A Multi-center, Proof-of-mechanism Study of Multiple, Oral Doses of Fevipiprant (QAW039) in COPD Patients With Eosinophilia
Phase: PHASE2
Conditions: Chronic Obstructive Pulmonary Disease
Sponsor: Novartis Pharmaceuticals

Novartis Research and Development
QAW039
Clinical Trial Protocol CQAW039E12201
A multi-center, proof-of-mechanism study of multiple, oral 
doses of fevipiprant (QAW039) in COPD patients with 
eosinophilia
Document type:
Amended Protocol Version
EUDRACT number:
2018-004267-32
Version number:
v02 (Clean version)
Clinical Trial Phase:
II
Release date:
05-Nov-2019
Property of Novartis/sponsor
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 2.0 dated 01-Aug-2018

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Site Operations Manual (SOM)
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study procedures. Note: The SOM will not be a part of the Clinical Study Report.

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Table of contents
Site Operations Manual (SOM)...........................................................................................2
Table of contents .................................................................................................................3
List of tables ........................................................................................................................6
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms.................................................................................................................9
Amendment 2 (November 2019).......................................................................................10
Amendment 1 (April 2019) ...............................................................................................12
Protocol summary..............................................................................................................13
1
Introduction .......................................................................................................................16
1.1
Background............................................................................................................16
1.2
Purpose ..................................................................................................................17
2
Objectives and endpoints...................................................................................................17
3
Study design ......................................................................................................................18
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 ..........................................21
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................21
4.4
Purpose and timing of interim analyses/design adaptations..................................21
4.5
Risks and benefits..................................................................................................22
4.5.1
Blood sample volume............................................................................23
5
Population..........................................................................................................................23
5.1
Inclusion criteria ....................................................................................................23
5.2
Exclusion criteria...................................................................................................24
6
Treatment...........................................................................................................................26
6.1
Study treatment......................................................................................................26
6.1.1
Investigational and control drugs..........................................................27
6.1.2
Additional study treatments ..................................................................27
6.1.3
Treatment arms/group ...........................................................................27
6.2
Other treatment(s)..................................................................................................27
6.2.1
Concomitant therapy.............................................................................27
6.2.2
Prohibited medication ...........................................................................28
6.2.3
Rescue medication ................................................................................29
6.2.4
Restriction for study subjects................................................................29

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6.3
Subject numbering, treatment assignment, randomization....................................29
6.3.1
Subject numbering ................................................................................29
6.3.2
Treatment assignment, randomization ..................................................29
6.4
Treatment blinding.................................................................................................30
6.5
Dose escalation and dose modification..................................................................30
6.6
Additional treatment guidance...............................................................................30
6.6.1
Treatment compliance...........................................................................30
6.6.2
Recommended treatment of adverse events..........................................31
6.6.3
Emergency breaking of assigned treatment code..................................31
6.7
Preparation and dispensation.................................................................................31
7
Informed consent procedures ............................................................................................32
8
Visit schedule and assessments .........................................................................................33
8.1
Screening ...............................................................................................................37
8.1.1
Eligibility screening ..............................................................................37
8.1.2
Information to be collected on screening failures.................................37
8.2
Subject demographics/other baseline characteristics.............................................37
8.3
Efficacy..................................................................................................................38
8.3.1
Sputum eosinophil % of total cell count ...............................................38
8.3.3
Appropriateness of efficacy assessments..............................................38
8.4
Safety and tolerability............................................................................................39
8.4.1
Laboratory evaluations..........................................................................39
8.4.2
Electrocardiogram (ECG) .....................................................................40
8.4.3
Pregnancy and assessments of fertility .................................................41
8.5
Additional assessments..........................................................................................41
8.5.1
Clinical Outcome Assessments (COAs) ...............................................41
8.5.2
Subject diaries.......................................................................................42
8.5.3
Pharmacokinetics ..................................................................................42
9
Study discontinuation and completion ..............................................................................44
9.1
Discontinuation......................................................................................................44
9.1.1
Discontinuation of study treatment .......................................................44
9.1.2
Withdrawal of informed consent...........................................................46
9.1.3
Lost to follow-up...................................................................................46
9.1.4
Study stopping rules..............................................................................46
9.1.5
Early study termination by the sponsor.................................................47
9.2
Study completion and post-study treatment ..........................................................47
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10 Safety monitoring and reporting........................................................................................47
10.1
Definition of adverse events and reporting requirements......................................47
10.1.1
Adverse events ......................................................................................47
10.1.2
Serious adverse events ..........................................................................49
10.1.3
SAE reporting........................................................................................50
10.1.4
Pregnancy reporting ..............................................................................51
10.1.5
Reporting of study treatment errors including misuse/abuse................51
10.2
Additional Safety Monitoring................................................................................52
10.2.1
Liver safety monitoring.........................................................................52
10.2.2
Renal safety monitoring........................................................................53
11 Data Collection and Database management......................................................................53
11.1
Data collection.......................................................................................................53
11.2
Database management and quality control............................................................53
11.3
Site monitoring ......................................................................................................54
12 Data analysis and statistical methods ................................................................................55
12.1
Analysis sets ..........................................................................................................55
12.2
Subject demographics and other baseline characteristics......................................55
12.3
Treatments .............................................................................................................55
12.4
Analysis of the primary endpoint(s) ......................................................................55
12.4.1
Definition of primary endpoint(s).........................................................56
12.4.2
Statistical model, hypothesis, and method of analysis..........................56
12.4.3
Handling of missing values/censoring/discontinuations.......................57
12.4.4
Sensitivity and Supportive analyses......................................................57
12.5
Analysis of secondary endpoints ...........................................................................57
12.5.1
Safety endpoints....................................................................................57
12.6
Analysis of exploratory endpoints.........................................................................58
12.7
Interim analyses.....................................................................................................60
12.8
Sample size calculation..........................................................................................61
12.8.1
Primary endpoint(s)...............................................................................61
13 Ethical considerations and administrative procedures ......................................................62
13.1
Regulatory and ethical compliance........................................................................62
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13.2
Responsibilities of the investigator and IRB/IEC..................................................62
13.3
Publication of study protocol and results...............................................................62
13.4
Quality Control and Quality Assurance.................................................................62
14 Protocol adherence ............................................................................................................63
14.1
Protocol amendments.............................................................................................63
15 References .........................................................................................................................64
16 Appendices ........................................................................................................................66
16.1
Appendix 1: Clinically notable laboratory values .................................................66
16.2
Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.........................................................................................................66
16.3
Appendix 3: Specific Renal Alert Criteria and Actions and Event Follow-up......69
List of tables
Table 2-1
Objectives and related endpoints ..........................................................17
Table 6-1
Investigational and control drug............................................................27
Table 6-2
Prohibited medication ...........................................................................28
Table 8-1
Assessment Schedule ............................................................................34
Table 8-2
Assessments & Specifications...............................................................39
Table 8-3
Laboratory test details...........................................................................40
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................51
Table 16-1
Liver event and laboratory trigger definitions ......................................66
Table 16-2
Follow up requirements for liver events and laboratory triggers..........67
Table 16-3
Specific Renal Alert Criteria and Actions.............................................69
List of figures
Figure 3-1
Study design..........................................................................................18
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List of abbreviations
AE
adverse event
ALB
Albumin
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BUN
blood urea nitrogen
CK
creatinine kinase
CMO&PS
Chief Medical Office & Patient Safety
COPD
Chronic obstructive pulmonary disease
CRF
Case Report/Record Form (paper or electronic)
CRTh2
Chemoattractant Receptor-homologous molecule expressed on Th2 cells (also called 
DP2)
CSR
Clinical study report
CV
coefficient of variation
DP2
Prostaglandin D2 receptor 2 (also called CRTh2)
ECG
Electrocardiogram
eGFR
Estimated Glomerular Filtration Rate
EOT
End of treatment
FEV1
Forced Expiratory Volume in one second
FSH
Follicle Stimulating Hormone
FVC
Forced vital capacity
GCP
Good Clinical Practice
GCS
Global Clinical Supply
GGT
Gamma-glutamyl transferase
GOLD
Global Initiative for Chronic Obstructive Lung Disease
h
hour
HbsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HFA
Hydrofluoroalkane
HIV
human immunodeficiency virus
hs-CRP
high-sensitivity C-reactive Protein
IB
Investigator's Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use
ICS
Inhaled Corticosteroid
IDR
idiosyncratic drug reactions
IEC
Independent Ethics Committee
ILC-1
Innate Lymphoid Cell type 1
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ILC-2
Innate Lymphoid Cell type 2
IN
Investigator Notification
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
intrauterine device
IUS
intrauterine system
LABA
Long-acting Beta-agonist
LAMA
Long-acting muscarinic antagonist
LDH
lactate dehydrogenase
LFT
Liver function test
MCID
Minimal clinically important difference
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical dictionary for regulatory activities
mg
milligram(s)
mL
milliliter(s)
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PT
prothrombin time
QMS
Quality Management System
QTcF
QT interval corrected by Fridericia’s formula
SAE
serious adverse event
SD
standard deviation
SEP
Sputum eosinophil percentage
SmPC
Summary of Product Characteristics
SMQ
Standardized MedDRA Query
SoC
Standard of Care
SOM
Site Operations Manual
ULN
upper limit of normal
WOCBP
Women of child bearing potential
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Glossary of terms
Assessment
A procedure used to generate data required by the study
Control drug
A study drug (active or placebo) used as a comparator to reduce 
assessment bias, preserve blinding of investigational drug, assess internal 
study validity, and/or evaluate comparative effects of the investigational drug
Dosage
Dose of the study treatment given to the subject in a time unit (e.g. 100 mg 
once a day, 75 mg twice a day)
Electronic Data 
Capture (EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical study 
data using data collection systems, such as Web-based applications, 
interactive voice response systems and clinical laboratory interfaces. 
EDC includes the use of Electronic Case Report Forms (eCRFs) which are 
used to capture data transcribed from paper source forms used at the point 
of care.
End of the clinical 
trial
The end of the clinical trial is defined as the last visit of the last subject or at 
a later point in time as defined by the protocol
Enrollment
Point/time of subject entry into the study at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the 
protocol)
Investigational 
drug/treatment
The drug whose properties are being tested in the study
Medication pack 
number
A unique identifier on the label of each drug package in studies that 
dispense study treatment using an IRT system
Patient
An individual with the condition of interest
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.
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
Source 
Data/Document
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource
Study 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
A trial participant (can be a healthy volunteer or a patient)
Subject number
A unique number assigned to each subject upon signing the informed 
consent. This number is the definitive, unique identifier for the subject and 
should be used to identify the subject throughout the study for all data 
collected, sample labels, etc.
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested in 
the study
Withdrawal of study 
consent (WoC)
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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Protocol summary
Protocol 
number
CQAW039E12201
Full Title
A multi-center, proof-of-mechanism study of multiple, oral doses of fevipiprant 
(QAW039) in COPD patients with eosinophilia
Brief title
A proof-of-mechanism study of multiple, oral doses of fevipiprant (QAW039) in
COPD patients with eosinophilia
Sponsor and 
Clinical Phase
Novartis, Phase II
Investigation 
type
Drug
Study type
Interventional
Purpose and 
rationale
There remains an unmet medical need for phenotype-driven therapy for patients 
with COPD who have evidence of eosinophilic airway inflammation despite 
treatment with standard of care medications.
The purpose of this study is to determine whether fevipiprant (QAW039), when 
administered to COPD patients with eosinophilic airway inflammation on standard 
of care therapy, reduces the burden of sputum eosinophilia.
In addition, the clinical safety and efficacy profile of fevipiprant in COPD patients 
with eosinophilia will support its further development in this population.
Primary 
Objective(s) 
The primary objective of this study is to assess the change from baseline in 
sputum eosinophil levels (% of total count) in COPD patients with eosinophilia 
after multiple oral doses of fevipiprant when compared to placebo.
Secondary 
Objectives
To assess the safety and tolerability of fevipiprant in COPD patients with 
eosinophilia.
Study design
This is an exploratory, randomized, subject- and investigator-blind, placebo-
controlled, parallel group, proof-of-mechanism study in COPD patients 
with eosinophilia.
Patients should have moderate to severe COPD, with no past or current medical 
history of asthma, be on standard of care medications and demonstrate an 
eosinophilic phenotype, as defined by a sputum eosinophil count of ≥ 3% of the 
total cell count obtained from an induced sputum specimen and a peripheral 
eosinophil count ≥ 300 cells/μL of blood.
Key Inclusion 
criteria
1.
Acceptable and reproducible spirometry with post-bronchodilator FEV1/FVC
< 0.7 and post-bronchodilator FEV1≥ 30 and ≤ 80% of predicted at the
screening and baseline visits (GOLD stage II or III COPD).
2.
Patients with a physician-diagnosed history of COPD for at least 1 year prior
to screening visit, and a documented history of at least one COPD
exacerbation within the year prior to screening visit and on a stable therapy
regimen for COPD for at least 4 weeks prior to screening visit with inhaled
glucocorticoid + one or more long acting bronchodilator.
3.
Current or ex-smokers who have a smoking history of at least 10 pack-years
(10 pack-years are defined as 20 cigarettes a day for 10 years, or 10
cigarettes a day for 20 years, or equivalent).
4.
Documented elevated peripheral blood eosinophil count ≥ 300 cells/µL blood
either at the Screening visit or at any time in the preceding 3 months.

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Sputum eosinophils must be ≥ 3% of total cell count at the baseline sputum 
collection..
Key Exclusion 
criteria
1.
Patients with a past or current medical history of asthma.
2.
Patients with a past or current medical history of conditions other than
COPD or allergic rhinitis that could result in elevated sputum eosinophils
(e.g., asthma, hypereosinophilic syndrome, Churg-Strauss Syndrome).
Patients with known parasitic infestation within 6 months prior to screening
are also excluded.
3.
Patients who have had a respiratory tract infection or COPD worsening or
systemic steroid use within 4 weeks prior to screening visit or between
screening and randomization visits.
4.
Patients with history of concomitant chronic or severe pulmonary disease
(e.g., sarcoidosis, interstitial lung disease, cystic fibrosis, tuberculosis).
Exception: patients with concomitant mild or moderate pulmonary
hypertension or bronchiectasis are permitted to participate.
5.
Women of child-bearing potential, defined as all women physiologically
capable of becoming pregnant, unless they are using effective contraception
(also called basic contraception) methods during the study.
6.
Patients on any statin therapy with a CK level > 2 X ULN at screening or
baseline visit.
7.
Patients who have a clinically significant laboratory abnormality at the
screening or baseline visit including (but not limited to):

Total white blood cell count <2500 cells/uL

AST or ALT > 2.0 X ULN or total bilirubin > 1.3 X ULN

Estimated Glomerular Filtration Rate (eGFR) by the Modification of Diet
in Renal Disease (MDRD) equation or Bedside Schwartz equation <55
mL/minute/1.73 m2.
8.
Patients with any of the following cardiac related concerns:

A resting QTcF (Fridericia) ≥450 msec (male) or ≥460 msec (female) at
screening or baseline visit

A history of familial long QT syndrome or known family history of
Torsades de Pointe

Receiving any medications or other agents known to prolong the QT
interval

patients with a history of moderate or severe uncontrolled
tachyarrhythmias

History of a clinically significant cardiovascular event within 1 year prior
to the screening visit, such as acute myocardial infarction, congestive
heart failure, unstable arrhythmia

Patients who, in the judgment of the investigator have a clinically
significant ECG abnormality such as (but not limited to) sustained
ventricular tachycardia, or clinically significant second or third degree
AV block without a pacemaker
Study 
treatment

QAW039 450mg oral tablet

Matching placebo oral tablet
Key Efficacy 
assessments

Sputum eosinophil % of total cell count
Key safety 
assessments
Physical examination, ECG, vital signs, standard clinical laboratory evaluations 
(hematology, blood chemistry, and urinalysis), adverse event, and serious 
adverse event monitoring.

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Other 
assessments
Data analysis
The treatment effect of the primary variable will be assessed using the posterior 
difference between the treatment groups in the change from baseline in log10 
sputum eosinophil percentage at week 6 using a Bayesian model with 
adjustment for baseline sputum eosinophil percentage and smoking status as 
covariates. A robust mixture prior for the placebo response (based on 
CQAW039A2208 study) will be used in the Bayesian analysis.
Key words
QAW039, Chronic obstructive pulmonary disease, COPD, sputum, eosinophilic, 
eosinophilia, prostaglandin D2 receptor, DP2, CRTh2, fevipiprant.
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1
Introduction
1.1
Background
Chronic obstructive pulmonary disease (COPD) is characterized by persistent symptoms (e.g., 
dyspnea, cough) and airflow obstruction that is usually progressive (GOLD Guidelines 2018). 
The symptoms as well as airflow limitation in COPD are consequent to lung abnormalities 
(airway and/or alveolar) caused by exposure of the lungs to “noxious particles or gases” such 
as tobacco smoke (GOLD Guidelines 2018). COPD exacerbations are a major cause of poor 
health and death worldwide, and contribute to impaired health status (Seemungal et al 1998, 
Spencer et al 2004) and increased hospitalization costs (Andersson et al 2002) and predict 
mortality (Soler-Cataluña et al 2005).
The inflammation observed in COPD has generally been thought to be neutrophilic in origin 
(Tripple et al 2017). However, eosinophilic inflammation has been observed in the induced 
sputum of some patients with stable COPD (Tripple et al 2017, Saha and Brightling 2006), and 
blood eosinophil levels of 2% or greater appear to be associated with risk of exacerbations of 
COPD (Kerkhof et al 2017). Recently, the COPD Gene study showed that patients with 
moderate-to-severe COPD and blood eosinophil counts ≥300 cells/µl had an increased risk of 
exacerbations (Yun et al 2018). Eosinophilic airway inflammation may also be associated with 
underlying atopic disease, which may contribute to COPD symptoms and exacerbations 
(Jamieson et al 2013, Fattahi et al 2013). Therefore, as in asthma, eosinophilic inflammation 
may play a role in the pathophysiology of exacerbations in patients with COPD. An unmet 
medical need for phenotype-driven therapy exists for COPD patients who have evidence of 
eosinophilic inflammation despite treatment with standard of care medications such as inhaled 
glucocorticoids and long-acting bronchodilators.
The prostaglandin D2 receptor (DP2; also known as CRTh2) is a receptor for prostaglandin D2 
which mediates the activation and migration of eosinophils, basophils and Th2 cells 
(Domingo et al 2018, Hirai et al 2001), as well as type 2 innate lymphoid (ILC-2) cells 
(Xue et al 2014). Fevipiprant (QAW039) is a potent, selective, competitive, reversible DP2 
receptor antagonist currently in Phase 3 studies for the treatment of asthma. In a Phase 2 study
of patients with severe asthma and sputum eosinophilia, treatment with fevipiprant resulted in 
improvement in measures of asthma control as well as a significant reduction in sputum 
eosinophils (Gonem et al 2016). A reduction in sputum eosinophils was observed in the same 
range with the anti-IL5 antibodies, mepolizumab (Pavord et al 2012) and reslizumab 
(Castro et al 2011) in asthma. Although fevipiprant has not been evaluated in patients with 
COPD to date, another DP2 receptor antagonist, AZD1981, has been evaluated in a small study 
in patients with moderate-to-severe COPD during which cellular and histological changes in 
the airways were evaluated. In this study, AZD1981, compared with placebo, significantly 
reduced sputum eosinophils (AstraZeneca, data on file) suggesting a potential mechanistic 
effect for a DP2 receptor antagonist in COPD.
In addition to reducing airway eosinophils, fevipiprant inhibits the migration and activation of 
type 2 innate lymphoid (ILC-2) cells, resident cells in the lung, which secrete IL-4, IL-5 and 
IL-13 in response to DP2 (Zhou et al 2018). ILC-2 cells also convert to ILC-1 cells, which are 
increased in patients with COPD and are associated with infection-induced COPD 
exacerbations, are a significant source of TNF-α and IFN-λ (Silver et al 2016). 

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Given the above information on the potential role of the DP2 pathway in COPD, it is reasonable 
to evaluate fevipiprant’s pharmacodynamic activity in COPD patients with eosinophilia.
1.2
Purpose
The primary purpose of this proof-of-mechanism study is to determine whether fevipiprant 
(QAW039), when administered to COPD patients with eosinophilic airway inflammation on 
standard of care therapy, reduces the burden of sputum eosinophilia similar to that seen in 
patients with asthma.
2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

To assess the change from baseline
in sputum eosinophil levels in COPD
patients with eosinophilia after
multiple oral doses of fevipiprant
when compared to placebo

Sputum eosinophil % of total cell count
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To assess the safety and tolerability
of fevipiprant in COPD patients with
eosinophilia

Physical examination, ECG intervals, vital signs,
standard clinical laboratory evaluations
(hematology, blood chemistry, and urinalysis),
adverse events including COPD exacerbations
Exploratory objective(s)
Endpoint(s) for exploratory objective(s)
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3
Study design
Figure 3-1
Study design
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This is an exploratory, randomized, subject- and investigator-blind, placebo-controlled, parallel 
group, proof-of-mechanism study in COPD patients with eosinophilia, on standard of care 
therapy.
Standard of care (SoC) treatment in patients with COPD typically includes a regimen of inhaled 
corticosteroid (ICS) plus one or more long acting bronchodilator (long-acting beta2-agonist 
(LABA) or long-acting antimuscarinic antagonist (LAMA)). This can consist of double or triple 
inhaler therapy with short-acting bronchodilators taken as rescue medication on an “as needed” 
basis for symptoms. Rarely, systemic therapy with theophylline or roflumilast is added to the 
patient’s daily medical regimen, which are permitted in the study. To be eligible for the study, 
subjects are required to be on a stable therapy regimen of inhaled corticosteroid (ICS) plus one 
or more long acting bronchodilator (long-acting beta2-agonist (LABA) and/or long-acting 
antimuscarinic antagonist (LAMA)) for at least four weeks prior to the screening. Subjects will 
be expected to continue their SoC therapy for the duration of the study.
The study consists of a screening period (including an optional pre-screen visit) during which 
the subject’s phenotype and eligibility for the study will be assessed. All subjects who meet the 
eligibility criteria after the screening visit will undergo induction of their sputum to examine 
the baseline sputum cell counts. Subjects will be required to demonstrate both blood and sputum 
eosinophilia to be eligible for participation in the study:

Peripheral eosinophilia is defined as a documented elevated peripheral blood eosinophil
count ≥ 300 cells/μL of blood either at the Screening visit or at any time in the preceding 3
months (from an existing lab report or from a sample collected at the optional pre-screen
visit – see Section 8.1.1 Eligibility screening for more details).

Sputum eosinophilia is defined as sputum eosinophil count of ≥3% of total cell count on
an induced sputum sample
Eligible subjects will be randomized 3:2 to active (QAW039 450 mg orally daily) vs. placebo 
arms. Randomization will be stratified by current smoking status (current vs. ex-smoker). 
Subjects will continue their standard of care COPD and other medications during the entire 
course of the study (provided they are not prohibited medications - see Section 6.2.2).
Subjects will receive multiple doses of fevipiprant for six weeks, with safety, 
efficacy/pharmacodynamic and pharmacokinetic assessments performed.
Sputum induction will be repeated at the end of the treatment period and at the end of the study 
(approximately 4 weeks after the last dose).
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Safety assessments will include physical examination, ECG, vital signs, standard clinical 
laboratory evaluations (hematology, blood chemistry, and urinalysis), adverse event, and 
serious adverse event monitoring.
The study plans to recruit approximately 50 subjects (subjects who drop out from the study may 
be replaced so that 50 subjects complete the treatment period). 
4
Rationale
4.1
Rationale for study design
This exploratory, proof-of-mechanism study is designed to assess the pharmacodynamic, 
clinical safety and PK (drug concentrations) profiles of fevipiprant in COPD patients with 
eosinophilia. In order to optimize the rigor and integrity of the study and minimize bias, a 
randomized, subject- and investigator-blinded parallel group study design is used. This design 
is well-established in respiratory clinical trials (Snell et al 2013) and enables the study treatment 
to be given for an appropriate and practical length of time of 6 weeks to assess the efficacy and 
safety of the treatment (Gonem et al 2016).
4.1.1
Rationale for choice of background therapy
Subjects will continue their standard of care for COPD and other medications (with the 
exception of prohibited medications outlined in Section 6.2.2) during the course of the study.
To be eligible for the study, subjects are required to be on a stable therapy regimen of inhaled 
corticosteroid (ICS) plus one or more long acting bronchodilator (long-acting beta2-agonist 
(LABA) and/or long-acting antimuscarinic antagonist (LAMA)) for at least four weeks prior to 
the screening visit to minimize any impact of a change in background therapy on the endpoints 
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of the study. This is in line with standard of care treatment as described in the 
GOLD guidelines 2018 for patients with a history of exacerbations.
4.2
Rationale for dose/regimen and duration of treatment
Eosinophilic inflammation in the airway contributes to and drives exacerbations in a subset of 
patients with COPD as well as in asthma. A therapy that reduces sputum eosinophils in one 
indication should also do the same in the other. In the Phase 2 study CQAW039A2208, a 3.5-
fold (~70%) reduction in sputum eosinophils was observed in patients with asthma relative to 
placebo after a daily oral dose of 450 mg over 12 weeks (Gonem et al 2016). The 
pharmacodynamic effect on sputum eosinophils was seen from 6 weeks onwards. 
Six week duration is considered sufficient to observe an improvement in key primary, 
secondary and exploratory endpoints of the study,
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
Fevipiprant will be administered in addition to standard of care for COPD patients, with placebo 
control used to enable an unbiased comparison of safety and pharmacodynamic effects in 
active-treated subjects when compared to placebo-treated subjects.
4.4
Purpose and timing of interim analyses/design adaptations
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4.5
Risks and benefits
There is no benefit expected for subjects participating in this study.
The risk to subjects in this trial may be minimized by compliance with the eligibility criteria 
and study procedures, as well as close clinical monitoring, subject and study level stopping 
rules, minimal study duration and periodic review of safety data by the clinical team. Study 
subjects are expected to continue their standard of care medications, which further reduces any 
potential risks.
Induction of sputum with isotonic or hypertonic saline can be associated with transient cough, 
breathing discomfort, chest pain, and worsening of lung function. These risks are minimized by 
pre-treatment with bronchodilators and close lung function monitoring during sputum induction, 
with stopping criteria for sputum induction and/or escalation of saline concentration. Subjects 
will only be discharged from the study center if symptoms and lung function recovery allow or 
upon evaluation by a responsible physician that it is safe to discharge the subject.
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and must agree that in 
order to participate in the study they must adhere to the contraception requirements outlined in 
the exclusion criteria. If there is any question that the subject will not reliably comply, they 
should not be entered or continue in the study.
As of January 2018, over 2830 subjects have been exposed to fevipiprant in its clinical 
development program. Potential side effects of fevipiprant include: increased heart rate, non-
serious arrhythmia such as palpitations, headache, diarrhea, nausea, vomiting, nasopharyngitis, 
somnolence and dizziness.
Cardiovascular risks will be monitored based on changes in vital signs, ECGs and biochemical 
parameters. Monitoring of liver function tests (LFT) and renal function will be conducted.
In humans, one major metabolite of fevipiprant has been identified which is formed by 
glucuronidation (acyl glucuronide) and partially binds to plasma proteins. In the literature, in 
vivo binding of acyl glucuronides to proteins has been reported to be associated with rare 
idiosyncratic drug reactions (IDRs), although a causal connection of protein adduction to IDRs 
remains uncertain. There have been no IDRs observed with fevipiprant treatment in completed 
clinical trials as of January 2018. Surveillance of adverse events for identification of IDRs will 
be conducted during the course of this study.
Taking fevipiprant at the doses used in this study with the cholesterol-lowering drug simvastatin 
has been shown to cause a small increase in the peak blood level of simvastatin. Subjects on 
doses of simvastatin > 20 mg, doses of atorvastatin >40 mg, doses of pravastatin >40 mg, or 
doses of pitavastatin > 2 mg per day, as well as subjects on any statins with high creatine kinase 
(CK) levels (> 2 X ULN (upper limit of normal)) at screening will be excluded from the study. 
Subjects on statin medication who are included in the study will have regular monitoring for 
relevant symptoms and be subject to discontinuation based on persistent myalgia and/or blood 
CK levels.
Kindly refer to the Investigator's Brochure for further guidance on the risk-benefit assessment 
of fevipiprant.
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4.5.1
Blood sample volume
A volume smaller than a typical blood donation is planned to be collected over a period of 
approximately 4 months from each subject as part of the study. Additional samples may be 
required for safety monitoring.
Timings of blood sample collection are outlined in the Assessment Schedule (Table 8-1).
A summary blood log is provided in the Site Operations Manual (SOM). Instructions for all 
sample collection, processing, storage and shipment information is available in the Central 
Laboratory Manual.
5
Population
The study population will comprise of approximately 50 male or female patients with moderate 
to severe COPD on standard of care medications. They must demonstrate an eosinophilic 
phenotype as defined by a sputum eosinophil count of ≥3% of the total cell count obtained 
from an induced sputum specimen and documented evidence of a peripheral eosinophil count 
≥ 300 cells/μL of blood at the screening visit, or within three months prior to the screening visit.
Subject selection is to be established by checking through all inclusion and exclusion criteria 
following completion of all screening/baseline assessments. A relevant record (e.g. checklist) 
of the eligibility criteria must be stored with the source documentation at the study site. No
additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible subjects.
Deviation from any entry criterion excludes a subject from enrollment into the study.
Replacement subjects may be enrolled to replace subjects who discontinue the study for reasons 
other than safety.
Screening and Baseline safety laboratory tests can be repeated once, if deemed appropriate by 
the Investigator.
5.1
Inclusion criteria
Subjects eligible for inclusion in this study must meet all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed.
2. Able to communicate well with the investigator, to understand and comply with the
requirements of the study.
3. Male and female adult patients aged ≥ 40 to ≤ 80 years at screening visit.
4. Acceptable and reproducible spirometry with post-bronchodilator FEV1/FVC < 0.7 and
post-bronchodilator FEV1≥ 30 and ≤ 80% of predicted at the screening and baseline visits
(GOLD stage II or III COPD). Note: re-testing is allowed once.
5. Patients with a physician-diagnosed history of COPD for at least 1 year prior to screening
visit, and a documented history of at least one COPD exacerbation within the year prior to
screening.
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6. Patients on a stable therapy regimen for COPD for at least 4 weeks prior to screening visit
with inhaled glucocorticoid + one or more long acting bronchodilator.
7. Documented elevated peripheral blood eosinophil count ≥ 300 cells/µL blood either at the
Screening visit or at any time in the preceding 3 months. Sputum eosinophils must be ≥
3% of total cell count at the baseline sputum collection. Note: re-testing for each is
allowed once.
8. Current or ex-smokers who have a smoking history of at least 10 pack-years (10 pack-
years are defined as 20 cigarettes a day for 10 years, or 10 cigarettes a day for 20 years, or
equivalent).
9. Able to produce good quality induced sputum sample at the baseline sputum induction
visit. Note: can be repeated once.
5.2
Exclusion criteria
Subjects meeting any of the following criteria are not eligible for inclusion in this study.
1. Patients with a past or current medical history of asthma.
2. History of hypersensitivity to any of the study treatments or study drug excipients
(including milk or lactose) or to drugs of similar chemical classes.
3. Patients who have had a respiratory tract infection or COPD worsening or systemic steroid
use within 4 weeks prior to screening visit or between the screening and randomization
visits. Patients may be re-screened 4 weeks after recovery from their respiratory tract
infection or COPD worsening or completion of steroid treatment.
4. Patients with a current or past medical history of conditions other than COPD or allergic
rhinitis that could result in elevated sputum eosinophils (e.g., asthma, hypereosinophilic
syndrome, Churg-Strauss Syndrome). Patients with known parasitic infestation within 6
months prior to screening are also excluded.
5. Patients with history of concomitant chronic or severe pulmonary disease (e.g.,
sarcoidosis, interstitial lung disease, cystic fibrosis, tuberculosis). Exception: Patients with
concomitant mild or moderate pulmonary hypertension or bronchiectasis are permitted to
participate.
6. Patients with a clinical diagnosis of α-1 anti-trypsin deficiency (heterozygous genotype
may be enrolled).
7. Pregnant or nursing (lactating) women.
8. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using basic methods of contraception during the study.
Basic contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the
subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation
methods) and withdrawal are not acceptable methods of contraception.

Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking
investigational drug. In case of oophorectomy alone, only when the reproductive
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
Male sterilization (at least 6 months prior to screening). For female subjects on the
study, the vasectomized male partner should be the sole partner for that subject.

Barrier methods of contraception: Condom or Occlusive cap (diaphragm or
cervical/vault caps) if allowed as effective method of contraception by local
regulations. For United Kingdom: with spermicidal foam/gel/film/cream/ vaginal
suppository.

Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of
contraception or other forms of hormonal contraception that have comparable efficacy
(failure rate <1%), for example hormone vaginal ring or transdermal hormone
contraception or placement of an intrauterine device (IUD) or intrauterine system
(IUS).
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking investigational drug.
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least 
six weeks ago. In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment is she considered 
not of child bearing potential.
If local regulations deviate from the contraception methods listed above to prevent 
pregnancy, local regulations apply and will be described in the ICF.
9. Patients with any of the following cardiac related concerns:

A resting QTcF (Fridericia) ≥450 msec (male) or ≥460 msec (female) at screening or
baseline visit.

A history of familial long QT syndrome or known family history of Torsades de
Pointes.

Receiving any medications or other agents known to prolong the QT interval.

Patients with a history of moderate or severe uncontrolled tachyarrhythmias.

History of a clinically significant cardiovascular event within 1 year prior to the
screening visit, such as acute myocardial infarction, congestive heart failure, unstable
arrhythmias.

Patients who, in the judgment of the investigator have a clinically significant ECG
abnormality such as (but not limited to) sustained ventricular tachycardia, or clinically
significant second or third degree AV block without a pacemaker.
10. Patients on any statin therapy with a CK level > 2 X ULN at screening or baseline visit.
11. Patients who have a clinically significant laboratory abnormality at the screening or
baseline visit including (but not limited to):

Total white blood cell count <2500 cells/uL;

AST or ALT > 2.0 X ULN or total bilirubin > 1.3 X ULN;

Estimated Glomerular Filtration Rate (eGFR) by the Modification of Diet in Renal
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12. History of immunodeficiency diseases, or a positive HIV (ELISA and Western blot) test 
result at the screening visit.
13. Chronic infection with Hepatitis B (HBV) or Hepatitis C (HCV). A positive HBV surface 
antigen (HBsAg) test excludes a subject. Subjects with a positive HCV antibody test 
should have HCV RNA levels measured. Subjects with positive (detectable) HCV RNA 
should be excluded.
14. Patients who have a history of or current treatment for hepatic disease including but not 
limited to acute or chronic hepatitis, cirrhosis or hepatic failure.
15. Any severe, progressive or uncontrolled, acute or chronic, medical or psychiatric 
condition, or other factors such as abnormal vital signs, ECG or physical findings, or 
clinically relevant abnormal laboratory values, that in the judgment of the investigator 
may increase the risk associated with study participation/treatment or may interfere with 
interpretation of study results, and thus would make the patient inappropriate for entry into 
or continuing the study.
16. Donation or loss of 400 ml or more of blood within 8 weeks prior to screening, or longer if 
required by local regulation.
17. History of drug or alcohol abuse within the 12 months prior to dosing.
18. At screening, history or symptoms of malignancy of any organ system (except for a 
history of basal cell carcinoma and/or up to 3 squamous cell carcinomas of the skin, if 
successful treatment has been performed, with no signs of recurrence; actinic keratosis, if 
present at screening, should be treated according to standard therapy before 
randomization), treated or untreated, within the past 5 years, regardless of whether there is 
evidence of local recurrence or metastases.
19. Patients on prohibited treatment listed in Table 6-2.
20. Use of other investigational drugs at the time of enrollment, or within 5 half-lives of 
experimental drug at the time of enrollment, or within 30 days of last dose of experimental 
drug at the time of enrollment, whichever is longer; or longer if required by local 
regulations.
6
Treatment
6.1
Study treatment
Details on the requirements for storage and management of study treatment, and instructions to 
be followed for subject numbering, prescribing/dispensing, and taking study treatment are 
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6.1.1
Investigational and control drugs
Table 6-1
Investigational and control drug
Investigational/ 
Control Drug
(Name and 
Strength)
Pharmaceutical 
Dosage Form
Route of 
Administration
Supply Type
Sponsor (global 
or local)
QAW039 450mg
Tablet
Oral use
Double Blind 
supply; bottle
Sponsor (global)
QAW039 Placebo
Tablet
Oral use
Double Blind 
supply; bottle
Sponsor (global)
6.1.2
Additional study treatments
6.1.3
Treatment arms/group
Subjects will be assigned at or after visit 30 to one of the following two treatment arms/groups 
in a ratio of 3:2 active fevipiprant (QAW039) vs placebo.
6.2
Other treatment(s)
Oral contraception is permitted as a concomitant medication.
Prohibited medications are listed in Table 6-2.
6.2.1
Concomitant therapy
Subjects should remain on their baseline regimen of inhaled corticosteroid (ICS) plus one or 
more long acting bronchodilator (long-acting beta2-agonist (LABA) or long-acting 
antimuscarinic antagonist (LAMA) from at least four weeks prior to the Screening visit through 
to the End of Study/Early Termination visit, with short-acting bronchodilators taken as rescue 
medication on an “as needed” basis for symptoms.
Other concomitant medications can continue during the study, provided they are not prohibited 
(see Table 6-2).
All medications, procedures, and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the subject was enrolled into the study must be recorded 
on the appropriate Case Report Forms.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis medical monitor before 
randomizing a 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.
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6.2.2
Prohibited medication
Use of the treatments displayed in the below table are not allowed for the time defined in the 
'Prohibition period'.
Table 6-2
Prohibited medication
Medication
Prohibition period
Action taken
> 20 mg simvastatin
> 40 mg atorvastatin
> 40 mg pravastatin
> 2 mg pitavastatin
From 4 weeks prior to 
screening visit and for the 
duration of study
(Rationale: Risk of over-
exposure to concomitant 
medication due to OATP1B1 
inhibition)
Exclude subject from 
study/Discontinue study 
treatment if initiated after 
randomization
Cyclosporin, rifampin, 
probenecid, ritonavir, 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 Pgp))
From 4 weeks prior to 
screening visit and for the 
duration of study
(Rationale: Risk of over-
exposure to QAW039)
Exclude subject from 
study/Discontinue study 
treatment if initiated after 
randomization
Any medication or other 
agents, such as Azithromycin, 
known to significantly prolong 
the QT interval
From 4 weeks prior to 
screening visit and for the 
duration of study
(Rationale: To avoid risk of QT 
prolongation)
Exclude subject from 
study/Discontinue study 
treatment if initiated after 
randomization
Systemic glucocorticoids
From 4 weeks prior to 
screening visit and for the 
duration of study
(Rationale: Confounds primary 
objective)
Exclude subject from 
study/Discontinue study 
treatment if initiated after 
randomization
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6.2.3
Rescue medication
Unless clinically indicated, the type of rescue medication 
 a subject uses, the device 
used to deliver the medication (e.g., dry powder or HFA) and the way it is administered (e.g., 
with a spacer device) should not be adjusted.
6.2.4
Restriction for study subjects
For the duration of the study, subjects should be informed and reminded of the restrictions 
outlined in this section.
6.2.4.1
Dietary restrictions and smoking
Study participants should refrain from alcohol, caffeine and smoking for at least 4 hours prior 
to study visits. The study drug can be taken with or without food.
6.2.4.2
Other restrictions

For women of childbearing potential, the contraception requirements as outlined in the
Exclusion Criteria in Section 5.2

No strenuous physical exercise (e.g. weight training, aerobics, football) until after the End
of Study/Early Termination visit.
6.3
Subject numbering, treatment assignment, randomization
6.3.1
Subject numbering
The subject number assigned to a subject at screening remains the unique identifier for the 
subject throughout the study. For information on subject numbering, please see ‘Subject 
numbering’ section in the Site Operations Manual.
6.3.2
Treatment assignment, randomization
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. A subject 
randomization list will be produced by the Interactive Response Technology (IRT) provider 
using a validated system that automates the random assignment of subject numbers to 
randomization numbers. These randomization numbers are linked to the different treatment 
arms, which in turn are linked to medication numbers. A separate medication list will be 
produced by or under the responsibility of Novartis Global Clinical Supply (GCS) using a 
validated system that automates the random assignment of medication numbers to packs 
containing the study treatment.
Randomization will be stratified by current smoking status (current vs. ex smoker).
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The randomization scheme for subjects will be reviewed and approved by a member of the 
Randomization Office.
6.4
Treatment blinding
This is a subject and investigator-blinded study. Subjects, investigators and all site staff will 
remain blinded to study treatment throughout the study.
Unblinding a single subject at site for safety reasons (if necessary for subject management) will 
occur via an emergency system in place at the site.
The identity of the treatments will be concealed by the use of study drugs that are all identical 
in packaging, labeling, schedule of administration, appearance, and odor.
The sponsor may be unblinded to the study treatment at any time, especially in case of a safety 
concern.
The sample analysts will receive a copy of the randomization schedule (via request to the 
Randomization Office), to facilitate analysis of the samples.
The study statistician will be able to access the randomization list and is allowed to share 
unblinded information with the rest of the clinical team as appropriate for internal decision 
purposes. For example, unblinded summaries and unblinded individual data can be shared with 
the team for interim analyses.
Study programmers and other personnel involved in study data analysis (
are allowed to access treatment assignment information for the purpose of conducting analyses.
The clinical trial team is allowed to share unblinded results with other sponsor staff (e.g. 
decision boards) as required for internal decision making on the study or the project while the 
study is ongoing.
The sponsor does not intend to share unblinded data with study site staff or with study subjects 
while the study is ongoing.
6.5
Dose escalation and dose modification
Investigational or other study treatment dose adjustments are not permitted during the course 
of the study.
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.
The total number of doses of study drug administered since the last visit will be recorded in the 
Dosage Administration Record eCRF.
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6.6.2
Recommended treatment of adverse events
At present there is insufficient information to provide specific recommendations regarding 
treatment of adverse events (AEs). AEs should be treated per the judgement of the responsible 
physician.
Medication used to treat adverse events (AEs) must be recorded on the appropriate CRF.
6.6.3
Emergency breaking of assigned treatment code
Emergency code breaks must only be undertaken when it is required to in order to treat the 
subject safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study subject who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a subject, he/she must provide the 
requested subject identifying information and confirm the necessity to break the treatment code 
for the subject. The investigator will then receive details of the investigational drug treatment 
for the specified subject and a fax or email confirming this information. The system will 
automatically inform the monitor for the site and the study team that the code has been broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT at any time in case of emergency. The investigator will provide:

protocol number

subject number
In addition, oral and written information must be provided to the subject on how to contact the 
investigator in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time.
If a subject has their treatment code revealed they should discontinue study treatment. They 
should continue to be followed up in the study, as outlined in Section 9.1.1.
6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under the 
investigational and control drugs section (Section 6.1.1).
Fevipiprant will be administered to the subject via the oral route of administration, both at the 
study site on visit days and administered at home. The site should remind subjects not to take 
their medication on the morning of a study visit, but to bring it with them to take at the study 
site, following completion of pre-dose assessments.
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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.
If applicable, in cases where the subject's representative(s) gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible given 
his/her understanding. If the subject is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document.
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the subject source documents.
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the subject 
informed consent and should be discussed with the subject during the study as needed. Any new 
information regarding the safety profile of the investigational drug that is identified between IB 
updates will be communicated as appropriate, for example, via an investigator notification or 
an aggregate safety finding. New information might require an update to the informed consent, 
which then must be discussed with the subject.
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements.
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval.
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Subjects might be asked to complete an optional questionnaire to provide feedback on their 
clinical trial experience.
Refer to the Site Operations Manual for a complete list of ICFs included in this study.
8
Visit schedule and assessments
The Assessment Schedule (Table 8-1) lists all of the assessments when they are performed. All 
data obtained from these assessments must be supported in the subject’s source documentation.
Subjects should be seen for all visits/assessments as outlined in the Assessment Schedule 
(Table 8-1) or as close to the designated day/time as possible (visit windows are outline in the 
Site Operations Manual).
Notes:

Baseline sputum and Baseline Visit can be combined, if this facilitates site scheduling.

Sputum induction visits can be rescheduled/repeated if sputum induction is
contraindicated/not possible or insufficient/poor quality sample is produced at the planned
visit. A window of 3 days or more should occur between consecutive sputum induction
assessments and the visit should occur within two weeks of the original planned visit.

Assessments scheduled for a study visit can be split across multiple days to facilitate
resourcing at site.

Missed or rescheduled visits should not lead to automatic discontinuation.
Subjects who prematurely discontinue treatment/from the study will be encouraged to return 
for scheduled study visits depending on the cause for discontinuation (either scheduled as soon 
as possible and/or for the Early Termination visit approximately 28 days after their last 
treatment). The Investigator should contact Novartis for guidance.
At the End of Study/Early Termination visit, all dispensed investigational product should be 
reconciled, and the adverse event and concomitant medications recorded on the CRF.

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Table 8-1
Assessment Schedule
Period
Screening
Treatment
Follow-up 
Visit Name
Optional 
Pre-Screen
Screening
Baseline 
sputum 
induction
Baseline
Treatment
End of Study 
or Early 
Termination
Follow 
up 
Safety
Visit Numbers
1
201
301
100
110
120
1999
Days
3 months to
1 day prior 
to 
Screening
visit
-45 to -3*
1
21
42
70
100
Time (post-dose)
-
-
-
-
0h
2h
4h
0h
0h
2h
4h
-
-
Informed consent8
X
X
Inclusion / Exclusion criteria
S
S
Demography
X
Medical history, respiratory history, allergy history 
current medical conditions 
X
Smoking history
X
Alcohol Test and Drug Screen 
S
Hepatitis and HIV Screen
S
Physical Examination
S
S
S
S
Vital Signs
X
X
X
X
X
X
Electrocardiogram (ECG)
X
X
X
X
X
X
Body Height
X
Body Weight
X
X
X
X
Pregnancy and assessments of fertility
X
X
X
Clinical Chemistry
X
X
X
X
X
Peripheral blood eosinophil count6
X6
Hematology7
X
X
X
X
X
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Period
Screening
Treatment
Follow-up 
Visit Name
Optional 
Pre-Screen
Screening
Baseline 
sputum 
induction
Baseline
Treatment
End of Study 
or Early 
Termination
Follow 
up 
Safety
Visit Numbers
1
201
301
100
110
120
1999
Days
3 months to
1 day prior 
to 
Screening
visit
-45 to -3*
1
21
42
70
100
Time (post-dose)
-
-
-
-
0h
2h
4h
0h
0h
2h
4h
-
-
Urinalysis
X
X
X
X
Blood sample for serum IgE level
X
X
X
Induced Sputum7
X
X
X
Randomization
X
Drug dispensation
X
Study drug administered in clinic after pre-dose 
assessments are performed
X
X2
X2
Innate lymphoid cells (blood)
X
X
X
X
X
Prostaglandins (urine)
X
X
X6
X
X
X6
X
Study completion information
X
Adverse Events
X
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Period
Screening
Treatment
Follow-up 
Visit Name
Optional 
Pre-Screen
Screening
Baseline 
sputum 
induction
Baseline
Treatment
End of Study 
or Early 
Termination
Follow 
up 
Safety
Visit Numbers
1
301
100
110
120
1999
Days
3 months to
1 day prior 
to 
Screening
visit
-45 to -3*
1
21
42
70
100
Time (post-dose)
-
-
-
-
0h
2h
4h
0h
0h
2h
4h
-
-
Concomitant medications
X
Safety Follow up Call
S
* Please see the Site Operations manual for details of turnaround time needed for each assessment.
X Assessment to be recorded in the clinical database or received electronically from a vendor
S Assessment to be recorded as source data
1 Baseline sputum and Baseline Visit can be combined
2 Site to remind patient ahead of the visit NOT to take their medication at home prior to the visit
6 Optional sample
7 Due to diurnal variation in levels of eosinophils, recommend taking hematology and sputum sample in the morning
8 Informed consent needs to be collected at the optional prescreen visit or at the screening visit, but before study related assessments are performed
201
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8.1
Screening
It is permissible to re-screen a subject once if s/he fails the initial screening, if deemed feasible 
by the study site investigator. Subjects can be further rescreened; however, each case must be 
discussed and agreed with the Sponsor on a case-by-case basis. Further information on re-
screening is outlined in the Site Operations Manual.
8.1.1
Eligibility screening
Peripheral blood eosinophil level
All subjects must have documented elevated peripheral blood eosinophil count ≥ 300 cells/µL 
blood either at the Screening visit (central lab) or at any time in the preceding 3 months (local 
lab).   
The historic value can be from an existing lab report, or from the optional pre-screen visit, 
where a hematology sample can be collected and analyzed locally, from 3 months to one day 
prior to the Screening visit. Alternatively, the value can be taken from the Screening central lab 
report.
HIV and Hepatitis markers
All subjects will be screened for HIV, HBV and HCV. See the Central Lab Manual for further 
details on assessments and methods.
Alcohol test, Drug screen
All subjects will be screened for substances of abuse and cotinine. See the Central Lab manual 
for further details on assessments and methods.
8.1.2
Information to be collected on screening failures
Information on what data must be collected for screening failures and further information on 
re-screening is outlined in the Site Operations Manual.
8.2
Subject demographics/other baseline characteristics
Subject demographic and baseline characteristic data are to be collected on all subjects. 
Relevant medical history, respiratory and allergy history, including the number of COPD 
exacerbations in the prior year, known allergies, historic blood eosinophil levels (if applicable), 
smoking history/status and current medical conditions present before signing the informed 
consent will be recorded. Investigators will have the discretion to record abnormal test findings 
on the appropriate CRF whenever, in their judgment, the test abnormality occurred prior to the 
informed consent signature. Details are outlined in the Site Operations Manual.
The IgE level will be reported by the central lab.
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with CRF.

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8.3
Efficacy
Pharmacodynamic samples and measurements will be collected at the timepoints defined in the 
Assessment Schedule (Table 8-1). Follow instructions outlined in the Site Operations Manual 
and Central Laboratory Manual regarding sample collection, numbering, processing, and 
shipment and instructions.
Pharmacodynamic (PD) samples will be obtained and evaluated in all subjects at all dose levels, 
including the placebo group.
8.3.1
Sputum eosinophil % of total cell count
Sputum will be induced with isotonic or hypertonic saline with appropriate safety measures as 
per the Sputum induction protocol.
If sputum induction is contraindicated at the planned visit, or if insufficient/inadequate/poor 
quality sputum sample is obtained upon induction, the procedure can be repeated/rescheduled 
within two weeks after the planned visit (a window of 3 days or more should occur between 
consecutive sputum induction assessments).
If a repeat/reschedule of the sputum induction is necessary at the End of Treatment visit, the 
subject should continue to take their study medication until the assessment is repeated (up to a 
total of eight weeks treatment duration).
Induced sputum will be processed at site for the following analysis: 1. preparation of cytospin 
slides for differential cellular count (primary endpoint); 2. remaining supernatant from cytospin 
preparation used for biomarker assessments; 3. RNA profiling of sputum cells (if sufficient 
sputum plug samples are available).
Full details on the sputum induction process are provided in the Sputum induction protocol.
8.3.3
Appropriateness of efficacy assessments
Induced sputum eosinophil count is an accepted endpoint within the respiratory community for 
interventions that target airway eosinophils. 
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8.4
Safety and tolerability
Safety assessments are specified below with the Assessment Schedule (Table 8-1) detailing 
when each assessment is to be performed.
For details on AE collection and reporting, refer to AE (Section 10).
The methods, assessment and specification for each assessment are detailed in the Site 
Operations Manual.
Table 8-2
Assessments & Specifications
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.
Information for all physical examinations must be 
included in the source documentation at the study 
site. Clinically relevant findings that are present 
prior to signing informed consent must be 
recorded on the appropriate CRF that captures 
medical history. Significant findings made after 
signing informed consent which meet the 
definition of an adverse event must be recorded 
as an adverse event.
Vital signs
Vital signs include temperature, BP, pulse, 
respiratory rate measurements and pulse 
oximetry at rest.
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
Screening and Baseline safety laboratory tests can be repeated once, if deemed appropriate by 
the Investigator.
All abnormal lab results must be evaluated for criteria defining an adverse event and reported 
as such if the criteria are met. For those lab adverse events, repeated evaluations are mandatory 
until normalization of the result(s) or until the result is no longer considered to be clinically 
significant.

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Table 8-3
Laboratory test details
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, Platelets, Red blood 
cells, White blood cells, Differential (Basophils, 
Eosinophils, Lymphocytes, Monocytes, 
Neutrophils) absolute value and % of total cell 
count
Chemistry
Albumin, Alkaline phosphatase, ALT , AST , 
Gamma-glutamyl-transferase (GGT), Lactate 
dehydrogenase (LDH), Bicarbonate, Calcium, 
Magnesium, Phosphorus, Chloride, Sodium, 
Potassium, Creatinine, Creatine kinase, Total 
Bilirubin, (with Direct and Indirect Bilirubin 
assessments if above normal range), Total 
Cholesterol, Total Protein, Triglycerides, Blood 
Urea Nitrogen (BUN) or Urea, Uric Acid, 
Amylase, Lipase, Glucose (non-fasting), 
Estimated Glomerular Filtration Rate (eGFR)
Urinalysis
Macroscopic Panel (Dipstick) (Bilirubin, Blood, 
Glucose, Ketones, Leukocytes , Nitrite, pH, 
Protein, Specific Gravity, )
If Macroscopic Panel is abnormal, Microscopic 
Panel for RBC, WBC, epithelial cells, casts, 
crystals, bacteria and/or yeast
Immunology
IgE
HIV and Hepatitis markers
HIV Ab, HBsAg, HCV Ab (with RNA-PCR 
confirmation triggered in the event of a 
reactive/indeterminate HVC Ab result - will 
require a repeat sample to be collected)
Pregnancy Test
Serum / Urine pregnancy test - refer to 
'Pregnancy and assessments of fertility', 
Section 8.4.3
8.4.2
Electrocardiogram (ECG)
Full details of all procedures relating to the ECG collection and reporting are contained in the
Site Operations Manual.
PR interval, QRS duration, heart rate, RR interval, QT interval, QTcF
The Fridericia QT correction formula (QTcF) must be used for clinical decisions.
Unless auto-calculated by the ECG machine, the investigator must calculate QTcF at the 
Screening visit to assess eligibility. See the Site Operations Manual for additional details.
Clinically significant abnormalities must be reported as adverse events. See Section 16.1 for 
notable QTc values and action.

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8.4.3
Pregnancy and assessments of fertility
All pre-menopausal women who are not surgically sterile, i.e. women of child-bearing potential 
(WOCBP), will have pregnancy testing. A woman is considered post-menopausal and not of 
child-bearing potential if she reports 12 months of natural (spontaneous) amenorrhea with an 
appropriate clinical profile. Medical documentation of oophorectomy, hysterectomy, or tubal 
ligation, if available, must be retained as source documents. Subsequent hormone level 
assessment (FSH) to confirm the woman is not of child-bearing potential should also be 
available as source documentation if the subject has had surgical bilateral oophorectomy 
without a hysterectomy.
In WOCBP, at screening, a serum pregnancy test should be performed, while at other visits 
urinary pregnancy test will be performed. Additional pregnancy testing might be performed if 
requested by local requirements, any associated results will not be collected in the CRF.
8.5
Additional assessments
8.5.1
Clinical Outcome Assessments (COAs)
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8.5.3
Pharmacokinetics
PK samples will be collected at the visits defined in the Assessment Schedule (Table 8-1). 
Follow instructions outlined in the Central Laboratory Manual regarding sample collection, 
numbering, processing, and shipment. 
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9
Study discontinuation and completion
9.1
Discontinuation
9.1.1
Discontinuation of study treatment
Discontinuation of study treatment for a subject occurs when study treatment is stopped earlier 
than the protocol planned duration. Discontinuation of study treatment can be decided by either 
the subject or the investigator.
Study treatment must be discontinued under the following circumstances:

Subject decision - subjects may choose to discontinue study treatment for any reason at
any time.

The investigator believes that continuation would negatively impact the safety of the
subject, the integrity of the trial or the risk/benefit ratio of trial participation.

An adverse event graded as 'severe' or "serious" if it is considered related to study
treatment.

Any protocol deviation that results in a significant risk to the subject’s safety.

Pregnancy (see Section 8.4.3 and Section 10.1.4).

Female subjects non-compliant with the chosen effective method of contraception during
the study: The investigator must provide appropriate advice on the continued use of
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effective contraception for at least one week (at least 5 half-lives of QAW039) after study 
drug discontinuation.

Use of prohibited treatment as outlined in Table 6-2.

COPD exacerbation requiring use of systemic steroids and/or antibiotics.

Total white blood cell count <1000 cells/µL of blood.

If a liver or renal event occurs, follow guidelines outlined in Section 16.2 and Section 16.3
regarding confirmation of safety monitoring signal and discontinuation of study treatment.

If patients on statin therapy complain of persistent muscle pain without any obvious cause
for greater than 3 days accompanied by increase in CK levels > 10xULN or persistent
intolerable muscle pain regardless of the accompanying CK level.

Moderate or severe hypersensitivity reaction occurs, including any of the following:
anaphylaxis, fever, chills, urticaria, dyspnea, headache, myalgia, hypotension.

Any laboratory abnormalities that in the judgment of the investigator, taking into
consideration the subject’s overall status, prevents the subject from continuing
participation in the study.

The following deviations from the prescribed dose regimen for the study drug:
1. More than 10 missed doses
2. More than 7 consecutive missed doses

The appropriate personnel from the site and Novartis will assess whether investigational
drug treatment should be discontinued for any subject whose treatment code has been
broken inadvertently for any reason.
If discontinuation of study treatment occurs, the Investigator must determine the primary reason 
for the subject’s premature discontinuation of study treatment and record this information on 
the Dosage Administration CRF.
Subjects who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see Section 9.1.2, Withdraw of Informed Consent).
Subjects who prematurely discontinue from the study will be encouraged to return for 
scheduled study visits, depending on the cause for discontinuation (either scheduled as soon as 
possible and/or for the Early Termination visit approximately 28 days after their last treatment). 
The Investigator should contact Novartis for guidance. If they fail to return for these 
assessments for unknown reasons, every effort (e.g. telephone, e-mail, letter) should be made
to contact the subject/pre-designated contact as specified in Section 9.1.3 (Lost to follow-
up). This contact should preferably be done according to the study visit schedule.
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact:

new / concomitant treatments

adverse events/Serious Adverse Events
The investigator/deputy must also contact the IRT to register the subject’s discontinuation from 
study treatment.

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9.1.1.1
Replacement policy
Subjects who discontinue due to reasons other than safety may be replaced.
9.1.2
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject:

Does not want to participate in the study anymore, and

Does not allow further collection of personal data
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, 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 the time of withdrawal) according to applicable 
law.
For US: All biological samples not yet analyzed at the time of withdrawal may still be used for 
further testing/analysis in accordance with the terms of this protocol and of the informed consent 
form.
For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to applicable 
legal requirements.
9.1.3
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A subject should not be considered as lost to follow-up until due 
diligence has been completed or until the end of the study.
9.1.4
Study stopping rules
Enrollment in the study will be placed on hold if any of the following occurs:

Two or more similar study-drug related serious adverse events (SAEs)

The Sponsor considers that the number and/or severity of AEs, abnormal safety
monitoring tests or abnormal laboratory findings justify putting the study on hold.

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The study may resume following the safety review, if the Lead Investigator(s) and Sponsor 
agree it is safe to proceed.
9.1.5
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. In taking the decision to terminate, 
Novartis will always consider the subject welfare and safety. Should early termination be 
necessary, Novartis will contact the investigator with next steps, such as the subjects to be 
scheduled to be seen as soon as possible and to stop taking study drug, and to be 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. Depending on local regulations, the investigator or sponsor 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 
assessments at the End of Study/Early Termination visit and any repeat assessments associated 
with this visit have been documented and followed-up appropriately by the Investigator or, in 
the event of an early study termination decision, the date of that decision. Each subject will be 
required to complete the study in its entirety and thereafter no further study treatment will be 
made available to them.
All randomized subjects should have a safety follow-up call conducted 30 days after last 
administration of study treatment, or last study visit, whichever is later. The information 
collected is kept as source documentation. All SAEs reported during this time period must be 
reported as described in Section 10.1.3 and SOM). 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.

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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 under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2):
1. The severity grade:

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities
2. its relationship to the study treatment. If the event is due to lack of efficacy or progression
of underlying illness (i.e. progression of the study indication) the assessment of causality
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a
lack of efficacy or progression of underlying illness are not caused by the trial drug, they
happen in spite of its administration and/or both lack of efficacy and progression of
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a
single subject
3. its duration (start and end dates) or if the event is ongoing, an outcome of not
recovered/not resolved must be reported
4. whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which
seriousness criteria have been met
5. action taken regarding with study treatment
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

Dose not change

Drug interrupted/withdrawn
6. its outcome (i.e. recovery status or whether it was fatal)
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the subject.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms.
Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment.
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome.
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB).

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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 referenced 
in Appendix 1.
Follow the instructions found in the Site Operations Manual for data capture methodology 
regarding AE collection for subjects that fail screening.
10.1.2
Serious adverse events
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria:

fatal

life-threatening
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines).

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any
deterioration in COPD.

elective or pre-planned treatment for a pre-existing condition that is unrelated to the
indication under study and has not worsened since signing the informed consent

social reasons and respite care in the absence of any deterioration in the subject’s
general condition

treatment on an emergency outpatient basis for an event not fulfilling any of the
definitions of a SAE given above and not resulting in hospital admission

is medically significant, e.g. defined as an event that jeopardizes the subject or may
require medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 

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emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines).
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred.
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 after the last study visit 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.
Screen Failures: If a subject fails screening (e.g. a subject who is screened but is not treated or 
randomized), SAEs occurring after the subject has provided informed consent until the time the 
subject is deemed a Screen Failure must be reported to Novartis.
Randomized Subjects who discontinue prematurely: SAEs collected between the time a 
subject signs ICF until 30 days after the subject discontinued or stopped study treatment, or had 
their last study visit, whichever is later should be reported to Novartis/sponsor safety within 24 
hours of learning of its occurrence.
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 should only be reported 
to Novartis Safety if the investigator suspects a causal relationship to study treatment.

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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 pregnancy outcome. Any SAE experienced during pregnancy must be reported.
10.1.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dosing 
CRF (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.

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10.2
Additional Safety Monitoring
10.2.1
Liver safety monitoring
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study (irrespective of whether classified/reported as AE/SAE):

Liver laboratory triggers, which will require repeated assessments of the abnormal
laboratory parameter

Liver events, which will require close observation, follow-up monitoring and contributing
factors are recorded on the appropriate CRFs
Please refer to Table 16-1 in Appendix 2 Section 16.2 for complete definitions of liver 
laboratory triggers and liver events.
Every liver event defined in Section 16.2 should be followed up by the investigator or 
designated personnel at the trial site, as summarized below. Additional details on actions 
required in case of liver events and guidance on how to document them are outlined in Section 
9 (Appendix 3) of the Site Operations Manual.

Repeat liver chemistry tests (i.e. ALT, AST, TBL, ALB, 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 recorded on the appropriate CRF.

If the initial elevation is confirmed, close observation of the subject will be initiated,
including consideration of treatment interruption* if deemed appropriate.

Discontinuation of the investigational drug (refer to the Discontinuation of study treatment
Section 9.1.1 and Table 16-2), if appropriate.

Hospitalization of the subject if appropriate

Causality assessment of the liver event

Thorough follow-up of the liver event should include repeat liver chemistry tests and
additional investigation, 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 procedures performed must be recorded as appropriate in the 
CRF.
*Please see Section 9.1.1 for maximum duration of study drug interruption permitted.

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10.2.2
Renal safety monitoring
The following categories of abnormal renal laboratory values have to be considered during the 
course of the study:

Serum creatinine increase ≥ 25% compared to baseline during normal hydration status

Urine protein-creatinine ratio (PCR) ≥1g/g or ≥100 mg/mmol, OR new onset dipstick
proteinuria ≥ 3+ OR new onset dipstick hematuria ≥ 3+ (after excluding menstruation,
UTI, extreme exercise, or trauma)
Abnormal renal event findings must be confirmed after ≤ 5 days after first notification of the 
result.
Every renal laboratory trigger or renal event as defined in Table 16-3 should be followed up by 
the investigator or designated personnel at the trial site as summarized in Appendix 3 
(Section 16.3). Please also see Section 10 (Appendix 4) of the Site Operations Manual for 
further guidance.
*Please see Section 9.1.1 for maximum duration of study drug interruption permitted.
11
Data Collection and Database management
11.1
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (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 EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the investigator staff.
The investigator/designee is responsible for assuring that the data entered into the eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner. The 
Investigator must certify that the data entered 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 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 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 

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adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology.
Randomization codes and data about all study treatment (s) dispensed to the subject and all 
dosage changes will be tracked using an Interactive Response Technology (IRT). The system 
will be supplied by a vendor, who will also manage the database. The data will be sent 
electronically to Novartis at specific timelines.
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of Novartis.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
available for data analysis. Any changes to the database after that time can only be made after 
written agreement by Novartis management.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements 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 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.

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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 set (SAF) will include all subjects who received at least one dose of study drug 
whether or not being randomized. The safety set will be used in the analysis of all safety 
variables.
The PD analysis set will include all subjects with available PD data and no protocol deviations 
with relevant impact on PD data.
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 other baseline data including medical history, respiratory history, PRO data 
and current medical conditions present before signing the informed consent will be listed and 
summarized descriptively by treatment group for the Safety set.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented.
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term, by treatment group.
12.3
Treatments
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, minimum, 
and maximum will be presented.
The concentration data will be summarized by means of descriptive statistics using the safety 
set.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system, by treatment group.
12.4
Analysis of the primary endpoint(s)
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12.4.1
Definition of primary endpoint(s)
The primary variable of the study is the change from baseline in sputum eosinophil percentage 
at week 6. As sputum eosinophil percentage has been found to follow a log-normal distribution, 
the analysis will be based on log10-transformed scale. The baseline measurement is defined as 
sputum eosinophil percentage prior to the first dosing (on log10-transformed scale).
12.4.2
Statistical model, hypothesis, and method of analysis
The treatment effect of the primary variable will be analyzed using a Bayesian model 
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12.4.3
Handling of missing values/censoring/discontinuations
Induced sputum, from which the primary endpoint is derived, is collected only once post-
treatment (at 6 weeks). Only trial completers will be included in the statistical model. Handling 
of missing values is not planned.
For other endpoints that are collected in multiple time points
the repeated measures analysis includes all available information in terms of measurements at 
all times. If missing measurements are missing at random, an analysis of the available data 
provides consistent estimates of model parameters.
12.4.4
Sensitivity and Supportive analyses
12.4.4.1 Sensitivity analysis
The same Bayesian model stated in Section 12.4.2 will be repeated
12.4.4.2 Supportive analysis
The proportion and timing of starting concomitant systemic steroids will be summarized and 
compared between treatment groups as the supplemental estimate of the primary estimand using 
safety data set.
12.5
Analysis of secondary endpoints
12.5.1
Safety endpoints
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs).
Adverse events
All information obtained on adverse events will be displayed by treatment group and subject.
The number (and percentage) of subjects with treatment emergent adverse events (events started 
after the first dose of study medication or events present prior to start of treatment but increased 
in severity based on preferred term) will be summarized in the following ways:

by treatment, primary system organ class and preferred term.

by treatment, primary system organ class, preferred term and maximum severity.

by treatment, Standardized MedDRA Query (SMQ) and preferred term.
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, and other significant adverse events leading to discontinuation.
CCI
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The number and proportion of subjects with adverse events of special interest will be 
summarized by treatment group
A subject with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class.
Vital signs
Vital signs (i.e. blood pressure and pulse rate) will be summarized with standard descriptive 
statistics of raw data and changes from baseline for each visit separately. The numbers of 
subjects with vital signs meeting the definition of notably abnormal will be presented by 
parameter.
ECG
1. PR, QRS, QT, QTcF, and RR intervals will be obtained from ECGs for each subject during
the study. ECG data will be read and interpreted locally.
2. Categorical Analysis of QT/QTc interval data based on the number of subjects meeting or
exceeding predefined limits in terms of absolute QT/QTc intervals or changes from baseline
will be presented. In addition, a listing of these subjects will be produced (by treatment
group).
All ECG data will be listed by treatment group, subject and visit/time, abnormalities will be 
flagged. Summary statistics will be provided by treatment and visit/time.
Clinical laboratory evaluations
All laboratory data will be listed by treatment group, subject, and visit/time and if normal ranges 
are available abnormalities will be flagged. Summary statistics will be provided by treatment 
and visit/time.
12.6
Analysis of exploratory endpoints
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12.7
Interim analyses
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12.8
Sample size calculation
12.8.1
Primary endpoint(s)
Subjects will be randomized with a 3:2 ratio until approximately 50 subjects have completed 
the end of treatment visit, which equates to approximately 30 on fevipiprant and 20 on placebo. 
Subjects that drop out may be replaced.
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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 International Conference on Harmonisation (ICH) Harmonized Tripartite Guidelines 
for Good Clinical Practice, with applicable local regulations (including European Directive 
2001/20/EC, US CFR 21), and with the ethical principles laid down in the Declaration of 
Helsinki.
13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures (e.g. 
advertisements) and any other written information to be provided to subjects. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site 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 SOPs, and are performed according to written Novartis processes

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14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and Health Authorities, where required, it cannot be implemented.
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.
Andersson F, Borg S, Jansson SA, et al (2002) The costs of exacerbations in chronic 
obstructive pulmonary disease (COPD). Respir Med p. 700-8.
Castro M, Mathur S, Hargreave F, et al (2011) Reslizumab for poorly controlled, eosinophilic 
asthma: a randomized, placebo-controlled study. Am. J. Respir. Crit. Care Med. p. 1125-32.
Domingo C, Palomares O, Sandham DA, et al (2018) The prostaglandin D2 receptor 2 
pathway in asthma: a key player in airway inflammation. Respir. Res. p. 189.
Fattahi F, ten Hacken NH, Löfdahl CG, et al (2013) Atopy is a risk factor for respiratory 
symptoms in COPD patients: results from the EUROSCOP study. Respir. Res. p. 10.
GOLD Guidelines (2018) Global Strategy for the Diagnosis, Management and Prevention of 
Chronic Obstructive Pulmonary Disease - Global Initiative for Chronic Obstructive Lung 
Disease p. 1-123.
Gonem S, Berair R, Singapuri A, et al (2016) Fevipiprant, a prostaglandin D2 receptor 2 
antagonist, in patients with persistent eosinophilic asthma: a single-centre, randomised, 
double-blind, parallel-group, placebo-controlled trial. Lancet Respir Med p. 699-707.
Hirai H, Tanaka K, Yoshie O, et al (2001) Prostaglandin D2 selectively induces chemotaxis in 
T helper type 2 cells, eosinophils, and basophils via seven-transmembrane receptor CRTH2. J. 
Exp. Med. p. 255-61.
ICH E9 (2017) Estimands and Sensitivity Analysis in Clincal Trials.
Jamieson DB, Matsui EC, Belli A, et al (2013) Effects of allergic phenotype on respiratory 
symptoms and exacerbations in patients with chronic obstructive pulmonary disease. Am. J. 
Respir. Crit. Care Med. p. 187-92.
Jones PW, Harding G, Berry P, et al (2009) Development and first validation of the COPD 
Assessment Test. Eur. Respir. J. p. 648-54.
Jones PW, Quirk FH, Baveystock CM, et al (1992) A self-complete measure of health status 
for chronic airflow limitation. The St. George's Respiratory Questionnaire. Am. Rev. Respir. 
Dis. p. 1321-7.
Kerkhof M, Sonnappa S, Postma DS, et al (2017) Blood eosinophil count and exacerbation 
risk in patients with COPD. Eur. Respir. J.
Pavord ID, Korn S, Howarth P, et al (2012) Mepolizumab for severe eosinophilic asthma 
(DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet p. 651-9.
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Saha S, Brightling CE (2006) Eosinophilic airway inflammation in COPD. Int J Chron 
Obstruct Pulmon Dis p. 39-47.
Seemungal TA, Donaldson GC, Paul EA, et al (1998) Effect of exacerbation on quality of life 
in patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. p. 
1418-22.
Silver JS, Kearley J, Copenhaver AM, et al (2016) Inflammatory triggers associated with 
exacerbations of COPD orchestrate plasticity of group 2 innate lymphoid cells in the lungs. 
Nat. Immunol. p. 626-35.
Snell N, Foster M, Vestbo J (2013) Efficacy and safety of AZD1981, a CRTH2 receptor 
antagonist, in patients with moderate to severe COPD. Respir Med p. 1722-30.
Soler-Cataluña JJ, Martínez-García MA, Román Sánchez P, et al (2005) Severe acute 
exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax p. 
925-31.
Spencer S, Calverley PM, Burge PS, et al (2004) Impact of preventing exacerbations on 
deterioration of health status in COPD. Eur. Respir. J. p. 698-702.
Tripple JW, McCracken JL, Calhoun WJ (2017) Biologic Therapy in Chronic Obstructive 
Pulmonary Disease. Immunol Allergy Clin North Am p. 345-355.
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.
Yun JH, Lamb A, Chase R, et al (2018) Blood eosinophil count thresholds and exacerbations 
in patients with chronic obstructive pulmonary disease. J. Allergy Clin. Immunol. p. 2037-
2047.e10.
Zhou Y, Wang W, Zhao C, et al (2018) Prostaglandin E2 Inhibits Group 2 Innate Lymphoid 
Cell Activation and Allergic Airway Inflammation Through E-Prostanoid 4-Cyclic Adenosine 
Monophosphate Signaling. Front Immunol p. 501.

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16
Appendices
16.1
Appendix 1: Clinically notable laboratory values
The central laboratory will flag laboratory values falling outside of the normal ranges on the 
central laboratory reports. Investigators are responsible for reviewing these abnormal values for 
clinical significance, signing the laboratory reports to indicate their review, and reporting values 
considered clinically significant in the appropriate eCRF.
Any clinically significant abnormal laboratory value should be evaluated and followed-up by 
the investigator until normal or a cause for the abnormality is determined.
See Section 16.2 for specific liver event and laboratory test trigger definitions and follow-
up requirements.
For ECGs, a notable QTc value is defined as a QTcF (Fridericia) interval of ≥450 msec for 
males or ≥460 msec for females – all such ECGs will require assessment for clinical relevance 
and continuance of the subject by the Investigator in consultation with Novartis.
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
2.5 x ULN < ALT / AST < 3 x ULN
1.5 x ULN < TBL ≤ 2 x ULN
LIVER EVENTS
ALT or AST ≥ 3 × ULN
ALP > 2 × ULN (in the absence of known bone 
pathology)
TBL > 2 × ULN (in the absence of known Gilbert 
syndrome)
ALT or AST ≥ 2.5 x ULN and total bilirubin ≥ 1.5 
x ULN
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)
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.

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Table 16-2
Follow up requirements for liver events and laboratory triggers
Criteria
Actions required
Follow-up monitoring
Potential Hy’s Law casea

Discontinue the study 
treatment immediately

Hospitalize, if clinically 
appropriate

Establish causality

Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionb
(frequency at investigator 
discretion)
ALT or AST
≥ 3 × ULN

Discontinue the study 
treatment immediately

Hospitalize if clinically 
appropriate

Establish causality

Record the AE and 
contributing factors (e.g. 
conmeds, medical history, 
lab) in the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionb
(frequency at investigator 
discretion)
≥2.5 x ULN and total bilirubin 
≥1.5xULN

Discontinue the study 
drug and continue follow-
up monitoring

Establish causality

Record the AE and 
contributing factors (e.g. 
conmeds, medical history, 
lab) in the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until 
resolutionb (frequency at 
investigator discretion)
ALP (isolated)
> 2 × ULN (in the absence of 
known bone pathology)

Repeat LFT within 48 
hours

If elevation persists, 
establish causality

Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit
TBL (isolated)
> 2 × ULN (in the absence of 
known Gilbert syndrome)

Repeat LFT within 48 
hours

If elevation persists, 
discontinue the study drug 
immediately

Hospitalize if clinically 
appropriate
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionb
(frequency at investigator 
discretion)
Test for hemolysis (e.g. 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin)

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Criteria
Actions required
Follow-up monitoring

Establish causality

Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF
> 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

Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionb
(frequency at investigator 
discretion)
Any AE potentially indicative of 
a liver toxicity*

Consider study treatment 
interruption or 
discontinuation

Hospitalization if clinically 
appropriate

Establish causality

Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF
Investigator discretion
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN 
bResolution 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.
Based on investigator’s discretion investigation(s) for contributing factors for the liver event 
can include: 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.

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16.3
Appendix 3: Specific Renal Alert Criteria and Actions and Event 
Follow-up
Table 16-3
Specific Renal Alert Criteria and Actions
Serum Event
Serum creatinine increase 25 – 49% compared 
to baseline
Confirm 25% increase after 24-48h if possible
Follow up within 2-5 days
Serum creatinine increase 50 % compared to 
baseline (Acute Kidney Injury)
Follow up within 24-48h if possible
Consider drug interruption
Consider subject hospitalization /specialized 
treatment
Urine Event
Protein-creatinine ratio (PCR )≥1g/g or ≥100 
mg/mmol
Or
New onset dipstick proteinuria ≥ 3+
Or
New onset dipstick hematuria ≥ 3+ (after 
excluding menstruation, UTI, extreme exercise 
or trauma)
Confirm value after >24 hours but ≤ 5 days after 
first assessment
Perform urine microscopy
Consider drug interruption / discontinuation
For all renal events:
1.
Document contributing factors in the CRF: co-medication, other co-morbid conditions, and 
additional diagnostic procedures performed
2.
Monitor subject regularly (frequency at investigator’s discretion) until either: 

Event resolution: sCr within 10% of baseline or protein-creatinine ratio within 50% of 
baseline, or

Event stabilization: sCr level with ±10% variability over last 6 months or protein-creatinine 
ratio stabilization at a new level with ±50% variability over last 6 months.