other condition (e.g. inability to read, 
comprehend and write) which will limit the validity of consent for their child to participate 
in this study.
8. Hemoglobin levels outside normal ranges at screening.
9. Any surgical or medical condition which might significantly alter the absorption, 
distribution, metabolism, or excretion of drugs, or which may jeopardize the subject in 
case of participation in the study.


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10. Subjects who have a clinically significant ECG abnormality or clinically significant 
abnormal lab values reported at Screening Visit.
11. Subjects with a history of long QT syndrome or whose corrected QT interval (QTc) 
measured at Screening Visit (Fridericia method) is prolonged (≥ 450 msec for boys and 
girls).
12. Subjects receiving any medications in the classes specified in Table 6-3 unless they 
undergo the required washout period prior to Treatment Visit (Day 1) and follow the 
adjustment through the treatment period.
13. Subjects receiving medications in the classes listed in Table 6-2 should be excluded unless 
the medication has been stabilized for the specified period and the stated conditions have 
been met.
14. History of malignancy of any organ system, treated or untreated, within the past 5 years, 
regardless of whether there is evidence of local recurrence or metastases.
15. Subject is an immediate family member of the participating investigator, sub-investigator, 
study coordinator, or employee of the participating investigator.
16. History or presence of impaired renal function as indicated by clinically significantly 
abnormal creatinine or blood urea nitrogen (BUN) and/or urea values, or abnormal urinary 
constituents (e.g. albuminuria) according to investigator’s judgement.
17. Pregnant or nursing (lactating) females (Section 8.4.3).
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible subjects.
6
Treatment
6.1
Study treatment
6.1.1
Investigational and control drugs
All eligible subjects will be assigned to the investigational drug at Treatment (Day 1).
Table 6-1
Fevipiprant (QAW039)
Investigational/ 
Control Drug
(Name and Strength)
Pharmaceutical 
Dosage Form
Route of 
Administration
Sponsor (global 
or local)
Fevipiprant 75/225 mg
Chewable tablet
Oral use
Open-label subject 
specific supply; 
bottles
Sponsor global
6.1.2
Additional study treatments
No additional treatment beyond investigational drug is included in this trial.
Subjects may continue to use asthma rescue medication and SoC asthma therapy as outlined in 
the inclusion criteria.


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6.1.3
Treatment arms/group
All eligible subjects will be assigned to the investigational drug (Section 6.1.1) at Treatment 
(Day 1). Initially, subjects will be assigned fevipiprant 75 mg. Each cohort will be stratified 
into 2 age groups: ages 6 to < 9 years and ages 9 to < 12 years. Depending on the outcome of 
the interim analysis (Section 12.6), a second group of subjects may be assigned fevipiprant 225 
mg or fevipiprant 300 mg or fevipiprant 150 mg or fevipiprant 375 mg.
6.1.4
Treatment duration
The planned preferred treatment is 8 days, however an early end of treatment visit from Day 4-
8 is permitted. Subjects may discontinue from treatment earlier, refer to Section 9.1.1 .
6.2
Other treatment(s)
Not applicable
6.2.1
Concomitant therapy
The medications are only permitted under the circumstances indicated. This table is not 
considered all-inclusive. Medications should be assessed for adherence to the indication and 
other inclusion/exclusion criteria.
All medications, procedures and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the subject was enrolled into the study must be recorded 
in the concomitant medications/significant non-drug therapies or procedures pages.
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 
enrolling a subject or allowing a new medication to be started. If the subject is already enrolled, 
contact Novartis to determine if the subject should continue participation in the study.
6.2.1.1
Permitted concomitant therapy requiring caution and/or action
Table 6-2
Medications allowed under certain conditions
Class of medication
Condition under which medication is permitted
Topical Corticosteroids for treatment of 
eczema
Recommended doses and dosage regimens
Maintenance Immunotherapy for allergies
Stable dose for at least 3 months prior to Treatment (Day 1) and 
must continue unchanged for the duration of the study
Mucolytic agents not containing 
bronchodilators
If stabilized for at least 4 weeks prior to Treatment (Day 1) and 
throughout the trial.
Inactivated influenza vaccination, 
pneumococcal vaccination or any other 
inactivated vaccine
Not administered within 48 hours prior to a study visit
Nasal corticosteroids
Nasal or ocular preparation of 
antihistamines
Treatment regimen has been stable for at least one month prior to 
Treatment (Day 1). In the case of as needed use, providing an 
established pattern of use must be documented prior to Treatment 
(Day 1).
Systemic mast cell stabilizers (e.g. 
cromoglycate, nedocromil, ketotifen)
If stabilized for at least 4 weeks prior to Treatment (Day 1) and 
throughout the trial.


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6.2.2
Prohibited medication
Use of the treatments displayed in the below table are not allowed after the start of the study 
treatment. Each concomitant drug must be individually assessed against all exclusion criteria 
and the table below to see if it is allowed. If in doubt, the investigator should contact the 
Novartis medical monitor or designee before enrolling a subject 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.
Table 6-3
Prohibited medications
Class of medication
Minimum cessation period prior to 
Treatment (Day 1)
Leukotriene receptor-Antagonists (LTRAs)
LTRAs should be stopped at Screening Visit (14 
days), and in that case ICS should be up-
titrated/initiated as per investigator’s judgement and 
stabilized during the screening period.
Cyclosporine
6 months
Monoclonal antibodies, investigational or approved, 
for the treatment of asthma (e.g., omalizumab)
5 months
Oral corticosteroids
1 month
Any drug known to prolong QT interval
14 days or 5 half-lives, whichever is longer
Other investigational drugs
30 days or 5 half-lives, whichever is longer
Live attenuated vaccines
30 days
Rifampin, probenecid, ritonavir and valproic acid (i.e. 
medications blocking several pathways important for 
the elimination of QAW039 (broad range UGT 
inhibition and/or inhibition of OAT3, OATP1B3, MXR 
and P-gp))
7 days
6.2.3
Rescue medication
Rescue medication (SABA, short-acting-muscarinic-antagonists (SAMAs)), will not be 
provided during this study but can be used as needed.
6.3
Subject numbering, treatment assignment, randomization
6.3.1
Subject numbering
Each subject is identified in the study by a Subject Number (Subject No.), that is assigned when 
the subject is first enrolled for screening and is retained as the primary identifier for the subject 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential subject 
number suffixed to it, so that each subject is numbered uniquely across the entire database. 
Upon signing the informed consent form, the subject is assigned to the next sequential Subject 
No. available.
6.3.2
Treatment assignment, randomization
This study is a single-arm, non-randomized trial. For the purpose of the investigational drug 
accountability, tracking and age stratification, Interactive Response Technology (IRT) will be 


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used. All subjects will be stratified into 2 age groups: ages 6 to < 9 years and ages 9 to < 12 
years.
The first 6 subjects enrolled will be stratified into 2 age groups; 6 to < 9 years and 9 to < 12 
years. Safety data and available PK data from these subjects will be assessed prior to extending 
enrollment to Cohort B.
At Treatment (Day 1), the investigator or his/her delegate will contact the IRT after confirming 
that subject fulfills all the inclusion/exclusion criteria. For remote visits, study personnel will 
contact IRT prior to the remote home visit to have medication dispensed and administration of 
medication will not occur until after subject fulfills inclusion/exclusion criteria. The IRT will 
assign a unique medication number for the package(s) of study drug to be dispensed to the 
subject.
6.4
Treatment blinding
Treatment will be open to subjects, investigator staff, persons performing the assessments, and 
the Clinical Trial Team (CTT).
6.5
Dose escalation and dose modification
Not applicable
6.5.1
Dose modifications
Not applicable
6.5.2
Follow-up for toxicities
Not applicable
6.6
Additional treatment guidance
6.6.1
Treatment compliance
The investigator must promote compliance by instructing the subject to take the study treatment 
exactly as prescribed and by stating that compliance is necessary for the subject's safety and the 
validity of the study. The subject must also be instructed to contact the investigator if he/she is 
unable for any reason to take the study treatment as prescribed. Each subject will obtain a patient 
diary to record the time of dose intake during the Treatment period at home. Compliance will 
be assessed by the investigator and/or study personnel at EOT Visit using tablet counts, patient 
diary and information provided by the subject/legal guardian. This information should be 
captured in the source document at EOT Visit. All study treatment dispensed and returned must 
be recorded in the Drug Accountability Log. Pharmacokinetic parameters (measure of treatment 
exposure) will be determined in all subjects, as detailed in pharmacokintetis section.
6.6.2
Emergency breaking of assigned treatment code
Not applicable


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6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section.
A unique medication number is printed on the study medication label.
Investigator staff will identify the study medication kits to dispense to the subject by contacting 
the IRT and obtaining the medication number(s). The study medication has a 2-part label (base 
plus tear-off label), immediately before dispensing the medication kit to the subject, site 
personnel will detach the outer part of the label from the packaging and affix it to the source 
document.
All kits of study treatment assigned by the IRT will be recorded in the IRT system.
6.7.1
Handling of study treatment and additional treatment
6.7.1.1
Handling of study treatment
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels and in the Investigator’s Brochure. Clinical supplies are to 
be dispensed only in accordance with the protocol. Technical complaints are to be reported to 
the respective Novartis country organization (CO) 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 subject 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. Subjects will be asked 
to return all unused study treatment and packaging at the end of the study or at the time of 
discontinuation of study treatment.
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site.
6.7.1.2
Handling of additional treatment
Not applicable
6.7.2
Instruction for prescribing and taking study treatment
Table 6-4
Dose and treatment schedule
QAW039 
(Fevipiprant)
Dose
Frequency
QAW039 75 mg
75 mg
Daily (4-8 days)


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QAW039 
(Fevipiprant)
Dose
Frequency
QAW039 225 mg (or different dose 
150, 300, 375 mg)
225 mg
Daily (4-8 days)
Initially, subjects will be assigned fevipiprant 75 mg (one 75 mg CT daily). Depending on the 
outcome of the interim analysis (Section 12.6), a second group of subjects may be assigned 
fevipiprant 150 mg (two 75 mg CTs every day) or fevipiprant 225 mg (one 225 mg CT daily) 
or fevipiprant 300 mg (one 225 mg CT and one 75 mg CT every day) or fevipiprant 375 mg 
(two 75 mg and one 225 mg CTs every day).
Subjects will be instructed to chew the dose as described in Section 3.
All kits of study treatment assigned by the IRT will be recorded in the IRT system.
7
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/assent.
Since this study includes 6 to < 12 year old children, the subject's representative(s) gives 
consent , and 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.
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval.
8
Visit schedule and assessments
The study will consist of up to 14 days screening period, a 4-8 day treatment period for each 
dose cohort and a follow-up period of 30 days after the last investigational treatment.


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Subjects must be seen for all visits on the designated day. End of Treatment Visit must occur 
in the morning, prior to study drug dosing. At this visit, all dispensed investigational product 
will be reconciled by study staff and AEs and concomitant medications recorded on the CRF.
At End of Treatment Visit, PK blood samples will be taken pre-dose, 0.5, 1, 2, 3, 5 and 8 hours 
post dose. Urine samples post dose will be collected from dosing to 8 h post dose and pooled. 
All blood samples will be taken by either direct venipuncture or indwelling catheter inserted in 
the arm or vein at time points specified in Section 16.4 . Local or Topical anesthetic may be 
used per investigator's decision. Based on exploratory optimal design evaluation using 
modeling and simulation techniques, this schedule in at least 12 subjects are expected to be 
sufficient for a pooled population PK analysis which is planned to be used to support dose 
selection for pediatric Phase III studies.
Subjects who prematurely discontinue from the study for any reason should be scheduled for a 
visit as soon as possible, at which time all of the indicated assessments for discontinued subjects 
will be performed ( Table 8-1 ). PK assessment will not be done for subjects who discontinue 
from the study before the completion of 3 consecutive days of dosing. For subjects who have 
interrupted study drug compliance during the treatment period, the EOT Visit can be 
rescheduled for +1 to 2 days later to ensure study drug compliance of at least 3 consecutive 
days prior to the EOT Visit. In cases where the subject cannot make the scheduled EOT Visit 
or has mistakenly taken the study drug at home on the EOT Day, the Visit can be re-scheduled 
to the next available clinic/home day. It has to be confirmed by study personnel that study drug 
was taken by the subject on 3 consecutive days prior to the EOT Visit.
After the EOT Visit, there will be a 30 day Follow-up period. In case the study treatment was 
discontinued, the subject/parent/legal guardian will still be contacted for the safety evaluation 
30 days after the last study drug intake. SAEs/AEs occurred during 30 day Follow-up period 
will be captured in the eCRF.
Assessment schedule, Table 8-1 lists all of the assessments and indicates with an “X”, the 
visits when they are performed. All data obtained from these assessments must be supported in 
the subject’s source documentation.


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Table 8-1
Assessment Schedule
Period Screening
Treatment1
Safety Follow-up
Visit Name Screening Treatment
End of Treatment
Follow-up2
Days
up to -14
1
4 to 8
34 to 38
Time (post-dose)
-
-
0h3 0.5h
1h
2h
3h
5h
8h
-
Informed consent
X
Demography
X
Inclusion / 
Exclusion criteria
X
X
Medical 
history/current 
medical conditions
X
Concomitant 
medications 
(including Asthma)
X4
Prior and 
concomitant non-
drug therapies-
procedures
X4
Current medication 
review/adjust
S
Physical 
Examination
S
S
S4
Body Height
X
Body Weight
X
Vital Signs
X
X
X4
X
Clinical Chemistry
X
X4
Hematology
X
X4
Urine dipstick
S
S4
S5
PK blood collection
X
X
X
X
X
X
X


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Period Screening
Treatment1
Safety Follow-up
Visit Name Screening Treatment
End of Treatment
Follow-up2
Days
up to -14
1
4 to 8
34 to 38
Time (post-dose)
-
-
0h3 0.5h
1h
2h
3h
5h
8h
-
PK urine 
collection5
X
Pregnancy and 
assessments of 
fertility
S
S
S4
Electrocardiogram 
(ECG)
X
X4
X
Dispense patient 
diary card
S
Drug dispensation
S
Adverse Events
X4
Asthma 
Exacerbation 
Episodes
X4
Serious Adverse 
Events
X4
Study drug 
administration at 
visit
X
X
Record/interruption 
changes in study 
drug 
administrations to 
assess compliance
X
X4
Record time of 
study drug taken 
one day prior to 
end of treatment
X


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Period Screening
Treatment1
Safety Follow-up
Visit Name Screening Treatment
End of Treatment
Follow-up2
Days
up to -14
1
4 to 8
34 to 38
Time (post-dose)
-
-
0h3 0.5h
1h
2h
3h
5h
8h
-
Disposition 
(Treatment/Study 
disposition)
X
Reconcile study 
medication
S4
Collect unused 
study medication
S4
Collect patient 
diary card
S4
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 Treatment visits may be conducted at the clinic or remotely at the subject's home. Ensure light breakfast is provided about 30 minutes prior to all doses from treatment 
day 1 to end of treatment (0h). 
2 Not a visit to site. Call Patient to collect the information on AE/SAE occurred within 30 days after last dosage
3 0h refers to pre-dose
4 These assessments should be conducted for patients who discontinue.
5 Urine samples: Pre-dose, child should empty their bladder. This sample can be used for urine dipstick and then discarded. All urine from dosing to 8 h after dosing will 
be pooled. Children should be encouraged to empty their bladder directly before or after the 8 h blood collection and this urine should be part of the pool. After mixing, 
capturing the volume of the pool, and taking aliquots for PK, the urine should be used for a urine dipstick and the rest discarded. 


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8.1
Screening
Re-screening for subjects who screen-failed is permissible on a case-by-case basis. Please 
contact Novartis for guidance to get information on how to process screen failures.
8.1.1
Information to be collected on screening failures
Subjects who sign an informed consent form and subsequently found to be ineligible will be 
considered a screen failure. The reason for screen failure should be entered on the applicable 
Case Report Form. The demographic information, informed consent, and Inclusion/Exclusion 
pages must also be completed for screen failure subjects. No other data will be entered into the 
clinical database for subjects who are screen failures, unless the subject experienced a serious 
adverse event during the screening phase (see SAE section for reporting details). Adverse 
events that are not SAEs will be followed by the investigator and collected only in the source 
data.
Subjects who sign an informed consent and are considered eligible but fail to be started on 
treatment for any reason will be considered an early terminator. The reason for early termination 
should be captured on the appropriate disposition Case Report Form.
8.2
Subject demographics/other baseline characteristics
Subject demographic and baseline characteristic data to be collected on all subjects include: age, 
sex, race, ethnicity, source of subject referral, relevant medical history/current medical 
condition present before signing informed consent where possible, diagnoses and not symptoms
will be recorded.
Investigators will have the discretion to record abnormal test findings on the medical history 
CRF whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature.
8.3
Efficacy
Not applicable
8.3.1
Appropriateness of efficacy assessments
Not applicable
8.4
Safety
Safety assessments are specified below.
For details on AE collection and reporting, refer to AE section.


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Table 8-2
Physical assessments
Assessment
Specification
Physical examination
A complete physical examination will include the examination of general appearance, 
skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, 
lymph nodes, extremities, vascular, and neurological or any other evaluations the 
investigator considers appropriate based on the subjects clinical status at the clinic at 
the time of the visit.
Information for all physical examinations must be included in the source 
documentation at the study site. Clinically relevant findings that are present prior to 
signing informed consent must be included in the Medical History part of the CRF. 
Significant findings made after first administration of investigational drug which meet 
the definition of an Adverse Event must be recorded on the Adverse Event section of 
the CRF.
Vital sign
Vital signs include body temperature, blood pressure (BP) and pulse measurements. 
After the subject has been sitting for five minutes, with back supported and both feet 
placed on the floor, systolic and diastolic blood pressure will be measured three times 
using an automated validated device, e.g. OMRON, with an appropriately sized cuff. 
The repeat sitting measurements will be made at 1 - 2 minute intervals and the mean 
of the three measurements will be used. In case the cuff sizes available are not large 
enough for the subject's arm circumference, a sphygmomanometer with an 
appropriately sized cuff may be used.
Clinically notable vital signs are defined in Appendix 1 ( Section 16.1 ).
Height and weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg) in indoor 
clothing, but without shoes) will be measured.
8.4.1
Laboratory evaluations
A central laboratory will be used for analysis of all specimens collected. Details on the 
collections, shipment of samples and reporting of results by the central laboratory are provided 
to investigators in the laboratory manual.
All subjects with laboratory tests containing clinically significant abnormalities should be 
followed regularly until the values return to within the normal ranges or until a valid reason 
other than drug-related adverse experiences is identified, even after the medication has 
discontinued.
Clinically notable laboratory findings are defined in Section 16.1 .
Table 8-3
Laboratory Assessments 
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, Mean corpuscular volume (MCV), Platelets, Red blood cells, 
White blood cells, Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, 
Neutrophils, Other).
Chemistry
Albumin, Alkaline phosphatase (ALP), ALT, AST, Gamma-glutamyl-transferase (GGT), 
Lactate dehydrogenase (LDH), Calcium, Magnesium, Phosphorus, Sodium, Potassium, 
Creatinine, Direct Bilirubin, Total Bilirubin (TBL), Total Cholesterol, LDL, HDL, Total Protein, 
Triglycerides, Blood Urea Nitrogen (BUN) or Urea, Uric Acid
Amylase, Lipase, Glucose (non-fasting)
Urinalysis
Macroscopic Panel (Dipstick, performed locally): Bilirubin, Blood, Glucose, Ketones, 
Leukocytes, Nitrite, pH, Protein, Specific Gravity, Urobilinogen
Coagulation
International normalized ratio (INR), Activated partial thromboplastin time (APTT)
Pregnancy Test
Serum/Urine pregnancy test (refer to Pregnancy and assessments of fertility section)
HDL-High-density lipoprotein, LDL-Low-density lipoprotein 


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8.4.2
Electrocardiogram (ECG)
Local ECGs must be recorded after the subject rests (5-10 minutes if possible) in the supine 
position to ensure a stable baseline. The preferred sequence of cardiovascular data collection 
during study visits is ECG collection first, followed by vital signs, and blood sampling. The 
Fridericia QT correction formula (QTcF) should be used for clinical decisions.
Single 12 lead ECGs are collected. The original ECGs on non-heat-sensitive paper, 
appropriately signed, must be collected and archived at the study site.For any ECGs with subject 
safety concerns, two additional ECGs must be performed to confirm the safety finding. 
Clinically significant ECG findings throughout the study and especially at baseline before 
administration of study treatment must be discussed with the Novartis responsible person or 
designee. Any identifier details must be redacted e.g subject initials, date of birth.
In the event that a clinically significant ECG abnormality is identified at the site (e.g. severe 
arrhythmia, conduction abnormality of QTcF > 500 ms), the ECG is repeated to confirm the 
diagnosis. If the subject is hemodynamically compromised, the investigator or a medically 
qualified person must initiate appropriate safety procedures without delay (for example 
cardioversion).
Clinically significant abnormalities must be recorded on the CRF as either medical 
history/current medical conditions or adverse events as appropriate.
8.4.3
Pregnancy and assessments of fertility
Given the age of this subject population, there may be female subjects who have reached 
menarche (and therefore of child-bearing potential). Female subjects who fall in this category 
will have routine urine pregnancy tests as noted in the assessment schedule.
If there is evidence of sexual activity in female subjects of child-bearing potential, appropriate 
moral and legal actions for reporting should be taken by the investigator to ensure the safety of 
the child and minimize the risk of becoming pregnant.
Abstinence from sexual activity while participating in a clinical trial should be encouraged in 
this category of subjects. Otherwise, contraceptive methods should be discussed and may be 
provided as appropriate to sexually active pediatric subjects after careful consideration of any 
medical conditions, the individual situation, and cultural and legal aspects.
The basic contraception methods are (if allowed by local regulations):

Barrier method: Condom or Occlusive cap (diaphragm or cervical/vault caps).

Use of oral, injected or implanted hormonal methods of contraception or placement of an 
intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal 
contraception that have comparable efficacy (failure rate < 1%), for example hormone 
vaginal ring or transdermal hormone contraception.
In case local regulations deviate from the methods listed, local regulations apply and will be 
described in the Inform Consent Form (ICF).
8.4.4
Asthma Exacerbation
Asthma exacerbations will be recorded as Adverse Events.


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
A severe asthma exacerbation is defined as treatment with ‘rescue’ systemic 
corticosteroids for ≥ 3 days and hospitalization; or treatment with ‘rescue’ systemic 
corticosteroids for ≥ 3 days and emergency department visit (> 24 hours); or death due to 
asthma.

A moderate asthma exacerbation is defined as treatment with ‘rescue’ systemic 
corticosteroids for ≥ 3 days either as an outsubject or in emergency department visits 
(emergency department visit ≤ 24 hours).
8.5
Additional assessments
8.5.1
Pharmacokinetics
PK samples for plasma and urine fevipiprant and CCN362 concentrations will be collected at 
the time points defined in the Assessment schedule (Section 16.4). Follow instructions outlined 
in the Laboratory Manual regarding sample collection, numbering, processing and shipment.
Plasma and urine PK samples will be obtained and evaluated in all subjects at all dose levels. 
Concentrations in acidified plasma and urine of fevipiprant and CCN362 will be determined by 
a 
validated 
LC-MS/MS 
method. 
Concentrations 
below 
the 
lower 
limit 
of 
quantification (LLOQ) will be reported as “zero” and missing data will be labeled as such in 
the Bioanalytical Data Report.
 
 
 
Concentrations will be expressed in mass per volume units.
The following pharmacokinetic parameters will be determined using the actual recorded 
sampling times and non-compartmental method(s) with Phoenix WinNonlin (Version 6.4 or 
higher):
AUC0-24h,ss, Cmax,ss, Tmax,ss, Cmin,ss, CL/F (fevipiprant only), renal clearance (CLr), 
amount and fraction of dose excreted over the PK collection interval.
The linear trapezoidal rule will be used for AUC calculation.
9
Study discontinuation and completion
9.1
Discontinuation
9.1.1
Discontinuation of study treatment
Discontinuation of study treatment for a subject occurs when study drug is stopped earlier than 
the protocol planned duration, and can be initiated by the subject, subject’s parent/legal 
guardian, or the investigator.
The investigator must discontinue study treatment for a given subject if, on balance, he/she 
believes that continuation would negatively impact the risk/benefit of trial participation.


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Study treatment must be discontinued under the following circumstances:

subject`s or parent/legal guardian’s wish

Administration of a prohibited medication

ECGs: 

If the absolute QTcF ≥ 450 msec or an increase from baseline of > 60 msec on 2 
adequate ECGs at least a minute apart

2nd or 3rd degree AV block

Atrial or ventricular arrhythmias (as judged clinically significant by the investigator)

Any severe AE or SAE considered possibly related to the study medication

Adverse events for which continuation of the study drug would be detrimental

If a subject develops a medical condition that requires use of prohibited treatment as 
per Section 6.2.2 , or if subject exhibits a behavior of non-compliance regarding 
prohibited medications.

Pregnancy (see Section 10.1.4 )

Any situation in which study participation might result in a safety risk to the subject

Clinically significant abnormal laboratory value(s) for children 6 to < 12 years, as per the 
discretion of the physician

Any other protocol deviation that results in a significant risk to the subject’s safety
If discontinuation of study treatment occurs, the subject should NOT be considered withdrawn 
from the study. The subject should return to the clinic as soon as possible, after discontinuation 
of study drug, for a study treatment discontinuation visit (End of Treatment will act as an early 
discontinuation visit in this case) and directly move into the 30 day follow-up period. Treatment 
discontinuation visit assessments detailed in the Table 8-1 should be completed and recorded 
in the eCRF. The investigator must determine the primary reason for the subject’s premature 
discontinuation of study treatment and record this in the Study Disposition eCRF.
The investigator must contact the IRT to register the subject’s discontinuation from study 
treatment.
The data which must continue to be collected for all discontinued subjects are adverse event 
and serious adverse events for up to 30 days after drug discontinuation until the end of the study 
follow-up visit. Documentation of attempts to contact the subject must be recorded in the source 
documentation.
If the subject fails to return for an end of study visit for unknown reasons, every effort should 
be made to contact them.
9.1.2
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject:

Does not want to participate in the study anymore, and

Dose not want any further visits or assessments and

Does not want any further study related contacts


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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 and Japan: 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 European Union (EU) and Rest of World (RoW): All biological samples not yet analyzed 
at the time of withdrawal will no longer be used, unless permitted by applicable law. They will 
be stored according to applicable legal requirements.
9.1.3
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A subject should not be considered as lost to follow-up until due 
diligence has been completed.
9.1.4
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. In taking the decision to terminate, 
Novartis will always consider the 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.
9.2
Study completion and post-study treatment
Study completion is defined as when the last subject finishes their Study Completion visit, and 
any repeat assessments associated with this visit have been documented and followed-up 


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appropriately by the Investigator, or in the event of an early study termination decision, the date 
of that decision. 
Subjects that completed the study or prematurely discontinued will not be given further access 
to the investigational treatment. 
The investigator must provide follow-up medical care for all subjects who completed or 
prematurely withdrawn from the study, or must refer them for appropriate ongoing care.
All treated subjects should have a safety follow-up call conducted 30 days after last 
administration of study treatment. The information to be collected at this follow-up visit 
includes concomitant medications, adverse events and asthma exacerbation episodes. All SAEs 
reported 
during 
this 
time 
period 
must 
be 
reported 
as 
described 
in Section 10.1.3 . Documentation of attempts to contact the subject should be recorded in the 
source documentation.
10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The investigator has the responsibility for managing the safety of individual subject and 
identifying adverse events.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of adverse events must be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject during or between visits or through physical examination findings, laboratory test 
findings, or other assessments.
Adverse events must be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information (as far as possible) 
(if the event is serious refer to Section 10.1.2 ):
1. The severity grade.

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities
2. its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected’. The rationale for this guidance is that the symptoms of a 


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lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single subject
3. its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported.
4. whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met
5. action taken regarding with study treatment.
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

Dose not changed

Dose Reduced/increased

Drug interrupted/withdrawn
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the subject.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms.
Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment.
Information about adverse drug reactions for the investigational drug can be found in the IB.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms

they are considered clinically significant

they require therapy
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in subjects with 
the underlying disease. Alert ranges for laboratory and other test abnormalities are included 
in Section 16.1 .
10.1.2
Serious adverse events
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the following 
criteria:

fatal

life-threatening


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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 insubject 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

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 outsubject 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.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred. 
10.1.3
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject 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.
Consider the following 2 categories to determine SAE reporting timeframes:
1. Screen Failures: SAEs occurring after the subject has provided informed consent until the 
time the subject is deemed a Screen Failure must be reported to Novartis.
2. Enrolled and/or Treated Subjects: SAEs collected between time subject signs ICF until 30 
days after the subject has discontinued or stopped study treatment.


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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 Novartis Chief Medical Office 
and Patient Safety (CMO&PS) 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 after the last study visit following the last 
administration of study treatment should only be reported to Novartis Safety if the investigator 
suspects a causal relationship to study treatment.
10.1.4
Pregnancy reporting
Pregnancies
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 investigational 
treatment. Any SAE experienced during pregnancy must be reported.
10.1.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the drug administration record (DAR) eCRF irrespective of whether or not associated with an 
AE/SAE and reported to Safety only if associated with an SAE. Misuse or abuse will be 


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collected and reported in the safety database irrespective of it being associated with an AE/SAE 
within 24 hours of Investigator’s awareness.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Drug 
Administration (DAR) 
eCRF (Yes/No)
Document in AE eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with an 
AE
Only if associated with an 
SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please see the, 
respective sections.
10.2
Additional Safety Monitoring
10.2.1
Liver safety monitoring
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.
The following two categories of abnormalities/adverse events have to be considered during the 
course of the study (irrespective of whether classified/reported as AE/SAE):

Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter

Liver events, which will require close observation, follow-up monitoring and contributing 
factors are recorded on appropriate CRFs
Please refer to Table 16-1 in Section 16.2 for complete definitions of liver laboratory triggers 
and liver events.
Every liver event defined in Table 16-1 should be followed up by the investigator or 
designated personnel at the trial site, as summarized below. Additional details on actions 
required in case of liver events are outlined in Table 16-2 . Repeat liver chemistry tests (ALT, 
AST, TBL, PT/INR, ALP and GGT) 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 reported on 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


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
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.
11
Data Collection and Database management
11.1
Data collection
Data not requiring a separate written record will be defined in the protocol and the assessment 
schedule and can be recorded directly on the CRFs. All other data captured for this study will 
have an external originating source (either written or electronic) with the CRF not being 
considered as source.
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the Electronic Data Capture (EDC) system until they have been trained. 
Automatic validation programs check for data discrepancies in the eCRFs, allow modification 
and/or verification of the entered data by the investigator staff.
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate.
After final database lock, the investigator will receive copies of the subject data for archiving 
at the investigational site.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
11.2
Database management and quality control
Novartis personnel (or designated Contract Research Organization (CRO)) will review the data 
entered by investigational staff for completeness and accuracy. Electronic data queries stating 
the nature of the problem and requesting clarification will be created for discrepancies and 
missing values and sent to the investigational site via the EDC system. Designated investigator 
site staff are required to respond promptly to queries and to make any necessary changes to the 
data.
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Data about all study treatment (s) dispensed to the subject and all dosage administrated will be 
tracked using an Interactive Response Technology (IRT). The system will be supplied by a 


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vendor, who will also manage the database. The data will be sent electronically to Novartis (or 
a designated CRO) at specific timelines.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked. Any changes to the database after that time can only 
be made after written agreement by Novartis development management.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a 
Novartis/delegated CRO representative will review the protocol and data capture requirements 
(i.e. eSource DDE or eCRFs) with the investigators and their staff. During the study, Novartis 
employs several methods of ensuring protocol and GCP compliance and the quality/integrity of 
the sites’ data. The field monitor will visit the site to check the completeness of subject records, 
the accuracy of data capture/data entry, the adherence to the protocol and to Good Clinical 
Practice, the progress of enrollment, and to ensure that study treatment is being stored, 
dispensed, and accounted for according to specifications. Key study personnel must be available 
to assist the field monitor during these visits. Continuous remote monitoring of each site’s data 
may be performed by a centralized Novartis/delegated CRO/Clinical Research Associate 
(CRA) organization. Additionally, a central analytics organization may analyze data & identify 
risks & trends for site operational parameters, and provide reports to Novartis clinical teams to 
assist with trial oversight.
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject’s file. The investigator must also keep the original informed consent form signed by the 
subject (a signed copy is given to the subject).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
subjects will be disclosed.
12
Data analysis and statistical methods
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
12.1
Analysis sets
For all analysis sets, subjects will be analyzed according to the study treatment(s) received.
The safety analysis set will include all subjects that received any study drug.


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The PK analysis set will include all subjects with at least one available valid (i.e. not flagged 
for exclusion) PK concentration measurement, who received any study drug and with no 
protocol deviations that impact on PK data.
12.2
Subject demographics and other baseline characteristics
Demographic and baseline characteristics measured including age, age stratum (6 to <9 years 
and 9 to <12 years), gender, race, ethnicity, height, weight, body mass index (BMI), relevant 
medical history, prior medication (taken before first dose of study drug) and concomitant 
medications, vital signs (body temperature, systolic and diastolic BP, radial pulse rate) and QTc 
using Fridericia’s correction will be summarized by cohort on safety analysis set.
Continuous variables will be summarized using descriptive statistics (mean, median, standard 
deviation, minimum, and maximum) and categorical variables will be summarized in terms of 
the number and percentage of subjects in each category.
Baseline is defined as the last measurement before first dose of study drug.
No statistical analyses will be provided for baseline comparability among the cohort.
12.3
Treatments
Dosage and date of administration at the clinic (Treatment Day 1 and End of Treatment (at 
steady state)) and at home (1 day prior End of Treatment e.g. treatment Day 7) will be listed for 
all subjects in safety set.
Subjects taking prohibited concomitant medications will be noted in the summary of protocol 
deviations. Treatment compliance with study medication over the study period will be 
summarized by cohort.
12.4
Analysis of the primary endpoint(s)
The primary objective of the study is to determine the pharmacokinetics of fevipiprant at steady 
state after at least four consecutive days of dosing based on AUC0-24h,ss, Cmax,ss and CL/F.
12.4.1
Definition of primary endpoint(s)
The AUC0-24h,ss, Cmax,ss and CL/F for fevipiprant at steady state will be the primary 
variables. PK analysis set will be used for analysis of all PK parameters.
12.4.2
Statistical model, hypothesis, and method of analysis
The primary variables, AUC0-24h,ss, Cmax,ss and CL/F will be analyzed by standard non-
compartmental analysis and summarized by cohort through descriptive summary statistics 
(including mean, SD, CV% mean, Geometric mean, CV% geometric mean, median, minimum 
and maximum). Additionally, CL/F will also be summarized across cohort.
Plasma concentrations will be assessed at the EOT Visit (pre-dose, 0.5, 1, 2, 3, 5, 8h) and will 
be expressed in mass per volume units. All concentrations below the lower limit of 
quantification (LLOQ) or missing data will be labeled as such in the concentration data listings. 
Concentrations below the limit of quantification will be treated as zero in summary statistics 


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and for the calculation of parameters and the pre-dose concentration on the EOT Visit will also 
be used as 24 h concentrations to derive AUC0-24h,ss.
PK data from this study will be analyzed together with PK data from other studies in adult 
subjects using a population pharmacokinetic modeling approach with the aim to support dose 
selection for pediatric phase III studies. The modeling approach will be specified in a separate 
analysis plan and results will be reported separately from the CSR.
12.4.3
Handling of missing values/censoring/discontinuations
Subjects with no valid PK concentration measurements, will be excluded from the analysis. 
Under missing completely at random assumption, subjects included in the analysis will be 
considered as representative of all subjects received treatment.
No other methodology is planned to address missing data.
12.4.4
Sensitivity and Supportive analyses
Not applicable
12.5
Analysis of secondary endpoints
The secondary endpoints will be analyzed as described below.
12.5.1
Safety endpoints
For all safety analyses, the safety set will be used.
Adverse events
AEs (including asthma exacerbations) starting on or after the time of the first intake of study 
drug and until the day after the last intake of study drug will be classified as a treatment-
emergent AEs. Any AEs that started during the study after signing informed consent and before 
the time of the first intake of study drug will be classified as a prior AEs and will not be included 
in tabulations of treatment-emergent AEs.
Treatment-emergent AEs will be summarized, by system organ class and preferred term, overall 
by system organ class, preferred term and maximum severity, suspected drug-related AEs by 
system organ class and preferred term. Treatment-emergent SAEs will be summarized, by 
system organ class and preferred term. The summarization will be provided by cohort.
If a subject reported more than one AE with the same preferred term, the AE will be counted 
only once. If a subject reported more than one AE within the same primary system organ class, 
the subject will be counted only once at the system organ class level.
Vital signs
Vital signs measurements include body temperature, systolic and diastolic blood pressure (SBP 
and DBP) and pulse rate. Summary statistics will be provided by cohort and visit/time-point.


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ECG evaluations
ECG measurements include ventricular rate, QT interval, RR interval, PR interval, QRS 
duration, and Friderica’s QTc (calculated as QTcF = QT / 3√ RR (in seconds), where 3√ denotes 
the cube root). Summary statistics will be provided by cohort and visit/time-point.
Clinical laboratory evaluations
Laboratory data consist of hematology and biochemistry including peripheral blood eosinophils.
Summary statistics for continuous laboratory parameters will be provided by cohort and 
visit/time-point. Frequency tables of results for categorical laboratory parameters will be 
provided by visit/time point.
12.5.2
Pharmacokinetics
Other pharmacokinetic variables of Fevipiprant at steady state
The pharmacokinetic variables Tmax,ss, Cmin,ss, (CL/F)/kg, CLr, amount and fraction of dose 
excreted over the PK collection interval of QAW039 at steady state will be secondary variables. 
All pharmacokinetic variables will be summarized similarly as mentioned for primary variable 
(Section 12.4).
Summary statistics for plasma and urine concentrations will be provided by cohort and time 
point (only 1 time interval for urine). If any concentration value will be set to be zero for any 
time-point then Geo-mean, CV% geo-mean will not be presented for that time point. Mean and 
individual concentration-time profile will be displayed graphically by cohort.
Metabolite CCN362 at steady state
Cmax,ss, Tmax,ss, AUC0-24h,ss, Cmin,ss, CLr, amount and fraction of dose excreted over the 
PK collection interval at steady state of CCN362, the major metabolite of fevipiprant will be 
summarized similarly as mentioned for primary variable (Section 12.4).
Summary statistics for plasma and urine concentrations of analyte CCN362 will be provided by 
cohort and time point (only 1 time interval for urine). If any concentration value will be set to 
be zero for any time-point then Geo-mean, CV% geo-mean will not be presented for that time 
point. Mean and individual concentration-time profile will be displayed graphically by cohort.
12.6
Interim analyses
A planned interim analysis will be conducted to support decision making when 6 subjects (3 
subjects from each of the 2 age strata) receiving 75 mg dose complete the treatment. The interim 
analysis will be performed based on preliminary PK data e.g. protocol times can be used to 
calculate PK parameters. At interim analysis, based on PK data from the 75 mg dose level the 
high dose will be chosen:
For detailed information, please refer to Section 12.7.
Additional interim analyses may be conducted in case of any safety concerns or when at least 6 
subjects on high dose have completed the treatment (in case where sample size on high dose is 


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adjusted to be more than 6 after 1st interim analysis) and the sample size of high dose can be 
refined based on emerging PK data.
12.7
Sample size calculation
12.7.1
Primary endpoint(s)
Sample size is guided by statistical precision and requirements for pharmacokinetic data from 
pediatric subjects for inclusion in population PK modelling. Based on exploratory optimal 
design evaluation using modeling and simulation techniques, at least 12 subjects is expected to 
be sufficient for a pooled population PK analysis which is planned to be used to support dose 
selection for pediatric phase III studies. Since adult data on fevipiprant does not show a 
clinically relevant deviation from dose proportionality, data from the low and high dose cohort 
are equally valuable to inform the population PK model. Drop-outs and non-completers will be 
replaced.
At first stage it is required to have PK data from 6 subjects receiving 75 mg dose to assess safety, 
as well as mean and variability of PK data to enable at the second stage to have the right dose 
and number of subjects. Moreover, data from 6 subjects will provide ~80% probability for 
acceptable precision in calculating the geometric mean. More specifically, the inclusion of 6 
subjects would result in the 95% confidence interval (CI) of the geometric mean of QAW039 
AUC0-24h,ss being in the range of (68%U, 147%U). U is the observed geometric mean, 
assuming a coefficient of variation of 31% based on data from previous study 
([QAW039A2111] study). This level of precision balances needs for reliable parameter 
estimation and clinical feasibility and is in agreement with guidance provided by health 
authorities. (General Clinical Pharmacology Considerations for Pediatric Studies for Drugs and 
Biological Products, FDA).
An interim analysis will be conducted when 6 subjects (3 subjects from each of 2 age strata) 
receiving the 75 mg dose will complete the treatment and provide the planned PK samples. At 
interim analysis, the following outcomes are foreseen based on AUC0-24h,ss:
In terms of exposure i.e. mean AUC0-24h,ss:
1. If mean AUC0-24h,ss is as expected, i.e. comparable to 150 mg dose in adult/adolescents, 
then 225 mg dose will be used in high dose cohort.
2. If mean AUC0-24h,ss is relevantly more than expected while comparing with exposure of 
150 mg dose in adult/adolescents, dose lower than 225 mg e.g. 150 mg dose will be used 
in high dose cohort.
3. If mean AUC0-24h,ss is relevantly less than expected while comparing with exposure of 
150 mg dose in adult/adolescents, dose higher than 225 mg e.g. 300 mg or 375 mg dose 
will be used in high dose cohort.
In terms of variability i.e. coefficient of variation (CV%) of AUC0-24h,ss:
1. If CV% of AUC0-24h,ss is less than or equal to 31% at interim, then 6 subjects will be 
recruited for the second cohort so that total number of subjects completing treatment is 12.
2. If CV% of AUC0-24h,ss is more than 31% at interim analysis, more than 6 subjects will 
be recruited at the high dose level to provide ~80% probability for acceptable precision in 
calculating the geometric mean, more specifically to have the 95% confidence intervals 


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(CI) of geometric means of QAW039 AUC0-24h,ss approximately within the range of 
(68%U, 147%U), where U is the observed geometric mean. The number of subjects on 
higher dose will be based on observed CV% at interim analysis.
The following table provides the range in which 95% CIs will fall with 80% probability in terms 
of percentage of observed geometric-mean, at different sample and different observed CV% at 
interim:
N 
(sampl
e size)
Observed CV % at interim
35%
40%
45%
50%
55%
60%
65%
70%
75%
80%
7
69%-
146%
65%-
153%
62%-
161%
59%-
168%
57%-
176%
54%-
185%
52%-
193%
50%-
201%
48%-
209%
46%-
217%
8
71%-
140%
68%-
146%
65%-
153%
63%-
160%
60%-
166%
58%-
173%
56%-
180%
54%-
187%
52%-
194%
50%-
201%
9
74%-
136%
71%-
141%
68%-
147%
65%-
153%
63%-
159%
61%-
165%
59%-
171%
57%-
177%
55%-
183%
53%-
189%
10
75%-
133%
73%-
138%
70%-
143%
67%-
148%
65%-
154%
63%-
159%
61%-
164%
59%-
169%
57%-
175%
56%-
180%
11
77%-
130%
74%-
135%
72%-
140%
69%-
144%
67%-
149%
65%-
154%
63%-
159%
61%-
163%
59%-
168%
58%-
173%
12
78%-
128%
75%-
133%
73%-
137%
71%-
141%
69%-
146%
67%-
150%
65%-
154%
63%-
159%
61%-
163%
60%-
167%
13
79%-
127%
77%-
131%
74%-
135%
72%-
139%
70%-
143%
68%-
147%
66%-
151%
65%-
155%
63%-
159%
61%-
163%
14
80%-
125%
78%-
129%
75%-
133%
73%-
137%
71%-
140%
69%-
144%
68%-
148%
66%-
152%
64%-
155%
63%-
159%
15
81%-
124%
78%-
128%
76%-
131%
74%-
135%
72%-
138%
70%-
142%
69%-
145%
67%-
149%
66%-
152%
64%-
156%
16
81%-
123%
79%-
126%
77%-
130%
75%-
133%
73%-
136%
71%-
140%
70%-
143%
68%-
147%
67%-
150%
65%-
153%
17
82%-
122%
80%-
125%
78%-
128%
76%-
132%
74%-
135%
72%-
138%
71%-
141%
69%-
144%
68%-
147%
66%-
151%
18
83%-
121%
81%-
124%
79%-
127%
77%-
130%
75%-
133%
73%-
136%
72%-
140%
70%-
142%
69%-
145%
67%-
148%
For example, if we observe a CV% of 55% in the interim data, then 12 subjects are required to 
complete treatment with the high dose and to provide the planned PK samples to give ~80% 
probability for the 95% confidence intervals (CI) of geometric means of QAW039 AUC0-
24h,ss to fall approximately within the range of (68%U, 147%U). The sample size for the high 
dose can vary from 6 to 18 subjects, so that total number of subjects completing treatment (75 
mg or high dose) and providing planned PK samples is maximum of 24. For example, if we 
observe a CV% of 80% in the interim data, then 18 subjects will be recruited at the high dose 
to provide the planned PK samples, though the 95% CI of geometric means of QAW039 AUC0-
24h,ss will fall outside the range of (68%U, 147%U).
13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 


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local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki.
13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures (e.g. 
advertisements) and any other written information to be provided to subjects. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made.
13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last subject last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.).
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings.
13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures 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 standard operating procedures, and are performed according to written 
Novartis processes.
14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 


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additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented.
14.1
Protocol Amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation.
Only amendments that are required for subject safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations.


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15
References
References are available upon request
Anon (2007) Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management 
of Asthma-Summary Report 2007. J. Allergy Clin. Immunol; S94-138.
Bastain TM, Islam T, Berhane KT, et al (2011) Exhaled nitric oxide, susceptibility and new-
onset asthma in the Children's Health Study. Eur. Respir. J. p. 523-31.
Coverstone A, Bacharier LB, Fitzpatrick AM (2015) Severe asthma in school-age children: 
evaluation and phenotypic advances. Curr Allergy Asthma Rep p. 20.
Fanta CH (2009) Asthma. N. Engl. J. Med. p. 1002-14.
Global Initiative for Asthma (GINA) (2018). Global Strategy for Asthma Management and 
Prevention.
Holford N, Heo YA, Anderson B (2013) A pharmacokinetic standard for babies and adults. J 
Pharm Sci p. 2941-52.
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.
Pearce N, Aït-Khaled N, Beasley R, et al (2007) Worldwide trends in the prevalence of 
asthma symptoms: phase III of the International Study of Asthma and Allergies in Childhood 
(ISAAC). Thorax p. 758-66.
Sykes DA, Bradley ME, Riddy DM, et al (2016) Fevipiprant (QAW039), a Slowly 
Dissociating CRTh2 Antagonist with the Potential for Improved Clinical Efficacy. Mol. 
Pharmacol. p. 593-605.
Ward BW, Clarke TC, Freeman G, et al (2015) Early release of selected estimates based on 
data from the January-September 2014 National Health Interview Survey.
Wilson DH, Adams RJ, Tucker G, et al (2006) Trends in asthma prevalence and population 
changes in South Australia, 1990-2003. Med. J. Aust. p. 226-9.
Xue L, Salimi M, Panse I, et al (2014) Prostaglandin D2 activates group 2 innate lymphoid 
cells through chemoattractant receptor-homologous molecule expressed on TH2 cells. J. 
Allergy Clin. Immunol. p. 1184-94.


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16
Appendices
16.1
Appendix 1: Clinically notable laboratory values and vital signs
There are no specific notable range criteria for this study; however, the Central Laboratory will 
flag laboratory values falling outside of the normal range on the Central Laboratory Report 
(which the investigator should sign off) and the investigator will report any values considered 
clinically significant in the eCRF.
16.2
Appendix 2: Liver event and Laboratory trigger Definitions and 
Follow-up Requirements
Table 16-1
Liver Event and Laboratory Trigger Definitions
Definition/ threshold
LIVER LABORATORY 
TRIGGERS
3 x ULN < ALT / AST ≤ 5 x ULN
1.5 x ULN < TBL ≤ 2 x ULN
LIVER EVENTS
ALT or AST > 5 × ULN
ALP > 2 × ULN (in the absence of known bone pathology)
TBL > 2 × ULN (in the absence of known Gilbert syndrome)
ALT or AST > 3 × ULN and INR > 1.5
Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and TBL > 2 × ULN 
[mainly conjugated fraction] without notable increase in ALP to > 2 × ULN)
Any clinical event of jaundice (or equivalent term)
ALT or AST > 3 × ULN accompanied by (general) malaise, fatigue, abdominal pain, 
nausea, or vomiting, or rash with eosinophilia
Any adverse event potentially indicative of a liver toxicity*
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-related 
conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver neoplasms TBL: total 
bilirubin; ULN: upper limit of normal
LFT-Liver function test, ULN-upper limit of normal
Table 16-2
Follow-Up Requirements for Liver Events and Laboratory Triggers
Criteria
Actions required
Follow-up monitoring
Potential Hy’s Law casea

Discontinue the study treatment 
immediately

Hospitalize, if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc
(frequency at investigator 
discretion)
ALT or AST
> 8 × ULN

Discontinue the study treatment 
immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc
(frequency at investigator 
discretion)
> 3 × ULN and INR > 1.5

Discontinue the study treatment 
immediately

Hospitalize, if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc
(frequency at investigator 
discretion)


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Criteria
Actions required
Follow-up monitoring
> 5 to ≤ 8 × ULN

Repeat LFT within 48 hours

If elevation persists, continue follow-up 
monitoring

If elevation persists for more than 2 
weeks, discontinue the study drug

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc
(frequency at investigator 
discretion)
> 3 × ULN accompanied 
by symptomsb

Discontinue the study treatment 
immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc
(frequency at investigator 
discretion)
> 3 to ≤ 5 × ULN (subject 
is asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate close 
observation of the subject
Investigator discretion
Monitor LFT within 1 to 4 weeks
ALP (isolated)
> 2 × ULN (in the 
absence of known bone 
pathology)

Repeat LFT within 48 hours

If elevation persists, establish causality

Complete liver CRF
Investigator discretion
Monitor LFT within 1 to 4 weeks or 
at next visit
TBL (isolated)
> 2 × ULN (in the 
absence of known Gilbert 
syndrome)

Repeat LFT within 48 hours

If elevation persists, discontinue the 
study drug immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc
(frequency at investigator 
discretion)
Test for hemolysis (e.g. 
reticulocytes, haptoglobin, 
unconjugated [indirect] bilirubin)
> 1.5 to ≤ 2 × ULN 
(subject is asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate close 
observation of the subject
Investigator discretion
Monitor LFT within 1 to 4 weeks or 
at next visit
Jaundice

Discontinue the study treatment 
immediately

Hospitalize the subject

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc
(frequency at investigator 
discretion)
Any AE potentially 
indicative of a liver 
toxicity*

Consider study treatment interruption or 
discontinuation

Hospitalization if clinically appropriate

Establish causality

Complete liver CRF
Investigator discretion
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN b(General) 
malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia cResolution is defined as an 
outcome of one of the following: (1) return to baseline values, (2) stable values at three subsequent monitoring 
visits at least 2 weeks apart, (3) remain at elevated level after a maximum of 6 months, (4) liver transplantation, 
and (5) death.


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16.3
Appendix 3: Blood Volume Table
Table 16-3
Blood volume
Study phase
Time (h)2
Safety
PK
Dose 
Reference ID
Sample no.
mL
Screening 
(days -14 to -1)
5
Treatment Day 
1 (Baseline)
End of 
Treatment
0 (pre-dose)
5
101/11
101
1
0.5
11
102
1
1
11
103
1
2
11
104
1
3
11
105
1
5
11
106
1
8
11
107
1
Sub-total 
blood volume
10
7
TOTAL Blood 
volume (mL)
17
1only one PK sample is collected at pre-dose, but the time difference to the doses on day prior to EOT and 
EOT day will be derived, requiring 2 dose reference IDs.
2Times are relative to the last dose on Day 4-8.
Table 16-4
PK urine sample
Time (h)2
PK urine Samples3
Study Visits
Start
End
Dose 
Reference ID
Sample No.
Volume (ml)
End of 
Treatment (Day 
4-8)
0
8
11
201
2 x 1.5 mL
2Times are relative to the last dose on Day 4- 8.
3Urine samples: Pre-dose, child should empty their bladder. This sample can be used for urine dipstick and 
then discarded. All urine from post-dose up to 8h will be pooled for analysis including urine dipstick.


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16.4
Appendix 4: Pharmacokinetic/Vital signs/ECG/Lab assessment 
timed schedule (End of treatment)
Table 16-5
PK/VS/ECG/Lab assessment schedule (EOT)
Time point vs. 0 
(dose time, 
hours)*
Vital Signs
(Systolic/ diastolic 
BP /radial pulse)
ECG
PK
Hematology/ 
chemistry
Pre-dose
x
x
X*
x
0.5
X
1
X
2
x
x
X
3
X
5
X
8
X
Note: For Time points where multiple procedures occur, the following order is recommended: e.g. vital signs, 
PK, and lab. The PK blood draw should be as close as possible to the scheduled time.
*In case a local anesthetic is used for placing the indwelling catheter, the time for it to take effect has to be 
accounted for prior to any assessment.
16.5
Appendix 5: Definition of pharmacokinetic parameters
Table 16-6
Pharmacokinetic parameters
Parameter
Definition
AUC0-24h,ss
The AUC calculated to the end of a dosing interval (24 h) at steady-state (amount x 
time x volume-1)
Cmax,ss
The maximum (peak) observed plasma concentration at steady state (mass x 
volume-1)
Tmax,ss
The time to reach maximum (peak) plasma concentration at steady state (time)
Cmin,ss
The minimum observed plasma concentration at steady state (mass x volume-1)
Ae
The amount of drug excreted into urine (mass); can be used to derive a fraction of 
the dose excreted into urine (%)
CL/F
The total body clearance of drug from the plasma following extravascular 
administration (volume x time-1)
CLr
The renal clearance of drug from the plasma (volume x time-1)
(CL/F)/kg
The total body clearance of drug from the plasma following extravascular 
administration normalized to body weight ((volume x time-1)/kg)


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16.6
Appendix 6: List of idiosyncratic drug reactions (IDRs) for 
investigators
Table 16-7
Definition of potential idiosyncratic drug reactions
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.

SAP_000.pdf: 
Clinical Development
QAW039
CQAW039B2201 / NCT03650400
A multicenter, open-label, 8 day treatment study to assess 
the pharmacokinetics, safety and tolerability of fevipiprant 
delivered via a once daily chewable tablet in children aged 
6 to <12 years with asthma
Statistical Analysis Plan (SAP)
Author:
Trial Statistician, 
Trial Statistician (CRO), 
Document type:
SAP Documentation
Document status:
Amendment 1
Release date:
28-Feb-2020
Number of pages:
21
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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SAP Amendment 1
CQAW039B2201


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For business use only
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SAP Amendment 1
CQAW039B2201
Table of contents
Table of contents .................................................................................................................3
List of abbreviations............................................................................................................5
1
Introduction .........................................................................................................................6
1.1
Study design.............................................................................................................6
1.2
Study objectives and endpoints ...............................................................................7
2
Statistical methods...............................................................................................................8
2.1
Data analysis general information ...........................................................................8
2.1.1
General definitions..................................................................................8
2.2
Analysis sets ............................................................................................................9
2.3
Patient disposition, demographics and other baseline characteristics .....................9
2.3.1
Patient disposition...................................................................................9
2.3.2
Patient demographics and baseline charecteristics ...............................10
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................10
2.4.1
Study treatment / compliance................................................................10
2.4.2
Prior, concomitant and post therapies...................................................10
2.5
Analysis of the primary objective..........................................................................11
2.5.1
Primary endpoint...................................................................................11
2.5.2
Statistical hypothesis, model, and method of analysis..........................11
2.5.3
Handling of missing values/censoring/discontinuations.......................11
2.5.4
Supportive and Sensitivity analyses......................................................11
2.6
Analysis of the secondary objectives.....................................................................11
2.6.1
Safety analyses......................................................................................11
2.6.2
Pharmacokinetic endpoints ...................................................................14
2.7
Interim analysis......................................................................................................15
3
Sample size calculation .....................................................................................................15
4
Change to protocol specified analyses ..............................................................................17
5
Appendix ...........................................................................................................................17
5.1
Imputation rules.....................................................................................................17
5.1.1
Study treatment .....................................................................................17
5.1.2
AE date imputation ...............................................................................17
5.1.3
Concomitant medication date imputation .............................................17
5.2
AEs coding/grading ...............................................................................................17
5.3
Data pooling and assessment windows..................................................................17
5.4
Laboratory parameters – definition of clinically notable values ...........................19


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5.5
Vital signs and ECG – definition of clinically notable values...............................20
5.6
Statistical methodology and assumptions..............................................................21
5.7
Rule of exclusion criteria of analysis sets..............................................................21
6
Reference...........................................................................................................................21


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List of abbreviations
AE
Adverse Event
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
AUC
Area under curve
b.i.d
twice a day
BMI
Body Mass Index
BUN
Blood Urea Nitrogen
CRF
Case Report/Record Form (paper or electronic)
CT
Chewable tablet
ECG
Electrocardiogram
FDA
Food and Drug Administration
IgE
Immunoglobulin E
ICS
Inhaled Corticosteroid
LABA
Long Acting Beta-2 Agonist
MedDRA
Medical Dictionary for Regulatory Activities
PDS
Programming dataset specification
PT
Preferred term
SoC
System organ class
o.d.
Once a day
PK
Pharmacokinetic
QTc
Corrected QT interval
SAE
Serious Adverse Event
SAF
Safety analysis set
SOC
System Organ Class


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1
Introduction
This document contains details of the statistical methods that will be used in the phase II 
clinical trial CQAW039B2201. This study is designed to evaluate the pharmacokinetics, 
safety and tolerability of fevipiprant delivered via once daily chewable tablet (CT) in children 
aged 6 to <12 years with asthma.
The study was terminated by sponsor prematurely on December 16, 2019. Decision was taken 
to discontinue Study CQAW039B2201 based on evaluation of the QAW039 (fevipiprant) 
development program in asthma including results from the recently completed LUSTER-1/-2 
(CQAW039A2307/A2314) studies. The last Patient Last Visit, LPLV, was on January 22, 
2020. All patients from Cohort A completed the study. 5 subjects of Cohort B were treated, 
none of them completed the trial and none reached scheduled Day 8 visit. 
This statistical analysis plan is an abbreviated approach of presenting the limited data 
collected in the study and does not reflect the full analysis scope described in Section 12 of 
the study protocol (Version 01, Amendment 1 to original protocol released on 13-Feb-2019).
Important information is given in the following sections and details are provided, as 
applicable, in section 5: Appendix.
1.1
Study design
This study uses a multicenter, open-label design to assess the pharmacokinetics, safety, and 
tolerability of fevipiprant CT in children aged 6 to < 12 years with asthma (figure 1-1). The 
study includes an 4-8 day, open-label treatment period in which subjects receive fevipiprant 
CT once daily (o.d.) in addition to their rescue medication (e.g. short-acting β-agonists 
[SABAs]) and potentially standard-of-care (SoC) asthma therapy (inhaled corticosteroids 
[ICS] with or without an additional controller therapy). 
There will be 2 treatment dose cohorts studied (fevipiprant 75 mg o.d. and one higher dose 
selected based on PK obtained at 75 mg/day, [e.g. 150, 225, 300, or 375 mg once daily]). 
Within each dose cohort, subjects will be stratified approximately 1:1 ratio into 2 age groups: 
ages 6 to < 9 years and ages 9 to < 12 years.
Six subjects will be included in Cohort A and 6 to18 subjects in Cohort B. Approximately 20 
subjects will need to be screened in order to include 12 subjects into the treatment period 
(screen failure rate ~40%). After the interim analysis, additional subjects may need to be 
recruited so that total number of subjects completing treatment is maximum 24, in this case 
approximately 40 subjects will need to be screened. It is intended that 12 to 24 patients will 
complete the study. Dropouts, non-completers and patients who are not eligible for PK
assessment at End of treatment (e.g. because they did not take study drug for 3 consecutive 
days prior to EOT visit) will be replaced. Detailed information regarding sample size 
calculation is provided in section 3.


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A planned interim analysis will be conducted to support decision making when 6 subjects (3 
subjects from each of the 2 age strata) receiving the 75 mg dose level complete the treatment 
and provide the planned PK and safety data. At interim analysis, safety, as well as mean and 
variability of PK data of the 75 mg dose level will be assessed to have the right dose and 
number of subjects for the higher dose at the second stage. For detailed information, please 
refer to Section 3.
Figure 1-1
Study design
*Cohort B will be at 225 mg CT o.d. or at a different dose (e.g. 150, 300 or 375 mg)
1.2
Study objectives and endpoints
Section 2 of the study protocol lists the following primary and secondary objectives.
Table 1-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

To determine the key pharmacokinetic 
parameters of fevipiprant at steady state (ss), 

Area under the curve (AUC0-24h,ss), 
maximum plasma concentration (Cmax,ss), 


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Objective(s)
Endpoint(s)
after at least four consecutive days of dosing
and oral clearance (CL/F)
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To evaluate the urinary excretion of fevipiprant 
and CCN362 at steady state

CLr, amount and fraction of dose excreted 
over the PK collection interval 

To evaluate the safety & tolerability of 
fevipiprant over treatment period

Safety laboratory values (including 
peripheral blood eosinophils), vital signs, 
ECG, adverse events

To evaluate the pharmacokinetics of CCN362, 
the major metabolite of fevipiprant at steady 
state

Cmax,ss, time of maximum plasma 
concentration (Tmax,ss), AUC0-24h,ss, 
minimum plasma concentration (Cmin,ss) of 
CCN362

To evaluate additional pharmacokinetic 
parameters of fevipiprant at steady state

Tmax,ss, Cmin,ss, (CL/F)/kg of fevipiprant
2
Statistical methods
2.1
Data analysis general information
The final analysis will be performed 
. The most recent version of SAS
available in the statistical programming environment
will be used for the 
analysis. 
2.1.1
General definitions 
2.1.1.1
Study day
Study day will be defined as the number of days since the date of first dose of study treatment. 
The date of first dose of study treatment will be defined as Day 1 and the day before the first 
dose of study treatment will be defined as Day -1.
Therefore, for a particular date, study day will be calculated as follows:

for dates on or after the first date of study treatment,
Study day = Assessment date – Date of first dose of study treatment + 1;

for dates prior to the first date of study treatment,
Study day = Assessment date – Date of first dose of study treatment.
If a patient has not taken study treatment, the date when the study treatment has been assigned, 
will be used instead of the date of first dose of study treatment. Then, the date when the study 
treatment has been assigned is defined as Day 1 and the day before is defined as Day -1.
2.1.1.2
Baseline definition
For baseline assessments, checks will be performed to ensure the assessments were indeed 
taken prior to the first dose of study treatment. If baseline assessment (as mentioned in below 


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table) is missing or not confirmed to be pre-dose, the last value taken at any scheduled or
unscheduled visit before the first administration of study treatment will be used for baseline. 
Otherwise, the baseline will be set to missing without imputation.
Parameter
Baseline assessment
Laboratory data
(hematology, biochemistry)
Screening visit
Vital signs 
(body temperature, pulse rate, systolic and diastolic blood 
pressures)
Treatment Day 1 Pre-dose
Height, weight and BMI
Screening visit
ECG
Screening visit
2.1.1.3
Post-baseline measurement
Post-baseline measurements are defined as those assessments after the first dose of study 
treatment. 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.
2.2
Analysis sets
The following analysis sets are defined:

The Safety Set will consist of all patients who received at least one dose of study 
treatment including non-eligible patients who received study treatment in error. Patients 
will be analyzed according to the treatment they received. The safety set will be used in 
the analysis of all safety variables.

The PK analysis set will include all subjects with at least one available valid (i.e. not 
flagged for exclusion) PK concentration measurement, who received any study drug and 
with no protocol deviations that impact on PK data. Patients will be analyzed according to 
the treatment they received.
2.3
Patient disposition, demographics and other baseline 
characteristics
2.3.1
Patient disposition
For treatment epoch, the overall number of patients who entered, completed, and discontinued 
that phase will be summarized including the reasons for discontinuation.


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The number of patients included in each analysis set will be tabulated.
Protocol deviations as well as reason for exclusion from analysis sets will be listed.
2.3.2
Patient demographics and baseline charecteristics
Demographic and baseline characteristics measured including age, age stratum (6 to <9 years 
and 9 to <12 years), gender, race, ethnicity, height, weight and body mass index (BMI) will be 
summarized by cohort on safety analysis set.
Continuous variables will be summarized using descriptive statistics (mean, median, standard 
deviation, minimum, and maximum) and categorical variables will be summarized in terms of 
the number and percentage of subjects in each category.
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. 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
Dosage and date of administration at clinic (Treatment Day 1 and End of Treatment (at steady 
state)) and at home (1 day prior End of Treatment e.g. treatment Day 7) will be listed for all 
subjects in safety set.
2.4.1.1
Duration of exposure
Duration of exposure to study treatment will be calculated as the number of days starting from 
the first dose date up to and inclusive the last dose date. The duration of exposure will be 
summarized by cohort for the safety set as a continuous variable with the standard descriptive 
statistics. 
2.4.2
Prior, concomitant and post therapies
Prior and concomitant medications will be listed on the Safety set. 


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2.5
Analysis of the primary objective
2.5.1
Primary endpoint
The primary objective of the study is to determine the pharmacokinetics of fevipiprant based 
on AUC0-24h,ss, Cmax,ss and CL/F.
The AUC0-24h,ss, Cmax,ss and CL/F for fevipiprant at steady state after at least four 
consecutive days will be the primary variables. PK analysis set will be used for analysis of all 
PK parameters. Due to termination of study no PK data of Cohort B are available, thus all 
summaries of PK data will be done for Cohort A only.
2.5.2
Statistical hypothesis, model, and method of analysis
The primary variables, AUC0-24h,ss, Cmax,ss and CL/F will be analyzed by standard non-
compartmental analysis and summarized for Cohort A, through descriptive summary statistics 
(including mean, SD, CV% mean, Geometric mean, CV% geometric mean, median, minimum 
and maximum). .
Plasma concentrations will be assessed at EOT visit (pre-dose, 0.5, 1, 2, 3, 5, 8h) and will be 
expressed in mass per volume units. All concentrations below the lower limit of quantification 
(LLOQ) or missing data will be labeled as such in the concentration data listings. 
Concentrations below the limit of quantification will be treated as zero in summary statistics
and for the calculation of parameters and the pre-dose concentration on EOT visit will also be 
used as 24 h concentrations to derive AUC0-24h,ss.
2.5.3
Handling of missing values/censoring/discontinuations
Subjects with no valid PK concentration measurements, will be excluded from the analysis. 
Under missing completely at random assumption, subjects included in the analysis will be 
considered as representative of all subjects received treatment. Drop-outs and non-completers 
will be replaced.
No other methodology is planned to address missing data.
2.5.4
Supportive and Sensitivity analyses
Not applicable
2.6
Analysis of the secondary objectives
The secondary endpoints will be analyzed as described below.
2.6.1
Safety analyses
All safety evaluation will be based on the safety set.


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2.6.1.1
Adverse events (AEs)
All adverse events including asthma exacerbations will be coded with MedDRA using the 
most actual version at the time of database lock. AEs (including asthma exacerbations) 
starting on or after the time of the first intake of study drug and until the 7 days (30 days for 
SAEs) after the last intake of study drug will be classified as a treatment-emergent AEs. Any 
AEs that started during the study after signing informed consent and before the time of the 
first intake of study drug will be classified as prior AEs and will not be included in tabulations 
of treatment-emergent AEs.
The number and percentage of patients who reported treatment-emergent adverse events will 
be summarized by primary system organ class (SOC), preferred term (PT), and cohort forall 
adverse events by maximum severity
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 Cohort A. If a patient reported more than one adverse event with the same 
preferred term, the adverse event will be counted only once for that preferred term level. If a 
patient reported more than one adverse event within the same primary system organ class, the 
patient will be counted only once at the system organ class level.
2.6.1.1.1 AE reporting for CT.gov and EudraCT
For the legal requirements of clinicaltrials.gov and EudraCT, two required tables on treatment 
emergent adverse events which are not serious adverse events with an incidence greater than 
X% (where X lies between 0-5 %, will be decided later) and on treatment emergent serious 
adverse events and SAE suspected to be related to study treatment will be provided by system 
organ class and preferred term on the safety set population.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if 
at least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and 
SAEs irrespective of study treatment relationship will be provided by SOC and PT.


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2.6.1.2
Laboratory data
All laboratory samples will be processed through the central laboratory. Laboratory data 
consist of hematology and biochemistry including peripheral blood eosinophils. 
Laboratory data measured more than 7 days after last dose of study treatment are regarded as 
post-treatment data and will not be summarized. All data will be included in the analyses 
regardless of rescue medication use. All data will be listed.
The number and percentage of patients with newly occurring or worsening laboratory 
abnormalities meeting the clinically notable criteria (see Section 5.4 for definition of 
notable values) summarized by cohort, laboratory parameter at any time on treatment 
considering all post-baseline data from scheduled, unscheduled and premature 
discontinuation visits.
For a patient to meet the criterion of a newly occurring clinically notable value, the patient 
needs to have a baseline value that is not clinically notable for that parameter. For a patient to 
meet the criterion of a worsening clinically notable value, the patient needs to have a baseline 
value that is clinically notable and also have a worse post-baseline value. For patients with 
missing baseline value, any post-baseline notable value will be considered as newly occurring. 
A listing of all patients with notable laboratory values will be provided.
For summary tables 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.
Laboratory data, if collected in local LAB CRF page, will be listed only as appropriate.
2.6.1.3
ECG
ECG measurements include ventricular 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 7 days after last dose of study treatment are regarded as post 
treatment data and will not be summarized. All data will be included in the analyses 
regardless of rescue medication use. All data will be listed.

The number and percentage of patients with newly occurring or worsening notable QTcF 
values (see Section 5.5 for definition of notable values) summarized by cohort at any time 
on treatment considering all post-baseline data from scheduled, unscheduled and 
premature discontinuation visits


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The same approach as for notable laboratory values will be used to define a newly occurring 
notable QTc value and a worsening notable QTc value.
2.6.1.4
Vital signs
Vital signs measurements include body temperature, systolic and diastolic blood pressure 
(SBP and DBP) and pulse rate.
Vital signs data measured more than 7 days after last dose of study treatment are regarded as 
post-treatment data and will not be summarized. All data will be included in the analyses 
regardless of rescue medication use. All data will be listed.
The number and percentage of patients with newly occurring or worsening notable vital signs 
values (see Section 5.5 for definition of notable values) summarized by cohort, parameter at 
any time on treatment considering all post-baseline data from scheduled, unscheduled and 
premature discontinuation visits
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.
2.6.2
Pharmacokinetic endpoints  
Other pharmacokinetic variables of Fevipiprant at steady state
The pharmacokinetic variables Tmax,ss, Cmin,ss, (CL/F)/kg, CLr, amount and fraction of 
dose excreted over the PK collection interval of QAW039 at steady state will be secondary 
variables. All pharmacokinetic variables will be summarized similarly as mentioned for 
primary variable (Section 2.5).
Summary statistics for plasma and urine concentrations will be provided for cohort A by time 
point (only 1 time interval for urine). If any concentration value will be set to be zero for any 
time-point then Geo-mean, CV% geo-mean will not be presented for that time point.
Metabolite CCN362 at steady state
Cmax,ss, Tmax,ss, AUC0-24h,ss, Cmin,ss, CLr, amount of dose excreted over the PK 
collection interval at steady state of CCN362, the major metabolite of fevipiprant will be 
summarized similarly as mentioned for primary variable (Section 2.5).
Summary statistics for plasma and urine concentrations of analyte CCN362 will be provided 
for Cohort A by time point (only 1 time interval for urine). If any concentration value will be 
set to be zero for any time-point then Geo-mean, CV% geo-mean will not be presented for 
that time point. 


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2.7
Interim analysis
A planned interim analysis will be conducted to support decision making when 6 subjects (3 
subjects from each of the 2 age strata) receiving 75 mg dose complete the treatment. The 
interim analysis will be performed based on preliminary PK data e.g. protocol times can be 
used to calculate PK parameters. At interim analysis, based on PK data from the 75 mg dose 
level the high dose will be chosen.
For detailed information, please refer to Section 3.
3
Sample size calculation
Sample size is guided by statistical precision and requirements for pharmacokinetic data from 
pediatric subjects for inclusion in population PK modelling. Based on exploratory optimal 
design evaluation using modeling and simulation techniques, at least 12 subjects is expected 
to be sufficient for a pooled population PK analysis which is planned to be used to support 
dose selection for pediatric phase III studies. Since adult data on fevipiprant does not show a 
clinically relevant deviation from dose proportionality, data from the low and high dose 
cohort are equally valuable to inform the population PK model . Drop-outs and non-
completers will be replaced.
At first stage it is required to have PK data from 6 subjects receiving 75 mg dose to assess 
safety, as well as mean and variability of PK data to enable at the second stage to have the 
right dose and number of subjects. Moreover, data from 6 subjects will provide ~80% 
probability for acceptable precision in calculating the geometric mean. More specifically, the 
inclusion of 6 subjects would result in the 95% confidence interval (CI) of the geometric 
mean of QAW039 AUC0-24h,ss being in the range of (68%U, 147%U). U is the observed 
geometric mean, assuming a coefficient of variation of 31% based on data from previous 
study (QAW039A2111 study). This level of precision balances needs for reliable parameter 
estimation and clinical feasibility and is in agreement with guidance provided by health 
authorities. (General Clinical Pharmacology Considerations for Pediatric Studies for Drugs 
and Biological Products, FDA).
An interim analysis will be conducted when 6 subjects (3 subjects from each of two age strata) 
receiving the 75 mg dose will complete the treatment and provide the planned PK samples. At 
interim analysis, the following outcomes are foreseen based on AUC0-24h,ss:
In terms of exposure i.e. mean AUC0-24h,ss:
1) If mean AUC0-24h,ss is as expected, i.e. comparable to 150 mg dose in adult/adolescents, 
then 225 mg dose will be used in high dose cohort. .
2) If mean AUC0-24h,ss is relevantly more than expected while comparing with exposure of 
150 mg dose in adult/adolescents, dose lower than 225 mg e.g. 150 mg dose will be used in 
high dose cohort.


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3) If mean AUC0-24h,ss is relevantly less than expected while comparing with exposure of 
150 mg dose in adult/adolescents, dose higher than 225 mg e.g. 300 mg or 375 mg dose will 
be used in high dose cohort.
In terms of variability i.e. coefficient of variation (CV%) of AUC0-24h,ss:
1) If CV% of AUC0-24h,ss is less than or equal to 31% at interim, then 6 subjects will be 
recruited for the second cohort so that total number of subjects completing treatment is 12.
2) If CV% of AUC0-24h,ss is more than 31% at interim analysis, more than 6 subjects will be 
recruited at the high dose level to provide ~80% probability for acceptable precision in 
calculating the geometric mean, more specifically to have the 95% confidence intervals (CI) 
of geometric means of QAW039 AUC0-24h,ss approximately within the range of (68%U, 
147%U), where U is the observed geometric mean. The number of subjects on higher dose 
will be based on observed CV% at interim analysis.
The following table provides the range in which 95% CIs will fall with 80% probability in 
terms of percentage of observed geometric-mean, at different sample and different observed 
CV% at interim:
N 
(sample 
size)
Observed CV % at interim
35%
40%
45%
50%
55%
60%
65%
70%
75%
80%
7
69%-
146%
65%-
153%
62%-
161%
59%-
168%
57%-
176%
54%-
185%
52%-
193%
50%-
201%
48%-
209%
46%-
217%
8
71%-
140%
68%-
146%
65%-
153%
63%-
160%
60%-
166%
58%-
173%
56%-
180%
54%-
187%
52%-
194%
50%-
201%
9
74%-
136%
71%-
142%
68%-
147%
65%-
153%
63%-
159%
61%-
165%
59%-
171%
57%-
177%
55%-
183%
53%-
189%
10
75%-
133%
73%-
138%
70%-
143%
67%-
148%
65%-
154%
63%-
159%
61%-
164%
59%-
169%
57%-
175%
56%-
180%
11
77%-
130%
74%-
135%
72%-
140%
69%-
144%
67%-
149%
65%-
154%
63%-
159%
61%-
163%
59%-
168%
58%-
173%
12
78%-
128%
75%-
133%
73%-
137%
71%-
141%
69%-
146%
67%-
150%
65%-
154%
63%-
159%
61%-
163%
60%-
167%
13
79%-
127%
77%-
131%
74%-
135%
72%-
139%
70%-
143%
68%-
147%
66%-
151%
65%-
155%
63%-
159%
61%-
163%
14
80%-
125%
78%-
129%
75%-
133%
73%-
137%
71%-
140%
69%-
144%
68%-
148%
66%-
152%
64%-
155%
63%-
159%
15
81%-
124%
78%-
128%
76%-
131%
74%-
135%
72%-
138%
70%-
142%
69%-
145%
67%-
149%
66%-
152%
64%-
156%
16
81%-
123%
79%-
126%
77%-
130%
75%-
133%
73%-
136%
71%-
140%
70%-
143%
68%-
147%
67%-
150%
65%-
153%
17
82%-
122%
80%-
125%
78%-
128%
76%-
132%
74%-
135%
72%-
138%
71%-
141%
69%-
144%
68%-
147%
66%-
151%
18
83%-
121%
81%-
124%
79%-
127%
77%-
130%
75%-
133%
73%-
136%
72%-
140%
70%-
142%
69%-
145%
67%-
148%
For example, if we observe a CV% of 55% in the interim data, then 12 subjects are required to 
complete treatment with the high dose and to provide the planned PK samples to give ~80% 
probability for the 95% confidence intervals (CI) of geometric means of QAW039 AUC0-


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24h,ss to fall approximately within the range of (68%U, 147%U). The sample size for the 
high dose can vary from 6 to 18 subjects, so that total number of subjects completing 
treatment (75 mg or high dose) and providing planned PK samples is maximum of 24. For 
example, if we observe a CV% of 80% in the interim data, then 18 subjects will be recruited 
at the high dose to provide the planned PK samples, though the 95% CI of geometric means of 
QAW039 AUC0-24h,ss will fall outside the range of (68%U, 147%U).
4
Change to protocol specified analyses
This statistical analysis plan is an abbreviated approach of presenting the limited data 
collected in the study and does not reflect the full analysis scope described in Section 12 of 
the study protocol (Version 01, Amendment 1 to original protocol released on 13-Feb-2019).
The following changes to the protocol specified analyses will be done:

Definition of treatment emergent for safety adjusted: treatment end + 1 day will be 
replaced by treatment end date + 7 days for laboratory, vital signs, ECG and AEs, and 
to + 30 days for SAEs, to follow standard of QAW program.
5
Appendix
This appendix gives details about statistical methods in addition to the report text. All 
analyses will be performed by the most recent version of SAS available in the statistical 
programming environment.
5.1
Imputation rules
5.1.1
Study treatment
Missing/partial start date or end date of study treatment will not be imputed.
5.1.2
AE date imputation
Rules for imputing AE end date or start date will be provided in Programming Dataset 
Specification (PDS) document in details.
5.1.3
Concomitant medication date imputation
Rules for imputing the CM end date or start date will be provided in Programming Dataset 
Specification (PDS) document in details.
5.2
AEs coding/grading
The MedDRA version which will be available at the time of database lock, will be used for 
the coding purpose of the adverse events.
5.3
Data pooling and assessment windows


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Data from unplanned or unscheduled visits or the early treatment/study discontinuation visits 
will be listed, as appropriate. For patients who do not complete the study treatment, the 
treatment discontinuation visit will be an unscheduled visit.
Clinical laboratory measurements, vital signs and ECG data from unplanned or unscheduled 
visits will only be included in the summaries of the notable values. All efficacy data from 
these visits will not be used for missing data imputation unless specified otherwise.
Laboratory, vital signs, and ECG values that have complete date and time values will be 
slotted into pre- or post-dose assessment based on the actual date/time. For values with 
missing date/time, scheduled visit date and time will be used. This rule will be applied to data 
from scheduled visits only. If a measurement scheduled as pre-dose is actually performed 
post-dose, or vice versa, the data will not be used for by time point assessments.


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5.4
Laboratory parameters – definition of clinically notable values
The following table shows the criteria for clinically notable laboratory values. Not all 
parameters have notable criteria defined.
Laboratory parameter (unit)
Bound for notably low values
Bound for notably high values
Hematology
Hematocrit (v/v)
     Male 6-12
     Female 6-12
0.31
0.31
Hemoglobin (g/L)
    Male 6-12
    Female 6-12
97
92
Thrombocytes (x10E9/L)
75 
500
WBC’s (x10E9/L)
2.8 
16.0 
Chemistry
Alkaline Phosphatase (IU/L)
-
3xULN 
Total Bilirubin (µmol/L)
-
34.2 
Creatinine (µmol/L)
105 
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 
v = volume, ULN = upper limit of normal 


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5.5
Vital signs and ECG – definition of clinically notable values
The following table shows the 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)
< 80 (all)
> 150 (all)
Diastolic blood pressure (mmHg)
< 45 (all)
> 105 (all)
Pulse rate (bpm)
< 50 (all)
> 150 (6-8), >130 (9-12)
Notable change from baseline
Systolic blood pressure (mmHg)
≤ 90 and decrease from 
baseline by ≥ 15 
≥ 140 and increase from 
baseline by ≥ 15
Diastolic blood pressure (mmHg)
≤ 55 and decrease from 
baseline by ≥ 15
≥ 95 and increase from baseline 
by ≥ 15
Pulse rate (bpm)
≤ 60 and decrease from 
baseline by ≥ 15
≥ 140 and increase from 
baseline by ≥ 15 (6-8)
≥ 120 and increase from 
baseline by ≥ 15 (9-12)
The following table shows the clinical notable criteria for QTcF.
ECG parameter (unit)
Clinically notable range
Notable value criterion for newly occurring or worsening cases
QTc (msec)
> 450 msec for males and females
QTc (msec)
> 500 msec for males and females
Notable change from baseline
QTc
30 – 60 msec
QTc
> 60 msec


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5.6
Statistical methodology and assumptions
Not applicable as no inferential analyses will be conducted.
5.7
Rule of exclusion criteria of analysis sets 
The following table provides the protocol deviations (PD) and other criteria leading to partial 
or complete exclusion from analyses sets
Deviation ID
Description of Deviation
Deviations leading to exclusion from all analyses sets
INCL02A
Subject entered the study without the parent/legal guardian signing the informed consent
INCL02B
Subject entered the study without  signing the assent where local law requires assent
Deviations leading to exclusion from PK analysis set
TRT01
Subject did not receive a total of at least four consecutive, daily doses of study drug
6
Reference
General Clinical Pharmacology Considerations for Pediatric Studies for Drugs and Biological 
Products, FDA