Clinical trial NCT03287414
Conditions: Idiopathic Pulmonary Fibrosis
Keywords: idiopathic pulmonary fibrosis VAY736
Sponsor: Novartis Pharmaceuticals
Start date: 2017-12-20; Completion date: 2022-02-14
Enrollment: 30 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to investigate the safety, tolerability and efficacy of VAY736 as potential therapy for the treatment of idiopathic pulmonary fibrosis (IPF).

Detailed description:
This was an exploratory (non-confirmatory) randomized, patient-, investigator-, sponsor- blinded, placebo controlled study of VAY736 in IPF patients. This study investigated the safety and efficacy of 300 mg VAY736 administered subcutaneously (s.c.) every 4 weeks for 48 weeks.

Participants were randomized in a 1:1 ratio on top of local standard of care (SOC), to receive VAY736 or placebo. Randomized subjects entered the treatment epoch (for up to 48 weeks), followed by two follow-up epochs: the PK/safety follow-up epoch and the PD/safety follow-up epoch. The PK/safety follow-up epoch lasted for 20 weeks. When the PK/safety follow-up epoch was completed, participants in the placebo arm were discharged from the study; but participants in the active arm (those who had received VAY736) continued into the PD/safety follow-up epoch. Participants in the PD/safety follow-up epoch were followed until B-cell recovery (in the peripheral blood), defined as: B cells \>=50/μL or B cells \>= 80% of baseline (whichever occurred first). If a participant had not recovered his/her B-cells after a period of 2 years from the last dose of VAY736, then this participant was discharged from the study.

Arms: arm 1: Participants received 300 mg VAY736 administered subcutaneously every 4 weeks for 48 weeks on top of current standard-of-care therapy arm 2: Participants received placebo administered subcutaneously every 4 weeks for 48 weeks on top of current standard-of-care therapy
Interventions: intervention 1: VAY736 intervention 2: Placebo intervention 3: Standard of Care (SoC)
Intervention descriptions: intervention 1: 300 mg VAY736 administered subcutaneously every 4 weeks for 48 weeks intervention 2: Placebo administered subcutaneously every 4 weeks for 48 weeks intervention 3: Background standard-of-care treatment for IPF: nintedanib, pirfenidone, or no background therapy

Protocol documents:
Prot_000.pdf: 
Novartis Institutes for BioMedical Research
VAY736
Clinical Trial Protocol CVAY736X2207
A subject-, investigator-, and sponsor-blinded, randomized, 
placebo-controlled, multicenter study to investigate 
efficacy, safety, and tolerability of VAY736 in patients with 
idiopathic pulmonary fibrosis
Document type:
Amended Protocol Version
EUDRACT number:
2017-002667-17
Version number:
v07 (Clean)
Clinical Trial Phase:
II
Release date:
23-Mar-2020
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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Site Operations Manual (SOM)
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study conduct. Note: The SOM will not form part of the Clinical Study Report.
Notification of serious adverse events
Dear Investigator,
You must report a serious adverse event (SAE) (initial or follow-up) to Novartis as summarized 
below. Refer to Section 9.2 of the protocol for SAE criteria and additional requirements.  See 
also page 2 of the Site Operations Manual for further details on the method of reporting a SAE.

Complete SAE report

Submit SAE report to Novartis Chief Medical Office and Patient Safety (CMO & PS)
within 24 hours after awareness of the SAE

Notify the Novartis Medical Lead

The fax number(s) and email address(es) are located in the Site Operations Manual.


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Table of contents
Site Operations Manual (SOM)...........................................................................................2
Notification of serious adverse events.................................................................................2
Table of contents .................................................................................................................3
List of tables ........................................................................................................................7
List of figures ......................................................................................................................7
List of abbreviations............................................................................................................8
Pharmacokinetic definitions and symbols.........................................................................12
Glossary of terms...............................................................................................................13
Protocol summary..............................................................................................................26
1
Introduction .......................................................................................................................29
1.1
Background............................................................................................................29
1.2
Nonclinical data.....................................................................................................30
1.2.1
Teratogenicity and reproductive toxicity data.......................................30
1.3
Clinical data...........................................................................................................30
1.3.1
Human safety and tolerability data .......................................................30
1.3.2
Human pharmacokinetic data................................................................31
1.3.3
Human pharmacodynamic data.............................................................31
1.4
Study purpose ........................................................................................................31
2
Objectives and endpoints...................................................................................................32
2.1
Primary objective(s)...............................................................................................32
2.2
Secondary objective(s)...........................................................................................32
2.3
Exploratory objective(s) ........................................................................................33
3
Investigational plan ...........................................................................................................35
3.1
Study design...........................................................................................................35
3.1.1
Rationale of study design......................................................................37
3.2
Rationale for dose/regimen, route of administration and duration of treatment....38
3.3
Rationale for choice of comparator .......................................................................39
3.4
Rationale for choice of background therapy..........................................................39
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3.5
Purpose and timing of interim analyses/design adaptations..................................39
3.6
Risks and benefits..................................................................................................40
3.6.1
Risks of Imaging Procedures ................................................................40
3.6.2
Blood sample volumes..........................................................................41
4
Population..........................................................................................................................41
4.1
Inclusion criteria ....................................................................................................41
4.2
Exclusion criteria...................................................................................................42
5
Restrictions for Study Subjects .........................................................................................45
5.1
Contraception requirements...................................................................................45
5.2
Prohibited treatment...............................................................................................45
5.3
Dietary restrictions and smoking...........................................................................46
5.4
Other restrictions ...................................................................................................46
6
Treatment...........................................................................................................................47
6.1
Study treatment......................................................................................................47
6.1.1
Investigational treatment and control drug(s) .......................................47
6.1.2
Additional study treatment....................................................................47
6.2
Treatment arms......................................................................................................47
6.3
Treatment assignment and randomization.............................................................47
6.4
Treatment blinding.................................................................................................48
6.5
Treating the subject................................................................................................49
6.6
Permitted dose adjustments and interruptions of study treatment.........................50
6.7
Emergency breaking of assigned treatment code ..................................................50
6.8
Treatment exposure and compliance .....................................................................50
6.9
Recommended treatment of adverse events ..........................................................50
6.10
Rescue medication.................................................................................................51
6.11
Concomitant treatment...........................................................................................52
7
Study completion and discontinuation ..............................................................................52
7.1
Study completion and post-study treatment ..........................................................52
7.2
Discontinuation of study treatment........................................................................52
7.3
Withdrawal of informed consent ...........................................................................54
7.4
Lost to follow-up ...................................................................................................55
7.5
Study Stopping rules..............................................................................................55
7.6
Early study termination by the sponsor .................................................................56
8
Procedures and assessments ..............................................................................................56
8.1
Assessment schedule .............................................................................................56
8.2
Informed consent procedures.................................................................................65


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8.3
Subject screening...................................................................................................65
8.4
Subject demographics/other baseline characteristics.............................................66
8.4.1
Alcohol Test, Drug Screen, and Cotinine Test .....................................66
8.4.2
Hepatitis screen .....................................................................................66
8.4.3
HIV screen ............................................................................................66
8.4.4
Tuberculosis test....................................................................................66
8.4.5
Autoimmune Serology ..........................................................................66
8.4.6
Thyroid Hormones ................................................................................66
8.5
Efficacy / Pharmacodynamics ...............................................................................66
8.5.1
Spirometry.............................................................................................67
8.5.2
Diffusing Capacity (DLCO)..................................................................67
8.5.3
High Resolution CT of Chest................................................................67
8.5.4
6-Minute Walk Test ..............................................................................68
8.5.6
Clinical Outcome Assessments (COAs) ...............................................68
8.6
Safety.....................................................................................................................68
8.6.1
Physical Examination............................................................................68
8.6.2
Body Weight .........................................................................................69
8.6.3
Vital Signs.............................................................................................69
8.6.4
Clinical Chemistry ................................................................................69
8.6.5
Hematology...........................................................................................69
8.6.6
Urinalysis ..............................................................................................69
8.6.7
Immunoglobulin....................................................................................69
8.6.8
Electrocardiogram (ECG) .....................................................................69
8.6.9
Pregnancy and assessments of fertility .................................................70
8.7
Pharmacokinetics...................................................................................................70
8.8
Other assessments..................................................................................................71
8.8.3
Immunogenicity ....................................................................................71
9
Safety monitoring..............................................................................................................72
9.1
Adverse events.......................................................................................................72
9.2
Serious adverse event reporting.............................................................................74
9.2.1
Definition of SAE .................................................................................74
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9.2.2
SAE reporting........................................................................................75
9.3
Liver safety monitoring .........................................................................................75
9.4
Renal safety monitoring.........................................................................................77
9.5
Reporting of study treatment errors including misuse/abuse ................................77
9.6
Pregnancy reporting...............................................................................................78
10 Data review and database management.............................................................................78
10.1
Site monitoring ......................................................................................................78
10.2
Data collection.......................................................................................................79
10.3
Database management and quality control............................................................79
10.4
Data Monitoring Committee..................................................................................80
10.5
Adjudication Committee........................................................................................80
11 Data analysis......................................................................................................................80
11.1
Analysis sets ..........................................................................................................81
11.2
Subject demographics and other baseline characteristics......................................81
11.3
Treatments .............................................................................................................81
11.4
Analysis of the primary variable(s) .......................................................................81
11.4.1
Primary Variable(s)...............................................................................81
11.4.2
Statistical model, hypothesis, and method of analysis..........................81
11.4.3
Handling of missing values/censoring/discontinuations.......................82
11.4.4
Sensitivity analyses ...............................................................................82
11.5
Analysis of secondary variable(s)..........................................................................82
11.5.1
Efficacy / Pharmacodynamics...............................................................82
11.5.2
Safety.....................................................................................................84
11.5.3
Pharmacokinetics ..................................................................................84
11.5.4
Pharmacokinetic / pharmacodynamic interactions................................85
11.5.5
Other assessments .................................................................................85
11.6
Analysis of exploratory variables ..........................................................................85
11.7
Sample size calculation..........................................................................................87
11.8
Power for analysis of key secondary variables......................................................87
11.9
Interim analyses.....................................................................................................88
12 Ethical considerations........................................................................................................89
12.1
Regulatory and ethical compliance........................................................................89
12.2
Responsibilities of the investigator and IRB/IEC..................................................89
12.3
Publication of study protocol and results...............................................................89
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12.4
Quality Control and Quality Assurance.................................................................89
13 Protocol adherence ............................................................................................................90
13.1
Protocol Amendments ...........................................................................................90
14 References .........................................................................................................................91
15 Appendix 1: Liver Event and Laboratory Trigger Definitions and Follow-up 
Requirements.....................................................................................................................94
16 Appendix 2: Specific Renal Alert Criteria and Actions....................................................97
17 Appendix 3: ATS/ERS/JRS/ALAT Diagnostic Guidelines ..............................................99
List of tables
Table 5-1
Prohibited Medications .........................................................................45
Table 6-1
Blinding Table.......................................................................................49
Table 8-1
Assessment schedule.............................................................................57
Table 9-1
Guidance for capturing study treatment errors......................................77
Table 15-1
Liver Event and Laboratory Trigger Definitions ..................................94
Table 15-2
Follow-up requirements for liver events and laboratory triggers..........94
Table 15-3
Exclusion of underlying liver disease ...................................................96
Table 16-1
Specific Renal Alert Criteria and Actions.............................................97
Table 16-2
Renal Event Follow-up .........................................................................98
Table 17-1
High-resolution computed tomography criteria for UIP pattern 
(Table 4 in Raghu et al 2011)................................................................99
Table 17-2
Histopathological Criteria for UIP pattern (Table 5 in Raghu et al 
2011) ...................................................................................................100
Table 17-3
Combination of HRCT and surgical lung biopsy for the diagnosis 
of IPF (Table 6 in Raghu et al 2011)...................................................100
List of figures
Figure 3-1
Study Design .........................................................................................36
Figure 17-1
Diagnostic algorithm for IPF (Figure 3 in Raghu et al 2011)...............99


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List of abbreviations
6MWD
Six Minute Walk Distance
6MWT
Six Minute Walk Test
ADCC
Antibody-dependent cell-mediated cytotoxicity
AE
adverse event
AE-IPF
Acute exacerbation of idiopathic pulmonary fibrosis
ALAT
Latin American Thoracic Association 
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANA
Anti-nuclear antibody
ANC
Absolute Neutrophil Count
anti-CCP
Cyclic citrullinated peptide antibody
anti-dsDNA
Double-stranded deoxyribonucleic acid antibody
anti-HBc
Total hepatitis B core antibody
anti-HCV
Hepatitis C antibody
anti-RNP
Ribonucleoprotein antibody
AST
aspartate aminotransferase
ATS
American Thoracic Society
BAFF
B Cell Activating Factor
BAFF-R
B Cell Activating Factor Receptor
BDR
Bioanalytical Data Report
BUN
blood urea nitrogen
CFR
U.S. Code of Federal Regulation
CHF
Congestive heart failure
CK
creatinine kinase
CMO&PS
Chief Medical Office & Patient Safety
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CSR
CTCAE
Clinical Study Report
Common Terminology Criteria for Adverse Events
CV
coefficient of variation
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CVA
Cerebrovascular Accident
DAR
Dose Administration Record
DLCO
Diffusing Capacity of the Lungs
DM/PM
Dermatomyositis/polymyositis
DMC
Data Monitoring Committee
ECG
Electrocardiogram
eCRF
electronic Case Report Form
EDC
Electronic Data Capture
EF
Ejection fraction
ELISA
Enzyme-linked immunosorbent assay
EOS
End of Study
ERS
European Respiratory Society
FDA
Food and Drug Administration
FEV1
Forced Expiratory Volume in first second
FPFV
First patient first visit
FVC
Forced Vital Capacity 
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
h
hour
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
hCG
Human chorionic gonadotropin
HCV
Hepatitis C virus
HDL
High-density lipoproteins
HIV
human immunodeficiency virus
HRCT
High-resolution computed tomography
i.v.
intravenous
IA
Interim Analysis
IB
Investigator Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use


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IEC
Independent Ethics Committee
IG
Immunogenicity
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IN
Investigator Notification
INR
International Normalized Ratio
IPF
Idiopathic Pulmonary Fibrosis
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
Intrauterine device
IUS
Intrauterine system
IVIG
Intravenous immunoglobulin
JRS
Japanese Respiratory Society
LDH
lactate dehydrogenase
LDL
Low-density lipoproteins
mAb
Monoclonal antibodies
MedDRA
Medical dictionary for regulatory activities
mg
milligram(s)
MI
Myocardial Infarction
mL
milliliter(s)
MOA
Mode of Action
NYHA
New York Heart Association
PBO
Placebo
PD
pharmacodynamic(s)
PFS
Progression Free Survival
PK
pharmacokinetic(s)
PM
Polymyositis
PRO
Patient Reported Outcome
pSS
primary Sjogren's Syndrome
PT
prothrombin time
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RA
Rheumatoid arthritis
RF
Rheumatoid factor
RO
Receptor Occupancy
s.c.
subcutaneous
SAE
serious adverse event
Scl
Scleroderma
SD
standard deviation
SGRQ-I
St. George's Respiratory Questionnaire
SLB
Surgical Lung Biopsy
SLE
Systemic lupus erythematosus
SOC
Standard of Care
SOM
Site Operations Manual
SRP
Signal recognition particles
SSA
Sjogren's syndrome-related antigen A
SSB
Sjogren's syndrome-related antigen B
SUSAR
Suspected Unexpected Serious Adverse Reactions
TB
Tuberculosis
TBL
total bilirubin
TIA
Transient Ischemic Attack
ULN
upper limit of normal
WHO
World Health Organization
WoC
Withdrawal of Consent
WOCBP
Women of Child Bearing Potential


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Pharmacokinetic definitions and symbols
Ctrough
The lowest plasma (or serum or blood) concentration observed during a dosing 
interval at steady state [mass / volume]
T1/2
The terminal elimination half-life [time]


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Glossary of terms
Assessment
A procedure used to generate data required by the study
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.
Enrollment
Point/time of subject entry into the study at which informed consent 
must be obtained (i.e. prior to starting any of the procedures described 
in the protocol)
Epoch
Interval of time in the planned conduct of a study. An epoch is 
associated with a purpose (e.g. screening, randomization, treatment, 
follow-up) which applies across all arms of a study.
Investigational 
drug
The study drug whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and Directive 
2001/20/EC and is synonymous with “investigational new drug,” 
"Investigational Medicinal Product," or “test substance”
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 or combination of drugs administered to the study 
participants as part of the required study procedures; includes 
investigational drug(s), control(s) or background therapy


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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 
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
CVAY736X2207
Full Title
A subject-, investigator-, and sponsor-blinded, randomized, placebo-
controlled, multicenter study to investigate efficacy, safety, and tolerability of 
VAY736 in patients with idiopathic pulmonary fibrosis
Brief title
Study of pharmacodynamics, pharmacokinetics, safety and tolerability of 
VAY736 in patients with idiopathic pulmonary fibrosis
Sponsor and 
Clinical Trial 
Phase
Novartis
Phase II
Intervention type
Biologic
Study type
Interventional
Purpose and 
rationale
The purpose of this study is to investigate the safety, tolerability and efficacy 
of VAY736 as potential therapy for the treatment of idiopathic pulmonary 
fibrosis (IPF). 
Primary 
Objective(s)
To assess the efficacy of VAY736 in patients with IPF by looking at the change 
from baseline to end-of-treatment (48 weeks of treatment) in forced vital 
capacity (FVC).
Secondary 
Objectives

To assess the impact of VAY736 on safety

To assess the impact of VAY736 on survival

To assess the impact of VAY736 on "progression-free survival (PFS)”

To assess the impact of VAY736 on "disease progression"

To assess the impact of VAY736 on a "Composite Endpoint”

To assess the impact of VAY736 on pulmonary physiology

To assess the impact of VAY736 on exercise capacity

To assess the impact of VAY736 on gas exchange

To assess the immunogenicity of VAY736 in IPF patients

To assess the pharmacokinetics of VAY736 after multiple s.c. doses in
IPF patients
Study design
This study will investigate the safety and efficacy of 300 mg VAY736 
administered subcutaneously (s.c.) every 4 weeks for 48 weeks. 
Approximately, 58 subjects will be randomized in a 1:1 ratio on top of local 
standard of care (SOC), to receive VAY736 or placebo.  Randomization will 
be stratified by SOC treatment (3 levels: nintedanib, pirfenidone, or neither). 
The population will consist of patients with IPF following ATS/ERS/JRS/ALAT 
diagnostic guidelines, utilizing HRCT and/or surgical lung biopsy (SLB) as 
medically indicated. Randomized subjects will participate in a 48 week 
treatment epoch, 
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 This study will utilize an independent, blinded adjudication 
committee to assess cause of death in case of mortality (IPF- vs. non-IPF-
related deaths) and to assess the veracity of diagnoses of acute exacerbations 
of IPF (Section 10.5). An independent Data Monitoring Committee will 
periodically review safety data (Section 10.4). 
Population

Male and female subjects 40 to 80 years of age inclusive
Key Inclusion 
criteria

A diagnosis of definite or probable IPF within 5 years of the screening
visit, as defined by ATS/ERS/JRS/ALAT Diagnostic Guidelines

FVC 40-90% predicted (inclusive)

DLCO, corrected for hemoglobin, 25-79% predicted (inclusive)

FEV1/FVC >70%

Unlikely to die from cause other than IPF within the next 3 years, in the
opinion of the investigator

Unlikely to undergo lung transplantation during this trial
Key Exclusion 
criteria

Emphysema > fibrosis on screening HRCT (must be confirmed by
central reader)

History of major organ, hematopoietic stem cell or bone marrow
transplant

Clinically diagnosed AE-IPF or other significant clinical worsening within
3 months of randomization

NYHA class III/IV CHF, EF<25%

Current smoker

Prior use of any B-cell depleting therapy (e.g., rituximab, ofatumumab, or
other anti-CD20 mAb, anti-CD40, anti-CD19,anti-CD22 mAb, anti-CD52
mAb, or anti-BAFF mAb)
Study treatment

VAY736 300 mg s.c.

Placebo s.c.
Pharmacokinetic 
assessments

Serum VAY736 concentrations
Efficacy/PD 
assessments

Spirometry

DLCO

6MWT

Oxygen Saturation

B cell count monitoring
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Key safety 
assessments

Physical Examinations

Monitoring of laboratory markers in blood and urine

ECG

Serious Adverse Events and Adverse Events
Other 
assessments
Data analysis
Change from baseline to end-of-treatment (48 weeks of treatment) in forced 
vital capacity (FVC)
Key words
Idiopathic Pulmonary Fibrosis (IPF)
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1
Introduction
1.1
Background
Unmet Medical Need
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial lung disease, 
associated with a median survival of 2-5 years from initial diagnosis Raghu et al 2011. 
IPF affects approximately 1.5 million patients worldwide. Recently, nintedanib and pirfenidone 
were shown to slow the rate of IPF progression by targeting the biology of fibroblasts 
King et al 2014, Richeldi et al 2014. However, it was shown that nintedanib and pirfenidone 
cannot halt the progression of IPF disease. Furthermore, neither nintedanib nor pirfenidone was 
able to demonstrate a significant impact on IPF mortality. Therefore, a considerable unmet 
medical need remains.
Rationale for targeting B cells in IPF
There is supporting evidence to suggest that host immune response plays a pivotal role in the 
pathogenesis of IPF. Immunofluorescent patterns in IPF lung tissue demonstrate the presence 
of immunoglobulins within the alveolar walls of IPF specimens Schwarz et al 1978. Immune 
complexes are present in alveolar fluid obtained from patients with IPF Dall'Aglio et al 1988. 
Transcript analysis demonstrates an increase in expression of immunoglobulin genes in IPF 
Zuo et al 2002. Tertiary lymphoid tissue (germinal centers and lymphoid aggregates) is present 
in lung tissue obtained from patients with IPF Marchal-Sommé et al 2006. Radiographic 
imaging demonstrates the presence of mediastinal and hilar lymphadenopathy in up to 58% of 
IPF patients Hunninghake et al 2003,
Attili et al 2006. Circulating autoantibodies and 
pulmonary immune complex deposits are seen in a majority of IPF patients Magro et al 2003,
Magro et al 2006, Grigolo et al 1998, Fujita et al 1999, Dobashi et al 2000, Ogushi et al 2001,
Yang et al 2002, Fischer et al 2006, Takahashi et al 2007, Kurosu et al 2008, Taillé et al 2011. 
In addition, the presence of autoimmune antibodies in IPF confers a poor prognosis 
Kahloon et al 2013.
Furthermore, in IPF, B cell abnormalities are common and plasma concentrations of B cell 
activating factor (BAFF) are elevated Xue et al 2013, drawing a potential link between IPF, 
abnormal B cells, and autoimmune inflammation. B cell markers, such as CXCL13, are also 
significantly increased in IPF Vuga et al 2014, DePianto et al 2015. A mechanistic role has 
been suggested for B cells and BAFF in driving the fibrotic response of the lung 
François et al 2015, Komura et al 2008.
Taken together, these findings support the idea of specifically targeting B cells to inhibit fibrosis 
in patients with IPF.


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VAY736 is expected to have a durable effect on B cells in the lung
VAY736 is a human monoclonal antibody (mAb) of type IgG1/κ, which specifically binds to 
the BAFF-receptor (BAFF-R) on B cells.
VAY736 is designed to work by a unique dual mode of action:
1. VAY736 rapidly depletes B cells by triggering antibody-dependent cell-mediated
cytotoxicity (ADCC); and
2. VAY736 blocks the BAFF-R on residual B cells in tissue to prevent further activation by
rising circulating and local levels of BAFF.
Through this dual mode of action, VAY736 is expected to be more efficacious than either 
B-cell depletion or BAFF neutralization alone.
1.2
Nonclinical data
1.2.1
Teratogenicity and reproductive toxicity data
1.3
Clinical data
The pharmacokinetics, safety and tolerability of VAY736 have been evaluated in phase 1 and 
2a studies.
1.3.1
Human safety and tolerability data
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1.3.2
Human pharmacokinetic data
1.3.3
Human pharmacodynamic data
1.4
Study purpose
The purpose of this study is to investigate the safety, tolerability and efficacy of VAY736 for 
the treatment of IPF. 
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2
Objectives and endpoints
2.1
Primary objective(s)
Primary objective(s)
Endpoints related to primary objective(s)

To assess the efficacy of 
VAY736 in patients with 
idiopathic pulmonary
fibrosis

Change from baseline to end of treatment epoch 
(48 weeks of treatment) in Forced Vital Capacity 
(FVC).
2.2
Secondary objective(s)
Secondary objective(s)
Endpoints related to secondary objective(s)

To assess the impact of 
VAY736 on safety

Adverse Events

To assess the impact of 
VAY736 on survival 

a) All-cause mortality
b) IPF-related mortality

To assess the impact of 
VAY736 on "progression-free 
survival (PFS)"

a) Events, defined as: death (all-cause mortality) 
OR "progression" (relative reduction in FVC ≥ 
10%)
b) Events, defined as: death (IPF-related mortality) 
OR "progression" (relative reduction in FVC ≥ 
10%)

To assess the impact of 
VAY736 on "disease 
progression"

a) Progression, defined as: relative reduction in 
FVC ≥10%
b) Progression, defined as: relative reduction in 
Diffusing Capacity of the Lungs (DLCO) ≥ 15%
c) Progression, defined as: absolute reduction in 
Six Minute Walk Distance (6MWD) ≥ 50 m

To assess the impact of 
VAY736 on a "Composite 
Endpoint"

a) Events, defined as: death (all-cause mortality), 
OR relative reduction in FVC≥10%, OR relative 
reduction in DLCO ≥15%, OR relative reduction in 
6MWD ≥50m
b) Events, defined as: death (IPF-related morality), 
OR relative reduction in FVC≥10%, OR relative 
reduction in DLCO ≥15%, OR relative reduction in 
6MWD ≥50m

To assess the impact of 
VAY736 on pulmonary 
physiology 

a) Change from baseline to the end of treatment 
epoch (48 weeks of treatment) in DLCO


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Secondary objective(s)
Endpoints related to secondary objective(s)

To assess the impact of 
VAY736 on exercise capacity

a) Change from baseline to the end of treatment 
epoch (48 weeks of treatment) in 6-minute walk 
distance
b) Change from baseline to the end of treatment 
epoch (48 weeks of treatment) in distance-
saturation product

To assess the impact of
VAY736 on gas exchange

Change from baseline to the end of treatment epoch 
(48 weeks of treatment) in resting oxygen 
saturation (on room air)

To assess the immunogenicity 
of VAY736

Serum anti-VAY736 antibodies

To assess the 
pharmacokinetics of VAY736 
after multiple s.c. doses

Serum VAY736 concentrations
2.3
Exploratory objective(s)
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3
Investigational plan
3.1
Study design
This is an exploratory (non-confirmatory) randomized, patient-, investigator-, sponsor- blinded, 
placebo controlled study of VAY736 in IPF patients. This study will investigate the safety and 
efficacy of 300 mg VAY736 administered s.c. every 4 weeks for 48 weeks. Approximately 
58 subjects will be randomized in a 1:1 ratio on top of local standard of care (SOC), to receive 
VAY736 or placebo.  Randomization will be stratified by SOC treatment (3 levels: nintedanib, 
pirfenidone, or neither). The randomization scheme will be performed separately within each 
stratum to ensure balance of the treatment groups with respect to the SOC treatment.
A screening epoch of 6 weeks will be used to assess eligibility. The population will consist of 
patients with IPF following American Thoracic Society (ATS)/European Respiratory Society 
(ERS)/Japanese Respiratory Society (JRS)/Latin American Thoracic Association (ALAT) 
diagnostic guidelines, utilizing High-Resolution Computed Tomography (HRCT) and/or 
surgical lung biopsy (SLB) as medically indicated. A central reader (imaging expert) will 
review the screening HRCT to validate an accurate diagnosis of IPF; and a central reader 
(pathology expert) will review any prior SLB, if an SLB was necessary for the diagnosis of IPF 
(i.e., SLB was obtained in the normal course of a diagnostic evaluation). Once eligibility has 
been assessed during the screening epoch, eligible subjects will be randomized to one of the 
two treatment arms.
Randomized subjects will participate in a 48 week treatment epoch, 
Please refer to the Assessment Schedule (Table 8-1) for a list of procedures to be performed at 
each visit. Efficacy assessments will be performed quarterly (Weeks 1, 13, 25, 37, and 49) 
during the treatment epoch. Safety assessments will be performed at monthly or quarterly 
intervals during the treatment epoch. HRCT will be performed at screening and again at the end 
of the treatment epoch. 
 Pregnancy 
tests will be performed monthly in applicable patients during the treatment epoch. This study 
will utilize an independent, blinded adjudication committee to assess cause of death in case of 
mortality (IPF- vs. non-IPF-related deaths) and to assess the veracity of diagnoses of acute 
exacerbations of IPF (Section 10.5). An independent Data Monitoring Committee will 
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periodically review safety data (Section 10.4). 
Figure 3-1
Study Design
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3.1.1
Rationale of study design
The rationale for key elements of this study are as follows:

Placebo controls: Use of a placebo group is critical to establish the natural history of 
disease with regard to the endpoints-of-interest (pre-specified primary, secondary, and 
exploratory endpoints; safety and tolerability endpoints) within the specific population-of-
interest and under the specific conditions of this trial. Comparison of endpoints between the 
active and placebo groups forms the most rigorous test of efficacy. A placebo group also 
helps to establish a baseline frequency for safety and tolerability events in the population-
of-interest, so that safety and tolerability events in the active group may be either attributed 
to the study drug (if the frequency of events exceeds baseline expectations) or attributed to 
the underlying disease, concomitant medication, or study procedures (if the frequency of 
events in the active group is approximately equal to the frequency of events in the placebo 
group).
***(Note: Placebo treatment is an "add-on" to standard-of-care; the investigational treatment is 
also an "add-on" to standard-of-care.)***

Randomization/Stratification: Randomization/Stratification is used to avoid "selection 
bias" in the assignment of subjects to the treatment groups. Randomization/Stratification 
also serves to balance the treatment groups with respect to many known and unknown 
confounding variables; and randomization forms the basis of assumptions for our statistical 
tests.

Subject-, Investigator-, Sponsor blinding:
 
 Conscious and unconscious biases are avoided ("detection bias" and 
"reporting bias", pertaining to outcome assessment) by ensuring that patients, investigators 
and the Sponsor are unaware of treatment assignment.

Use of central readers for interpretation of diagnostic imaging and lung biopsy 
specimens: An element of subjectivity is inherent in the interpretation of radiographic 
images and lung biopsy specimens. Therefore, in order to create a more homogeneous 
population for the purposes of this scientific investigation, central readers will be used to 
standardize these potentially subjective elements of the inclusion/exclusion criteria.

Adjudication committee: To determine cause-of-death and to make the diagnosis of AE-
IPF are both difficult tasks, heavily reliant on clinical judgement, and potentially 
confounded by an element of subjectivity. Therefore, an adjudication committee will be 
used to standardize the assessment and categorization of these important and clinically 
meaningful endpoints (IPF-related mortality and incidence of AE-IPF) (Section 10.5).
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3.2
Rationale for dose/regimen, route of administration and duration 
of treatment
The rationale for a 48 week treatment period is as follows:
The purpose of this clinical investigation is to measure the effect of VAY736 on the process of 
remodeling in the lungs of patients with IPF. However, remodeling is a slow process. A proper 
investigation of remodeling will require a substantial investment in time in order to reduce the 
risk of a false negative study due to: either (1) no change in the primary endpoint (change from 
baseline to the completion of the treatment epoch in FVC) at earlier time points; or (2) such a 
small change in the primary endpoint at earlier time points that it is not possible to detect without 
substantial increase in statistical power (i.e., a substantial increase in the sample size).
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3.3
Rationale for choice of comparator
As described above, VAY736 is added on to SOC, so the best available comparator is placebo 
added on SOC.
3.4
Rationale for choice of background therapy
Given the serious nature of IPF, it is important that Principal Investigators are allowed to 
prescribe background therapy that is consistent with the standard-of-care for IPF, as defined in 
the 2015 ATS/ERS/JRS/ALAT Clinical Practice Guideline Raghu et al 2015. In fact, adherence 
to the standard-of-care for background therapy is seen as an ethical imperative in the context of 
such a serious disease.
The 2015 IPF Guideline helps to define the standard-of-care for the treatment of IPF: 
conditional recommendation is given for the use of nintedanib in patients with IPF; and 
conditional recommendation is given for the use of pirfenidone in patients with IPF. 
The guideline provides no recommendation for the use of one treatment over another. Nor does 
the guideline provide any recommendations for or against the use of combination therapy. 
Clinicians are advised to individualize treatment decisions by discussing the options with their 
patients; and clinicians are reminded that many individuals might not want treatment, given 
uncertainty in the conditional recommendations (uncertainty is due to adverse effects and the 
high cost of therapy Wilson and Raghu 2015).
In essence, the 2015 IPF Guideline establishes three categories of background standard-of-care 
treatment for IPF: 
1.
Treatment with nintedanib alone
2.
Treatment with pirfenidone alone
3.
No background therapy
3.5
Purpose and timing of interim analyses/design adaptations
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3.6
Risks and benefits
There is no proven direct medical benefit for subjects who will participate in this study. 
However, a patient's participation in this study will facilitate and advance research in the field 
of drug development for the treatment of IPF which is still a significant unmet medical need 
(Section 1.1).
The identified safety risks of BAFF receptor blockade with VAY736 are systemic injection 
reactions and upper respiratory tract infections. 
The risk to subjects in this trial will be minimized by adherence to the eligibility criteria, close 
clinical monitoring, and compliance with criteria for treatment interruption outlined in the 
protocol (Section 7.2). Drug-drug interactions are unlikely with biologics, however, sites and 
patients must strictly observe and adhere to the list of prohibited medications listed in the 
protocol (Section 5.2).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 outlined in the Section 4.2 (Exclusion Criteria). If there is any question that the 
subject will not reliably comply, they should not be entered or continue in the study.
There may be unknown risks of VAY736 which may be serious
3.6.1
Risks of Imaging Procedures
Radiation dose considerations from CT scans – Patients enrolled in this trial will have non-
contrast HRCT scans of the lungs at inclusion 
 
The inclusion scans will consist of two supine scans (one inspiratory and one expiratory) and 
one prone (inspiratory, if breath-hold is possible in this position), as described in more detail in
Section 8.5.3 of this protocol. 
Using validated dose reduction schemes, the effective radiation dose per scan is expected to be 
as follows: approximately 6 mSv total for inclusion scans and 3 mSv for follow-up. (Breakdown: 
Inclusion scans- about 3 mSv for the supine inspiratory, 2 mSv for the supine expiratory, and 1 
mSv for the prone inspiratory. 
 This is considered to be a minor to intermediate risk level 
corresponding to the benefit to the patient (category IIb based on ICRP62) and is balanced 
against the possible substantial societal benefit gained from the trial (EC Radiation protection, 
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1998 and ICR 62, 1992). The radiation dose from CT scans will be in accordance with local 
clinical practice and regulations.
3.6.2
Blood sample volumes
A maximum of 515 mL of blood is planned to be collected throughout the study, which may 
last up to three years (one year treatment, with a two year follow-up period). The maximum 
volume collected at any one visit will not exceed 50 mL. Additional samples may be required 
for safety monitoring.
Timings of blood sample collection are outlined in the Assessment schedule (Section 8.1).
A summary blood log is provided in the SOM. Instructions for all sample collection, processing, 
storage and shipment information is also available in the SOM and central laboratory manual.
See Section 8.9 regarding the potential use of residual samples.
4
Population
4.1
Inclusion criteria
Those eligible for inclusion in this study must fulfill all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed.
2. Male and female subjects 40 to 80 years of age inclusive
3. A diagnosis of definite or probable IPF within 5 years of the screening visit, as defined by 
Figure 3, Tables 4-6 of the ATS/ERS/JRS/ALAT Diagnostic Guidelines
(Raghu et al 2011, Appendix 3)
5. FVC 40-90% predicted (inclusive)
6. DLCO, corrected for hemoglobin, 25-79% predicted (inclusive) 
7. FEV1/FVC >70%
8. Unlikely to die from cause other than IPF within the next 3 years, in the opinion of the 
investigator
9. Unlikely to undergo lung transplantation during this trial
10. Able to communicate well with the investigator, to understand and comply with the 
requirements of the study.


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4.2
Exclusion criteria
Those fulfilling any of the following criteria are not eligible for inclusion in this study:
1. Emphysema > fibrosis on screening HRCT (must be confirmed by central reader)
2. Active viral, bacterial or other infections requiring systemic treatment at the time of
screening or enrollment, or history of recurrent clinically significant infection or of
bacterial infections with encapsulated organisms
3. History of major organ, hematopoietic stem cell or bone marrow transplant
4. History of hypersensitivity to any of the study drugs or to drugs of similar chemical
classes (e.g., mAb of IgG1 class) or to any of the constituents of the study drug (sucrose,
L-Arginine hydrochloride, L-histidine, polysorbate 80, hydrochloric acid)
5. Receipt of live/attenuated vaccine within a 2 month period before first dose (V101).
(NOTE: In accordance with local immunization guidelines, pneumococcal vaccination is
recommended for subjects in this trial (based on age and associated risks). Pneumococcal
vaccination should be completed at least 4 weeks prior to the first dosing visit. Although,
no data exists on the effectiveness of pneumococcal vaccination in patients treated with
VAY736, reduced immune responses have been observed after pneumococcal vaccination
in patients treated with rituximab (Bingham el al 2010, van Assen et al 2010). Therefore,
the Investigator should be aware that pneumococcal vaccination may be less effective in
patients treated with VAY736; and the Investigator should exercise judgement (consider
risk/benefit) with regards to patients who may require pneumococcal re-vaccination
during this study.)
6. History of primary or secondary immunodeficiency, including a positive Human
Immunodeficiency Virus (HIV) (Enzyme-linked Immunosorbent Assay (ELISA) and
Western blot) test result
7. History of malignancy of any organ system (other than localized basal cell carcinoma of
the skin, in situ cervical cancer), treated or untreated, within the past 5 years, regardless of
whether there is evidence of local recurrence or metastases
8. Any one of the following screening values of complete blood count laboratory values:
Hemoglobin levels below 8.0 g/dL; Total leukocyte count less than 2,000/μL; Platelets
<100.0 x 109/L; Absolute neutrophil count (ANC) <1.5 x 109/L
9. Any surgical, medical (e.g., uncontrolled hypertension, heart failure or diabetes),
psychiatric or additional physical condition that the Investigator feels may jeopardize the
patient in case of participation in this study
10. Positive hepatitis B surface antigen (HBsAg); or positive total hepatitis B core antibody
(anti-HBc); or positive hepatitis C antibody (anti-HCV) unless it can be documented that
the patient has received highly-effective HCV-specific antiviral therapy, HCV RNA levels
are measured, and HCV RNA is undetectable; (i.e., any acute, latent or chronic infection
with hepatitis B or hepatitis C)
11. Evidence of active or latent tuberculosis (TB) infection, as determined by Quantiferon test
(after anti-TB treatment, patients with history of or latent TB may become eligible
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12. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female
after conception and until the termination of gestation, confirmed by a positive human
chorionic gonadotropin (hCG) laboratory test
13. Clinically diagnosed AE-IPF or other significant clinical worsening within 3 months of
randomization
14. Other known causes of interstitial lung disease (e.g., domestic or occupational
environmental exposures, drug toxicity) or other identifiable interstitial lung disease
15. Definitive diagnosis of a connective tissue disease (such as systemic sclerosis, DM/PM,
RA, Sjogren's syndrome, or SLE)
16. Initiation of pulmonary rehabilitation within 60 days of randomization (i.e., at the time of
randomization, patients may continue “maintenance” pulmonary rehabilitation [clinical
summary from the Rehabilitation Center must be provided]; new prescriptions for
pulmonary rehabilitation are prohibited)
17. Myocardial Infarction (MI), Cerebrovascular Accident (CVA), Transient Ischemic Attack
(TIA), or hospitalization for arrhythmia or unstable angina within 6 months
18. New York Heart Association (NYHA) class III/IV Congestive Heart Failure (CHF),
Ejection Fraction (EF) <25%
19. Other investigational treatments within 6 months of screening
20. Disability (other than dyspnea) that may limit the completion of 6MWT (angina,
claudication, etc.)
21. Current smoker
22. Any current treatment for IPF (except for pirfenidone or nintedanib; but not both)
23. Historical (within 6 months prior to screening) treatment for IPF with experimental or off-
label modalities including but not limited to oral corticosteroids, N-Acetylcysteine,
cyclophosphamide, mycophenolate, azathioprine, cyclosporine A, etanercept, or
plasmapheresis.
a.
Treatment for any indication with any of the following drugs within 6 months
prior to screening: oral corticosteroids, N-Acetylcysteine, cyclophosphamide,
mycophenolate, azathioprine, cyclosporine A, etanercept, or plasmapheresis.
(Note: The aforementioned treatments are systemically distributed and,
therefore, might potentially affect the lung regardless of target indication).
24. Prior use of any B-cell depleting therapy (e.g., rituximab, ofatumumab, or other anti-CD20
mAb, anti-CD40, anti-CD19, anti-CD22 mAb, anti-CD52 mAb, or anti-BAFF mAb)
25. Receiving any treatment for pulmonary hypertension OR treatment for pulmonary
hypertension anticipated during this trial (in other words, treatment for pulmonary
hypertension is prohibited during this trial), including but not limited to epoprostanil,
iloprostanil, treprostanil, selexipag, bosentan, ambrisentan, macitentan, sildenafil,
tadalafil, and riociguat.
26. History of alcohol and/or drug abuse within the last 2 years
27. Elective surgery planned to take place during this trial


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A total of approximately 58 patients will be enrolled in the study and randomized. If more than 
20% of the randomized patients have not completed the 48 weeks of treatment, per protocol,
then patients may be replaced.
The investigator must ensure that all subjects being considered for the study meet the above 
eligibility criteria. No additional criteria should be applied by the investigator, in order that the 
study population will be representative of all eligible subjects.
Subject selection is to be established by checking through all eligibility criteria at screening. 
A relevant record (e.g. checklist) of the eligibility criteria must be stored with the source 
documentation at the study site.
Deviation from any entry criterion excludes a subject from enrollment into the study.
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
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5
Restrictions for Study Subjects
For the duration of the study, the subjects should be informed and reminded of the restrictions 
outlined in this section.
5.1
Contraception requirements
Women of Child Bearing Potential
WOCBP must be informed that taking the study treatment may involve unknown risks to the 
fetus if pregnancy were to occur during the study, and agree that in order to participate in the 
study they must adhere to the contraception requirement outlined in the Section 4.2 (Exclusion 
Criteria). If there is any question that the subject will not reliably comply, they should not be 
entered or continue in the study.
Please refer to Section 4.2 (Exclusion criteria) for details of contraception requirements for the 
study.
5.2
Prohibited treatment
Use of the treatments displayed in Table 5-1 are NOT allowed during the treatment epoch. Any 
newly initiated concomitant drug must be individually assessed against the table below to see 
if it is allowed. If in doubt, the investigator must contact the Novartis medical monitor or 
designee before allowing a new medication to be started. 
Table 5-1
Prohibited Medications
Medication
Prohibited 
epoch
Action to be taken
Oral corticosteroids (except to treat 
AE-IPF)
Treatment 
epoch
Discontinue prohibited medication as soon as 
possible; if not possible, then discontinue 
study treatment; report in electronic Case 
Report Form (eCRF)
N-acetylcysteine
Treatment 
epoch
Discontinue prohibited medication as soon as 
possible; if not possible, then discontinue 
study treatment; report in eCRF
Azathioprine
Treatment 
epoch
Discontinue prohibited medication as soon as 
possible; if not possible, then discontinue 
study treatment; report in eCRF
Cyclophosphamide
Treatment 
epoch
Discontinue prohibited medication as soon as 
possible; if not possible, then discontinue 
study treatment; report in eCRF
Mycophenolate
Treatment 
epoch
Discontinue prohibited medication as soon as 
possible; if not possible, then discontinue 
study treatment; report in eCRF
Cyclosporine
Treatment 
epoch
Discontinue prohibited medication as soon as 
possible; if not possible, then discontinue 
study treatment; report in eCRF
Colchicine
Treatment 
epoch
Discontinue prohibited medication as soon as 
possible; if not possible, then discontinue 
study treatment; report in eCRF


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Medication
Prohibited 
epoch
Action to be taken
Prostacyclins (epoprostanil, 
iloprostanil, treprostanil, selexipag)
Treatment 
epoch
Discontinue prohibited medication as soon as 
possible; if not possible, then discontinue 
study treatment; report in eCRF
Endothelin receptor antagonists 
(ambrisentan, bosentan, 
macitentan)
Treatment 
epoch
Discontinue prohibited medication as soon as 
possible; if not possible, then discontinue 
study treatment; report in eCRF
PDE5 inhibitors (tadalafil, 
sildenafil)
Treatment 
epoch
Discontinue prohibited medication as soon as 
possible; if not possible, then discontinue 
study treatment; report in eCRF
Riociguat
Treatment 
epoch
Discontinue prohibited medication as soon as 
possible; if not possible, then discontinue 
study treatment; report in eCRF
Abatacept
Treatment 
epoch
Discontinue study treatment, report in eCRF
anti-TNF (infliximab, golimumab, 
certolizumab, adalimumab, 
etanercept)
Treatment 
epoch
Discontinue study treatment, report in eCRF
anti-CD19 (blinatumomab)
Treatment 
epoch
Discontinue study treatment, report in eCRF
Other experimental therapies
Treatment 
epoch
Discontinue study treatment, report in eCRF
Live/attenuated vaccines
Treatment 
epoch
Discontinue study treatment, report in eCRF
anti-CD22 (epratuzumab)
Treatment 
epoch
Discontinue study treatment, report in eCRF
Anti-CD20 (rituximab, 
ofatumumab, ocrelizumab, 
veltuzumab)
Treatment 
epoch
Discontinue study treatment, report in eCRF
Combination therapy with 
Pirfenidone and nintedanib
Treatment 
epoch
Discontinue study treatment, report in eCRF
anti-CD52 (alemtuzumab)
Treatment 
epoch
Discontinue study treatment, report in eCRF
Elective surgery during the treatment epoch is prohibited.
5.3
Dietary restrictions and smoking
Current smokers are excluded at screening, but there are no dietary restrictions for the study.
5.4
Other restrictions
No strenuous physical exercise (e.g. weight training, football) until after Study Completion 
evaluation. Low intensity exercise (e.g. cycling, walking on a treadmill) is allowed.


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6
Treatment
6.1
Study treatment
VAY736 is formulated for s.c. injection. 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 outlined in the SOM and Pharmacy 
Manual.
250 mg i.v. methylprednisolone (with or without additional antihistamine and/or paracetamol 
medication, at the discretion of the investigator) is mandatory prior to the first dose of VAY736.  
Methylprednisolone will be administered as a 30 minute infusion approximately one hour prior 
to administration of study treatment. 
6.1.1
Investigational treatment and control drug(s)
Vials of VAY736 150 mg and placebo will be supplied by Novartis as open label patient specific 
kits for at site administration.
6.1.2
Additional study treatment
No additional treatment beyond investigational drug and control drug are included in this trial.
6.2
Treatment arms
Subjects will be assigned to either VAY736 or Placebo treatment arms in a ratio of 1:1. Refer 
to Section 3.1 and Section 3.2 for information on dosing schedule and rationale.
6.3
Treatment assignment and randomization
Randomization will be stratified by SOC treatment (3 levels: nintedanib, pirfenidone, or no 
treatment) as these are the only IPF treatments permitted outside of study treatment assignment.  
Randomized treatment will be assigned to individual subjects by way of a randomization 
number,
The randomization number is only used to identify which treatment the subjects have been 
randomized to receive. 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 SOM.
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 
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randomization numbers. These randomization numbers are linked to the different treatment 
arms, which in turn are linked to medication numbers. 
Follow the details outlined in the SOM regarding the process and timing of treatment 
assignment and randomization of subjects.
6.4
Treatment blinding
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.
Site staff
With the exception of an unblinded pharmacist, all site staff (including study investigator and 
study nurse) will be blinded to study treatment throughout the Treatment 
 See 
Section 7.2 for details on early discontinuation. For detailed information about the scheduled 
unblinding of subjects, please refer to the SOM.
Unblinding a single subject at site for safety reasons (necessary for subject management) will 
occur via an emergency system in place at the site (see Section 6.7).
Drug product will be supplied in unblinded subject kits, so an unblinded pharmacist who is 
independent of the study team will be required in order to maintain the blind. This unblinded 
pharmacist will receive the treatment allocation from the IRT system. Appropriate measures 
must be taken by the unblinded pharmacist to ensure that the treatment assignments are 
concealed from the rest of the site staff.
Sponsor staff
The following unblinded sponsor roles are required for this study:
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All unblinded personnel will otherwise keep randomization lists and data or information that 
could unblind other study team members confidential and secure until clinical database lock/end 
of the blinded epochs.
Table 6-1
Blinding Table
Time or Event
UI: Allowed to be unblinded on individual patient level
B:  Remains blinded
NA: Not applicable to this study
Role
Randomization 
list generated
Treatment 
allocation & 
dosing
Safety event 
(single subject 
unblinded)
IA
Subjects/Patients
B
B
UI
B
Site staff
B
B
UI
B
Unblinded site staff
B
UI
UI
UI
Drug Supply and Randomization Group
UI
UI
UI
UI
Unblinded sponsor staff
B
UI
UI
UI
Statistician/statistical programmer/data 
analysts
B
B
UI
UI
Adjudication Committee
B
B
B
B
All other sponsor staff not identified 
above (trial team, project team, 
management & decision boards, support 
functions)
B
B
UI
UI
6.5
Treating the subject
VAY736 will be administered to the subject via s.c. injection. See the SOM for further details.
Sponsor qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
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6.6
Permitted dose adjustments and interruptions of study treatment
Study treatment dose adjustments are not permitted.
6.7
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 study 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 (select as applicable) in case of emergency. The investigator 
will need to provide: 

protocol number

study drug name (if available)

subject number.
In addition, the investigator must provide oral and written information to inform the subject 
how to contact his/her backup in cases of emergency when he/she is unavailable to ensure that 
un-blinding can be performed at any time.
An assessment will be done by the appropriate site personnel and sponsor after an emergency 
unblinding to assess whether or not study treatment should be discontinued for a given subject 
and, if applicable, whether the subject can continue with follow up assessments.
6.8
Treatment exposure and compliance
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all subjects 
treated with VAY736, as detailed in Section 8.7.
As dosing will be completed within the clinic, assessment of compliance is not applicable.
6.9
Recommended treatment of adverse events
Acute exacerbation of IPF: In the event of an acute exacerbation of IPF, the study drug should 
be discontinued, pulse-dose corticosteroids may be administered (at the discretion of the 
Investigator), and the patient should be referred for additional clinical evaluation as appropriate.
Acute injection reactions: First-dose mild-to-moderate injection reactions were observed in 
the phase 1/2a studies in a substantial subset of patients (see IB). These reactions were 
anticipated based on mode of action of VAY736, whereby B cell killing leads to release of 
intracellular cytokines, a mechanism referred to as antibody-dependent cellular cytotoxicity 
(ADCC). Events reported so far were mainly mild-to-moderate and occurred only after the first 


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administration of VAY736. However, only very few patients were exposed to multiple doses 
of VAY736. Reactions included but were not limited to symptoms like chills, headache, fever 
and nausea, occurred within 24 hours of VAY736 administration and promptly resolved 
following administration of paracetamol or steroids (e.g., prednisone 50 mg orally).
Reactions are to be considered similar to other B cell depleting antibodies (e.g., rituximab) and 
can be mitigated by pre-medication. Of note, in the previous studies of VAY736 paracetamol 
was found to be ineffective to prevent acute injection reactions. By contrast, prednisone 50 mg 
given orally to a few patients reduced but did not completely prevent these reactions in all 
premedicated patients (see IB for details). Therefore, for purposes of keeping study personnel 
and patients blinded and maintain the integrity of the study, a mandatory premedication with 
i.v. methylprednisolone (with or without additional antihistamine and/or paracetamol
medication at the discretion of the investigator) prior to the first VAY736 or placebo dose will
be administered in the current trial.
Hypersensitivity reactions: In the event of a hypersensitivity reaction the Investigator should 
consider the criteria for treatment interruption (Section 7.2) and the patient should be treated 
with antihistamines and glucocorticoids. Depending on severity, these patients may also require 
100% oxygen, volume expansion, catecholamines and transfer to an intensive care setting. 
Plasmapheresis to decrease the systemic concentration of VAY736 may be considered 
dependent on the patient’s condition. Patients should be observed for at least four hours after 
resolution of signs and symptoms, and those who have experienced severe infusion reactions 
should be closely observed for 24 hours after resolution because of the risk for a biphasic 
episode.
Infections: In the event of an infection, the Investigator should consider the criteria for 
treatment interruption (Section 7.2), as well as consider early treatment with specific 
antimicrobial therapy on the basis of clinical diagnosis or suspicion thereof (e.g., antiviral 
treatment for herpes simplex or zoster) in consultation with infectious disease experts, as 
appropriate. The Investigator should also consider measuring total serum immunoglobulins and 
treatment with intravenous immunoglobulin (IVIG), as appropriate.
Vaccinations: It is recommended that, if possible and taking in account the overall status of the 
patient, potential study participants should complete all pre-planned immunizations in 
accordance with current immunization guidelines at least 4 weeks prior to VAY736 
administration. Live vaccinations should not be given to patients within 2 months of planned 
exposure to VAY736 or during the period of B cell depletion due to VAY736.
Medication used to treat AEs must be recorded on the Concomitant medications/Significant 
non-drug therapies CRF.
6.10
Rescue medication
Use of rescue medication (corticosteroids) are allowed for the treatment of acute exacerbation 
of IPF, at the discretion of the Investigator, but must be recorded on the Concomitant 
medications/Significant non-drug therapies CRF.


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6.11
Concomitant treatment
The investigator must instruct the subject to notify the study site about any new medications 
he/she takes after the subject was enrolled into the study.
All prescription medications, over-the-counter drugs and significant non-drug therapies 
(including physical therapy and blood transfusions) administered or taken within the timeframe 
defined in the entry criteria prior to the start of the study and during the study, must be recorded 
on the Concomitant medications/Significant non-drug therapies CRF.
Medication entries should be specific to trade name, the single dose and unit, the frequency and 
route of administration, the start and discontinuation date and the reason for therapy.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact Novartis before randomizing a subject 
or, if the subject is already enrolled, to determine if the subject should continue participation in 
the study.
7
Study completion and discontinuation
7.1
Study completion and post-study treatment
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 SAEs must be reported as described in Section 9.2 and the SOM. Documentation of attempts 
to contact the subject should be recorded in the source documentation.
7.2
Discontinuation of study treatment
Discontinuation of study treatment for any individual patient is defined as: when study drug is 
stopped earlier than planned, as specified in the protocol.
Discontinuation of study treatment can be initiated by either the patient, the investigator, or 
Novartis.
The appropriate personnel from the site and Novartis will assess whether study treatment should 
be discontinued for any subject whose treatment code has been broken inadvertently for any 
reason.
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The investigator must discontinue study treatment for a given patient if, on balance, he/she 
believes that continuation would negatively impact the risk/benefit of trial participation.
In addition study treatment must be discontinued under any of the following circumstances:

Patient wish

Pregnancy

Patient receives a lung transplantation

Patient experiences an infection with an opportunistic organism

Use of a prohibited treatment as outlined in Table 5-1

Any protocol deviation that results in a significant risk to the subject's safety

Any situation in which study participation might result in a safety risk to the patient

Patient having received a live/attenuated vaccine

Adverse events, abnormal laboratory values, or abnormal test results that indicate a safety
risk to the patient (for liver events, refer to Appendix 1; and renal events, refer to
Appendix 2).

Emergence of the following specific adverse event: acute exacerbation of idiopathic
pulmonary fibrosis (AE-IPF) as per the International Working Group Report (Collard et al
2016)

Patient is non-compliant with study treatment, as defined by missing more than one dose
The investigator must contact the IRT to register the subject’s discontinuation 
from study treatment.
Patients that become pregnant during the study should be followed up as per the 
Assessment schedule. The Investigator may determine whether any assessments should not be 
performed if, in conjunction with the patient’s treating physician/obstetrician, the assessment is 
considered not to be clinically appropriate.
Patients may voluntarily withdraw from the study for any reason at any time. They may be 
considered withdrawn if they state an intention to withdraw, fail to return for visits, or become 
lost to follow-up for any other reason. If a subject withdrawal occurs for any reason, the 
investigator must make every effort to determine the primary reason for a subject’s withdrawal 
from the study and record this information on the eCRF. For patients who are lost to follow-up 
(i.e., those patients whose status is unclear because they fail to appear for study visits without 
stating an intention to withdraw), the investigator should show “due diligence” by documenting, 
in the source documents, the steps that were taken to contact the patient (e.g., dates of telephone 
calls, registered letters, etc.).
If discontinuation of study treatment occurs, the patient should NOT automatically be 
considered withdrawn from the study UNLESS they withdraw their consent. As long as the 
patient has not withdrawn, a patient who has discontinued study treatment should continue to 
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For patients who discontinue treatment early:
If a patient discontinues treatment early, for whatever reason, the patient is encouraged to 
complete the protocol scheduled visits to assess safety and spirometry. If the patient opts not to 
complete the scheduled visits, then clarify whether the patient desires to withdraw.
For patients who desire to withdraw:
7.3
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time.
Withdrawal of consent occurs only when a subject:

Does not want to participate in the study anymore, and

Does not allow further collection of personal data
In this situation, the investigator must make every effort (e.g. telephone, e-mail, letter) to 
determine 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 described in 
Section 7.2 and the Assessment Schedule (Table 8-1). 
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. 
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7.4
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 should 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 cannot be formally considered lost to follow-up until 
his/her scheduled EOS visit would have occurred.
7.5
Study Stopping rules
Study drug considerations: 
However, injection/infusion 
reactions (hypersensitivity, cytokine release, anaphylaxis) can occur with administration of 
biologics, in particular those biologics which are lymphocyte-depleting by ADCC; and there is 
an increased susceptibility to infection with any therapy that targets elements of the immune 
system.
Disease considerations: IPF is a serious and complicated disease with a high rate of IPF-related 
serious adverse events (~30% in historical populations; Chowdhury 2014) and IPF affects older 
patients who commonly suffer from additional comorbidities (such as diabetes, chronic 
obstructive pulmonary disease, coronary artery disease). Therefore, suspected drug-related AEs 
may be confounded by presentation that is similar to IPF-related AEs or similar to other disease-
related AEs.
Thus, unblinded safety reviews will be conducted by an independent and external DMC, on a 
regularly-scheduled and ad hoc basis. In addition, blinded safety data, including events-of-
special-interest and disease-specific events, will be evaluated by the Sponsor on a continuous, 
ongoing basis.
The study can be terminated by the Sponsor at any time for any reason. This may include 
reasons related to the benefit-risk assessment of participating in the study, for practical reasons
(including slow enrollment), discontinuation of study drug development, or for regulatory or 
medical reasons. In taking the decision to terminate, Novartis will always consider subject 
welfare and safety.
But given the seriousness and complexity of IPF, some decisions to stop this study (e.g., related 
to benefit-risk assessment; related to safety) will be based on recommendations of the DMC.
The following guidance is provided:

If the DMC concludes that the study drug caused a single SAE where there is reason to
conclude that the study drug caused the event (as such, meeting the criteria for being a
serious adverse reaction (SAR)) then study enrollment will be paused, and no further
dosing will occur, pending a full DMC safety review. If the DMC is concerned about the
incidence and/or severity of AEs in the study then study enrollment will be paused
pending a full DMC safety review.
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Should early termination be necessary, all patients must be seen as soon as possible. 
7.6
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), discontinuation of study drug development, or for regulatory or medical 
reasons. In taking the decision to terminate, Novartis will always consider subject welfare and 
safety. Should this be necessary, subjects must be seen as soon as possible and treated as a 
prematurely discontinued subject. The investigator may be informed of additional procedures 
to be followed in order to ensure that adequate consideration is given to the protection of the 
subject’s interests. The investigator will be responsible for informing IRBs/IECs of the early 
termination of the trial.
8
Procedures and assessments
8.1
Assessment schedule
Subjects should be seen for all visits/assessments as outlined in the assessment schedule or as 
close to the designated day/time as possible.
Missed or rescheduled visits should not lead to automatic discontinuation. Subjects who 
prematurely discontinue the study for any reason should be scheduled for a visit as soon as 
possible, at which time all of the assessments listed for the final visit will be performed. At this 
final visit, all dispensed investigational product should be reconciled, and the adverse event and 
concomitant medications recorded on the CRF.
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Table 8-1
Assessment schedule
Epoch Screening
Treatment2
Visit Name Screening
Treatment
Visit Numbers1
1
10113
103
104
105
106
107
108
109
110
111
112
113
114
115
199
Weeks
-6 to -1
1
5
9
13
17
21
25
29
33
37
41
45
45
49
49
Days
-42 to -1
1
29
±2
57 ±5 85 ±5 113 ±5
141 ±5
169 ±5
197 
±5
225 ±5
253 ±5
281 ±5
309 ±5
312 ±5
337
±5
337
±5
Time (post-dose)
-
-
-
-
-
-
-
-
-
-
-
-
-
72h
-
-
Informed consent
X
Demography
X
Alcohol Test, Drug 
Screen, and 
Cotinine Test
S
Hepatitis screen
S
Tuberculosis test
S
HIV screen
S
Pregnancy and 
assessments of 
fertility3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Body Height and 
Weight4
X
X
Physical 
Examination
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Body Temperature
X
X
X
X
X
X
Blood Pressure, 
Oxygen saturation, 
and Pulse Rate 
X
X
X
X
X
X
Clinical Chemistry
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
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Epoch Screening
Treatment2
Visit Name Screening
Treatment
Visit Numbers1
1
10113
103
104
105
106
107
108
109
110
111
112
113
114
115
199
Weeks
-6 to -1
1
5
9
13
17
21
25
29
33
37
41
45
45
49
49
Days
-42 to -1
1
29
±2
57 ±5 85 ±5 113 ±5
141 ±5
169 ±5
197 
±5
225 ±5
253 ±5
281 ±5
309 ±5
312 ±5
337
±5
337
±5
Time (post-dose)
-
-
-
-
-
-
-
-
-
-
-
-
-
72h
-
-
Electrocardiogram 
(ECG)
X
X
X
X
Diffusing Capacity 
(DLCO)
X
X5
X
X
X
X
Spirometry
X
X5
X
X
X
X
High Resolution 
CT of Chest
X17
X
Thyroid Hormones
X
Autoimmune 
Serology18
X19
6-Minute Walk Test
X
X
X
X
X
Autoantibody 
Profiling
X
X
Immunogenicity8
X
X
X
X
X
PK blood 
collection8
X
X
X
X
X
X9
X
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Epoch Screening
Treatment2
Visit Name Screening
Treatment
Visit Numbers1
1
10113
103
104
105
106
107
108
109
110
111
112
113
114
115
199
Weeks
-6 to -1
1
5
9
13
17
21
25
29
33
37
41
45
45
49
49
Days
-42 to -1
1
29
±2
57 ±5 85 ±5 113 ±5
141 ±5
169 ±5
197 
±5
225 ±5
253 ±5
281 ±5
309 ±5
312 ±5
337
±5
337
±5
Time (post-dose)
-
-
-
-
-
-
-
-
-
-
-
-
-
72h
-
-
Study drug 
administration
X11
X
X
X
X
X
X
X
X
X
X
X
Methylprednisolon
e
X11
Telephone follow-
up
Epoch completion 
information
X 
X
Concomitant 
medications
As Required
Adverse Events
As Required
Serious Adverse 
Events
As Required
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1 Visit structure given for internal programming purpose only
2 All assessments to be conducted before dosing
3 As required (see Section 8.6 Safety for additional information)
4 Body Height at screening only
5 To be completed prior to dosing
8 One additional pharmacokinetic and immunogenicity sample should be collected in case of a hypersensitivity reaction or adverse event that could be related to 
immunogenicity
9 PK sample to be collected 72 hours post previous dose.
11 250 mg i.v. methylprednisolone (with or without additional antihistamine and/or paracetamol medication, at the discretion of the investigator) is mandatory prior to the 
first dose (V101). Additional information on this process can be found in the SOM.
12 The purpose of this assessment is to report Adverse Events and changes in Concomitant Medication.
13 The subject will remain in clinic for 6 hours post-dose for observation
17 If the HRCT was performed at the time of the initial screening, then it will not be repeated if the patient is re-screened. 
18 Results are not required to confirm eligibility.
19If the blood sample for autoantibodies was collected and analyzed by the Central Lab at the time of the initial screening, then repeat samples will not be collected if the 
patient is re-screened. 
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8.2
Informed consent procedures
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent.
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 a proposed ICF that complies with the International 
Conference on Harmonization (ICH) E6 Good Clinical Practice (GCP) guideline and regulatory 
requirements and is considered appropriate for this study. The ICF will also include a section 
related to optional future research which will require a separate signature if the subject agrees 
to future research.  The procedures set out in the main consent form concerning the storage, 
maintenance of privacy, and release of the data or specimens for the main study will also be 
adhered to for any future research. Any changes to the proposed ICF suggested by the 
investigator must be agreed to by Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the IB. This information will be included in the subject ICF 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 (IN) or an Aggregate Safety Finding. 
New information might require an update to the ICF and then must be discussed with the subject.
Ensure subjects are informed of the contraception requirements outlined in the Section 4.2
(Exclusion criteria) and in Section 5.1 (Contraception requirements).
A copy of the approved version of all consent forms must be provided to the Novartis monitor 
after IRB/IEC approval.
Refer to the SOM for a complete list of ICFs included in this study.
8.3
Subject screening
It is permissible to re-screen a subject if s/he fails the initial screening; however, each case must 
be discussed and agreed with the Sponsor on a case-by-case basis.
A new ICF will need to be signed if the investigator chooses to re-screen a subject after the 
subject has failed screening, and the subject will be assigned a new subject number. 
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Re-screened patients will complete all assessments listed for the Screening Visit in the 
Assessment Schedule (Section 8.1) with the following exceptions:

If the HRCT was performed at the time of the initial screening, then it will not be
repeated.

If the blood sample for autoantibodies was collected and analyzed by the Central Lab
at the time of the initial screening, then repeat samples will not be collected.
Information on what data should be collected for screening failures is outlined in the SOM.
8.4
Subject demographics/other baseline characteristics
Subject demographic and baseline characteristic data will be collected on all subjects.  Relevant 
medical history/current medical conditions data will also be collected until signature of 
informed consent.  Details are outlined in the SOM.
Investigators have the discretion to record abnormal test findings on the medical history CRF, 
if in their judgment, the test abnormality occurred prior to the informed consent signature.
8.4.1
Alcohol Test, Drug Screen, and Cotinine Test
All subjects will be screened for substances of abuse and cotinine. See the SOM for details.
8.4.2
Hepatitis screen
All subjects will be screened for Hepatitis B and C. See the SOM for details.
8.4.3
HIV screen
All subjects will be screened for HIV. See the SOM for details. 
8.4.4
Tuberculosis test
All subjects will be screened for Tuberculosis. See the SOM for additional details.
8.4.5
Autoimmune Serology
All subjects will be screened for the following auto-antibodies at screening: RF, ANA, anti-
dsDNA, anti-CCP, Scl-70, SSA (anti-Ro), SSB (anti-La), anti-RNP, anti-Smith, Jo-1, PL-7, PL-
12, EJ, OJ, SRP, Ku, Mi-2, anti-PM/Scl. Results are not required to confirm eligibility. 
8.4.6
Thyroid Hormones
All subjects will be screened for the following thyroid function tests at Visit 101: free thyroxine, 
total thyroxine, triiodothyronine and thyroid-stimulating hormone.
8.5
Efficacy / Pharmacodynamics
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8.5.1
Spirometry
Spirometry testing will be performed according to the ATS guidelines (Miller et al 2005) at 
screening to assess patients’ eligibility for the study and as detailed in the Assessment schedule
(Section 8.1).
The spirometry equipment will be supplied to each site for the study. The same spirometry 
equipment should be used for all assessments performed by a subject. A limited number of staff, 
as designated by the investigator, will evaluate all patients at all visits throughout the entire trial. 
Where possible the same technician should perform all maneuvers for an individual subject. All 
staff conducting the spirometry tests must have received appropriate training which must be 
documented. Information on the procedures can be found in the SOM.
8.5.2
Diffusing Capacity (DLCO)
Diffusion capacity will be determined according to ATS guidelines (Graham et al 2017). 
Measurements will include DLCO and VA. Additional information is provided in the SOM.
8.5.3
High Resolution CT of Chest
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8.5.4
6-Minute Walk Test
A standardized six-minute walk test (6MWT) will be carried out by a trained technician in 
accordance with the guidelines (Holland et al 2014). See SOM for details.
8.5.6
Clinical Outcome Assessments (COAs)
8.6
Safety
Safety assessments are specified below; methods for assessment and recording are specified in 
the SOM, with the Assessment schedule (Section 8.1) detailing when each assessment is to be 
performed.
The safety assessments include:

Adverse events, vital signs, physical exams, safety labs (hematology, chemistry,
urinalysis), and electrocardiogram (ECG)

Immunoglobulins
8.6.1
Physical Examination
See Site Operations Manual for details.
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8.6.2
Body Weight
Body weight will be recorded during the study. Refer to the Assessment schedule
(Section 8.1).
8.6.3
Vital Signs
Body temperature, blood pressure, oxygen saturation and pulse rate will be recorded at multiple 
time points during the study. Please refer to the Assessment schedule (Section 8.1) and the SOM 
for additional information.
8.6.4
Clinical Chemistry
The chemistry panel will include: albumin, alkaline phosphatase, total and direct bilirubin, 
calcium, chloride, creatinine, creatine kinase (CK), aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), α-amylase, γ-glutamyltransferase (GGT), glucose, sodium, potassium, 
inorganic phosphorus, total protein, lactate dehydrogenase (LDH), serum bicarbonate,
magnesium, blood urea nitrogen (BUN), uric acid and lipase.
8.6.5
Hematology
The hematology panel will include: hemoglobin, hematocrit, red blood cell count, white blood 
cell count including differential cell counts (lymphocytes, monocytes, neutrophils, eosinophils, 
and basophils) and platelet count.
8.6.6
Urinalysis
A urine sample (approx. 30 mL) will be obtained midstream in order to avoid contamination 
with epithelial cells and sediments, and to allow proper assessments.
Semi-quantitative ‘dipstick’ evaluation of the urine for the following parameters will be 
performed centrally: specific gravity, pH, glucose, protein, bilirubin, ketones, nitrite, leukocytes 
and blood.
If the dipstick result is positive for albumin, nitrite, leucocytes and/ or blood, the sample will 
be sent for culture and for microscopic analysis of white blood cells, red blood cells and casts.
8.6.7
Immunoglobulin
8.6.8
Electrocardiogram (ECG)
Full details of all procedures relating to the ECG collection and reporting are contained in the 
SOM.
ECG parameters will include: PR interval, QRS duration, heart rate, RR interval, QT interval, 
QTc. The Fridericia QT correction formula (QTcF) must be used for clinical decisions.
Clinically significant abnormalities must be reported in the AE CRF.
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8.6.9
Pregnancy and assessments of fertility
Pregnancy Testing
All WOCBP will have pregnancy testing. See the Assessment schedule (Section 8.1), for timing 
of the protocol required pregnancy testing; additional pregnancy testing may be performed to 
meet local requirements*. A serum pregnancy test is required for the screening visit (Visit 1), 
but urine pregnancy testing is acceptable for all other visits. A positive urine pregnancy test 
requires immediate interruption of study treatment until serum β-hCG is performed and found 
to be negative.
*Additional pregnancy testing might be performed if requested per local requirements.
Refer to Section 9.6 for details on Reporting Pregnancy.
Assessments of Fertility
Refer to Section 4.2 for criteria to determine women that are not of child bearing potential.
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source. Subsequent hormone level assessment to confirm the woman is not of child bearing 
potential must also be available as source documentation in the following cases:

surgical bilateral oophorectomy without a hysterectomy

reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical
profile.
In the absence of the above medical documentation, FSH testing is required of any female 
subject, regardless of reported reproductive/menopausal status at Screening.
8.7
Pharmacokinetics
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8.8
Other assessments
8.8.3
Immunogenicity
Immunogenicity (IG) samples will be obtained and evaluated in all subjects including the 
placebo group.
In case of suspected allergic hypersensitivity, the subject should return to the site and a sample 
to assess immunogenicity will be collected.
In case of positive immunogenicity, backup of previous pre-dose PK samples could be used to 
better characterize the onset of immunogenicity response.
Follow instructions outlined in the SOM and central laboratory manual regarding sample 
collection, numbering, processing, and shipment.
Immunogenicity analytical method(s)
A bridging ELISA method that is designed to detect the presence of anti-VAY736 antibodies 
in human serum will be used. The method contains three components: (1) Screen assay, which 
identifies initial positive or negative samples, (2) Confirmation assay, which assesses specificity 
of the positive screen samples, and (3) Titration assay which estimates the level of antibody for 
the confirmed positive samples.
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The detailed method for immunogenicity assessment will be described in the Bioanalytical Data 
Report.
9
Safety monitoring
9.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject 
after providing written informed consent for participation in the study until the end of study 
visit. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the study treatment are also considered 
an adverse event irrespective if a clinical event has occurred. See Section 9.5 for an overview 
of the reporting requirements.
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 finding, laboratory test 
finding, or other assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms,

they are considered clinically significant,

they require therapy.
Clinically significant abnormal laboratory values or test results should 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 patients with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
subject and identifying adverse events. Alert ranges for liver and kidney related events are 
included in Appendix 1 and Appendix 2, respectively.
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Adverse events should be recorded on the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, and accompanied by the following information:
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

Yes or

No
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 9.2 for definition of SAE) and which seriousness
criteria have been met
5. Action taken regarding investigational treatment.
All adverse events must be treated appropriately. Treatment may include one or more of
the following:

no action taken (e.g. further observation only)

investigational treatment dosage increased/reduced

investigational treatment interrupted/withdrawn

concomitant medication or non-drug therapy given

hospitalization/prolonged hospitalization (see Section 9.2 for definition of SAE)
6. its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving,
recovered/resolved with sequelae; fatal; or unknown).
Information about common side effects already known about the investigational drug can be 
found in the IB or will be communicated between IB updates in the form of Investigator 
Notifications (IN).  Once an adverse event is detected, it must be followed until its resolution 
or until it is judged to be permanent, and assessment should be made at each visit (or more 
frequently, if necessary) of any changes in severity, the suspected relationship to the 
investigational drug, the interventions required to treat it, and the outcome.
The investigator must also instruct each subject to report any new adverse event (beyond the 
protocol observation period) that the subject, or the subject’s personal physician, believes might 
reasonably be related to study treatment. This information must be recorded in the investigator’s 
source documents; however, if the AE meets the criteria of an SAE, it must be reported to 
Novartis.
Refer to the SOM for data capture methodology regarding AE collection for subjects that fail 
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9.2
Serious adverse event reporting
9.2.1
Definition of SAE
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the following 
criteria:

is fatal or life-threatening

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any
deterioration in condition (e.g., evaluate candidacy for lung transplantation)

elective or pre-planned treatment for a pre-existing condition (that is unrelated to the
indication under study and has not worsened since the start of study drug

treatment on an emergency outpatient basis for an event not fulfilling any of the
definitions of a SAE given above and not resulting in hospital admission

social reasons and respite care in the absence of any deterioration in the subject’s
general condition

is medically significant, e.g. defined as an event that jeopardizes the subject or may
require medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of a SAE refers to a reaction in which the 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 ICH-E2D Guidelines).
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. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization or development of dependency or 
abuse (please refer to ICH-E2D Guidelines).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All AEs (serious and non-serious) are captured on the CRF; SAEs also require individual 
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9.2.2
SAE reporting
Screen Failures
Note the following requirement for Screen Failures: SAEs occurring after the subject has 
provided informed consent until the time the subject is deemed a Screen Failure must be 
reported to Novartis.
Randomized Subjects
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until a minimum of 30 days after the last administration of study 
treatment must be reported to Novartis within 24 hours of learning of its occurrence as described 
below. The subject will be followed for up to two years after last administered dose.
Any SAEs experienced after this period should only be reported to Novartis if the investigator 
suspects a causal relationship to study treatment.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
Follow-up information provided must describe whether the event has resolved or continues, if 
and how it was treated, whether the blind was broken or not (if applicable) and whether the 
subject continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event must be reported as a follow-up to that event regardless of 
when it occurs.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment a Chief Medical Office and 
Patient Safety (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.
Follow the detailed instructions outlined in the SOM regarding the submission process for 
reporting SAEs to Novartis. Note: SAEs must be reported to Novartis within 24 hours of the 
investigator learning of its occurrence/receiving follow-up information.
9.3
Liver safety monitoring
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
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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 15-1 - Appendix 1 for complete definitions of liver laboratory triggers and 
liver events.
Follow-up of liver events
Every liver event defined in Table 15-1 - Appendix 1 should be followed up by the investigator 
or designated personnel at the trial site, as summarized below. Additional details on actions 
required in case of liver events are outlined in Table 15-2 - Appendix 1.

Repeat liver chemistry tests (ALT, AST, Total Bilirubin (TBL), Prothrombin Time
(PT)/International Normalized Ratio (INR), Alkaline Phosphatase (ALP) and Gamma-
Glutamyl Transferase (G-GT)) to confirm elevation within 48-72 hours.
These liver chemistry repeats should always be performed using the central laboratory, with the 
results provided via the standard electronic transfer. If results will not be available from the 
central laboratory within 24 hours, then the repeats can also be performed at a local laboratory 
to monitor the safety of the subject. If a liver event is subsequently reported, any local liver 
chemistry tests previously conducted that are associated with this event should have results 
reported on the unscheduled local laboratory 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 Section 7.2 (Discontinuation of study
treatment)), if appropriate

Hospitalization of the subject if appropriate

Causality assessment of the liver event

Thorough follow-up of the liver event should include

Repeating liver chemistry tests two or three times weekly. Testing should include
ALT, AST, ALP, PT/INR, and GGT. If total bilirubin is elevated > 2 x Upper Limit
of Normal (ULN), fractionation into direct and indirect bilirubin is required. To rule
out muscular origin of transaminase elevations, CPK should be measured along with
liver chemistry tests. Frequency of retesting can decrease to once a week or less if
abnormalities stabilize or the study drug has been discontinued and the subject is
asymptomatic. Retesting should be continued up to resolution.

Obtaining a more detailed history of symptoms and prior or concurrent diseases.

Obtaining a history of concomitant drug use (including nonprescription medications
and herbal and dietary supplement preparations), alcohol use, recreational drug use,
and special diets.

Exclusion of underlying liver disease, as specified in Table 15-3 - Appendix 1.

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
Obtaining a history of exposure to environmental chemical agents.

Considering gastroenterology or hepatology consultations.
All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF. Refer to the SOM for additional details. 
9.4
Renal safety monitoring
Every renal laboratory trigger or renal event as defined in Table 16-1 - Appendix 2 must be 
followed up by the investigator or designated personnel at the trial site. Recommended follow-
up assessments are listed in Appendix 2.
All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF. Refer to the SOM for additional details.
9.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient/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.
All study treatment errors and uses outside of what is foreseen in the protocol will be collected 
in the dose administration record (DAR) CRF. Study treatment errors are only to be reported to 
Chief Medical Office and Patient Safety (CMO&PS) department if the treatment error is 
associated with an SAE.
All instances of misuse or abuse must be documented in the adverse event (AE) CRF 
irrespective of the misuse/abuse being associated with an AE/SAE. In addition, all instances of 
misuse or abuse must be reported to Novartis Chief Medical Office and Patient Safety (CMO& 
PS). As such, instances of misuse or abuse are also to be reported using the SAE form/CRF. 
Table 9-1 summarizes the reporting requirements.
Table 9-1
Guidance for capturing study treatment errors
Treatment error type
Document in Dose
Administration (DAR) CRF 
Document in AE 
CRF
Complete SAE 
form/CRF 
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 
Section 9.1 and Section 9.2, respectively.


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9.6
Pregnancy reporting
To ensure subject safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Chief Medical Office and Patient Safety (CMO&PS) 
Department. Pregnancy follow-up should be recorded on the same form and should include an 
assessment of the possible relationship to the study treatment.
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.
The study drug must be discontinued, though the subject may stay in the study, if she wishes to 
do so. All assessments that are considered as a risk during pregnancy must not be performed. 
The subject may continue all other protocol assessments.
10
Data review and database management
10.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (eCRFs) with the 
investigators and their staff. During the study Novartis employs several methods of ensuring 
protocol and GCP compliance and the quality/integrity of the sites’ data. The 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 
ensure that study drug is being stored, dispensed, and accounted for according to specifications. 
Key study personnel must be available to assist the monitor during these visits.
Continuous remote monitoring of each site’s data may be performed by Novartis and/or the 
Contract Research Organization (CRO) working on behalf of Novartis. Additionally, a central 
analytics organization may analyze data and 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 the recording of data that will be used for all primary and safety 
variables. Additional checks of the consistency of the source data with the CRFs are performed 


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according to the study-specific monitoring plan. No information in source documents about the 
identity of the subjects will be disclosed.
10.2
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to 21 U.S. Code of Federal 
Regulation (CFR) Part 11 requirements. Designated investigator site staff will not be given 
access to the EDC system until they have been trained. Automatic validation programs check 
for data discrepancies and, by generating appropriate error messages, allow the data to be 
confirmed or corrected before transfer of the data to the CRO working on behalf of Novartis.
The Investigator must certify that the data entered into the Electronic Case Report Forms are 
complete and accurate. After database lock, the investigator will receive copies of the subject 
data for archiving at the investigational site.
Data not requiring a separate written record will be defined in the SOM and 
Assessment schedule (Section 8.1) and can be recorded directly on the CRFs. All other data 
captured for this study will have an external originating source (either written or electronic) 
with the CRF not being considered as source.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
10.3
Database management and quality control
The CRO working on behalf of Novartis will review the data entered into the CRFs by 
investigational staff for completeness and accuracy and instruct the site personnel to make any 
required corrections or additions. Queries are sent to the investigational site using an electronic 
data query. Designated investigator site staff is required to respond to the query and confirm or 
correct the data. If the electronic query system is not used, a paper Data Query Form will be 
faxed to the site. Site personnel will complete and sign the faxed copy and fax it back to the 
CRO working on behalf of Novartis who will make the correction to the database. The signed 
copy of the Data Query Form is kept at the investigator site.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions and adverse events will be coded using the Medical 
dictionary for regulatory activities (MedDRA) terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
Randomization codes and data about all study drug(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 database will be sent 
electronically to Novartis (or a designated CRO).
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of Novartis.


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The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unblinded and made available for data analysis. 
Any changes to the database after that time can only be made after written agreement by 
Novartis management. 
10.4
Data Monitoring Committee
The study will be using a Data Monitoring Committee (DMC). A DMC is a group of 
professionals, experienced in clinical care and/or clinical research, assembled to provide 
additional safety oversight to a clinical study. The DMC will operate in accordance with a DMC 
charter which will be completed prior to FPFV. The DMC will meet on a regular basis to review 
trial safety data; and the DMC will meet on an ad-hoc basis to review individual SAEs. 
Additional information can be found about the DMC in Section 7.5.
10.5
Adjudication Committee
The study will be using an Adjudication Committee. The committee will be reviewing a subset 
of SAE(s), in a blinded fashion, in order to confirm the diagnosis of accute exacerbation of IPF 
and, if necessary, determine the cause of any deaths (these are efficacy endpoints). 
The Adjudication Committee will have a charter completed prior to FPFV. 
11
Data analysis
The primary efficacy and safety analysis will occur when the last randomized patient completes
the treatment epoch unless the study is stopped for futility or early efficacy at the interim 
analysis, in which case the interim analysis will be called the primary efficacy and safety
analysis. 
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
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11.1
Analysis sets
For all analysis sets, subjects will be analyzed according to the study treatment(s) received.
The safety analysis set will include all subjects that received any study drug.
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.
The IG analysis set will include all subjects with at least one available valid (i.e. not flagged for 
exclusion) IG concentration measurement, who received any study drug and with no protocol 
deviations that impact on IG data.
11.2
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment group and subject. 
Summary statistics will be provided by treatment group.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment group and subject.
11.3
Treatments
Data for study drug administration (rescue medication) and concomitant therapies will be listed 
by treatment group and subject.
11.4
Analysis of the primary variable(s)
The primary objective of the study is to assess the efficacy of VAY736 on top of current 
standard-of-care therapy (pirfenidone, nintedanib, or no IPF-specific treatment) using FVC (ml) 
at the end of treatment epoch (48 weeks of treatment) in patients with idiopathic pulmonary 
fibrosis.
11.4.1
Primary Variable(s)
The primary efficacy endpoint is the change from baseline in FVC (ml).
11.4.2
Statistical model, hypothesis, and method of analysis
The following hypothesis will be tested for VAY736+SoC versus placebo+SoC:
H0: There is no difference or worsening in change from baseline in FVC (ml) from baseline to 
48 weeks of treatment between VAY736+SoC and placebo+SoC
H1: There is an improvement in change from baseline in FVC (ml) from baseline to 48 weeks 
of treatment between VAY736+SoC and placebo+SoC
Test will be conducted at a one-sided 10% level and 2-sided 80% CI of the estimates will be 
displayed.


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The primary variable, change from baseline in FVC (ml), after 48 weeks of treatment will be
analyzed using Mixed Effects Model for Repeated Measures (MMRM). The model will include 
treatment and visit as fixed effects, standard of care treatment (Nintedanib, Pirfenidone, neither) 
as factor and baseline value as a covariate, treatment-by-visit and baseline-by-visit as 
interaction terms. The patient effect will be assumed to be random and unstructured covariance 
matrix will be assumed for within-patient variation. The main comparison will be a contrast 
between treatment groups at 48 weeks of treatment. This approach assumes data is Missing At 
Random (MAR).
Summary statistics of change from baseline in FVC by epoch and treatment will be presented.
11.4.3
Handling of missing values/censoring/discontinuations
Given the severity of disease and the likelihood of some missing data, this study will also 
include approaches to assess treatment under the assumption of missing not at random.
11.4.4
Sensitivity analyses
A sensitivity analysis that uses alternative approaches to missing data will also be evaluated.
11.5
Analysis of secondary variable(s)
11.5.1
Efficacy / Pharmacodynamics
Survival analysis
At the end of the treatment epoch, the Kaplan-Meier estimates of the proportion of patients with 
the event of interest, along with 80% two-sided confidence intervals using Greenwood’s 
formula, will be provided. In addition, the Kaplan-Meier estimates will be plotted against time. 
The two treatment groups will be compared using a one-sided logrank test at the 
10% significance level. The hazard ratio and its associated 80% two-sided confidence intervals 
will be estimated.
Event of interest is defined as:
1. All-cause mortality
2. IPF-related mortality
Progression-free survival (PFS) analysis
Same survival analysis as defined above will be produced at the end of the treatment epoch for 
the following event of interest:
1. Events, defined as: death (all-cause mortality) OR "progression" (relative reduction in
FVC ≥ 10%)
2. Events, defined as: death (IPF-related mortality) OR "progression" (relative reduction in
FVC ≥ 10%)


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Disease progression
At the end of the treatment epoch, the Kaplan-Meier estimates of the proportion of patients with 
progression, along with 80% two-sided confidence intervals using Greenwood’s formula, will 
be provided. The two treatment groups will be compared using a one-sided logrank test at the 
10% significance level. The hazard ratio and its associated 80% two-sided confidence intervals 
will be estimated.
1. Progression, defined as: relative reduction in FVC ≥ 10%
2. Progression, defined as: relative reduction in DLcO ≥ 15%
3. Progression, defined as: absolute reduction in 6MWD ≥ 50 m
Composite endpoint
At the end of the treatment epoch, the Kaplan-Meier estimates of the proportion of patients with 
event of interest, along with 80% two-sided confidence intervals using Greenwood’s formula, 
will be provided, where events of interest is defined as below. The two treatment groups will 
be compared using a one-sided logrank test at the 10% significance level. The hazard ratio and 
its associated 80% two-sided confidence intervals will be estimated.
1. death (all-cause mortality), OR relative reduction in FVC≥10%, OR relative reduction in
DLcO ≥15%, OR relative reduction in 6MWD ≥50m
2. death (IPF-related morality), OR relative reduction in FVC≥10%, OR relative reduction
in DLcO ≥15%, OR relative reduction in 6MWD ≥50m
Pulmonary physiology
Change from baseline to the end of treatment epoch in DLCO will be analyzed by fitting the 
same model as described for the primary endpoint above in addition to summary statistics by 
treatment.
Exercise capacity
Change from baseline to the end of treatment epoch in 6-minute walk distance and in distance-
saturation product will be analyzed by fitting the same model as described for the primary 
endpoint above in addition to summary statistics by treatment.
Gas exchange
Change from baseline to the end of treatment epoch in resting oxygen saturation (on room air) 
will be analyzed by fitting the same model as described for the primary endpoint above in 
addition to summary statistics by treatment.
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11.5.2
Safety
Vital signs
All vital signs data will be listed by treatment group, subject, and epoch/visit/time and if ranges 
are available abnormalities (and relevant orthostatic changes) will be flagged. Summary 
statistics will be provided by epoch, treatment and visit/time.
ECG evaluations
All ECG data will be listed by treatment group, subject and epoch/visit/time, abnormalities will 
be flagged. Summary statistics will be provided by epoch, treatment and visit/time.
Clinical laboratory evaluations
All laboratory data will be listed by treatment group, subject, and epoch/visit/time and if normal 
ranges are available abnormalities will be flagged. Summary statistics will be provided by epoch, 
treatment and visit/time.
Adverse events
All information obtained on adverse events will be displayed by treatment group, epoch and 
subject.
The number and percentage of subjects with treatment-emergent adverse events will be 
tabulated by body system and preferred term with a breakdown by treatment. A subject with 
multiple treatment-emergent adverse events within a body system is only counted once towards 
the total of this body system.
A treatment-emergent adverse event is defined as any adverse event that develops on or after 
the time of the first drug intake or any event already present that worsens following exposure 
to the study treatment. 
All adverse events will be listed.
11.5.3
Pharmacokinetics
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11.5.4
Pharmacokinetic / pharmacodynamic interactions
11.5.5
Other assessments
Immunogenicity
11.6
Analysis of exploratory variables 
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11.7
Sample size calculation
In total 58 subjects are going to be randomized to the study in a 1:1 randomization. Assuming 
a treatment period of 48 weeks with 2 arms, VAY736+Standard-of-Care (SoC) vs. 
Placebo+SoC, and standard deviation of 250 ml for FVC (ml); a total sample size of 58 patients 
with 48 weeks data will give at least 80% power to detect a treatment improvement in change 
from baseline in FVC (ml) between VAY736+SoC and Placebo+SoC of 160ml in patients with 
Idiopathic Pulmonary Fibrosis (IPF).  
The sample size calculation is based on the primary efficacy endpoint of change from baseline 
in FVC (ml) at week 48. The criteria for this calculation aimed for a 90% level of proof that 
difference in change in FVC from baseline to week 48 between VAY736+SoC and 
placebo+SoC > 0 and the mean treatment+SoC effect is at least 110 ml better than placebo+SoC 
effect. The former targets proof that the treatment+SoC produces a statistically significant 
improvement in change from baseline in FVC, while the latter targets proof of clinical relevance. 
 The overall type I error at the end of study will be 
approximately 12% under this sample size.
If more than 20% of the randomized patients have not completed the 48 weeks of treatment, per 
protocol, then patients may be replaced.
R software version 3.0.3 (Fisch et 2015) was used.
11.8
Power for analysis of key secondary variables
Not applicable
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11.9
Interim analyses
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12
Ethical considerations
12.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US Code of Federal Regulations 
Title 21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles 
laid down in the Declaration of Helsinki.
12.2
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.
For multi-center trials, a Coordinating Investigator will be selected by Novartis by the time of 
Last Patient Last Visit to be a reviewer and signatory for the clinical study report. 
12.3
Publication of study protocol and results
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report the 
results of this trial will be either submitted for publication and/or posted in a publicly accessible 
database of clinical trial results.
12.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections.
Audits of investigator sites, vendors, and Novartis systems are performed or overseen by 
Novartis Pharma Auditing and Compliance Quality Assurance (or CRO working on behalf of 
Novartis), a group independent from those involved in conducting, monitoring or performing 
quality control of the clinical trial. The clinical audit process uses a knowledge/risk based 
approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.


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13
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 is an 
investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol.
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.
13.1
Protocol Amendments
Any change 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.
Amendments that are intended to eliminate an apparent immediate hazard to subjects 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, the reporting 
requirements identified in Section 9 (Safety Monitoring) must be followed and the Study Lead 
informed.


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References
References are available upon request.
Attili AK, Kazerooni EA, Gross BH, et al (2006) Thoracic lymph node enlargement in usual 
interstitial pneumonitis and nonspecific-interstitial pneumonitis: prevalence, correlation with 
disease activity and temporal evolution. J Thorac Imaging p. 288-92.
Bingham CO 3rd, Looney RJ, Deodhar A, et al (2010) Immunization responses in rheumatoid 
arthritis patients treated with rituximab: results from a controlled clinical trial. Arthritis 
Rheum; 62(1): 64-74
Chowdhury B (2014) Center for Drug Evaluation and Research Application number
205832Orig1s000 Summary review.
Collard HR, Ryerson CJ, Corte TJ, et al (2016) Acute exacerbation of idiopathic pulmonary 
fibrosis. American Thoracic Society. Am J Respir Crit Care Med Vol 194, Iss 3, p. 265-275
Dall'Aglio PP, Pesci A, Bertorelli G, et al (1988) Study of immune complexes in 
bronchoalveolar lavage fluids. Respiration p. 36-41.
DePianto DJ, Chandriani S, Abbas AR, et al (2015) Heterogeneous gene expression 
signatures correspond to distinct lung pathologies and biomarkers of disease severity in 
idiopathic pulmonary fibrosis. Thorax p. 48-56.
Dobashi N, Fujita J, Murota M, et al (2000) Elevation of anti-cytokeratin 18 antibody and 
circulating cytokeratin 18: anti-cytokeratin 18 antibody immune complexes in sera of patients 
with idiopathic pulmonary fibrosis. Lung p. 171-9.
Fisch R, Jones I, Jones J, et al (2015) Bayesian Design of Proof-of-Concept Trials. 
Therapeutic Innovation & Regulatory Science. p. 155-162.
Fischer A, Pfalzgraf FJ, Feghali-Bostwick CA, et al (2006) Anti-th/to-positivity in a cohort of 
patients with idiopathic pulmonary fibrosis. J. Rheumatol. p. 1600-5.
François A, Gombault A, Villeret B, et al (2015) B cell activating factor is central to 
bleomycin- and IL-17-mediated experimental pulmonary fibrosis. J. Autoimmun. p. 1-11.
Fujita J, Dobashi N, Ohtsuki Y, et al (1999) Elevation of anti-cytokeratin 19 antibody in sera 
of the patients with idiopathic pulmonary fibrosis and pulmonary fibrosis associated with 
collagen vascular disorders. Lung p. 311-9.
Graham BL, Brusasco V, Burgos F, et al (2017) 2017 ERS/ATS standards for single-breath 
carbon monoxide uptake in the lung. Eur. Respir. J.
Grigolo B, Mazzetti I, Borzì RM, et al (1998) Mapping of topoisomerase II alpha epitopes 
recognized by autoantibodies in idiopathic pulmonary fibrosis. Clin. Exp. Immunol. p. 339-
46.
Holland AE, Spruit MA, Troosters T, et al (2014) An official European Respiratory 
Society/American Thoracic Society technical standard: field walking tests in chronic 
respiratory disease. Eur. Respir. J. p. 1428-46.


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Hunninghake GW, Lynch DA, Galvin JR, et al (2003) Radiologic findings are strongly 
associated with a pathologic diagnosis of usual interstitial pneumonia. Chest p. 1215-23.
ICH E2D (2004) Clinical Safety Data Management: Definitions and Standards for expedited 
reporting. Accessed from: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC5
00002807.pdf Accessed on: 02Dec2016.
Kahloon RA, Xue J, Bhargava A, et al (2013) Patients with idiopathic pulmonary fibrosis 
with antibodies to heat shock protein 70 have poor prognoses. Am. J. Respir. Crit. Care Med. 
p. 768-75.
King TE, Bradford WZ, Castro-Bernardini S, et al (2014) A phase 3 trial of pirfenidone in 
patients with idiopathic pulmonary fibrosis. N. Engl. J. Med. p. 2083-92.
Komura K, Yanaba K, Horikawa M, et al (2008) CD19 regulates the development of 
bleomycin-induced pulmonary fibrosis in a mouse model. Arthritis Rheum. p. 3574-84.
Kurosu K, Takiguchi Y, Okada O, et al (2008) Identification of annexin 1 as a novel 
autoantigen in acute exacerbation of idiopathic pulmonary fibrosis. J. Immunol. p. 756-67.
Magro CM, Allen J, Pope-Harman A, et al (2003) The role of microvascular injury in the 
evolution of idiopathic pulmonary fibrosis. Am. J. Clin. Pathol. p. 556-67.
Magro CM, Waldman WJ, Knight DA, et al (2006) Idiopathic pulmonary fibrosis related to 
endothelial injury and antiendothelial cell antibodies. Hum. Immunol. p. 284-97.
Marchal-Sommé J, Uzunhan Y, Marchand-Adam S, et al (2006) Cutting edge: 
nonproliferating mature immune cells form a novel type of organized lymphoid structure in 
idiopathic pulmonary fibrosis. J. Immunol. p. 5735-9.
Miller MR, Hankinson J, Brusasco V, et al (2005) Standardisation of spirometry. Eur. Respir. 
J. p. 319-38.
Morris GC, Wiggins RC, Woodhall SC, et al (2014) MABGEL 1: first phase 1 trial of the 
anti-HIV-1 monoclonal antibodies 2F5, 4E10 and 2G12 as a vaginal microbicide. PLoS One. 
p. 1-26.
Ogushi F, Tani K, Endo T, et al (2001) Autoantibodies to IL-1 alpha in sera from rapidly 
progressive idiopathic pulmonary fibrosis. J. Med. Invest. p. 181-9.
Raghu G, Collard HR, Egan JJ, et al (2011) An official ATS/ERS/JRS/ALAT statement: 
idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am. 
J. Respir. Crit. Care Med. p. 788-824.
Raghu G, Rochwerg B, Zhang Y, et al (2015) An Official ATS/ERS/JRS/ALAT Clinical 
Practice Guideline: Treatment of Idiopathic Pulmonary Fibrosis. An Update of the 2011 
Clinical Practice Guideline. Am. J. Respir. Crit. Care Med. p. e3-19.
Richeldi L, du Bois RM, Raghu G, et al (2014) Efficacy and safety of nintedanib in idiopathic 
pulmonary fibrosis. N. Engl. J. Med. p. 2071-82.


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Schwarz MI, Dreisin RB, Pratt DS, et al (1978) Immunofluorescent patterns in the idiopathic 
interstitial pneumonias. J. Lab. Clin. Med. p. 929-38.
Taillé C, Grootenboer-Mignot S, Boursier C, et al (2011) Identification of periplakin as a new 
target for autoreactivity in idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. p. 
759-66.
Takahashi T, Wada I, Ohtsuka Y, et al (2007) Autoantibody to alanyl-tRNA synthetase in 
patients with idiopathic pulmonary fibrosis. Respirology p. 642-53.
van Assen S, Holvast A, Benne CA, et al (2010) Humoral responses after influenza 
vaccination are severely reduced in patients with rheumatoid arthritis treated with rituximab. 
Arthritis Rheum; 62(1):75-81
Vuga LJ, Tedrow JR, Pandit KV, et al (2014) C-X-C motif chemokine 13 (CXCL13) is a 
prognostic biomarker of idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. p. 966-
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Wilson KC, Raghu G (2015) The 2015 guidelines for idiopathic pulmonary fibrosis: an 
important chapter in the evolution of the management of patients with IPF. Eur. Respir. J. p. 
883-6.
Xue J, Kass DJ, Bon J, et al (2013) Plasma B lymphocyte stimulator and B cell differentiation 
in idiopathic pulmonary fibrosis patients. J. Immunol. p. 2089-95.
Yang Y, Fujita J, Bandoh S, et al (2002) Detection of antivimentin antibody in sera of patients 
with idiopathic pulmonary fibrosis and non-specific interstitial pneumonia. Clin. Exp. 
Immunol. p. 169-74.
Zuo F, Kaminski N, Eugui E, et al (2002) Gene expression analysis reveals matrilysin as a 
key regulator of pulmonary fibrosis in mice and humans. Proc. Natl. Acad. Sci. U.S.A. p. 
6292-7.


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15
Appendix 1: Liver Event and Laboratory Trigger Definitions 
and Follow-up Requirements
Table 15-1
Liver Event and Laboratory Trigger Definitions
Definition/ threshold
LIVER LABORATORY 
TRIGGERS

3 x ULN < ALT / AST ≤ 5 x ULN

1.5 x ULN < TBL ≤ 2 x ULN
LIVER EVENTS

ALT or AST > 5 × ULN

ALP > 2 × ULN (in the absence of known bone pathology)

TBL > 2 × ULN (in the absence of known Gilbert syndrome)

ALT or AST > 3 × ULN and INR > 1.5

Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and
TBL > 2 × ULN [mainly conjugated fraction] without notable increase
in ALP to > 2 × ULN)

Any clinical event of jaundice (or equivalent term)

ALT or AST > 3 × ULN accompanied by (general) malaise, fatigue,
abdominal pain, nausea, or vomiting, or rash with eosinophilia

Any adverse event potentially indicative of a liver toxicity*
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver
neoplasms TBL: total bilirubin; ULN: upper limit of normal
Table 15-2
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 resolutionc
(frequency at investigator 
discretion)
ALT or AST
> 8 × ULN

Discontinue the study treatment
immediately

Hospitalize if clinically
appropriate

Establish causality

Record the AE and contributing
factors (e.g., conmeds, med hx,
lab) in the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc
(frequency at investigator 
discretion)
> 3 × ULN and INR >
1.5

Discontinue the study treatment
immediately

Hospitalize, if clinically
appropriate

Establish causality
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc
(frequency at investigator 
discretion)


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Criteria
Actions required
Follow-up monitoring

Record the AE and contributing 
factors (e.g., conmeds, med hx, 
lab) in the appropriate CRF
> 5 to ≤ 8 × ULN

Repeat LFT within 48 hours

If elevation persists, continue 
follow-up monitoring

If elevation persists for more than 
2 weeks, discontinue the study 
drug

Establish causality

Record the AE and contributing 
factors (e.g., conmeds, med hx, 
lab) in the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc
(frequency at investigator 
discretion)
> 3 × ULN accompanied 
by symptomsb

Discontinue the study treatment 
immediately

Hospitalize if clinically 
appropriate

Establish causality

Record the AE and contributing 
factors (e.g., conmeds, med hx, 
lab) in the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc
(frequency at investigator 
discretion)
> 3 to ≤ 5 × ULN 
(subject is 
asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate 
close observation of the subject
Investigator discretion
Monitor LFT within 1 to 4 weeks
ALP (isolated)
> 2 × ULN (in the 
absence of known bone 
pathology)

Repeat LFT within 48 hours

If elevation persists, establish 
causality

Record the AE and contributing 
factors (e.g., conmeds, med hx, 
lab) in the appropriate CRF
Investigator discretion
Monitor LFT within 1 to 4 weeks 
or at next visit
TBL (isolated)
> 2 × ULN (in the 
absence of known 
Gilbert syndrome)

Repeat LFT within 48 hours

If elevation persists, discontinue 
the study drug immediately

Hospitalize if clinically 
appropriate

Establish causality

Record the AE and contributing 
factors (e.g., conmeds, med hx, 
lab) in the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc
(frequency at investigator 
discretion)
Test for hemolysis (e.g., 
reticulocytes, haptoglobin, 
unconjugated [indirect] bilirubin)
> 1.5 to ≤ 2 × ULN 
(subject is 
asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate 
close observation of the subject
Investigator discretion
Monitor LFT within 1 to 4 weeks 
or at next visit
Jaundice

Discontinue the study treatment 
immediately

Hospitalize the subject
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc


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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
(frequency at investigator 
discretion)
Any AE potentially 
indicative of a liver 
toxicity*

Consider study treatment 
interruption or discontinuation

Hospitalization if clinically 
appropriate

Establish causality

Record the AE and contributing 
factors (e.g., conmeds, med hx, 
lab) in the appropriate CRF
Investigator discretion
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN 
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable 
values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level 
after a maximum of 6 months, (4) liver transplantation, and (5) death.
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.
Table 15-3
Exclusion of underlying liver disease
Disease
Assessment
Hepatitis A, B, C, E

IgM anti-HAV; HBSAg, IgM anti-HBc, (Hepatitis B virus) HBV DNA; 
anti-Hepatitis C Virus (HCV), HCV RNA, IgM & IgG anti-HEV, HEV 
RNA
CMV, HSV, EBV 
infection

IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti-EBV
Autoimmune hepatitis

ANA & ASMA titers, total IgM, IgG, IgE, IgA
Alcoholic hepatitis

Ethanol history, GGT, MCV, CD-transferrin
Nonalcoholic 
steatohepatitis

Ultrasound or MRI
Hypoxic/ischemic 
hepatopathy

Medical history: acute or chronic CHF, hypotension, hypoxia, hepatic 
venous occlusion. Ultrasound or MRI.
Biliary tract disease

Ultrasound or MRI, ERCP as appropriate.
Wilson disease

Caeruloplasmin
Hemochromatosis

Ferritin, transferrin
Alpha-1-antitrypsin 
deficiency

Alpha-1-antitrypsin


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Appendix 2: Specific Renal Alert Criteria and Actions
Table 16-1
Specific Renal Alert Criteria and Actions
Renal Event
Actions
Confirmed serum creatinine increase 
25 – 49%

Consider causes and possible interventions 

Follow up within 2-5 days
Serum creatinine increase  50 % +
OR if <18 years old, eGFR < 35 
mL/min/1.73 m2

Consider causes and possible interventions 

Repeat assessment within 24-48h if possible

Consider drug interruption or discontinuation unless 
other causes are diagnosed and corrected

Consider patient hospitalization and specialized 
treatment
New onset dipstick proteinuria ≥3+
OR
Protein-creatinine ratio (PCR) ≥ 1g/g 
Cr (or mg/mmol equivalent as 
converted by the measuring 
laboratory)

Consider causes and possible interventions 

Assess serum albumin & serum total protein 

Repeat assessment to confirm

Consider drug interruption or discontinuation unless 
other causes are diagnosed and corrected
New onset hematuria ≥ 3+ on urine 
dipstick
Assess & document

Repeat assessment to confirm

Distinguish hemoglobinuria from hematuria

Urine sediment microscopy

Assess sCr 

Exclude infection, trauma, bleeding from the distal 
urinary tract/bladder, menstruation

Consider bleeding disorder
+ Corresponds to KDIGO criteria for Acute Kidney Injury
Additional specialized assessments are available to assess renal function or renal pathology. 
(Note: In exceptional cases, when a nephrologist considers a renal biopsy, it is recommended 
to make slide specimen available for evaluation by Novartis to potentially identify project-wide 
patterns of nephrotoxicity.)
Whenever a renal event is identified, a detailed patient history and examination are indicated to 
identify and potentially eliminate risk factors that may have initiated or contributed to the event:

Blood pressure assessment (after 5-minute rest, with an appropriate cuff size)

Signs and symptoms like fever, headache, shortness of breath, back or abdominal pain, 
dysuria or hematuria, dependent or periorbital edema

Changes in blood pressure, body weight, fluid intake, voiding pattern, or urine output


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
Concomitant events or procedures such as trauma, surgical procedures, cardiac or hepatic 
failure, contrast media or other known nephrotoxin administration, or other diseases or 
causes, e.g., dehydration due to delirium, tumor lysis
Table 16-2
Renal Event Follow-up
FOLLOW-UP OF RENAL EVENTS
Assess, document and record in CRF

Urine dipstick and sediment microscopy evidence of DIN: crystals, red blood cells 
(dysmorphic/glomerular vs. non-dysmorphic/non-glomerular), white blood cells, tubular epithelial 
cells

Blood pressure and body weight 

Serum creatinine, BUN, electrolytes (sodium, potassium, phosphate, calcium), bicarbonate and 
uric acid

Urine output
Review and record possible contributing factors to the renal event (co-medications, other co-morbid 
conditions) and additional diagnostic procedures (MRI etc.) in the CRF
Monitor patient regularly (frequency at investigator’s discretion) until -

Event resolution: (sCr within 10% of baseline or PCR < 1 g/g Cr, or ACR <300 mg/g Cr) 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.

Analysis of urine markers in samples collected over the course of the DIN event


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Appendix 3: ATS/ERS/JRS/ALAT Diagnostic Guidelines
Figure 17-1
Diagnostic algorithm for IPF (Figure 3 in Raghu et al 2011)
Table 17-1
High-resolution computed tomography criteria for UIP pattern (Table 4 
in Raghu et al 2011)


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Table 17-2
Histopathological Criteria for UIP pattern (Table 5 in Raghu et al 2011)
Table 17-3
Combination of HRCT and surgical lung biopsy for the diagnosis of 
IPF (Table 6 in Raghu et al 2011)
Raghu et al 2011

SAP_001.pdf: 
Biostatistics & Statistical Programming / 
Novartis Institutes for BioMedical Research
VAY736
CVAY736X2207
A subject-, investigator-, and sponsor-blinded, randomized,
placebo-controlled, multicenter study to investigate 
efficacy, safety, and tolerability of VAY736 in patients with 
idiopathic pulmonary fibrosis
Statistical Analysis Plan (SAP)
Author(s):
Document type:
SAP Documentation – NIBR 
Document status:
Final - Amendment 1 
Release date:
06 August 2020
Number of pages:
40
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Personal Protected Data


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Table of contents
Table of contents .................................................................................................................4
List of tables ........................................................................................................................5
1
Introduction .........................................................................................................................6
1.1
Scope of document ..................................................................................................6
1.2
Study reference documentation ...............................................................................6
1.3
Study objectives.......................................................................................................6
1.3.1
Primary objectives...................................................................................6
1.3.2
Secondary objectives...............................................................................7
1.3.3
Exploratory objectives ............................................................................8
1.4
Study design and treatment....................................................................................10
2
First interpretable results (FIR) .........................................................................................11
3
Interim analyses.................................................................................................................11
4
Statistical methods.............................................................................................................13
4.1
Analysis sets ..........................................................................................................13
4.2
General presentation of descriptive summaries and listings..................................14
4.3
General definitions.................................................................................................15
5
Statistical methods for Pharmacokinetic (PK) parameters................................................16
5.1
Variables................................................................................................................16
5.2
Descriptive analyses ..............................................................................................16
5.3
Statistical model, assumptions and hypotheses .....................................................17
5.3.1
Model checking procedures ..................................................................17
5.3.2
Graphical presentation of results...........................................................17
6
Statistical methods for Pharmacodynamic (PD) parameters.............................................17
6.1
Primary objective...................................................................................................17
6.1.1
Variables ...............................................................................................17
6.1.2
Descriptive analyses..............................................................................17
6.1.3
Statistical model, assumptions and hypotheses.....................................17
6.2
Secondary objectives .............................................................................................20
6.2.1
Variables ...............................................................................................20
6.2.2
Descriptive analyses..............................................................................21
6.2.3
Statistical model, assumptions and hypotheses.....................................22
6.3
Exploratory objectives...........................................................................................22
6.3.2
Descriptive analyses..............................................................................24
7
Statistical methods for safety and tolerability data............................................................25
7.1
Variables................................................................................................................25
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7.2
Descriptive analyses ..............................................................................................25
7.3
Graphical presentation...........................................................................................28
9
Reference list.....................................................................................................................31
10 Appendix ...........................................................................................................................32
10.1
Appendix 1: Definition of benefit for individual endpoints..................................32
10.2
Appendix 2: Implementation of the sensitivity analyses.......................................33
List of tables
Figure 1-1
Study design..........................................................................................11
Table 4-1
Protocol deviation codes and analysis sets............................................14
Table 6-1
COVID-19 date....................................................................................19
Table 7-1
Notable vital signs and body weight .....................................................25
Table 7-2
ECG abnormalities................................................................................26
Table 7-3
Liver enzyme abnormalities..................................................................26
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1
Introduction 
1.1
Scope of document
The RAP documents contain detailed information to aid the production of Statistics & 
Programming input into the Clinical Study Report (CSR) for trial “CVAY736X2207”.
The Statistical analysis plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol. It includes statistical and analytical plans for the analyses described 
hereafter;
1.2
Study reference documentation
This SAP has been developed using Clinical Trial Protocol version v07
1.3
Study objectives
1.3.1
Primary objectives
Primary Objective
Endpoints 

To assess the efficacy of VAY736 in
patients with idiopathic pulmonary
fibrosis.

Change from baseline to end of treatment
epoch (48 weeks of treatment) in Forced
Vital Capacity (FVC).
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1.3.2
Secondary objectives
Secondary Objectives
Endpoints

To evaluate the impact on VAY736 on
safety

Adverse Events

To assess the impact of VAY736 on
survival

a) All-cause mortality
b) IPF-related mortality

To assess the impact of VAY736 on
"progression free survival (PFS)"

a) Events, defined as: death (all-cause
mortality) OR "progression" (relative
reduction in FVC ≥ 10%)
b) Events, defined as: death (IPF-related
mortality) OR "progression" (relative
reduction in FVC ≥ 10%)

To assess the impact of VAY736 on
"disease progression"

a) Progression, defined as: relative
reduction in FVC ≥10%
b) Progression, defined as: relative
reduction in Diffusing Capacity of the
Lungs (DLCO) ≥ 15%
c) Progression, defined as: absolute
reduction in Six Minute Walk Distance
(6MWD) ≥ 50 m

To assess the impact of VAY736 on a
"Composite Endpoint"

a) Events, defined as: death (all-cause
mortality), OR relative reduction in
FVC≥10%, OR relative reduction in
DLCO ≥15%, OR relative reduction in
6MWD ≥50m
b) Events, defined as: death (IPF-related
morality), OR relative reduction in
FVC≥10%, OR relative reduction in
DLCO ≥15%, OR relative reduction in
6MWD ≥50m

To assess the impact of VAY736 on
pulmonary physiology

a) Change from baseline to the end of
treatment epoch (48 weeks of treatment)
in DLCO
b) Change from baseline to the end of
treatment epoch (48 weeks of treatment)
in Total Lung Capacity (TLC).


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
To assess the impact of VAY736 on
exercise capacity

a) Change from baseline to the end of
treatment epoch (48 weeks of treatment)
in 6-minute walk distance
b) Change from baseline to the end of
treatment epoch (48 weeks of treatment)
in distance-saturation product
c) Change from baseline to the end of
treatment epoch (48 weeks of treatment)
in post Six Minute Walk Test (6MWT)
Borg Scale

To assess the impact of VAY736 on gas
exchange

Change from baseline to the end of
treatment epoch (48 weeks of treatment)
in resting oxygen saturation (on room
air)

To assess the immunogenicity of
VAY736

Serum anti-VAY736 antibodies

To assess the pharmacokinetics of
VAY736 after multiple s.c. doses

Serum VAY736 concentrations
1.3.3
Exploratory objectives
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1.4
Study design and treatment
This is an exploratory (non-confirmatory) randomized, patient-, investigator-, sponsor blinded, 
and placebo controlled study of VAY736 in IPF patients. This study will investigate the safety 
and efficacy of 
 VAY736 administered s.c. every 4 weeks for 48 weeks. Approximately 
58 subjects will be randomized in a 1:1 ratio on top of local standard of care (SOC), to receive 
VAY736 or placebo. Randomization will be stratified by SoC medication (3 levels: nintedanib, 
pirfenidone, or no treatment). The randomization scheme will be performed separately within 
each stratum to ensure balance of the treatment groups with respect to the SoC medication.
A screening epoch of 6 weeks will be used to assess eligibility.
Randomized subjects will participate in a 48 week treatment epoch
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A scheme of the study design is provided in the figure below.
Figure 1-1
Study design
2
First interpretable results (FIR)
First interpretable results (FIR) will be provided for this trial.
The template shows the analysis / results to be presented in the FIR. Study outputs required to 
be created at the time of the FIR will be highlighted in TFL shells document and marked as 
“Key” in the Programming Deliverables Tracker (PDT) output list. 
3
Interim analyses 
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4
Statistical methods
4.1
Analysis sets
For subjects for which the actual treatment received does not match the randomized treatment,
the treatment actually received will be used for the analysis and/or some visits may be excluded.
The Safety analysis set will include all subjects that received any study drug.
The PD analysis set will include all subjects from safety analysis set with available PD data 
and no protocol deviations with relevant impact on PD data.
The PK analysis set will include all subjects from safety analysis set with at least one available 
valid (i.e. not flagged for exclusion) PK concentration measurement and with no protocol 
deviations that impact on PK data.
The IG analysis set will include all subjects from safety analysis set with at least one available 
valid (i.e. not flagged for exclusion) IG concentration measurement and with no protocol 
deviations that impact on IG data.
Protocol deviations will be identified during the data cleaning process. A comprehensive list of 
all Protocol Deviations is maintained within the Data Review Plan.
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The analysis sets and protocol deviation are related as follows:
Table 4-1
Protocol deviation codes and analysis sets 
If updates to this table are needed, an amendment to the SAP needs to be implemented prior to
DBL.
To understand impact of Covid-19 situation all protocol deviation linked to Covid-19 will be 
identified and listed separately.  
4.2
General presentation of descriptive summaries and listings
The following summary statistics will be presented unless otherwise stated specifically. 
Qualitative/categorical data (e.g., gender, race) will be summarized by frequency counts and 
percentages. Percentages will be calculated using the number of patients in the relevant 
treatment arm or subgroup as the denominator.
Continuous data (e.g., age, body weight) will be summarized using appropriate descriptive 
statistics (i.e. mean, standard deviation (SD), median, minimum and maximum) by treatment 
arm. 
Based on the nature of the data, few analyses require additional statistics such as geometric 
mean, geometric coefficient of variation (CV) and it will be specifically requested in respective 
section.
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In general, listings will be presented 

with country/center/subject identifier and age/sex/race as mandatory columns unless
otherwise specified

by treatment, patient and chronological time
4.3
General definitions
Study treatment:
Study treatment will be noted as VAY736/Placebo throughout this document and CSR 
deliverables.
Study day:
The study day for safety/efficacy assessments (e.g. adverse event onset, laboratory abnormality 
occurrence, vital sign measurement, Electrocardiogram (ECG), PK sampling, FVC values, etc.,) 
will be calculated using the randomization date as the reference date. For assessments occurring:
on or after the randomization date, the study day will be calculated as (date of 
assessment/occurrence) – (date of randomization) + 1. Then study day 1 will be the day of 
randomization.
before the randomization date, the study day will be calculated as (date of 
assessment/occurrence) – (date of randomization).
For example, if a serious adverse event starts 1 day before the randomization date, the study 
day displayed on the listing will be negative, i.e. -1.
Baseline: 
For all evaluations, the last available pre-dose assessment before or on the date of randomization 
is taken as ‘baseline’ value or ‘baseline’ assessment.
Unscheduled assessment:
There will be no analysis visit window defined, by consequence descriptive summary statistics 
by visit will not include unscheduled/repeat assessment. 
For all analyses regarding abnormal assessments or analyses based on worst post–baseline value 
(e.g. laboratory, ECGs, vital signs), all post-baseline values will be included (scheduled, 
unscheduled, repeat). All unscheduled and repeat measurements will be included in listings.
Treatment analysis epoch:
Treatment epoch will be defined as any post-baseline assessment performed between the first 
dose of study drug date and the date of Week 49 visit if not missing or the date of last visit 
attended in treatment epoch (End of Study Treatment visit 199) in case of drop-out or the death 
date if subject died in treatment epoch.
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5
Statistical methods for Pharmacokinetic (PK) parameters
5.1
Variables 
No derivation of PK parameters is planned for this study but a modeling of the data may be 
performed possibly pooling these data with data coming from previous studies. This optional 
analysis will be described and reported separately in a modeling plan and a modeling report as 
appropriate.
5.2
Descriptive analyses
Summary statistics will include mean (arithmetic and geometric), Standard 
Deviation (SD), Coefficient of Variation (CV) (arithmetic and geometric), median, minimum 
and maximum. At each visit, geometric means and CVs will not be reported in case of 
concentrations below LLOQ or zero values.
Arithmetic CV is defined as: SD*100/Arithmetic mean.
Geometric CV is defined as: 100*sqrt(exp(sdlogs**2)-1), where sdlogs represents the SD of 
log-e transformed data.
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5.3
Statistical model, assumptions and hypotheses
Modeling of the data may be performed as appropriate. As the PK data from the current study 
may be pooled with data from previous studies, the PK analysis will be described and reported 
separately in a modeling plan and modeling report.
5.3.1
Model checking procedures
Not applicable.
5.3.2
Graphical presentation of results
Individual concentration-time profiles and mean profiles with SD bars will be presented.
6
Statistical methods for Pharmacodynamic (PD) parameters
6.1
Primary objective
The primary objective of the study is to assess the efficacy of VAY736 on top of current 
standard-of-care therapy (pirfenidone, nintedanib, or no treatment) using FVC (L) at the end of 
treatment epoch (48 weeks of treatment) in patients with idiopathic pulmonary fibrosis.
6.1.1
Variables 
The primary endpoint is the change from baseline in FVC (L). 
6.1.2
Descriptive analyses
Summary statistics of change from baseline in FVC by treatment and visit will be presented by 
epoch. In addition to the overall summary a summary by baseline standard-of-care medication 
(stratification factor: pirfenidone, nintedanib, or no treatment) will be produced.
Individual data will be listed by treatment, epoch and visit.
6.1.3
Statistical model, assumptions and hypotheses
The following hypothesis will be tested for VAY736+SoC versus Placebo+SoC:
H0: There is no difference or worsening in change from baseline in FVC (L) from baseline to 
48 weeks of treatment between VAY736+SoC and placebo+SoC
H1: There is an improvement in change from baseline in FVC (L) from baseline to 48 weeks of 
treatment between VAY736+SoC and placebo+SoC
Test will be conducted at a one-sided 10% level and 2-sided 80% CI of the estimates will be 
displayed. Sense of the one-sided test for each criteria is given in table of appendix 1 (section 
10.1).
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The primary variable, change from baseline in FVC (L) will be analyzed using a Mixed Effects 
Model for Repeated Measures (MMRM) in the PD analysis set and considering all assessments 
collected during the treatment epoch. The model will include treatment and visit as fixed effects, 
standard of care treatment (Nintedanib, Pirfenidone, or no treatment) as factor and baseline 
value as a covariate, treatment-by-visit and baseline-by-visit as interaction terms. The within 
subject correlation will be modeled using a repeated statement in SAS Proc Mixed with 
unstructured covariance matrix. In case of non convergence the model, an alternative AR(1) 
covariance may be implemented. The posterior will be derived as a t-distribution using a PROC 
MIXED as detailed in section 3. The main comparison will be a contrast between treatment 
groups at 48 weeks of treatment. This approach assumes data is Missing At Random (MAR).
6.1.3.1
Model checking procedures
The analyses of residuals will be performed to assess model assumptions.
6.1.3.2
Sensitivity analysis
Missing not at random (MNAR) analysis
Given the severity of disease and the likelihood of some missing data, the analysis will also 
include approaches to assess treatment under the assumption of missing not at random (MNAR).
Missing data will be imputed using methods specific to non-monotone and monotone missing 
patterns. In a first step, non-monotone missing data will be imputed 1000 times using MCMC 
method. Then monotone missing data will be imputed by pattern-mixture model (MNAR) 
performed on the 1000 samples (O’Kelly & Ratitch 2014). A conservative analysis where 
missing values in the active group are imputed based on the behavior observed in the placebo
group (unconditional reference approach) will be used. The objective is to assess if a potential 
effect observed in the analysis based on MAR assumption is still present when a more 
conservative procedure is used. The detail of the sensitivity analyses is described in the 
appendix 2 (section 10.2).
Analysis of potential Covid-19 impact
As primary analysis may exclude some data due to Covid-19, a sensitivity analysis will also 
include all PD data regardless of protocol deviations linked to Covid-19. 
Covid-19 may interfere with study outcomes due to the following:
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
Missing visits with missing FVC assessment and/or missing treatment doses due to
restriction in travel or closed site. These missing data are considered as missing
completely at random therefore introducing no systematic bias in treatment effect.

Missing visits due to adverse event linked to Covid-19

Infection by Covid-19.

Alteration in recruitment after the start of pandemic as some patients might want to
avoid participation in the study due to the Covid-19 risk.
The date of when Covid-19 occurred in different countries is tabulated below. Any patient data 
collected after that date may be confounded by complications due to the pandemic. For example, 
if a patient has any on-treatment observation collected after the start date for the specific region, 
that patient’s estimated treatment effect is considered potentially affected by the pandemic.
Table 6-1
COVID-19 date
Region/Country
Start Date
End Date
China
01-Jan-2020
End date has not yet been defined
South Korea
20-Feb-2020
End date has not yet been defined
Japan
21-Feb-2020
End date has not yet been defined
Italy
23-Feb-2020
End date has not yet been defined
Rest of the World
01-Mar-2020
End dates have not yet been defined
If sufficient data is present the interaction of covid-19 by treatment will be assessed by means 
of descriptive statistics:

Demographics of patients recruited pre- and during COVID period by treatment and for
all

Number of patients with missed visits  pre- and during COVID period overall and by
treatment and for all

Adverse events pre- and during COVID period by treatment and for all

Boxplots of FVC change from baseline pre- and during COVID period by treatment
and for all
6.1.3.3
Graphical presentation of results
Plot of model estimates of mean change from baseline and their standard error will be presented 
over the treatment epoch.
Plot of observed mean change from baseline and their standard error will be presented over the 
whole study period i.e. double-blind period 
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6.2
Secondary objectives
6.2.1
Variables 
6.2.1.1
Survival (all-cause mortality and IPF-related mortality)
Only events restricted to treatment epoch will be analyzed. 
Survival all-cause mortality (S1) is defined as time from randomization to death due to any 
cause.
Survival IPF related mortality (S2) is defined as time from randomization to death due to IPF 
related cause.
IPF-related death will be assessed by an Adjudication Committee.
Survival time will be derived in days as follows: 
(date of death or censoring date – date of randomization) + 1
For S1, if a patient is not known to have died (all-cause mortality) at the end of the treatment 
epoch, survival time will be censored at the latest date in treatment epoch where the patient was 
known to be alive.
For S2, if a patient is not known to have died due to IPF related cause at the end of the treatment 
epoch, survival time will be censored at the latest date in treatment epoch where the patient was 
known to be alive or died due to non-IPF related cause.
6.2.1.2
Progression-free Survival
Only events restricted to treatment epoch will be analyzed. 
Progression free survival (PFS) is defined as follows:

PFS1: time from randomization to progression (relative reduction in FVC ≥ 10%) or
death due to all causes

PFS2: time from randomization to progression (relative reduction in FVC ≥ 10%) or
death due to IPF related causes
For PFS1, if a subject has not progressed nor died at the end of the treatment epoch, PFS will 
be censored at the date of last non-missing assessment of FVC
For PFS2, if a subject has not progressed nor died (IPF related mortality) at the end of the 
treatment epoch, PFS will be censored at the maximum date of (the last non-missing assessment 
of FVC during treatment epoch and the non-IPF related death).
6.2.1.3
Disease Progression
Only events restricted to treatment epoch will be analyzed. 
Disease progression is defined as the time from randomization to progression.
The following progression events will be considered:

Progression, defined as: relative reduction in FVC ≥ 10%;


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
Progression, defined as: relative reduction in DLCO ≥ 15%;

Progression, defined as: absolute reduction in 6MWD ≥ 50 m.
For the subjects who have not progressed at the end of the treatment epoch, disease progression 
will be censored at the date of the last FVC, DLCO or 6MWD assessment in treatment epoch 
as applicable.
6.2.1.4
Composite endpoint
Only events restricted to treatment epoch will be analyzed. 
Time to composite events will be considered, where events of interest are defined as below:

Death (all-cause mortality), OR relative reduction in FVC ≥10%, OR relative reduction
in DLCO ≥15%, OR relative reduction in 6MWD ≥50 m;

Death (IPF-related mortality), OR relative reduction in FVC ≥10%, OR relative
reduction in DLCO ≥15%, OR relative reduction in 6MWD ≥50 m.
For the subjects who do not experience the events at the end of the treatment epoch, the time to 
event will be censored at the latest date of the FVC, DLCO or 6MWD assessments in the 
treatment epoch.
6.2.1.5
Pulmonary Physiology
Change from baseline in DLCO and in TLC during the treatment epoch
6.2.1.6
Exercise capacity
Change from baseline in 6-minute walking distance (6MWD), in distance-saturation product
(DSP) and in post 6-minute walking test (6MWT) Borg dyspnea score during the treatment 
epoch.
Note: DSP = 6MWD * end of test oxygen saturation.
6.2.1.7
Gas Exchange
Change from baseline in resting oxygen saturation during treatment epoch
6.2.2
Descriptive analyses
A list and a summary of the events (Survival, Progression-free Survival, Disease Progression 
and Composite Endpoint) within and outside the treatment epoch (as applicable) will be 
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provided. In the analyses on composite events a summary of the single events (the one occurring 
first) will be provided too. 
Summary statistics of change from baseline by treatment and visit will be presented for DLCO 
and TLC, 6-minute walking distance, in distance-saturation product and in post 6MWT, resting 
oxygen saturation 
6.2.3
Statistical model, assumptions and hypotheses
6.2.3.1
Time to Events analyses 
The Kaplan-Meier estimates of the proportion of patients with the event of interest in each 
treatment group, along with 80 % two-sided confidence intervals using Greenwood’s formula, 
will be provided. The two treatment groups will be compared using a one-sided log rank test at 
the 10% significance level. The hazard ratio and its associated 80% two-sided confidence 
interval will be estimated based on a Cox regression model using treatment group as main factor.
6.2.3.2
Pulmonary Physiology, Exercise capacity, Gas Exchange
The same MMRM model described for the primary endpoint will be used in these analyses
using SAS Proc Mixed. 
 An ANCOVA 
model will be fitted with treatment group as main factor, standard of care therapy (stratification 
factor) as a cofactor and baseline as covariate.
6.2.3.3
Model checking procedures
For the Time to Events Analyses, the assumption of proportional hazard will be visually 
assessed reviewing the Kaplan-Meier curves.
For the other analyses, the analyses of residuals will be performed to assess model assumptions.
6.2.3.4
Graphical presentation of results
6.2.3.4.1 Time to Events Analyses
Kaplan-Meier curves by treatment will be plotted.
6.2.3.4.2 Other analyses
Plots of mean values (with error bars representing SD) by treatment and visit will be released.
6.3
Exploratory objectives
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6.3.2
Descriptive analyses
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7
Statistical methods for safety and tolerability data
7.1
Variables
Adverse events, vital signs (blood pressure, pulse rate, body temperature), ECG intervals, 
laboratory measurements, as well as subject demographics, baseline characteristics, and 
treatment information.
7.2
Descriptive analyses
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment group and subject. 
Summary statistics will be provided by treatment group.
Treatment
Data for study drug administration (rescue medication) and concomitant therapies will be listed 
by treatment group and subject. 
Summary statistics will be provided for treatment compliance by treatment group.
The use of the standard of care medication (pirfenidone, nintedanib, or no treatment) will be 
summarized by treatment group.
Vital signs
All vital signs data (including pulse rate, systolic and diastolic blood pressure in sitting 
position, temperature and oxygen saturation) will be listed by treatment, subject, and visit and 
abnormalities as described below will be flagged. 
Table 7-1
Notable vital signs and body weight
Vital Sign Variable
Notable Criteria
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Pulse (beats/min)
>120 bpm or < 50 bpm
Systolic BP (mmHg) 
≥ 160 mmHg or ≤ 90 mmHg
Diastolic BP (mmHg)
≥ 100 mmHg or ≤ 50 mmHg
Temperature (°C)
>38.3 °C/ 101°F
Body weight (kg)
More than 7% decrease from baseline weight
ECG evaluations
All ECG data (heart rate, QRS duration, RR, PR, QT and QTcF intervals) will be listed by 
treatment, subject and visit, and abnormalities as described below will be flagged. Summary 
statistics of value will be provided by treatment and visit.
Table 7-2
ECG abnormalities
ECG abnormalities Variable
Notable Criteria
QT (ms)
  Increase ≥ 30 ms
  Increase ≥ 60 ms
  New > 450 ms
  New > 480 ms
  New > 500 ms
QTcF (ms)
  Increase ≥ 30 ms
  Increase ≥ 60 ms
  New > 450 ms
  New > 480 ms
  New > 500 ms
PR (ms)
increase > 25% or new > 200 ms 
New > 200 and ≤ 220 ms
New > 220 ms
QRS (ms)
increase >25% or new > 110 ms
New > 110 and ≤ 120 ms
New > 120 ms
RR (ms) / HR (bpm)
RR increase > 25% or HR > 100 bpm
RR decrease > 25% or HR < 60 bpm
Clinical laboratory evaluations
All laboratory data will be listed by treatment, subject, and visit and if normal ranges are 
available abnormalities will be flagged. Summary statistics will be provided by treatment and 
visit. Newly occurring liver enzyme abnormalities described in Table 7-3 will be summarized 
in treatment epoch. Newly occurring abnormality is defined when the abnormality occurs post 
baseline during the treatment epoch for patient without this abnormality at baseline . 
Table 7-3
Liver enzyme abnormalities
Definition
ALT > 5x ULN
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Definition
ALT > 10x ULN
ALT > 20x ULN  
ALT or AST > 3x ULN
ALT or AST > 5x ULN
ALT or AST > 8x ULN 
ALT or AST > 3x ULN & TBL > 1.5x ULN  
ALT or AST > 3x ULN & TBL > 2x ULN 
ALP > 1.5x ULN
ALP > 2x ULN       
AST = Aspartate aminotransferase; also known as SGOT, ALT = Alanine aminotransferase; also 
known as SGPT, ALP = Alkaline phosphatase, TBL = Total bilirubin, 
Listing and summary tables will be provided for the final analysis 
Adverse events
All information obtained on adverse events will be displayed by treatment and subject.
The number and percentage of subjects with adverse events occurring after the first dosing will 
be tabulated by body system and preferred term with a breakdown by treatment. A subject with 
multiple adverse events within a body system is only counted once towards the total of this 
body system and treatment. The same summary will be done for serious event.
The number and percentage of subjects with adverse events occurring after the first dosing by 
maximum severity of adverse events will be tabulated by body system and preferred term with 
a breakdown by treatment.
The number and percentage of subjects with adverse events occurring after the first dosing 
classified as related to study drug will be tabulated by body system and preferred term with a 
breakdown by treatment. The same summary will be done for serious event.
An overall summary of AEs will present incidence and occurrence of all AEs, AEs of mild 
intensity, AEs of moderate intensity, AEs of severe intensity, study drug-related AEs, serious 
AEs and AEs leading to discontinuation of study treatment.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:
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
a single occurrence will be counted if there is ≤1 day gap between the end date of the
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date
of the preceding AE and the start date of the consecutive AE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT. 
Listing and summary tables, by epoch, will be provided for the final analysis 
7.3
Graphical presentation 
Boxplots to visualize trends in longitudinal safety data (vitals, ECG, lab parameter) will be 
created. 
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9
Reference list
Carpenter JR, Roger JH, Kenward MG (2013) Analysis of longitudinal trials with protocol 
deviation: a framework for relevant, accessible assumptions and inference via multiple 
imputation. Journal of Biopharmaceutical Statistics, 23(6):1352–1371. 
Ratitch, B. and O’Kelly, M. (2011), Implementation of Pattern-Mixture Models Using 
Standard SAS/STAT Procedures, in Proceedings of PharmaSUG 2011 (Pharmaceutical 
Industry SAS Users Group), SP04, Nashville.
European Medicines Agency (2010), Guideline on Missing Data in Confirmatory Clinical 
Trials.
O'Kelly, M., and Ratitch, B. (2014), Clinical Trials with Missing Data: A Guide for 
Practitioners, West Sussex: Wiley.[https://doi.org/10.1002/9781118762516.fmatter].
Rubin, D. B. (1976), “Inference and Missing Data,” Biometrika, 63, 581–592.
Rubin, D. B. (1987), Multiple Imputation for Nonresponse in Surveys, New York: John Wiley 
& Sons.
Patel AS, Siegert RJ, Brignall K, Gordon P, Steer S, Desai SR, Maher TM, Renzoni EA, 
Wells AU, Higginson IJ, Birring SS. The development and validation of the King’s Brief 
Interstitial Lung Disease (K-BILD) health status questionnaire. Thorax 2012; 67 (9), 804-810 
[R12-4171] 
St George’s Respiratory Questionnaire Manual, University of London 2009
A Composite Physiologic Index Derived from Disease Extent Observed by Computed 
Tomography, ATS Journals Vol 167. pp 962–969, 2003.


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10
Appendix
10.1
Appendix 1: Definition of benefit for individual endpoints
Measurement
Endpoint
Direction of benefit*
Spirometry
FVC
Increase
Lung Volumes
TLC
Increase
Diffusion lung capacity
DLCO
Increase
6MWT
6MWD
Increase
Borg dyspnea score
Decrease
* In the direction of
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10.2
Appendix 2: Implementation of the sensitivity analyses 
This appendix is adapted from Ratitch, B. and O’Kelly, M. (2011).
SAS PROC MI permits to perform control-based imputation. In this appendix, we will assume 
that data are stored in a SAS dataset, DIN, with the following variables:

SUBJID – subject identification number

SOC_TYPE - stratification factor (with 0 representing no background therapy, 1
nintedanib, 2 pirfenidone)

SOC_T1 - stratification factor (with 1 representing nintedanib and 0 other cases)

SOC_T2 - stratification factor (with 1 representing pirfenidone and 0 other cases)

DRUGNUM - treatment arm (with 0 representing control arm, and 1 representing the
Active group)

BASE, W5, W9-W49, corresponding to the criteria at BASE(baseline), and post-
baseline visits W5 (week 5), W9 (week 9) up to W49 (week 49) by 4 weeks

LASTVIS – last study visit (takes values 0 through 49)
A- General MAR-based multiple imputation
If a dataset has some subjects with non-monotone missingness, the most frequently used
imputation method in PROC MI is based on the Markov Chain Monte Carlo methodology and 
assumes a multivariate normal distribution over all variables included in the imputation model. 
For datasets with monotone missingness, a number of different methods are available for 
continuous as well as categorical variables, including some parametric and non-parametric 
methods. Fortunately, standard software facilitates using the MCMC method to impute data 
only partially – just enough to obtain a dataset with monotone missingness. Then the remaining 
missing items can be imputed using other available methods if deemed more suitable. This two-
step procedure is the one we use, and is illustrated below using the example dataset described 
in Section 3 and above in this appendix.
In PROC MI the MCMC method is used to partially impute non-monotone data with the 
impute=monotone option to obtain a dataset with monotone missingness.
proc mi data=DIN out=DIN_MONO nimpute=1000 seed=123181;
var DRUGNUM SOC_T1 SOC_T2 BASE W5 W9-W49;
mcmc chain=multiple impute=monotone nbiter=200 niter=100;
run;
Note that the SOC type factor is dichotomized in 2 continuous variables as in this first call 
only numeric variable can be used.
Values of the MCMC parameters NBITER (the number of MCMC updates allowed for the 
sampler to converge to the posterior distribution, and NITER (the number of iterations between 
each saved draw from the posterior) may need to be increased to allow the MCMC estimates 
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Assumptions underlying this partial imputation step would be of the MAR type, i.e., that 
subjects with intermediate missing data follow the same model as other subjects in their 
respective treatment arm that continue the study. This is a reasonable assumption for this partial 
imputation process because subjects tend to miss intermediate visits due to scheduling conflicts 
or other reasons generally unrelated to their medical condition under study. 
If the proportion of non-monotone missing data is small compared to the number of subjects 
that discontinue from the study permanently, imputing these few non-monotone values using 
the partial MCMC method under MAR assumptions would have a small impact on the overall 
analyses. Note that we will use 1000 imputations. This number is much larger than the default 
in most software packages. This high number of imputations decrease at the best the uncertainty 
of the imputation and using as many as 1000 or so imputations does not present any 
computational difficulties with the current technology.
The output data set DIN_MONO from the above call to PROC MI can now be used as input to 
a subsequent call of PROC MI to impute the remaining monotone missing values. Since dataset 
DIN_MONO already contains 1000 copies of the data with partial imputations, the subsequent 
call to PROC MI will use a BY _Imputation_ statement and request one imputed dataset
(nimpute=1 option) within each BY group. This second call will be based on a Not Missing
At Random (NMAR) approach as described in B part.
B- NMAR data imputation
Reference-based pattern imputation (unconditional reference)
Assuming that non-monotone missing data have already been imputed using the MCMC 
method as described above we will then break the imputation process into a sequence of MIs, 
where each MI is intended to impute missing values at one time-point only, as follows.
i.
In order to impute missing data at time-point 1 (W5) and based on the definition of
the link function, first prepare an input dataset, making sure that it will contain only
the intended donor pattern (P1: control subjects with non-missing values) and
recipient patterns (P2: control arms with missing data and P4 active group with
missing data). Separate the input dataset DIN_MONO into two datasets:
DIN_MONO_IMP1, containing all control subjects and those subjects from the
active group that have values at W4 missing (patterns P1, P2 and P4); and
DIN_MONO_REST1, containing the subjects from the active group with non-
missing values (pattern P4.
data DIN_MONO_IMP1
DIN_MONO_REST1;
set DIN_MONO;
*** subjects from the VAY736 non-missing values at W5 ***;
if DRUGNUM=1 and LASTVIS>=5 then output DIN_MONO_REST1;
***All other included VAY736 with missing W5 ***;
else output DIN_MONO_IMP1;
run;
i.
Call PROC MI to impute missing data at time-point 1
using dataset
DIN_MONO_IMP1 as input.


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proc mi data= DIN_MONO_IMP1 out= DIN_REG_IMP1 nimpute=1
seed=234;
by _Imputation_;
var SOC_TYPE BASE W5;
monotone regression (W5 = SOC_TYPE BASE);
run;
Note that treatment arm is not included as an effect in the model (it is not included 
in the VAR statement). Since subjects from the active group with non-missing 
values at time-point t are not included in the input dataset, they will not contribute 
to the estimation of an imputation model for time-point t. The imputation model will 
be estimated using control subjects only, while this call to PROC MI will impute 
missing data at time-point t for all subjects who need imputation at that time-point. 
This way, subjects from active group will be imputed based on the control subjects’ 
model.
ii.
Assemble a dataset containing all subjects while including the just-imputed visit t
data so that they can serve as predictors for the imputation of the next visit.
data DIN_IMP1;
set DIN_REST1 DIN_REG_IMP1;
run;
iii.
Repeat steps (i)-(iii) for all other time-points sequentially using a reconstructed
dataset (e.g., DIN_IMP1) as a starting point in step (i).
C- Modelling on M complete datasets
Once all missing data has been imputed then an ANCOVA of the change from baseline of 
FVC (CHANGE) at week 49 visit will be applied by _Imputation_ as per model below:
proc mixed data=DIN_FULLIMP;
by _Imputation;
where VISIT='Week 49'
class DRGNUM SOC_TYPE;
model CHANGE = DRGNUM SOC_TYPE BASE / s ddfm=kr;
lsmeans DRGNUM / diff=control('0') cl;
ods output Diffs=DIFF_MI LSMeans=LSM_MI;
quit;
D- Pooling analysis
Once the result by Imputation are computed then the parameter estimates will be combined as 
per Rubin (1976, 1987) method using PROC MIANALYZE.
proc mianalyze parms=DIFF_MI;
modeleffects DRGNUM;
stderr STDERR;
ods output parameterestimates=MiDIFF;
run;


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Signatures
Personal Protected Data