Clinical trial NCT02345070
Conditions: Idiopathic Pulmonary Fibrosis
Sponsor: Sanofi
Start date: 2015-05-01; Completion date: 2017-08-14
Enrollment: 327 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objective:

To evaluate, in comparison with placebo, the efficacy of 2 dose levels/regimens of SAR156597 administered subcutaneously during 52 weeks on lung function of participants with Idiopathic Pulmonary Fibrosis (IPF).

Secondary Objectives:

To evaluate the efficacy of 2 dose levels/regimens of SAR156597 compared to placebo on IPF disease progression.

To evaluate the safety of 2 dose levels/regimens of SAR156597 compared to placebo in participants with IPF.

Detailed description:
The total study duration of study was expected up to 68 weeks (screening period of 4 weeks, treatment period of 52 weeks, and 12 weeks of follow up).

Arms: arm 1: Participants received one injection of placebo (matched to SAR156597) subcutaneously once every week (qw) for 52 weeks. arm 2: Participants received one injection of SAR156597 200 mg subcutaneously once every 2 weeks (q2w) alternating with placebo (matched to SAR156597) for 52 weeks. arm 3: Participants received one injection of SAR156597 200 mg subcutaneously qw for 52 weeks.
Interventions: intervention 1: SAR156597 intervention 2: placebo
Intervention descriptions: intervention 1: Pharmaceutical form: solution for injection Route of administration: subcutaneous intervention 2: Pharmaceutical form: solution for injection Route of administration: subcutaneous

Protocol documents:
Prot_000.pdf: 


Amended Clinical Trial Protocol 2  
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Protocol Amendment 4 - Denmark 
Version number: 1 (electronic 1.0) 
Date: 20-Jan-2015 
 
Amended Clinical Trial Protocol 1 - United 
Kingdom 
 
Version number: 1 (electronic 1.0) 
 
Date: 20-Jan-2015 
Protocol Amendment 3 - United Kingdom 
Version number: 1 (electronic 1.0) 
Date: 20-Jan-2015 
Amended Clinical Trial Protocol 1 - 
Germany 
Version number: 1 (electronic 1.0) 
Date: 20-Jan-2015 
Protocol Amendment 2 - Germany 
Version number: 1 (electronic 1.0) 
Date: 20-Jan-2015 
Amended Clinical Trial Protocol 1 - Global 
Version number: 1 (electronic 1.0) 
Date: 19-Dec-2014 
Protocol Amendment 1 
Version number: 1 (electronic 1.0) 
Date: 19-Dec-2014 
Clinical Trial Protocol 
Version number: 1 (electronic 2.0) 
Date: 14-Nov-2014 
EudraCT or IND number : 2014-003933-24 
 
 
 
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NAMES AND ADDRESSES OF 
COORDINATING 
INVESTIGATOR 
 
Name: 
Address: 
 
 
Tel: 
Fax: 
E-mail: 
 
 
MONITORING TEAM’S 
REPRESENTATIVE 
  
Name: 
Address: 
 
 
 
Tel: 
Fax: 
E-mail: 
 
 
SPONSOR 
  
Company: 
Address: 
 
 
 
 
 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
 
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CLINICAL TRIAL SUMMARY 
 
COMPOUND:SAR156597  
STUDY No: DRI11772  
TITLE 
Efficacy and safety of SAR156597 in the treatment of Idiopathic 
Pulmonary Fibrosis (IPF): A randomized, double-blind, placebo-
controlled, 52-week dose-ranging study. 
INVESTIGATOR/TRIAL LOCATION 
International 
PHASE OF DEVELOPMENT 
Phase 2 
STUDY OBJECTIVE(S) 
 
Primary objective 
• 
To evaluate, in comparison with placebo, the efficacy of 2 dose 
levels/regimens of SAR156597 administered subcutaneously during 
52 weeks on lung function of patients with IPF 
 
Secondary objective(s)  
• 
To evaluate the efficacy of 2 dose levels/regimens of SAR156597 
compared to placebo on IPF disease progression 
 
• 
To evaluate the safety of 2 dose levels/regimens of SAR156597 
compared to placebo in patients with IPF 
 
• 
To evaluate the pharmacokinetics (trough plasma concentrations)  
of SAR156597 administered subcutaneously during 52 weeks 
 
• 
To assess the potential immunogenicity of SAR156597 
 
• 
To evaluate the effect of SAR156597 on circulating biomarkers 
 
• 
To explore the effect of SAR156597 on quality of life 
 
STUDY DESIGN 
• 
Multinational, randomized, double-blind, placebo-control, 3 parallel 
groups  
• 
Patients will be randomized in a 1:1:1  ratio to receive SC 
administrations of  SAR156597 or placebo in one of the following 
regimens: 
o 
SAR156597  200mg every week (qw) 
o 
SAR156597  200mg every 2 weeks (q2w) alternating with 
placebo every other week (for blind purposes)  
o 
Placebo every week (qw) 
• 
Patient stratification at baseline according to background therapy in 
authorized countries: 
o 
Patient with background therapy with either pirfenidone or 
nintedanib versus patient without background therapy 
• 
Duration of treatment: 52 weeks 
STUDY POPULATION  
Main selection criteria 
Inclusion criteria  
• 
Consenting male or female patients 
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• 
Documented diagnosis of IPF according to the following criteria: 
• 
Exclusion of other known causes of interstitial lung disease 
(e.g. domestic and occupational environmental exposures, 
connective tissue disease, and drug toxicity)* 
AND 
• 
Combination of patterns of usual interstitial pneumonia (UIP) 
on HRCT images of chest, and on surgical lung biopsy (when 
obtained)*             
 
 OR 
Presence of Possible UIP pattern* on HRCT images of chest 
AND additional evidence of traction bronchiectasis as 
assessed by an experienced chest radiologist (Central  
Review**) 
* As defined in the current 2011 ATS/ERS/JRS/ALAT guidelines 
** The patterns of UIP on HRCT images of chest and histopathology in 
surgical lung biopsy (if done) will be reviewed by central reviewers (a 
radiologist and a pathologist experienced in interstitial lung diseases) to 
confirm diagnosis of IPF for consistency. 
 
Exclusion criteria 
• 
Age ≤40 years 
• 
IPF disease diagnosis >5 years 
• 
Forced vital capacity (FVC) <40% of predicted value 
• 
Carbon monoxide diffusing lung capacity (DLCO) corrected for 
hemoglobin <30% of predicted value 
• 
Severe chronic obstructive bronchitis as characterized by 
FEV1/FVC <0.70 
• 
Need for 24 hrs of oxygen therapy or oxygen saturation <88% after 
10 minutes breathing ambient air at rest 
• 
Known diagnosis of significant respiratory disorders (eg, asthma, 
tuberculosis, sarcoidosis, aspergillosis, or cystic fibrosis) other than 
IPF 
• 
Pulmonary artery hypertension requiring a specific treatment 
• 
Currently listed and/or anticipated to be listed for lung 
transplantation within the next 6 months (active list) 
• 
History of vasculitis or connective tissue disorders or ANCA positive 
• 
History of myocardial infarction within 6 months prior to screening 
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Total expected number of patients 
Approximately N=300 (100 patients per group) 
STUDY TREATMENT(s) 
 
Investigational medicinal 
product(s) 
 
Formulation 
SAR156597 or placebo 
• 
SAR156597 in lyophilized form (each vial containing 125 mg total of 
SAR156597 plus excipients, to be reconstituted with 1.1 mL of 
sterile water for injection to achieve a final concentration of 100 
mg/mL of SAR156597) 
• 
Placebo consisting of 1.5 mL of liquid per vial containing the same 
excipients at the same concentrations as for the reconstituted 
SAR156597 formulation 
Route(s) of administration 
Subcutaneous (SC) 
Dose regimen 
Patients will receive SC administrations of SAR156597 or placebo in one 
of the following regimens:  
• 
SAR156597 200mg qw     
• 
SAR156597 200mg q2w alternating with placebo every other week    
• 
Placebo qw 
Noninvestigational medicinal 
product(s) (if applicable) 
 
 
NA 
ENDPOINT(S) 
 
Efficacy 
Primary endpoint 
• 
Absolute change from baseline in % predicted FVC at 52 weeks 
Secondary endpoint(s) 
• 
Disease progression as defined by the number of the following 
events: decrease in absolute % predicted FVC ≥10%, or decrease 
in absolute % predicted DLCO ≥15%, or lung transplant, or death at 
52 weeks 
• 
All-cause mortality at 52 weeks 
Exploratory endpoint(s) 
• 
Acute exacerbations 
• 
Respiratory hospitalizations and non-elective hospitalizations 
• 
Change in 6-Minute Walk Test distance (6-MWT) 
• 
Changes in HRCT lung interstitial evaluation score 
• 
Change on quality of life score as measured on the St George's 
Respiratory Questionnaire (SGRQ) and on the EuroQol 
questionnaire, 5 level system (EQ-5D-5L) 
 
Safety 
• 
Adverse events (AEs)/treatment-emergent adverse events (TEAEs) 
• 
Physical examination and body weight 
• 
Vital signs and 12-lead electrocardiogram 
• 
Clinical laboratory evaluations including hematology, biochemistry 
and urinalysis 
• 
 
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• 
Tolerability at the investigational medicinal product  (IMP) injection 
site: 
- Erythema (diameter and graded severity) 
- Swelling/induration/edema (diameter and graded severity) 
- Pain assessment 
Immunogenicity 
Testing for anti-drug antibodies (ADA) 
Biomarker quantification  
• 
Blood biomarkers which may predict response to drug, disease 
progression and provide evidence of drug action will be collected 
including but not limited to inter-cellular adhesion molecule 1 
(ICAM1), TARC, periostin and HE4 
• 
Archived  blood samples will be performed for future assay of 
protein and mRNA biomarkers related  to the diagnosis, 
progression, or therapeutic responsiveness of IPF 
Pharmacokinetics 
Population PK analysis of plasma SAR156597 concentrations to predict 
PK parameters at steady state (Cmax, tmax, AUC0-168 &/or AUC0-336) 
and time to reach steady state. 
 
ASSESSMENT SCHEDULE 
The study will comprise 10 on-site visits AND 9 phone calls: 
 
• 
Visits: 
 
- V1 screening visit between D -28 and Day -1 
- V2 baseline visit at D1 (first dosing) 
- during the treatment period*:  
- visit every 2 weeks from V2 to V5 
- every 6 weeks from V5 to V6 
- every 12 weeks from V6 to V8 
- every 16 weeks from V8 to V9 (Week 52; last         dosing) 
- V10 follow-up visit at Week 64 
- A time window of ±2 days will be allowed for each visit 
 
• 
Phone calls: 
 
- For safety considerations at Weeks 8, 16, 20, 28, 32, 40, 44, 48 
during the treatment period and at Week 58 during the follow-up 
period. 
 
*IMP administration being every week. 
STATISTICAL CONSIDERATIONS 
 
Sample size determination: 
Based on prior clinical trial experience in IPF patients, it is estimated that 
the standard deviation (SD) of the absolute change in % predicted FVC 
at 52 weeks is approximately 12%.  For the primary efficacy parameter of 
absolute change in % predicted FVC, 92 patients per treatment group will 
yield 80% power to detect a 5 percentage point difference between the 
treatment groups and placebo.  Additional patients will be randomized in 
each regimen to allow for dropouts; therefore, approximately 100 patients 
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will be randomized into each treatment group, for a total sample size of 
approximately 300 patients for the study. 
Analysis sets: 
Safety analyses will be conducted on the Safety population, which 
includes all randomized patients who receive at least 1 injection of 
investigational medicinal product. Efficacy analyses will be performed on 
the modified intent to treat population (primary population), which 
includes all patients who receive at least 1 injection of investigational 
medicinal product, have a valid baseline % predicted FVC measurement, 
and have at least 1 post-baseline % predicted FVC measurement. The 
primary statistical analysis will be performed once all patients have 
completed the Week 52 assessment and the database has been cleaned 
and locked. 
Primary efficacy analysis 
A rank-based analysis of covariance (ANCOVA) will be performed on the 
change from baseline in % predicted FVC. The ANCOVA model will 
include treatment group as the main factor and the baseline % predicted 
FVC as a continuous covariate.  
Analysis of secondary endpoints 
Analysis of time to event endpoints will be performed using the log-rank 
test and Cox proportional hazards regression model. 
Safety analysis 
TEAEs and serious AEs (SAEs) (will be summarized for each treatment 
group by primary system organ class (SOC), high level group term 
(HLGT), high level term (HLT), and preferred term (PT), as well as by 
severity and relationship to study treatment. The rate of potentially 
clinically significant abnormalities (PCSAs) will also be summarized by 
treatment group. Additionally, listings of all AEs, SAEs, and AEs leading 
to treatment discontinuation will be generated.  Clinical laboratory 
evaluations, vital signs, electrocardiograms (ECGs), a selected panel of 
biomarkers, and ADA will be tabulated by treatment group. These safety 
analyses will be compared qualitatively between the treatment groups. 
DURATION OF STUDY PERIOD (per 
patient)  
The study will last 68 weeks per patient as follows: 
• 
4 weeks of screening 
• 
52 weeks of study treatment 
• 
12 weeks of follow-up with no study treatment 
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1 
FLOW CHARTS 
1.1 
GRAPHICAL STUDY DESIGN 
 
 
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2 
TABLE OF CONTENTS 
 
AMENDED CLINICAL TRIAL PROTOCOL 2 ................................................................................................1 
1 
FLOW CHARTS...............................................................................................................................9 
1.1 
GRAPHICAL STUDY DESIGN ........................................................................................................9 
1.2 
STUDY FLOW CHART ..................................................................................................................10 
2 
TABLE OF CONTENTS ................................................................................................................13 
3 
LIST OF ABBREVIATIONS ..........................................................................................................19 
4 
INTRODUCTION AND RATIONALE.............................................................................................20 
4.1 
INTRODUCTION............................................................................................................................20 
4.2 
RATIONALE...................................................................................................................................22 
4.2.1 
Study design ..................................................................................................................................22 
4.2.2 
Design rationale .............................................................................................................................22 
4.2.3 
Rationale for the use of outcome measures ..................................................................................23 
4.2.3.1 
Pulmonary Function Tests (PFTs) .................................................................................................23 
4.2.3.2 
Six-Minute Walk Test (6MWT) and Pulse Oximetry ......................................................................23 
4.2.3.3 
Lung High Resolution Computed Tomography (HRCT) ................................................................23 
4.2.3.4 
St George Respiratory Questionnaire (SGRQ)..............................................................................23 
4.2.3.5 
EuroQol Questionnaire, 5 level system (EQ-5D-5L)......................................................................23 
4.2.3.6 
Biomarkers.....................................................................................................................................24 
4.2.3.7 
Genetic testing ...............................................................................................................................24 
5 
STUDY OBJECTIVES ...................................................................................................................25 
5.1 
PRIMARY.......................................................................................................................................25 
5.2 
SECONDARY ................................................................................................................................25 
6 
STUDY DESIGN ............................................................................................................................26 
6.1 
DESCRIPTION OF THE PROTOCOL...........................................................................................26 
6.2 
DURATION OF STUDY PARTICIPATION ....................................................................................26 
6.2.1 
Duration of study participation for each patient .............................................................................26 
6.2.2 
Determination of end of clinical trial (all patients) ..........................................................................26 
6.3 
STUDY COMMITTEES..................................................................................................................27 
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SELECTION OF PATIENTS..........................................................................................................28 
7.1 
INCLUSION CRITERIA..................................................................................................................28 
7.2 
EXCLUSION CRITERIA ................................................................................................................28 
8 
STUDY TREATMENTS .................................................................................................................32 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) ..........................................................................32 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) ..................................................................33 
8.3 
BLINDING PROCEDURES............................................................................................................34 
8.3.1 
Methods of blinding........................................................................................................................34 
8.3.2 
Randomization code breaking during the study.............................................................................35 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................35 
8.5 
PACKAGING AND LABELING ......................................................................................................36 
8.6 
STORAGE CONDITIONS AND SHELF LIFE................................................................................36 
8.7 
RESPONSIBILITIES ......................................................................................................................37 
8.7.1 
Treatment accountability and compliance......................................................................................37 
8.7.2 
Return and/or destruction of treatments ........................................................................................37 
8.8 
CONCOMITANT MEDICATIONS ..................................................................................................38 
8.8.1 
Prohibited medications...................................................................................................................38 
8.8.2 
Authorized concomitant medications .............................................................................................38 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................40 
9.1 
EFFICACY .....................................................................................................................................40 
9.1.1 
Primary endpoint............................................................................................................................40 
9.1.2 
Secondary endpoints .....................................................................................................................40 
9.1.3 
Exploratory endpoints ....................................................................................................................40 
9.1.4 
Assessment methods and activity parameters ..............................................................................40 
9.1.4.1 
Pulmonary Function Tests will include:..........................................................................................40 
9.1.4.2 
Pulse oximetry................................................................................................................................41 
9.1.4.3 
Lung HRCT ....................................................................................................................................41 
9.1.4.4 
6-MWT ...........................................................................................................................................41 
9.1.4.5 
Patient Reported Outcome ............................................................................................................41 
9.2 
SAFETY ENDPOINTS ...................................................................................................................41 
9.2.1 
Adverse events ..............................................................................................................................42 
9.2.2 
Physical examination .....................................................................................................................42 
9.2.3 
Laboratory safety variables............................................................................................................42 
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9.2.4 
Vital signs.......................................................................................................................................43 
9.2.5 
Electrocardiogram variables ..........................................................................................................44 
9.2.6 
Hypersensitivity/Allergic or anaphylactic reactions ........................................................................44 
9.3 
OTHER ENDPOINTS.....................................................................................................................44 
9.3.1 
Pharmacokinetics...........................................................................................................................44 
9.3.1.1 
Sampling time ................................................................................................................................44 
9.3.1.2 
Pharmacokinetics handling procedure...........................................................................................44 
9.3.1.3 
Bioanalytical method......................................................................................................................45 
9.3.1.4 
Pharmacokinetics parameters .......................................................................................................46 
9.3.2 
Biomarkers.....................................................................................................................................46 
9.3.2.1 
Archival serum for future biomarkers.............................................................................................46 
9.3.2.2 
Bioanalysis methods ......................................................................................................................46 
9.3.3 
Pharmacogenetic ...........................................................................................................................46 
9.3.3.1 
Genetic samples for DNA ..............................................................................................................46 
9.3.3.2 
Protection of subject identity and genetic sample/data handling...................................................47 
9.3.3.3 
Optional stored DNA sample .........................................................................................................47 
9.4 
FUTURE USE OF SAMPLES ........................................................................................................48 
9.5 
APPROPRIATENESS OF MEASUREMENTS ..............................................................................48 
10 
STUDY PROCEDURES ................................................................................................................49 
10.1 
VISIT SCHEDULE..........................................................................................................................49 
10.1.1 
Visit 1: Screening (D-28 to D-1).....................................................................................................49 
10.1.2 
Visit 2: Baseline /Randomization/ Day 1........................................................................................51 
10.1.3 
Visit 3: on treatment / Week 2........................................................................................................53 
10.1.4 
Visit 4: on treatment / Week 4........................................................................................................53 
10.1.5 
Visit 5: on treatment / Week 6........................................................................................................54 
10.1.6 
Phone call: on treatment / Week 8, Week 16, Week 20, Week 28, Week 32, Week 40, 
Week 44, and Week 48..................................................................................................................55 
10.1.7 
Visit 6, Visit 7 and Visit 8: on treatment / Week 12, Week 24, and Week 36 ................................55 
10.1.8 
Visit 9: End of treatment / Week 52 (or Early termination).............................................................56 
10.1.9 
Phone call: Follow up post treatment / Week 58 ...........................................................................57 
10.1.10 Visit 10: End of study visit / Week 64.............................................................................................58 
10.2 
DEFINITION OF SOURCE DATA..................................................................................................58 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.......................................59 
10.3.1 
Temporary treatment discontinuation with investigational medicinal product(s) ...........................59 
10.3.2 
Permanent treatment discontinuation with investigational medicinal product(s) ...........................59 
10.3.3 
List of criteria for permanent treatment discontinuation.................................................................59 
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10.3.4 
Handling of patients after permanent treatment discontinuation ...................................................60 
10.3.5 
Procedure and consequence for patient withdrawal from study....................................................60 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................61 
10.4.1 
Definitions of adverse events.........................................................................................................61 
10.4.1.1 Adverse event ................................................................................................................................61 
10.4.1.2 Serious adverse event ...................................................................................................................61 
10.4.1.3 Adverse event of special interest...................................................................................................62 
10.4.2 
Serious adverse events waived from expedited regulatory reporting to regulatory 
authorities.......................................................................................................................................63 
10.4.3 
General guidelines for reporting adverse events ...........................................................................63 
10.4.4 
Instructions for reporting serious adverse events ..........................................................................64 
10.4.5 
Guidelines for reporting adverse events of special interest...........................................................65 
10.4.6 
Guidelines for management of specific laboratory abnormalities ..................................................65 
10.5 
OBLIGATIONS OF THE SPONSOR .............................................................................................67 
10.6 
SAFETY INSTRUCTIONS .............................................................................................................67 
10.6.1 
........................................67 
10.6.2 
Tolerability at the IMP injection ......................................................................................................69 
10.6.2.1 Local injection site reactions ..........................................................................................................69 
10.6.3 
Systemic allergy reaction ...............................................................................................................69 
10.6.3.1 Anaphylaxis....................................................................................................................................69 
10.6.3.2 Allergic adverse event with cutaneous involvement ......................................................................70 
10.7 
ADVERSE EVENTS MONITORING..............................................................................................70 
11 
STATISTICAL CONSIDERATIONS..............................................................................................71 
11.1 
DETERMINATION OF SAMPLE SIZE...........................................................................................71 
11.2 
DISPOSITION OF PATIENTS .......................................................................................................71 
11.3 
ANALYSIS POPULATIONS...........................................................................................................72 
11.3.1 
Efficacy populations .......................................................................................................................72 
11.3.1.1 Modified intent-to-treat population .................................................................................................72 
11.3.2 
Safety population ...........................................................................................................................72 
11.3.3 
Pharmacokinetic analysis population.............................................................................................72 
11.4 
STATISTICAL METHODS .............................................................................................................72 
11.4.1 
Extent of study treatment exposure and compliance.....................................................................72 
11.4.1.1 Extent of investigational medicinal product exposure....................................................................73 
11.4.1.2 Compliance ....................................................................................................................................73 
11.4.2 
Analyses of efficacy endpoints.......................................................................................................73 
11.4.2.1 Analysis of primary efficacy endpoint(s) ........................................................................................73 
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11.4.2.2 Analyses of secondary efficacy endpoints.....................................................................................74 
11.4.2.3 Multiplicity considerations ..............................................................................................................74 
11.4.3 
Analyses of safety data..................................................................................................................74 
11.4.4 
Analyses of pharmacokinetic, pharmacodynamics and biomarker variables ................................78 
11.5 
INTERIM ANALYSIS......................................................................................................................78 
12 
ETHICAL AND REGULATORY CONSIDERATIONS...................................................................79 
12.1 
ETHICAL AND REGULATORY STANDARDS ..............................................................................79 
12.2 
INFORMED CONSENT .................................................................................................................79 
12.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) ..............80 
13 
STUDY MONITORING...................................................................................................................81 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S).......................................................................81 
13.2 
RESPONSIBILITIES OF THE SPONSOR.....................................................................................81 
13.3 
SOURCE DOCUMENT REQUIREMENTS....................................................................................81 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST......................................................................................................................................82 
13.5 
USE OF COMPUTERIZED SYSTEMS..........................................................................................82 
14 
ADDITIONAL REQUIREMENTS...................................................................................................83 
14.1 
CURRICULUM VITAE....................................................................................................................83 
14.2 
RECORD RETENTION IN STUDY SITES ....................................................................................83 
14.3 
CONFIDENTIALITY .......................................................................................................................83 
14.4 
PROPERTY RIGHTS.....................................................................................................................84 
14.5 
DATA PROTECTION.....................................................................................................................84 
14.6 
INSURANCE COMPENSATION....................................................................................................85 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES .................................85 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE............................................................................................................................................85 
14.8.1 
By the Sponsor...............................................................................................................................85 
14.8.2 
By the Investigator .........................................................................................................................86 
14.9 
CLINICAL TRIAL RESULTS ..........................................................................................................86 
14.10 
PUBLICATIONS AND COMMUNICATIONS .................................................................................86 
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CLINICAL TRIAL PROTOCOL AMENDMENTS ..........................................................................88 
16 
BIBLIOGRAPHIC REFERENCES.................................................................................................89 
17 
APPENDICES................................................................................................................................92 
APPENDIX A 
SAINT GEORGE RESPIRATORY QUESTIONNAIRE .......................................................93 
APPENDIX B 
EUROQOL QUESTIONNAIRE ( EQ-5D-5L) .......................................................................99 
APPENDIX C 
...........................................................................................102 
APPENDIX D CLINICAL CRITERIA FOR DIAGNOSING ANAPHYLAXIS..............................................103 
APPENDIX E 
ASSESSMENT OF LOCAL INJECTION SITE REACTIONS............................................104 
APPENDIX F GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES BY SANOFI....................................................................................................105 
 
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3 
LIST OF ABBREVIATIONS 
 
6-MWT: 
6-Minute Walk Test distance (6-MWT) 
ADA: 
anti-drug antibodies 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALAT: 
Latin American Thoracic Association 
ALT: 
alanine transaminase 
ANCA: 
anti-neutrophil cytoplasmic autoantibody 
AST: 
aspartate transaminase 
ATS: 
American Thoracic Society 
CPK MB: 
Creatinine Phosphokinase Muscle Brain 
DLCO: 
carbon monoxide diffusing lung capacity 
DMC: 
Data Monitoring Committee 
DNA: 
deoxyribonucleic acid 
ECG: 
electrocardiogram 
e-CRF: 
electronic case report form 
EQ-5D-5L: 
EuroQol Questionnaire, 5 level system 
ERS: 
European Respiratory Society 
ESR: 
erythrocyte sedimentation rate 
FEV1: 
forced expiratory volume over 1 second 
FVC: 
forced vital capacity 
HLGT: 
High-Level Group Term 
HLT: 
High Level Term 
hsCRP: 
high-sensitivity C-reactive protein 
IMP: 
Investigational Medicinal Product 
JRS: 
Japanese Respiratory Society 
PCSA: 
Potentially Clinically Significant Abnormalities 
PFTs: 
pulmonary function tests 
PK: 
pharmacokinetic 
PT: 
Preferred Term 
q2w: 
every 2 weeks 
qw: 
weekly 
SAE: 
serious adverse event 
SC: 
subcutaneous 
SGRQ: 
St George Respiratory Questionnaire 
SOC: 
System Organ Class 
SpO2: 
oxygen saturation by pulse oximetry 
SUSAR: 
suspected unexpected adverse drug reaction 
TB: 
Tuberculosis 
ULN: 
upper limit of normal range 
WHO: 
World Health Organization 
β-HCG: 
beta-human chorionic gonadotropin 
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INTRODUCTION AND RATIONALE 
4.1 
INTRODUCTION 
Idiopathic pulmonary fibrosis (IPF) is a progressive, diffuse, and distinct chronic fibrosing 
interstitial pneumonia of unknown cause that is uniformly fatal with a median survival of 
approximately 3 years (1). The clinical course of IPF is variable and not predictable; the rate of 
decline and progression to death may take several clinical forms: slow physiologic deterioration 
with worsening severity of dyspnea, rapid deterioration, and progression to death, or periods of 
relative stability interposed with periods of acute respiratory decline sometimes manifested by 
hospitalizations for respiratory failure (2). Epidemiological data still qualify IPF as a “rare 
disease”, even though international studies seem to report an increasing incidence, with current 
estimates between 4.6 and 16.3 per 100 000 person-years and a prevalence of 13 to 20 cases per 
100 000 ((3), (4), (5)). There is a higher predominance of the disease in men (1.5 to 1.7:1) than in 
women and the frequency increases with age (5). The most important environmental risk factors 
are cigarette smoking, exposure to metal and wood dust(1), and infectious agents including both 
viruses and bacteria(6). Genetic transmission occurs in about 0.5% to 3.7% of patients with IPF 
(7). The diagnosis of IPF often requires a multidisciplinary approach, involving pulmonologists, 
radiologists, and pathologists experienced in the field of interstitial lung diseases(8). The 
pathogenic mechanisms are unclear, but a growing body of evidence indicates that the disease is 
the result of an abnormal behavior of the alveolar epithelial cells that provoke the migration, 
proliferation, and activation of mesenchymal cells, with the formation of fibroblast and 
myofibroblast foci. Activated myofibroblasts secrete exaggerated amounts of extracellular matrix 
molecules with the subsequent destruction of the lung architecture (9). Pirfenidone (Esbriet®, 
Roche), an oral drug that is hypothesized to inhibit the synthesis of transforming growth factor-
beta, was approved so far in Japan, China and in the European Union for the treatment of IPF. 
Very recently, the FDA approved pirfenidone as well as nintedanib (Ofev®),an oral kinase 
inhibitor for the treatment of IPF. Per labeling information, these two drugs were shown to 
significantly reduce the decline of lung function as compared to placebo. No statistically 
significant effect on death was demonstrated. Lung transplantation is the only therapy that 
prolongs survival in advanced IPF, although the post-transplantation 5-year survival for patients 
with IPF is about 48% (10). Interleukin 4 (IL)-4 and interleukin 13 (IL-13) are structurally related 
cytokines expressed by T helper type 2 lymphocytes and are ligands that share in common at least 
1 receptor subunit (IL-4R alpha) (11), (12). Elevations in IL-4 and IL-13 and their receptors have 
been linked to the pathogenesis of IPF (13), (14). In IPF patients, IL-13 and IL-4 levels in 
bronchial alveolar lavage fluid are elevated compared to normal controls (15). Such evidence 
suggests that therapies capable of suppressing or neutralizing these cytokines have the potential 
for delaying the progression of fibrosis in IPF patients. SAR156597 is an engineered humanized 
bispecific IgG4 antibody that binds and neutralizes both IL-4 and IL-13. It utilizes an innovative 
tetravalent bispecific tandem immunoglobulin format to combine the antigen binding domains of 
an anti-IL-4 antibody and an anti-IL-13 antibody into a single molecule. SAR156597 shows high 
affinity for IL-4 and IL-13 from both humans and cynomolgus monkeys, and each antibody has 
binding sites for 2 IL-4 and 2 IL-13 cytokines. 
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4.2 
RATIONALE 
4.2.1 Study design 
DRI11772 study will consist of the evaluation of the efficacy and safety of 2 dose levels/regimens 
of SAR156597 administered subcutaneously over a 52-week treatment period and, the 
determination of the optimal dose level/regimen for the treatment of patients with IPF. 
It will be a multinational, randomized, double-blind, placebo-controlled, 3-parallel group study 
conducted in out-patients suffering from IPF according to the American Thoracic Society/ 
European Respiratory Society/ Japanese Respiratory Society/ Latin American Thoracic 
Association (ATS/ERS/JRS/ALAT) guideline criteria and confirmed by a multidisciplinary panel 
of experts in IPF. 
Patients who discontinue treatment during the study will be followed for the full planned 52 week 
duration of the study in order to ensure the collection of efficacy outcomes on all randomized 
patients and minimize the potential for bias in analyses due to missing data. 
4.2.2 Design rationale 
The 52-week treatment duration is based on published data from clinical trials in IPF and also 
from IPF natural history data that respectively showed evidence for treatment-induced changes on 
surrogate endpoints and significant decline in respiratory function characteristic of disease 
progression over a 12-month period. 
The follow-up period of 12 weeks after dosing for adverse events (AEs) and pharmacokinetic 
(PK) analysis is appropriate taking into account the estimated half-life of about 11 to 15 days for 
SAR156597 from the TDU11325 and TDR11326 studies. 
Dose selection 
SAR156597 was safe and well tolerated at single SC doses up to 300 mg in healthy subjects as 
well as at repeated SC doses up to 200 mg during 6 weeks in patients with IPF, including at the 
injection site level. 
No in vivo data from an appropriate animal model of IPF is available to guide the desired 
pharmacologically active exposure of SAR156597.  However, modelling and simulation of the 
inhibition of Stat6 phosphorylation in monkey suggest that its inhibition will be fully achieved. 
Additionally, SAR156597 has been shown to reduce in a dose dependent manner (up to 200 mg 
once a week) the plasma level of TARC, a protein biomarker involved in the IL-4/IL-13 pathway, 
after 6 weeks of treatment in patients with IPF. 
As the desired dose frequency for patient convenience is once every 2 weeks, the weekly dose 
regimen for the 200 mg dose level will be compared to the every 2 weeks dose regimen for 200 
mg. 
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Finally, modelling and simulations based on the PK data from the multiple dose clinical study 
(TDR11326) have confirmed that a 200 mg dose administered once every 2 weeks and once a 
week give an acceptable safety margin in terms of exposure ratio (monkey AUC at 
NOAEL/human AUC) of ~6 and ~3 respectively. 
4.2.3 Rationale for the use of outcome measures 
4.2.3.1 Pulmonary Function Tests (PFTs) 
Pulmonary function tests (PFTs) will be assessed during the study. Pulmonary function tests, such 
as spirometry and carbon monoxide diffusing lung capacity (DLCO), are standard evaluations for 
patients with IPF. Changes in forced vital capacity (FVC) and DLCO have been shown to be 
correlated with survival (17). 
4.2.3.2 Six-Minute Walk Test (6MWT) and Pulse Oximetry 
The 6-MWT with oximetry will be used in this study. It is a safe and reproducible procedure for 
patients with IPF. Baseline desaturation during a 6MWT is a powerful predictor of subsequent 
mortality (18) 
4.2.3.3 Lung High Resolution Computed Tomography (HRCT) 
A significant correlation between high-resolution computed tomography (HRCT) visual score and 
lung function tests both at diagnosis and at follow-up has been shown and reported in the 
literature. The HRCT study is able to identify and quantify anatomic IPF and also to evaluate the 
progression of the disease. In clinical practice, the HRCT visual score of disease extent can be 
used in association with function tests to monitor IPF evolution, and to evaluate prognosis and 
therapy (19). 
4.2.3.4 St George Respiratory Questionnaire (SGRQ) 
Impact of IPF on quality of life will be assessed using the SGRQ (20). This questionnaire covers 
the measurement of symptoms, activity, and impacts. It has good discriminative and evaluative 
properties and is responsive to therapeutic trials. It takes 8 to 15 minutes to complete. 
4.2.3.5 EuroQol Questionnaire, 5 level system (EQ-5D-5L) 
The EQ-5D is a standardized instrument for use as a measure of health outcome.  
EQ-5D-5L is the 5-level system for the 5-dimensional format of the EQ-5D and covers the 
measurement of mobility, self-care, usual activities, pain/discomfort and anxiety/depression. 
EQ-5D-5L is designed for self-completion by subjects, taking less than 5 minutes to complete. 
Instructions to respondents are included in the questionnaire. 
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4.2.3.6 Biomarkers 
Peripheral blood will be collected for measurement of protein biomarkers in serum or plasma.  
The protein biomarkers have been selected either based on their potential link with SAR156597 
mechanism of action, based on reported association with survival in or pathogenesis of IPF or 
lung fibrosis. These include, but are not limited to, inter-cellular adhesion molecule 1 (ICAM1), 
TARC, periostin and Human Epipidymis protein 4 (HE4). In a previous observational longitudinal 
study (ASY12295), some of these biomarkers showed a higher circulating concentration at 
baseline in IPF patients compared to healthy controls, with estimated AUROC above or close to 
0.8.  On exploratory basis, the correlation between IPF disease biomarkers and lung function 
progression will be assessed at Week 24 and Week 52.  Moreover, in another previous clinical 
study with increasing doses of SAR156597 (TDR11326) promising results were observed for 
some of these markers, e.g. a trend in reduced blood concentration of TARC with increasing doses 
of SAR156597. Drug-related protein biomarkers will be assessed at baseline, Week 24 and Week 
52 to look for an effect on these proteins after 6 months and 12 months of SAR156597 treatment.  
 
Additional blood samples will be archived for potential future assay of protein and mRNA 
biomarkers related to the diagnosis, progression, or therapeutic responsiveness of IPF 
4.2.3.7 Genetic testing  
The genetic basis of IPF is not well understood.  Polymorphisms of various genes encoding for 
cytokines and mucins have been reported to be increased in sporadic IPF.  To obtain a better 
understanding of IPF pathogenesis and disease course in relation to the genomic profile, blood 
samples will be collected to further characterize the genotype of IPF subjects by analysis of a 
subset of selected genes already associated to IPF including but not limited to IL4 (21), IL4R (22), 
STAT6 (23) and MUC5B (24). 
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5 
STUDY OBJECTIVES 
5.1 
PRIMARY 
To evaluate, in comparison with placebo, the efficacy of 2 dose levels/regimens of SAR156597 
administered subcutaneously during 52 weeks on lung function of patients with IPF. 
5.2 
SECONDARY 
• To evaluate the efficacy of 2 dose levels/regimens of SAR156597 compared to placebo on IPF 
disease progression 
• To evaluate the safety of 2 dose levels/regimens of SAR156597 compared to placebo in 
patients with IPF 
• To evaluate the pharmacokinetic profile of SAR156597 200 mg administered subcutaneously 
every week and every two weeks during 52 weeks 
• To assess the potential immunogenicity of SAR156597 
• To evaluate the effect of SAR156597 on circulating biomarkers 
• To explore the effect of SAR156597 on quality of life 
 
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6 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE PROTOCOL 
This study will be a multinational, randomized, double-blind, placebo-controlled, 3 parallel 
groups study to assess the efficacy and safety of SAR156597 200 mg once a week and 200 mg 
once every two weeks administered subcutaneously over a 52 week period to patients with IPF. 
Approximately 300 patients will be randomized in a ratio 1:1:1 to the following three treatment 
arms:  
• SAR156597 (qw) arm (n=100): 
Patients will receive SAR156597 administered subcutaneously in 200 mg doses once every week 
(qw) 
• SAR156597(q2w) arm  (n=100): 
Patients will receive SAR156597 administered subcutaneously in 200 mg doses once every 2 
weeks (q2w) alternating with placebo subcutaneously once every 2 weeks  
 
• Placebo (qw) arm (n=100): 
Patients will receive placebo subcutaneously once every week.  
The study population will be stratified at baseline according to a background therapy with 
pirfenidone or nintedanib (standard of care for IPF in authorized countries). 
For a schematic presentation and a detailed flow chart, please refer to Section 1.2. 
6.2 
DURATION OF STUDY PARTICIPATION 
6.2.1 Duration of study participation for each patient 
The study will last up to 68 weeks as follows: 
• Up to 4 weeks of screening 
• 52 weeks of study treatment 
• 12 weeks of follow-up 
6.2.2 Determination of end of clinical trial (all patients) 
The end of the clinical trial is defined as the day the last patient completes his/her last visit 
planned in the protocol. 
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6.3 
STUDY COMMITTEES   
Central review of clinical documentation 
Clinical documentation such as patient history, HRCTs, and histology will be centrally reviewed 
by a radiologist and a pathologist specialized in interstitial lung diseases in order to confirm the 
diagnosis of IPF. HRCTs performed during the course of the study will also be reviewed and 
scored on a blinded basis to appropriately assess the changes over time. 
Data Monitoring Committee 
A Data Monitoring Committee (DMC) will be charged with monitoring the safety of the patients 
participating in this clinical trial. This committee is comprised of externally-based individuals 
with expertise in the diseases under study, biostatistics, or clinical research. The DMC will, in due 
time, give appropriate recommendations to the Sponsor on safety aspects during the conduct of 
the study, if needed. The DMC is justified by the early stage of development of SAR156597 that 
has gathered sparse safety information in patients with IPF so far 
 
. The DMC responsibilities and the data review processes are fully 
described in the DMC charter. In the above capacities, the DMC is advisory to the Sponsor. The 
Sponsor is responsible for promptly reviewing and for taking into account in a timely manner the 
recommendations of the DMC in terms of trial continuation with or without alterations or of 
potential trial termination 
Operational Committee 
An Operational Committee will be put in place for potential consultation on unexpected ethical, 
methodological, or technical questions that may arise during the course of the study. 
 
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7 
SELECTION OF PATIENTS 
7.1 
INCLUSION CRITERIA 
I 01. Adult male or female patients. 
I 02. Documented diagnosis of IPF according to the following criteria:  
o Exclusion of other known causes of interstitial lung disease (e.g. domestic and 
occupational environmental exposures, connective tissue disease, and drug 
toxicity)* 
AND 
o Combination of patterns of usual interstitial pneumonia (UIP) on HRCT images 
of chest, and on surgical lung biopsy (when obtained)*  
OR 
Presence of Possible UIP pattern* on HRCT images of chest AND additional 
evidence of traction bronchiectasis as assessed by an experienced chest 
radiologist (Central  Review**) 
* As defined in the current 2011 ATS/ERS/JRS/ALAT guidelines 
** The patterns of UIP on HRCT images of chest and histopathology in surgical lung biopsy (if 
done) will be reviewed by central reviewers (a radiologist and a pathologist experienced in 
interstitial lung diseases) to confirm diagnosis of IPF for consistency. 
I 03. Signed written informed consent. 
7.2 
EXCLUSION CRITERIA 
E 01. Age ≤40 years. 
E 02. IPF disease diagnosis >5 years. 
E 03. Forced vital capacity (FVC) <40% of predicted value. 
E 04. Carbon monoxide diffusing lung capacity (DLCO) corrected for hemoglobin <30% of 
predicted value. 
E 05. Severe chronic obstructive bronchitis as characterized by FEV1/FVC < 0.70. 
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E 06. Need for 24 hrs of oxygen therapy or oxygen saturation <88% after 10 minutes breathing 
ambient air at rest.  
E 07. Known diagnosis of significant respiratory disorders (e.g. asthma, tuberculosis, 
sarcoidosis, aspergillosis, or cystic fibrosis) other than IPF. 
E 08. Pulmonary artery hypertension requiring a specific treatment. 
E 09. Currently listed and/or anticipated to be listed for lung transplantation within the next 6 
months (on an active list). 
E 10. History of vasculitis or connective tissue disorders or ANCA positive. 
E 11. Known HIV or chronic viral hepatitis. 
E 12. Exclusion related to tuberculosis (TB): 
• Active tuberculosis (according to WHO guidelines (25) or a history of incompletely 
treated tuberculosis  
• Incompletely treated latent tuberculosis (according to WHO guidelines) 
• Positive or confirmed indeterminate (2 consecutive tests) QuantiFERON-TB 
Gold® test at screening (regardless of prior treatment status) 
E 13. Evidence of any clinically significant, severe or unstable, acute or chronically progressive 
medical (other than IPF) or surgical disorder, or any condition that may affect patient 
safety in the judgment of the investigator. 
E 14. Acute myocardial infarction within 6 months prior to screening. 
E 15. Clinically significant abnormal electrocardiogram (ECG) at screening that may affect the 
conduct of the study in the judgement of the investigator. 
E 16. Clinically significant laboratory tests at screening: 
• Alanine transaminase (ALT) or aspartate transaminase (AST) >2 times upper limit 
of normal range (ULN) 
• Hemoglobin <11 g/100 mL for male and <10 g/100 mL for female 
• Neutrophils <1500/mm3 (except <1000/mm3 for those of African descent) 
• Platelets <100 000/mm3 
• Creatinine ≥150 µmol/L 
E 17. Current history of substance and/or alcohol abuse. 
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E 18. Females who are lactating or who are pregnant. 
E 19. Women who are of childbearing potential not protected by highly-effective contraceptive 
method(s) of birth control (as defined in the informed consent form and /or in a local 
protocol addendum/amendment), and/or who are unwilling or unable to be tested for 
pregnancy. 
For Denmark only, per local requirement: Acceptable methods of contraception include: 
• Intra-uterine devices (IUD); 
• Hormonal contraceptives (contraceptive pills, implants, transdermal patches, hormonal 
vaginal devices or injections with prolonged release). 
For UK only, per local requirement: Acceptable forms of effective contraception include: 
• Established use of oral, intravaginal, or transdermal combined (estrogen and progestogen 
containing) hormonal contraception associated with inhibition of ovulation 
• Established use of oral, injectable, or implantable progestogen-only hormonal 
contraception associated with inhibition of ovulation 
• Placement of an intrauterine device (IUD) or intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Male sterilisation (provided that the partner is the sole sexual partner of the woman of 
childbearing potential study participant and that the sterilized partner has received 
medical assessment of the surgical success.) 
• True abstinence: When this is in line with the preferred and usual lifestyle of the subject. 
(Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception). 
Note: Women of childbearing potential must have a confirmed negative pregnancy test at 
screening and baseline visits. Postmenopausal women must be amenorrheic for at least 
12 months. Women of childbearing potential must use an effective contraceptive method 
throughout the entire duration of the study treatment and for 12 weeks after the last 
investigational medicinal product administration. 
[For Czech Republic only, per local requirement: 
E.19 Women who are of childbearing potential not protected by highly-effective 
contraceptive method(s) of birth control and/or who are unwilling or unable to be 
tested for pregnancy. 
Male participants with a female partner of childbearing potential not protected by 
highly effective contraceptive method(s) of birth control. 
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• Acceptable methods of contraception include: 
-  Method with reliability index <1 (such as IUD, sterilization of one of the 
partners provided that this partner is the only one for whole duration of the 
clinical trial, further hormonal implants, injections, patches, oral hormonal 
contraception) plus one supplementary barrier method of contraception 
always with spermicide. Men should always use condom. 
- These methods must be used during whole study treatment duration and 
3 months after the end of the investigational product administration 
Note: Women of childbearing potential must have a confirmed negative pregnancy test at 
screening and baseline visits. Postmenopausal women must be amenorrheic for at least 
12 months.] 
E 20. Use of any cytotoxic/immunosuppressive agent including but not limited to azathioprine, 
cyclophosphamide, methotrexate, and cyclosporine within 4 weeks prior to screening. 
E 21. Use of any cytokine modulators (etanercept, adalimumab, efalizumab, infliximab, 
golimumab, certolizumab, rituximab) within 12 weeks or 5 half-lives of screening 
(24 weeks for rituximab and 24 months for alefacept). 
E 22. Use of any investigational drug within 1 month of screening, or 5 half-lives, if known 
(whichever is longer), or within 12 weeks for stem cell therapy. 
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8 
STUDY TREATMENTS   
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) 
 
A complete description of the Investigational Medicinal Product (IMP) and its proper handling 
will be provided in a pharmacy manual. 
• Pharmaceutical form 
o SAR156597 solution for injection at 100 mg/mL: SAR156597 is supplied as a 
sterile freeze-dried powder for solution for injection. Each vial is overfilled with 
125 mg of SAR156597 freeze-dried powder, and the final solution for injection is 
obtained by reconstitution of the entire vial content with 1.1 mL of water for 
injection, leading to an amount of 125 mg of SAR156597 drug substance in a total 
volume of 1.25 mL, that is a 100 mg/mL of SAR156597 solution. 1 mL of this 100 
mg/mL SAR156597 solution can then be withdrawn for dose administration. 2 
drug product vials are thus needed to reach a 200 mg dose. 
o Placebo consists of liquid with the same excipients as those of the reconstituted 
SAR156597 formulation, filled at nominal volume of 1.5 mL. Two vials are 
necessary, 1 mL will be taken from each vial to prepare 2 mL syringe. 
• Method of preparation 
At the study site, reconstitution of the IMP must be done by personnel other than those 
administering the drug and making clinical observations (e.g. pharmacist) to maintain the 
treatment blind (Refer to Section 8.4). 
o At patient’s home, reconstitution must be done by healthcare professionals (e.g. 
visiting nurse) out of view of patients and their families/caregivers. 
o The IMP should be reconstituted the day of dosing (no more than 3 hours prior to 
SC injection), at room temperature. 
• Dose of drug per administration 
o SAR156597 qw arm: one injection of SAR156597 200 mg administered 
subcutaneously every week  
o SAR156597 q2w arm: one injection of SAR156597 200mg administered 
subcutaneously once every 2 weeks alternating with one injection of placebo 
administered subcutaneously once every 2 weeks 
o Placebo arm: one injection of placebo administered every week 
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• Route and method of administration 
The route and method of administration are subcutaneous in the abdomen. Subcutaneous 
injection sites should be alternated between the 4 quadrants of the abdomen (avoiding navel 
and waist areas) so that the same site is not injected for two consecutive weeks. Exact site of 
each injection will be documented on source document. 
 
The IMP is administered every 7 days +/- 2 days from initial IMP administration. This is 
permitted per protocol to accommodate special circumstances, eg. laboratory results pending, 
ongoing AE, patient scheduling difficulty.  
 
If IMP administration is missed or temporarily discontinued, the initial schedule of injections 
should be resumed. This does not apply to permanent treatment discontinuation. 
 
On days when the patient has a study visit, the IMP will be administered by the Investigator or 
delegate after clinic procedures and blood collection.   
 
For doses not administered at the study site, the IMP will be administered by qualified site 
personnel and /or healthcare professionals (e.g. visiting nurse service).  
 
Patients should be monitored by site personnel/visiting nurse for at least 30 minutes after each 
administration for potential signs and symptoms that may suggest a hypersensitivity reaction.  
[For Czech Republic only per local requirement: Patients should be monitored at the study 
site by site personnel for a minimum of 2 hours after the first administration of IMP and for a 
minimum of 1 hour after the next 5 administrations for potential signs and symptoms that may 
suggest a hypersensitivity reaction. For the subsequent IMP administrations, patients should 
be monitored by site personnel/visiting nurse for at least 30 minutes after each 
administration.]   
For doses not given at study site, a booklet will be provided to the patient to record 
information related to the injections; this booklet will be completed by the visiting nurse after 
each injection and will be kept as source data in the patient’s study file. Patients will be 
instructed to bring the booklet back at the subsequent site visit for Investigator’s review. 
 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) 
Not applicable 
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8.3 
BLINDING PROCEDURES 
8.3.1 Methods of blinding 
SAR156597 and placebo will be provided in treatment kits indistinguishable in appearance and 
will be labeled with a treatment kit number. The randomized treatment kit number list will be 
generated by Sanofi. 
In accordance with the double-blind design, study patients, Investigators, and study site personnel 
(except the personnel who conduct the reconstitution of the IMP  and preparation of syringes for 
injection) will remain blinded to study treatment and will not have access to the randomization 
(randomized treatment kit number) except under circumstances described in Section 8.3.2. 
To maintain blinding, since unreconstituted placebo and SAR156597 vials are not matched for 
appearance, the personnel involved with dose preparation will be required to agree not to reveal to 
other study personnel the type of IMP solution (SAR156597 vs. placebo) in the vials/syringes.  
For doses administered at patient’s home, visiting nurses will be requested to reconstitute the IMP 
out of view of patients and their families/caregivers and to sign a confidential agreement for not 
disclosing the IMP box content.  
Also to protect the blind, SAR156597 and placebo will be supplied in a 2 week treatment kit 
containing individually 2 Tamper Evident sealed treatment boxes (2 vials per box / 2 boxes per 
kit).  
Each inner box will contain 2 vials and will be labeled as “Box 1” (week 1 treatment) and “Box 
2” (week 2 treatment). Each weekly treatment box will be sealed with a tamper evident seal.   
The outer kit, also tamper evident sealed will contain the 2 inner boxes and extra tamper seals. 
After administration of week 1 treatment, the person preparing the dose will put the empty vials 
back in the original inner box 1, put the empty box 1 back in the outer kit and tamper evident 
sealed it until week 2 administration. After administration of week 2 treatment, the same 
procedure will be applied for box 2. 
During monitoring visit, the unblinded monitor will break the tamper evident seal to perform IMP 
accountability. The monitor will tamper seal the outer box after performing IMP accountability. 
The Investigator must not open the returned tamper sealed boxes. 
Refer to Section 10.5 for suspected unexpected serious adverse drug reaction unblinding by the 
Sponsor. 
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8.3.2 Randomization code breaking during the study 
In case of an adverse event (AE), the code should only be broken in circumstances when 
knowledge of the IMP is required for treating the patient. If possible, contact should be initiated 
with the monitoring team before breaking the code.  
Code breaking can be performed at any time by using the proper module of the interactive voice 
response system (IVRS)/interactive web response system (IWRS) and/or by calling any other 
phone number provided by the Sponsor for that purpose.  If the blind is broken, the Investigator 
should document the date, time of day, and reason for code breaking.   
If the blind is broken by the Investigator, for the above stated purpose, the patient must be 
withdrawn from treatment.  
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP 
Patient will be randomized following a 1:1:1 ratio to one of the three treatment arms via a 
centralized randomization system using IVRS/IWRS. 
A randomized treatment kit number list will be generated centrally by Sanofi. The investigational 
product (SAR156597 or placebo) will be packaged in accordance with this list. 
At V1 (screening) the study staff will contact the IVRS/IWRS to obtain a patient number for each 
patient who gives informed consent. 
The result from the central reviewer on diagnosis of IPF have to be obtained to validate the 
inclusion of patient before randomization as per inclusion criteria (See section Section 7.1) 
The population will be stratified according to background therapy at the moment of 
randomization: 
- 
Patient with background therapy with either pirfenidone or nintedanib  
- 
versus patient without background therapy  
- 
It is planned to include a maximum of 66% of patients with background therapy. 
Randomization will be performed at Visit 2 (Day 1) by a centralized randomization procedure 
using IVRS/IWRS. 
Patients who comply with all inclusion/exclusion criteria will be assigned before the IMP 
administration on Visit 2 (Day 1): 
• A treatment number in a preplanned order following the randomization list, and 
• A patient number according to the chronological order of inclusion. 
A patient cannot be randomized more than once in the clinical trial. 
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Patients who meet exclusion criteria may be re-screened once during the open screening period of 
study; a different patient identification will be issued. Re-screening is not permitted if the patient 
fails to meet inclusion criteria. There is no requirement for a waiting period between the screen-
failure date and the re-screening date. The IVRs/IWRS report will flag re-screened patients. 
Patients that are re-screened must sign a new consent form and all Visit 1 procedures must be 
repeated. 
The treatment kits are sufficient for 2 weeks of treatment. As the treatment duration is 52 weeks, a 
patient will be allocated by the IVRS to several treatment kit numbers corresponding to the same 
treatment arm assigned from randomization. 
The details of the centralized randomization procedure and IVRS are provided in a separate 
manual. 
8.5 
PACKAGING AND LABELING 
SAR156597 and Placebo will be supplied as a treatment box. Each box will contain 2 inner boxes. 
Each inner box will contain 2 vials. The inner boxes will be numbered as “Box 1” and “Box 2”. 
Box “1” or “2” will be used for administration at the instructed time. 
Packaging is in accordance with the administration schedule. The content of the labeling is in 
accordance with the local regulatory specifications and requirements. 
8.6 
STORAGE CONDITIONS AND SHELF LIFE 
All investigational Product should be stored between 2°C and 8°C (36°F and 46°F).The  
Investigators or other authorized persons (e.g. pharmacists) are responsible for storing the IMP in 
a secure and safe place in accordance with local regulations, labeling specifications, policies, and 
procedures.  
Control of IMP storage conditions, especially control of temperature (e.g. refrigerated storage) 
and information on in-use stability and instructions for handling the Sanofi compound should be 
managed according to the rules provided by the Sponsor. 
At home, the treatment kits will be stored by the patients in a refrigerator in accordance with the 
storage conditions indicated on the label of the IMPs. 
After the supply of IMP kits to patients at the study site visits, appropriate provisions will be in 
place for transportation of the IMP kits from the study site to the patient’s refrigerator. As an 
alternative to between study site visits, the IMP may be supplied from the site to the patient via a 
sponsor-approved courier company where allowed by local regulations and approved by the 
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8.7 
RESPONSIBILITIES 
The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense the 
IMP will be responsible for ensuring that the IMP used in the clinical trial is securely maintained 
as specified by the Sponsor and in accordance with applicable regulatory requirements. 
All IMP will be dispensed in accordance with the Investigator's prescription and it is the 
Investigator's responsibility to ensure that an accurate record of IMP issued and returned is 
maintained. 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) should be promptly notified to the 
Sponsor. Some deficiencies may be recorded through a complaint procedure. 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party, allow the IMP to be 
used other than as directed by this clinical trial protocol, or dispose of IMP in any other manner. 
 
8.7.1 Treatment accountability and compliance 
Measures taken to ensure and document treatment compliance and IMPs accountability include: 
• 
Proper recording of treatment kit number or packaging number as required on appropriate 
electronic case report form (e-CRF) page for accounting purposes. 
• 
All medication treatment kits (whether empty or unused) are returned by the patient at 
each visit when a treatment dispensing is planned. 
• 
The site unblinded personnel tracks treatment accountability/compliance comparing the 
treatment number recorded on the patient booklet with the treatment number of returned 
treatment kits (whether empty or unused) and fills in the patient treatment log. 
• 
The unblinded monitor in charge of the reconciliation then checks the data entered on the 
IMPs administration page by comparing them with the IMPs that has been retrieved and 
the patient treatment log form. 
8.7.2 Return and/or destruction of treatments 
Whenever possible all partially used, used or unused investigational product will be destroyed on 
site according to the standard practices of the site after reconciliation verification by the monitor. 
A detailed treatment log of the destroyed investigational product will be established with the 
Investigator (or the pharmacist) and countersigned by the Investigator and the monitoring team.  
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The Investigator will not destroy any investigational product unless the Sponsor provides written 
authorization. When destruction at site cannot be performed, all IMPs will be retrieved by the 
Sponsor.  
A detailed treatment log of the returned IMP will be established with the Investigator (or the 
pharmacist) and countersigned by the Investigator and the monitoring team. 
8.8 
CONCOMITANT MEDICATIONS 
A concomitant medication is any treatment received by the patient concomitantly to any IMP(s). 
An accurate record of all prescription medications (plus any herbal supplement or over the counter 
medications taken specifically for the IPF condition) must be kept on the appropriate record form, 
including the name of the medication (international nonproprietary name), start of administration, 
daily dosage, and duration for such use. 
8.8.1 Prohibited medications 
• Use of any cytotoxic/immunosuppressive (other than prednisone less than or equal to 
10 mg/day or equivalent) including but not limited to azathioprine, cyclophosphamide, 
methotrexate, and cyclosporine within 4 weeks prior to screening and during the course of 
the study.  
• Use of any cytokine modulators 
o Use of any biologic agent (such as etanercept, adalimumab, efalizumab, infliximab, 
golimumab, certolizumab) within 12 weeks or 5 half-lives of screening, and in the case 
of rituximab, use within 24 weeks of screening or no recovery of CD 19-positive B 
lymphocytes if the last dose of rituximab has been more than 24 weeks prior to 
screening. The use of these biologic agents is not authorized during the course of the 
study. 
o Alefacept within 24 months of screening and during the course of the study. 
• Use of any investigational drug within 1 month of screening, or 
5 pharmacodynamic/pharmacokinetic half-lives, if known (whichever is longer),and 
during the course of the study. Use of stem cell therapy within 12 weeks of screening, and 
during the course of the study. 
8.8.2 Authorized concomitant medications 
• Oral corticosteroids are permitted if ≤10 mg/day oral prednisone or equivalent and at 
stable dose for at least 4 weeks prior to the randomization (baseline) visit. No change is 
permitted unless the patient develops an AE. Dose and any change will be recorded on the 
patient e-CRF. 
• Pirfenidone or nintedanib administered at the recommended dosage for at least 12 weeks 
prior to the randomization (baseline). No change is permitted unless the patient develops 
an AE. Dose and any change will be recorded on the patient e-CRF. Pirfenidone or 
nintedanib cannot be started during the course of the study. 
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[For Czech Republic only, per local requirement: 
• N-acetylcysteine administered at the dosage recommended by local guidelines] 
 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 
9.1 
EFFICACY 
9.1.1 Primary endpoint 
The primary efficacy endpoint will evaluate the efficacy of SAR156597 on lung function and will 
be: 
− The absolute change from baseline in % predicted FVC at 52 weeks 
9.1.2 Secondary endpoints 
Two key secondary endpoints will evaluate other aspects of the efficacy of SAR156597 in IPF: 
− Patients experiencing Disease Progression as defined by the following events: decrease in 
absolute % predicted FVC≥10 percent or decrease in absolute percent predicted DLCO≥15 
percent or lung transplant or death at 52 weeks 
− Deaths (all cause) at 52 weeks 
9.1.3 Exploratory endpoints 
− Acute exacerbations at 52 weeks (per investigator’s judgment and adjudicated cases) 
− Respiratory hospitalizations and rate of non-elective hospitalizations at 52 weeks 
− Change from baseline in 6-MWT distance at 52 weeks 
− Change from baseline in HRCT lung interstitial score at 52 weeks 
− Change from baseline in the total score of the SGRQ at 52 weeks 
− Change from baseline in the total score of the EQ-5D-5L at 52 weeks 
9.1.4 Assessment methods and activity parameters 
9.1.4.1 Pulmonary Function Tests will include: 
• DLCO: carbon monoxide diffusing capacity, corrected for hemoglobin; 
• FVC: forced (expiratory) vital capacity; 
• FEV1: forced expiratory volume over one second (only done at screening and at baseline) 
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• TLC: total lung capacity (body plethysmography) (only done at screening and at baseline) 
• RV: residual volume (body plethysmography) (only done at screening and at baseline) 
DLCO will be measured locally at the investigational site; spirometry test will be done locally but 
measured by a central laboratory. 
Note: Two PFTs will be performed within 4 weeks prior to dosing one at screening and one at 
baseline. The first PFT will determine whether the patient qualifies for the study and the second 
will be averaged with the first one to establish a baseline value.  
9.1.4.2 Pulse oximetry 
Oxygen saturation will be assessed using pulse oximetry (SpO2). 
9.1.4.3 Lung HRCT 
For confirmation of diagnosis at baseline, a lung HRCT will have to be performed unless already 
done within 1 year prior to screening. The HRCT will be provided to the central review panel 
together with histology documentation if any. 
A second HRCT will be performed at the end of treatment to measure the effect on lung fibrosis 
using a specific scoring system. 
9.1.4.4 6-MWT 
The distance covered by the patient over a 6 minute walk will be measured by the investigational 
site staff at baseline and during the treatment and reported in meters in the e-CRF. If during visits 
6, 7, 8, 9 and 10, oxygen saturation is less than 88% under ambient air at rest, the patient should 
perform 6-MWT under 4L oxygen. 
9.1.4.5 Patient Reported Outcome 
The impact of the disease on patient’s Quality of Life will be measured at baseline and during the 
treatment using the St George Respiratory Questionnaire and the EuroQol questionnaire. 
9.2 
SAFETY ENDPOINTS  
The same safety assessment will be applied across all arms. Adverse events will be collected at 
each visit from the signing of the informed consent to the end of the follow-up period. The 
investigator will ask the patient how he/she has felt since the last study visit/phone call. The study 
specific and general safety monitoring are detailed in Section 10.4.1. To ensure the continuing 
safety of patients in this study, an independent DMC will be responsible for reviewing the safety 
data on a periodic basis throughout the course of the study as outlined in Section 6.3. 
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Body mass index (BMI) will be calculated automatically at each visit. 
9.2.5 Electrocardiogram variables 
A standard 12-lead ECG will be performed at each on site visit as per study flowchart  
(Section 1.2) and description of study procedures in Section 10. ECG data will be assessed by the 
Investigator based on the automatic device reading. 
At the post randomization visits, ECGs will be performed prior to investigational product 
administration. All ECGs will be performed with the subject in a reclined position. ECG 
parameters include: Heart rate, QRS duration, PR interval, QT interval, ST deviation, T-wave and 
Uwave morphology. 
9.2.6 Hypersensitivity/Allergic or anaphylactic reactions  
Assessment, categorization and treatment of systemic allergic reactions, if any, or of anaphylactic 
reactions as consensually defined (26) (25) will be specifically performed as detailed in 
Section 10.6.3.1 and following APPENDIX D, as appropriate. 
Local injection reactions will be assessed to determine if of allergic origin or not following details 
provided in Section 10.6.2 and Section 10.6.3.2 (see also APPENDIX D and APPENDIX E). 
9.3 
OTHER ENDPOINTS 
9.3.1 Pharmacokinetics  
9.3.1.1 Sampling time 
Samples for PK analysis will be collected at pre-dose (within 2 hours before each dose 
administration) during Visits 2, 4, 6, 7, 8 and 9.  
Pharmacokinetics samples during Visit 10 will be collected in the morning.  
An additional sample should be taken in a sub-group (at least 30 patients by cohort) between 5 
and 10 days after last dose (i.e. after Visit 9). The possibility to perform this additional sample 
will be discussed between Investigator and patient on a case by case basis. 
Anti-SAR156597 antibodies (ADA) samples will be collected at approximately the same times as 
the PK samples. 
9.3.1.2 Pharmacokinetics handling procedure 
Detailed procedure of sample preparation, storage and shipment are described in the specific 
laboratory manual. Five (5) ml blood volume is to be collected for each PK and ADA sample. 
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Table 1 – Plasma samples handling for PK (SAR156597) and immunogenicity (anti-SAR156597)  
Sample type 
SAR156597                            anti-SAR156597 
Matrix 
Plasma                                                Plasma 
Blood sample volume 
3mL (3 aliquots)                                             2mL (2aliquots) 
Anticoagulant 
CPD (Citrate Dextrose Phosphate) 
Storage conditions 
≤-20°C 
 
9.3.1.3 Bioanalytical method 
9.3.1.3.1 SAR156597 assay 
All plasma samples to be tested for SAR156597 samples will be analyzed by Bertin pharma 
(Saclay, France). 
A validated ELISA is used for the quantification of SAR156597 in human plasma. Biotinylated 
IL-4 coated on a streptavidin plate is used to capture SAR156597, which is then detected by 
SulfoTag-IL-13. This format, which uses electrochemiluminescence detection, is able to detect 
SAR156597 with an LLOQ of 0.05µg/mL. 
9.3.1.3.2 Anti-drug antibodies 
All anti-SAR156597 antibody samples will be analyzed by the Bioanalysis and Biomarkers 
domain in DSAR OC Montpellier (France). 
For the analysis of potential anti-SAR156597 antibodies (ADA) in human plasma, a validated 
bridging qualitative ELISA using electrochemiluminescence detection will be used. 
Positive samples in screening assay will then be tested in a confirmatory assay (competition with 
SAR156597) in order to demonstrate the presence of antibodies and eliminate false positive 
results generated from the initial screening assay. 
Interference of SAR156597 in the ADA assay will be documented so that the highest drug 
concentration that does not affect the limit of ADA detection is known and the interpretation of 
immunogenicity takes into account this parameter. 
Additional information on the bioanalytical method for anti-SAR156597 antibodies will be 
provided in the Laboratory Manual. 
Samples that are ADA positive will be further evaluated for their potential neutralizing activity 
with an assay currently in development. 
In the interim, the sponsor will store frozen specific aliquots for neutralizing activity testing if 
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9.3.1.3.3 Half-arm exchange molecule assessment  
If necessary, half-arm exchange of SAR156597 with endogeneous hIgG4 may be assessed on 
specific PK sample aliquots. 
9.3.1.4 Pharmacokinetics parameters 
SAR156597 concentrations at selected timepoints after the last dose will be reported using 
descriptive statistics. 
Additional PK parameters will be estimated using the population PK approach such as Cmax, 
tmax and AUC at steady state. 
PoP PK analysis will be presented in a separated stand alone report. 
9.3.2 Biomarkers  
IPF subjects will have serial peripheral blood collections for protein biomarker analyses and 
archival purposes (see Section 4.2.3 for detail list). 
The methodology for sample preparation is described in the lab manual. 
9.3.2.1 Archival serum for future biomarkers 
Blood samples will be prepared and stored for future assay of laboratory protein biomarkers 
related to the diagnosis, progression or therapeutic responsiveness of IPF. 
Peripheral whole blood will be collected and stored for future whole mRNA transcriptome 
analysis. 
9.3.2.2 Bioanalysis methods 
All the blood samples will be centralized at designated central lab. For each type of biomarker the 
analysis method will be detailed in the laboratory manual. 
9.3.3 Pharmacogenetic  
9.3.3.1 Genetic samples for DNA 
At the study visit specified in the study flow chart, for those subjects who signed the specific 
genetic analysis informed consent form, a single blood sample will be collected to enable possible 
investigation of genetic variants that may affect the status and treatment of IPF. 
Total blood will be collected using a 6mL vacutainer (BECTON Dickinson K2 EDTA) with 
HEMOGARD Closure, and gently invert tube at least 8 times permitting specimen to mix with 
tube’s anticoagulant. Under no circumstances will the tube be centrifuged. 
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Special procedures for storage and shipping of genetic samples will be provided in the lab manual. 
9.3.3.2 Protection of subject identity and genetic sample/data handling 
The Sponsor has included safeguards for protecting subject confidentiality.  The blood sample and 
DNA that is extracted will be assigned a second number, a Genetic ID (de-identification code) 
that is different from the Subject ID.  This “double coding” is performed to separate a subject’s 
medical information and DNA data.  The clinical study data (coded by Subject ID) will be stored 
in a distinct database at a different location from the database containing the genetic data (coded 
by Genetic ID).  The key linking Subject ID and Genetic ID will be maintained by a third party, 
under appropriate access control.  The matching of clinical data and genetic data, for the purpose 
of data analysis, will be possible only by using this key, which will be under strict access control.  
All data will be reported only in coded form in order to maintain confidentiality. 
Any remaining banked blood samples and associated DNA will be discarded according to local 
regulations and operating procedures within 15 years of issuance of the Clinical Study Report for 
DRI11772. 
9.3.3.3 Optional stored DNA sample 
For those patients who signed the optional pharmacogenetic informed consent form, a blood 
sample will be collected at the study visit as specified in the study flow chart and this sample will 
be stored.  
This sample may be used to determine a possible relationship between genes and response to 
treatment with SAR156597, how the body processes SAR156597 and possible side effects to 
SAR156597. Genes that may be studied include those for the IL4 receptor, IL4, MUC5B and 
additional genes that may potentially be part of the Th2 signaling pathway.  
This blood sample will be transferred to a site that will, on behalf of Sanofi, extract DNA from the 
sample and that is managed by a contractor which can be located outside the country where the 
study is conducted, within or outside of the European Union. 
This blood sample, and the DNA that is extracted from it, will be assigned a second number, a 
Genetic ID (deidentification code) that is different from the Subject ID. This “double coding” is 
performed to separate a subject’s medical information and DNA data. 
The clinical study data (coded by Subject ID) will be stored in the clinical data management 
system (CDMS), which is a distinct database in a separate environment from the database 
containing the pharmacogenetic data (coded by Genetic ID). The key linking Subject ID and 
Genetic ID will be maintained by a third party, under appropriate access control.  The matching of 
clinical data and pharmacogenetic data, for the purpose of data analysis, will be possible only by 
using this key, which will be under strict access control. All data will be reported only in coded 
form in order to maintain confidentiality. 
The DNA will be stored for up to 15 years from the completion of the clinical study report. 
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Special procedures for storage and shipping of pharmacogenetic samples are described in detail in 
lab manual. 
9.4 
FUTURE USE OF SAMPLES 
For subjects who have consented to it, 6 samples will be collected at the visit specified in the 
study flow chart and these samples will be stored. These samples may be used for other research 
purposes (excluding genetic analysis) related to IPF than those defined in the present protocol.  
These other research analyses will help to understand either disease subtypes or drug response, or 
to develop and/or validate a bioassay method, or to identify new drug targets or biomarkers.  
These samples will remain labelled with the same identifiers than the one used during the study 
(i.e., subject ID). They will be transferred to a Sanofi site (or a subcontractor site) which can be 
located outside of the country where the study is conducted. The Sponsor has included safeguards 
for protecting subject confidentiality and personal data (see Section 14.3 and Section 14.5). 
9.5 
APPROPRIATENESS OF MEASUREMENTS  
See also Section 4.2.3 
The primary endpoint will be the mean absolute change from baseline in percent predicted FVC at 
52 weeks. FVC is a widely used measure of pulmonary function and disease status in patients 
with IPF. Percent predicted FVC is a reliable, valid, and responsive measure of clinical status and 
a decline of 2-6% represents a small but clinically important difference. Regarding disease 
progression, a decline in % predicted FVC greater than or equal to 10% at 24 weeks was shown to 
be associated with a nearly five-fold increase in the risk of mortality over the subsequent year, 
whereas a decline of 5-10% conferred a more than twofold increase in the risk of 1-year mortality 
(26) (27). 
Secondary and exploratory efficacy outcome measures will address other aspects of disease 
progression and will include rate of deaths, rate of lung transplantations, rate of hospitalizations, 
and rate of acute exacerbations. Finally, the extent of lung fibrosis and the effect of drug treatment 
on fibrosis will be measured using a specific scoring system on lung HRCT. 
 
 
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10 
STUDY PROCEDURES 
10.1 
VISIT SCHEDULE 
 
It is preferred that all study visits take place in the morning when fasting blood samples are 
required. 
 
The study visits occur on the planned dates (relative to the first injection), as scheduled. The visit 
schedule should be adhered to within the ± 2 day visit window. 
 
If a patient is prematurely discontinued from treatment, all assessments planned at the End of 
Treatment visit should be performed. 
 
Prior to all screening assessments, after discussion of participation in the study, the written 
consent form (including voluntary participation in pharmacogenetic testing and for future use of 
samples) must be signed and dated. 
Although the screening assessments for this study are grouped under the heading of a single visit 
in this protocol, it is possible for them to be performed over more than 1 site visit if necessary, as 
long as the screening visit window prior to Day 1 is respected. Patients that fail screening for 
exclusion criteria, e.g. concomitant medications, required drug-specific discontinuation periods or 
laboratory tests, may be rescreened for study eligibility 1 additional time (refer to Section 8.4 for 
further instructions related to rescreening). 
10.1.1 
Visit 1: Screening (D-28 to D-1) 
Following a discussion of participation in the clinical trial, informed consent must be obtained and 
documented. These steps precede any study procedures. 
The following procedures will then be performed: 
• Call IVRS to assign a patient number 
• Record patient demographic information 
• Assess eligibility by review of Inclusion /Exclusion Criteria. This includes the review of 
prior and concomitant medications 
• Commence AE reporting 
• Patients who do not meet these inclusion/exclusion criteria should not continue the 
screening process and a screen failure call should be done in the IVRS 
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If any parameter on the dipstick is abnormal, a urine sample should be sent to the central 
laboratory for testing. If positive for proteins, microscopic analysis is performed by central 
laboratory.  
• Perform 12-lead electrocardiography (ECG) 
• Complete all remaining assessments for tuberculosis screen: history, QuantiFERON-TB 
Gold test : 
o The QuantiFERON® TB Gold test is an in vitro TB test that measures a memory 
Tcell mediated response (production of interferon γ) in TB-infected patients. This 
test is unaffected by bacillus Calmette- Guérin (BCG) vaccination or exposure to 
nontuberculous mycobacteria. The test received regulatory and policy approvals in 
the United States of America, Japan, European Union, Canada. Blood samples are 
incubated within 16 hours from blood collection and sent to the central laboratory 
for analysis the day after collection or as soon as possible. Patients with a positive 
or confirmed indeterminate (by 2 consecutive tests) QuantiFERON TB Gold test 
are excluded. 
• Perform Lung HRCT if not done within 1 year prior to screening. HRCT will be provided 
to the central review panel together with histology documentation if any. 
• Perform Pulmonary function tests: 
• carbon monoxide diffusing capacity, corrected for hemoglobin ( DLCO); 
• forced (expiratory) vital capacity (FVC) 
• forced expiratory volume over one second (FEV1) 
• total lung capacity (body plethysmography) (TLC) 
• residual volume (body plethysmography). (RV) 
• Perform Pulse oximetry 
• Schedule a visit within a maximum of 28 days ( Visit 2, D1) 
10.1.2 
Visit 2: Baseline /Randomization/ Day 1  
Prior to study drug administration, the Investigator or designee will: 
• Record all concomitant medication use with start date and dose in e-CRF 
• Inquire about AEs/SAEs 
• Record vital signs including blood pressure, heart rate and weight 
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swelling/induration/edema and other related observations) will also be 
conducted.  
 Ask patients to come back to the site 1 week later to receive second IMP 
administration and to be monitored for at least 1 hour after dosing] 
• Provide the patient with a booklet to record information pertaining to the injections to be 
performed at home at week 1 as well as the treatment kit. [For Czech Republic only, per 
local requirement: sentence deleted] 
• Schedule an appointment for Visit 3  
10.1.3 
Visit 3: on treatment / Week 2 
• Record all concomitant medication use 
• Inquire about AEs/SAEs. 
• Review patient  booklet to assess local tolerability at the injection site and treatment 
compliance [For Czech Republic only, per local requirement: sentence deleted] 
• Record vital signs including blood pressure, heart rate and weight 
• Perform a complete physical examination 
• Call IVRS to register visit and obtain next treatments number 
• Dispense and administer IMP 
[For Czech Republic only, per local requirement: 
 Dispense and administer IMP 
• 
Patients will be monitored for at least 1 hour after dosing  
 Ask patients to come back to the site 1 week later to receive fourth IMP 
administration and be monitored for at least 1 hour after dosing] 
• Schedule an appointment for Visit 4  
10.1.4 
Visit 4: on treatment / Week 4 
• Record all concomitant medication use 
• Inquire about AEs/SAEs 
• Review patient booklet to assess local tolerability at the injection site and treatment 
compliance [For Czech Republic only, per local requirement: sentence deleted] 
• Record vital signs including blood pressure, heart rate and weight 
• Perform a complete physical examination 
• Obtain (fasting) blood samples for complete clinical laboratory determinations including 
hematology and biochemistry profile,  
• Obtain urine for urinalysis (dipstick) 
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• For women of childbearing potential: 
o perform urine pregnancy test. The patients should be instructed to do the urine 
pregnancy test at home on a monthly basis during the intervals in between on-
treatment study visits for the duration of the study. In case of a positive pregnancy test, 
the patient should be advised to contact immediately the Investigator 
o dispense urine pregnancy test kit for monthly urine pregnancy test (1 month supply) 
• Perform 12-lead ECG 
• Perform blood sample for serum SAR156597 and for anti-SAR156597 antibodies (ADA) 
• Perform  blood sample for ANCA 
• Perform blood sample for complement (C3, C4 and CH50) 
• Call IVRS to register visit and obtain next treatments number 
• Dispense and administer IMP 
[For Czech Republic only, per local requirement: 
 Dispense and administer IMP 
• Patients will be monitored for at least 1 hour after dosing  
 Ask patients to come back to the site 1 week later to receive sixth IMP 
administration and be monitored for at least 1 hour after dosing] 
• Schedule an appointment for Visit 5 
10.1.5 
Visit 5: on treatment / Week 6 
• Record all concomitant medication use 
• Inquire about AEs/SAEs 
• Review patient booklet to assess local tolerability at the injection site and treatment 
compliance [For Czech Republic only, per local requirement: sentence deleted] 
• Record vital signs including blood pressure, heart rate and weight 
• Perform a complete physical examination 
• Call IVRS to register visit and obtain next treatments number 
• Dispense and administer IMP 
[For Czech Republic only, per local requirement: 
 Dispense and administer IMP 
• Patients will be monitored for at least 1 hour after dosing 
• For administration at patient’s home, arrangements must be made for 
qualified site personnel and/or professional caregiver to administer 
IMPs at 1-week interval 
 Provide the patient with a booklet to record information pertaining to the 
injections to be performed at home as well as the treatment kit] 
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• Schedule an appointment for phone call at week 8 
10.1.6 
Phone call: on treatment / Week 8, Week 16, Week 20, Week 28, Week 32, Week 40, 
Week 44, and Week 48 
• Record all concomitant medication use 
• Inquire about AEs/SAEs. 
• Ask about the result of urine pregnancy test 
• Assess local tolerability at the injection site   
10.1.7 
Visit 6, Visit 7 and Visit 8: on treatment / Week 12, Week 24, and Week 36 
• Record all concomitant medication use 
• Inquire about AEs/SAEs 
• Review patient booklet to assess local tolerability at the injection site and treatment 
compliance  
• Record vital signs including blood pressure, heart rate and weight 
• Perform a complete physical examination 
• Obtain (fasting) blood samples for complete clinical laboratory determinations including 
hematology and biochemistry profile 
• Obtain urine for urinalysis (dipstick) 
• For women of childbearing potential: 
o perform urine pregnancy test. The patients should be instructed to do the urine 
pregnancy test at home on a monthly basis during the intervals in between on-
treatment study visits for the duration of the study. In case of a positive pregnancy 
test, the patient should be advised to contact immediately the Investigator 
o dispense urine pregnancy test kits for monthly urine pregnancy tests ( sufficient 
monthly supplies to last until the next scheduled on-site visit. 
• Perform 12-lead ECG 
• Perform blood sample for serum SAR156597 and  for anti-SAR156597 antibodies (ADA) 
• Perform blood sample for ANCA 
• Perform blood sample for complement (C3, C4 and CH50) 
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• At Visit 7: Obtain blood samples for biomarkers assessment  and for archiving (potential 
future protein and mRNA biomarkers of interest) 
• Obtain blood samples for archiving 
 
• Perform Pulmonary function tests: DLCO and FVC 
• Perform a 6-MWT 
• Perform Pulse oximetry 
• Ask the patient to complete St George Respiratory Questionnaire 
• At Visit 8: ask the patient to complete the EuroQol Questionnaire (EQ-5D-5L) 
• Call IVRS to register visit and obtain next treatments number 
• Dispense and administer IMP 
• Schedule an appointment for next Visit 
 
10.1.8 
Visit 9: End of treatment / Week 52 (or Early termination) 
• Record all concomitant medication use 
• Inquire about AEs/SAEs 
• Review patient booklet to assess local tolerability at the injection site and treatment 
compliance  
• Record vital signs including blood pressure, heart rate and weight 
• Perform a complete physical examination 
• Obtain (fasting) blood samples for complete clinical laboratory determinations including 
hematology and biochemistry profile  
• Obtain urine for urinalysis (dipstick) 
• For women of child bearing potential: 
o perform urine pregnancy test. The patients should be instructed to do the urine 
pregnancy test at home on a monthly basis during the intervals in between on-study 
visits for the duration of the study. In case of a positive pregnancy test, the patient 
should be advised to contact immediately the Investigator 
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o dispense urine pregnancy test kits for monthly urine pregnancy tests ( 2 months 
supply) 
• Perform 12-lead ECG 
• Perform blood sample for serum SAR156597 and for anti-SAR156597 antibodies (ADA) 
• Perform  blood sample for ANCA 
• Perform blood sample for complement (C3, C4 and CH50) 
• Obtain blood samples for biomarkers assessment  
• Obtain blood samples for archiving 
 
• Obtain blood samples for archiving ( potential future protein and mRNA biomarkers of 
interest) 
• Perform Pulmonary function tests: DLCO and FVC 
• Perform Pulse oximetry 
• Perform a 6-MWT 
• Ask the patient to complete the St George Respiratory Questionnaire and the EuroQol 
Questionnaire (EQ-5D-5L) 
• Perform Lung HRCT 
• Call IVRS to obtain treatment number and to update the patient’s status (end of treatment) 
• Administer IMP 
• Schedule an appointment for next Visit 
10.1.9 
Phone call: Follow up post treatment / Week 58 
• Record all concomitant medication use 
• Inquire about AEs/SAEs 
• Ask about the result of urine pregnancy test 
• Assess local tolerability at the injection site and treatment compliance 
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10.1.10 Visit 10: End of study visit / Week 64 
• Record all concomitant medication use 
• Inquire about AEs/SAEs 
• Assess local tolerability at the injection site  
• Record vital signs including blood pressure, heart rate and weight 
• Perform a complete physical examination 
• Obtain (fasting) blood samples for complete clinical laboratory determinations including 
hematology and biochemistry profile,  
• Obtain urine for urinalysis (dipstick) 
• Perform urine pregnancy test for women of childbearing potential 
• Perform 12-lead ECG 
• Perform blood sample for serum SAR156597 and for anti-SAR156597 antibodies (ADA) 
• Perform  blood sample for ANCA 
• Perform blood sample for complement (C3, C4 and CH50) 
• Obtain blood samples for archiving 
 
• Perform Pulmonary function tests: DLCO and FVC 
• Perform Pulse oximetry 
• Perform a 6-MWT 
• Ask the patient to complete the  St George Respiratory Questionnaire 
• Call IVRS to update the patient’s status ( study completion) 
10.2 
DEFINITION OF SOURCE DATA 
All evaluations that are reported in the e-CRF and in the patient booklet must be supported by 
appropriately identified source documentation. 
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• Any laboratory abnormalities according to APPENDIX F 
• All efforts should be made to reassess in a clinically relevant timeframe (using either local 
or central lab) the clinical significance of lab abnormalities and corrective actions before 
making a decision of permanent discontinuation of the IMP for the concerned patient. 
• Any code breaking requested by the Investigator will lead to permanent treatment 
discontinuation 
• At the specific request of the Sponsor 
Any abnormal ECG parameter will be immediately rechecked for confirmation before making a 
decision of permanent discontinuation of the IMP for the concerned patient. 
10.3.4 Handling of patients after permanent treatment discontinuation 
Patients will be followed-up according to the study procedures as specified in this protocol up to 
the scheduled date of study completion, or up to recovery or stabilization of any AE to be 
followed-up as specified in this protocol, whichever comes last. 
If possible, and after the permanent discontinuation of treatment, the patients will be assessed 
using the procedure normally planned for the last dosing day with the IMP (End of treatment 
visit/Visit 9) and then will be asked to come to the scheduled on site visits for safety monitoring 
and respiratory function assessment (FVC and DLCO). 
All cases of permanent treatment discontinuation should be recorded by the Investigator in the 
appropriate pages of the e-CRF when considered as confirmed. 
10.3.5 Procedure and consequence for patient withdrawal from study  
The patients may withdraw from the study before study completion if they decide to do so, at any 
time and irrespective of the reason. 
If possible, the patients are assessed using the procedure normally planned for the end-of-study 
visit (Visit 10). Then, patients will receive a phone call from Investigators at week 52 for vital 
status assessment.   
For patients who fail to return to the site, the Investigator should make the best effort to contact 
the patient (e.g. contacting patient’s family or private physician, reviewing available registries or 
health care databases), and to determine his/her health status, including at least his/her vital status. 
Attempts to contact such patients must be documented in the patient’s records (e.g. times and 
dates of attempted telephone contact, receipt for sending a registered letter). 
The statistical analysis plan will specify how these patients lost to follow-up for their primary 
endpoints will be considered. 
Patients who have withdrawn from the study cannot be re-randomized (treated) in the study. Their 
inclusion and treatment numbers must not be reused.  
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10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING 
10.4.1 Definitions of adverse events  
10.4.1.1 Adverse event 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. 
Intensity of an AE is defined as: 
• Mild: no modification of daily activities and does not require mandatory 
corrective/symptomatic treatment 
• Moderate: hinders normal daily activities and/or requires mandatory 
corrective/symptomatic treatment 
• Severe: prevents daily activities and requires mandatory corrective/symptomatic treatment 
10.4.1.2 Serious adverse event 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
• Results in death, or 
• Is life-threatening, or 
 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
 
the patient was at risk of death at the time of the event; it does not refer to an event which 
 
hypothetically might have caused death if it were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization, or 
• Results in persistent or significant disability/incapacity, or 
• Is a congenital anomaly/birth defect 
• Is a medically important event 
 
Medical and scientific judgment should be exercised in deciding whether expedited 
 
reporting is appropriate in other situations, such as important medical events that may not 
 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
 
patient or may require medical or surgical intervention (ie, specific measures or corrective 
 
treatment) to prevent one of the other outcomes listed in the definition above. 
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Note: The following list of medically important events is intended to serve as a guideline for 
determining which condition has to be considered as a medically important event. The list is 
not intended to be exhaustive: 
o Intensive treatment in an emergency room or at home for: 
- 
Severe hypersensitivity reactions (e.g. anaphylaxis, allergic bronchospasm [see 
APPENDIX D for the clinical criteria for diagnosing anaphylaxis]) 
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc),  
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc). 
o ALT >3 x ULN + total bilirubin >2 x ULN or asymptomatic ALT increase 
>10 x ULN. See APPENDIX F 
o Acute exacerbation of IPF 
o Suicide attempt or any event suggestive of suicidality 
o Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling) 
o Bullous cutaneous eruptions 
o Cancers diagnosed during the study or aggravated during the study  
o Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the study 
(only if judged unusual/significant by the Investigators in studies assessing specifically 
the effect of a study drug on these diseases). 
o If any suspected transmission of an infectious agent via a medicinal product (e.g. 
product contamination).   
10.4.1.3 Adverse event of special interest 
An adverse event of special interest (AESI) is an AE (serious or non-serious) of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing monitoring and 
immediate notification by the Investigator to the Sponsor is required. Such events may require 
further pre-specified investigation/monitoring in order to characterize and understand them. 
Adverse events of special interest may be added or removed during a study by protocol 
amendment. 
• Pregnancy of a female subject entered in a study as well as pregnancy occurring in a female 
partner of a male subject entered in a study with IMP 
Pregnancy occurring in a female patient entered in the clinical trial or in a female partner of a 
male patient entered in the clinical trial. It will be qualified as an SAE only if it fulfills one of the 
seriousness criteria (see Section 10.4.1.2). 
- 
In the event of pregnancy in a female participant, IMP should be discontinued. 
- 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined. 
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• The Investigator should take appropriate measures to follow all AEs until clinical recovery 
is complete and laboratory results have returned to normal, or until progression has been 
stabilized, in order to ensure the safety of the patients, or until death. This may imply that 
observations will continue beyond the last planned visit per protocol, and that additional 
investigations may be requested by the monitoring team up to as noticed by the Sponsor.  
• When treatment is prematurely discontinued, the patient’s observations will continue until 
the end of the study as defined by the protocol for that patient. 
• Laboratory, vital signs or ECG abnormalities are to be recorded as AEs only if:  
o Symptomatic and/or  
o Requiring either corrective treatment or consultation, and/or  
o Leading to IMP discontinuation or modification of dosing, and/or  
o Fulfilling a seriousness criterion, and/or  
o Defined as an AESI 
o 
Instructions for AE reporting are summarized in TABLE 2. 
10.4.4 Instructions for reporting serious adverse events 
In the case of occurrence of a SAE, the Investigator must immediately: 
• ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the e-CRF; the system will automatically send a notification to the monitoring team after 
approval of the Investigator within the e-CRF or after a standard delay. 
• SEND (preferably by fax or e-mail) a photocopy of all examinations carried out and the 
dates on which these examinations were performed, to the representative of the monitoring 
team whose name, fax number, and email address appear on the clinical trial protocol. 
Care should be taken to ensure that the patient's identity is protected and the patient's 
identifiers in the clinical trial are properly mentioned on any copy of a source document 
provided to the Sponsor. For laboratory results, include the laboratory normal ranges. 
• All further data updates should be recorded in the e-CRF as appropriate, and further 
documentation as well as additional information (for laboratory data, concomitant 
medications, patient status, etc) should be sent (by fax or e-mail) to the monitoring team 
within 24 hours of knowledge of the SAE. In addition, every effort should be made to 
further document any SAE that is fatal or life threatening within a week (7 days) of the 
initial notification. 
• A back-up plan (using a paper CRF process) is available and should be used when the 
e-CRF system does not work. 
Any SAE brought to the attention of the Investigator at any time after the end of the study for the 
patient and considered by him/her to be caused by the IMP with a reasonable possibility, should 
be reported to the monitoring team. 
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Table 2 - Summary of adverse event reporting instructions 
Case Report Form completion 
Event category 
Reporting 
timeframe 
Specific events in this 
category 
AE 
form 
Safety Comple-
mentary Form 
Other specific 
forms 
Adverse Event (non-
SAE, non-AESI) 
Routine 
Any AE that is not SAE or AESI 
Yes 
No 
No 
Serious Adverse 
Event (non-AESI or 
AESI) 
Expedited 
(within 24 
hours) 
Any AE meeting seriousness 
criterion per Section 10.4.1.2 
Yes 
Yes 
No 
 
 
 
 
 
 
Adverse Event of 
Special Interest  
Expedited 
(within 24 
hours) 
Pregnancy 
Yes 
Yes 
No 
 
 
Symptomatic overdose 
Yes 
Yes 
No 
 
 
ALT≥3 ULN (if baseline ALT<ULN) 
and ALT≥2 x baseline (if baseline 
ALT≥ULN 
Yes 
Yes 
Yes 
 
 
 
 
Yes 
Yes 
Yes 
 
 
Anaphylactic reactions or acute allergic 
reactions 
Yes 
Yes 
Yes 
 
 
Severe injection site reactions 
Yes 
Yes 
Yes 
 
 
TB or initiation of medications for 
suspected TB   
Yes 
Yes 
Yes 
 
 
Acute renal failure 
Yes 
Yes 
No 
 
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10.6.2 Tolerability at the IMP injection 
10.6.2.1 Local injection site reactions  
Local injection site reactions that are considered as non-allergic events should be further 
characterized and evaluated with the assessment of the severity grading of related symptoms such 
as corresponding for pain, tenderness, erythema/redness, swelling, itching or other (See APPENDIX 
E).  Special e-CRF screens will need to be completed.  If such an AE was to occur, then do not 
report the individual components of the reaction but rather the term “local injection site reaction”, 
the individual components being described in the specific e-CRF screen.   
10.6.3 Systemic allergy reaction 
10.6.3.1 Anaphylaxis 
Allergic reaction is a potential risk associated with the administration of most therapeutic 
monoclonal antibodies. 
Acute allergic reactions may be defined as allergic reaction-mediated signs and symptoms 
experienced by patients during or shortly after the pharmacologic or biologic agent is given. 
These reactions may present in a variety of ways, including dizziness, headache, anxiety, dyspnea, 
hypotension, tachycardia, pruritus, rash, urticarial/angioedema, flushing, nausea, or vomiting. 
Anaphylaxis may represent the most severe form of infusion reaction, but these events may also 
occur via other immune-mediated mechanisms (e.g.cytokine-mediated). Allergic reactions may 
begin within few hours and persist up to 24 hours post dosing. Refer to APPENDIX D “Definition 
of anaphylaxis”, which describes the clinical criteria for the diagnosis of anaphylaxis. 
Patients should be monitored by site personnel or visiting nurse (if injection performed at patient’s 
home) for at least 30 minutes after each administration of investigational product for any signs or 
symptoms of a hypersensitivity reaction.  
[For Czech Republic only, per local requirement: Patients should be monitored at the study site 
by site personnel for at least 2 hours after the first administration of IMP and at least 1 hour after 
the next 5 administrations for any signs or symptoms of a hypersensitivity reaction. For the 
subsequent IMP administrations, patients should be monitored by site personnel or visiting nurse 
(if injection performed at patient’s home) for at least 30 minutes after each administration of 
IMP.] 
Patients should be treated symptomatically if any AEs are observed. General Allergic Reaction 
and/or Local Injection Site Reaction Complementary Form will have to be completed.   
Sometimes transient injection site reactions, irritant in nature, may occur, requiring no 
intervention and being of dubious significance. These reactions would not be considered to be 
allergic reactions, and should only be recorded on the Local Injection Site Reaction 
Complementary Form. 
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The IMP should be immediately interrupted (temporarily discontinued) if there is a suspicion of 
an allergic event related to IMP. Refer to Section 10.4.1.3 for hypersensitivity reactions to be 
reported as AESIs, and to Section 10.3 for hypersensitivity reactions requiring permanent 
treatment discontinuation. 
10.6.3.2 Allergic adverse event with cutaneous involvement 
Adverse events with cutaneous involvement which are obviously of allergic origin or injection 
site reactions which progress/expand/worsen/etc. should be evaluated by a dermatologist as soon 
as possible, and preferably within one week of the site first becoming aware of the event.   
The Investigator should evaluate the patient for possible etiologies (new medications, etc.) and 
extracutaneous symptoms and signs.  An unscheduled Central Laboratory assessment for 
hematology, chemistry, liver panel, PK, and ADA should be obtained. If it is possible, the site will 
take pictures of the skin lesions in order to provide the patient with them for the dermatologist’s 
visit. If the photos are obtained, then copies should be kept as source documents which may later 
be collected by the sponsor. The Investigator will provide a summary of the patient's case, reason 
for consultation, and information being requested to the consulting dermatologist.   
A full consultation report should be sent by the dermatologist to the Investigator.  The full report 
should contain, at a minimum, the following information; a detailed description of the skin 
reaction (such as the morphology [lesion type], shape of individual lesions, arrangement of 
multiple lesions [e.g. scattered, grouped, linear], distribution, color, consistency, presence of 
pruritus or pain, and other clinical signs) and, in case a skin biopsy was done based on the 
dermatologist’s or Investigator’s medical judgment, the results of this investigation (including 
histopathology and immunoflurosecence), with, if applicable, a specific diagnosis of the AE to be 
reported in the verbatim. The Investigator will email or fax the full report and the corrected AE 
form if necessary, to the Monitoring Team Representative within 24 hours.   
10.7 
ADVERSE EVENTS MONITORING 
All events will be managed and reported in compliance with all applicable regulations, and 
included in the final clinical study report. 
 
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11 
STATISTICAL CONSIDERATIONS 
11.1 
DETERMINATION OF SAMPLE SIZE 
Approximately 300 patients will be randomized in this study, 100 per treatment group.  Based on 
the enrollment in prior studies of this population approximately half of the patients are expected to 
be older than 65.  
The sample size calculations are based on the primary efficacy variable of % predicted FVC 
change from baseline to week 52, with the following assumptions:  
• A common standard deviation of 12% is assumed based on the data from previous trials 
(26) 
• A 5 % mean difference between each dose and placebo in change from baseline in % 
predicted FVC 
• A 2-sided 5% significance level with 80% power 
Ninety two (92) patients per treatment group will yield 80% power to detect a 5 percentage point 
difference between the treatment groups and placebo.  Additional patients will be randomized in 
each regimen to allow for dropouts; therefore, approximately 100 patients will be randomized into 
each treatment group, for a total sample size of approximately 300 patients for the study. 
As a rank-based method will be used for analysis the actual power may differ from these 
calculations, however, calculations based on the ASCEND study (28), which used the same 
analysis method and endpoint confirm that the planned analysis should have at least 80% power.  
No adjustment is made for multiplicity since a hierarchical testing procedure is proposed.  
Calculations were made using nQuery Advisor 7.0 
11.2 
DISPOSITION OF PATIENTS 
Screened patients are defined as any patient who met the inclusion criteria and signed the 
informed consent.  
Patients treated without being randomized will not be considered as randomized and will not be 
included in any efficacy population.   
For any patient randomized more than once, only the data associated with the first randomization 
will be used in any analysis population. The safety experience associated with any later 
randomization will be assessed separately. 
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The safety experience of patients treated and not randomized will be reported separately, and 
these patients will not be in the safety population. 
11.3 
ANALYSIS POPULATIONS 
11.3.1 Efficacy populations 
11.3.1.1 Modified intent-to-treat population 
The primary population for analysis will be the modified ITT (mITT) population: ITT population 
with an evaluable primary endpoint. This will consist of all patients who receive at least 1 
injection of investigational medicinal product, have a valid baseline % predicted FVC 
measurement, and have at least one post-baseline % predicted FVC measurement. 
11.3.2 Safety population 
Safety population - the population considered for the safety analysis will be the as-treated 
population defined as randomized population who did actually receive at least 1 dose or part of a 
dose of IMP analyzed according to the treatment actually received.   
In addition:  
• Non randomized but treated patients will not be part of the safety population, but their 
safety data will be presented separately.  
• Randomized patients for whom it is unclear whether they took the study medication will 
be included in the safety population as randomized. 
• For patients receiving more than 1 study treatment during the trial, the treatment group 
allocation for as-treated analysis will be the one received at the majority of injections 
11.3.3 Pharmacokinetic analysis population 
The population for all PK and ADA analysis will be all randomized and treated patients having at 
least one sample. 
11.4 
STATISTICAL METHODS 
11.4.1 Extent of study treatment exposure and compliance 
The extent of study treatment exposure and compliance will be assessed and summarized by 
actual treatment received within the safety population. 
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11.4.1.1 Extent of investigational medicinal product exposure 
Duration of IMP exposure is defined as:  last dose date – first dose date + 14 days, regardless of 
unplanned intermittent discontinuations.   
11.4.1.2 Compliance  
A given administration will be considered noncompliant if the patient did not take the planned 
dose of treatment as required by the protocol.  No imputation will be made for patients with 
missing or incomplete data. 
Treatment compliance, above-planned and under-planned dosing percentages will be summarized 
descriptively (N, Mean, SD, Median, Min, and Max). The percentage of patients with compliance 
<80% will be summarized. In addition, number and percentage of patients with at least 1 above-
planned dosing administration will be given, as well as the number and percentage of patients 
with 0, (0, 20%), and >20% under-planned dosing administrations. 
11.4.2 Analyses of efficacy endpoints 
11.4.2.1 Analysis of primary efficacy endpoint(s) 
Due to the non-normality of the endpoint distribution, a two-sided rank-based analysis of 
covariance (rank ANCOVA) model adjusted for baseline, will be used to compare the primary 
efficacy variable between each active treatment group and placebo: 
 
Change from baseline in the % predicted FVC at Week 52 
The rank ANCOVA will be performed as follows: 
1. 
The first step of the analysis is to compute the standardized ranks of the response variable 
(change from baseline in % predicted FVC at Week 52) and covariate (baseline % predicted FVC)  
2. 
The second step is to perform the ANCOVA analysis based upon these ranks.  Within the 
ANCOVA each active treatment group will be compared to placebo using a contrast.  
In the primary analysis, Week 52 assessments will be used regardless of whether the patient has 
previously discontinued treatment.  For patients with missing data at week 52, the week 52 value 
will be estimated based on a linear regression using all available % predicted FVC measurements.  
Predicted changes greater than zero (increases above baseline) will be set to zero.  For patients 
with no Week 52 value due to the patients death (or transplant), the value for analysis will be 
assigned the lowest (worst) rank. Sensitivity analyses including an analysis of the on-treatment 
data only will be described in the statistical analysis plan. 
 
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11.4.2.2 Analyses of secondary efficacy endpoints 
Disease progression, defined as decrease in absolute % predicted FVC ≥10%, or decrease in 
absolute % predicted DLCO ≥15%, or lung transplant, or death will be analyzed as a time to event 
variable.  Patients not meeting the definition for disease progression will be considered censored 
at the time of their week 52 FVC assessment.  For patients with a missing FVC assessment at 
week 52 the censoring time will be the time of the last measured FVC or DLCO assessment.   
The time to disease progression will be compared between each active group and placebo using a 
log-rank test.  The hazard ratio compared to placebo will be estimated from a Cox proportional 
hazards model. 
The incidence of all-cause mortality will be calculated, but no hypothesis testing will be 
performed for this endpoint. 
11.4.2.3 Multiplicity considerations 
The overall type I error rate for this study is 5%.  A hierarchical testing procedure will be used to 
control the type I error over the two doses.  The qw dose group will be compared to placebo first, 
and only if this comparison is significant will the q2w dose group be compared to placebo. 
The same procedure will be used for the disease progression endpoint if significance is achieved 
for both doses on the primary endpoint. 
11.4.3 Analyses of safety data 
The summary of safety results will be presented by treatment group on the basis of the safety 
population.  
All safety analyses will be performed on the safety population using the following common rules: 
• The baseline value is defined generally as the last available value before randomization. 
• For quantitative safety parameters based on central laboratory/reading measurements, 
descriptive statistics will be used to summarize results and change from baseline values by 
visit and treatment group. 
• The analysis of the safety variables will be essentially descriptive and no hypothesis 
testing is planned. 
The following definitions will be applied to laboratory parameters, vital signs and ECG: 
• The potentially clinically significant abnormality (PCSA) values are defined as abnormal 
values considered medically important by the Sponsor according to predefined 
criteria/thresholds based on literature review and defined by the Sponsor for clinical 
laboratory tests, vital signs, and ECG.  
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• PCSA criteria will determine which patients had at least 1 PCSA during the TEAE period, 
taking into account all evaluations performed during the TEAE period, including 
unscheduled or repeated evaluations.  The number of all such patients will be the 
numerator for the on-treatment PCSA percentage.   
The TEAE observation period is defined as the time from first dose of IMP up to 12 weeks after 
the last dose of IMP. 
Analysis of the adverse event data 
Treatment-emergent AEs, treatment-emergent SAEs, TEAEs leading to treatment discontinuation 
and treatment-emergent AESIs will be summarized for each treatment group based on MedDRA 
coding of verbatim terms reported by investigators.  
Analysis of TEAE 
Treatment emergent adverse event incidence tables will be presented by system organ class (SOC) 
(sorted by internationally agreed order), high-level group term (HLGT), high level term (HLT) 
and preferred term (PT), sorted in alphabetical order for each treatment group, the number (n) and 
percentage (%) of patients experiencing at least one TEAE. Multiple occurrences of the same 
event in the same patient will be counted only once in the tables within a treatment phase. The 
denominator for computation of percentages is the safety population within each treatment group. 
Analysis of all treatment-emergent SAEs 
All treatment-emergent SAEs will be presented by primary SOC, HLGT, HLT, and PT, showing 
number (%) of patients with at least 1 serious TEAE, sorted by SOC internationally agreed order. 
The other levels (HLGT, HLT, PT) will be presented in alphabetical order. Listings will be 
provided for all SAEs by treatment group and patient with flags indicating on-treatment status. 
Analysis of all TEAEs leading to permanent treatment discontinuation 
TEAEs leading to treatment discontinuation will be presented by primary SOC, HLGT, HLT, and 
PT, showing number (%) of patients with at least 1 TEAE leading to permanent treatment 
discontinuation, sorted by SOC internationally agreed order. The other levels (HLGT, HLT, PT) 
will be presented in alphabetical order. Listings will be provided for all TEAE leading to 
permanent treatment discontinuation by treatment group and patient. 
Analysis of treatment-emergent AESI 
Treatment-emergent AESI, by AESI category and PT, will show number (%) of patients overall, 
sorted by decreasing incidence of PT within each AESI category.  The AESIs include, but are not 
limited to, the following categories and details of the MedDRA coding will be provided in the 
statistical analysis plan:  tuberculosis, anaphylaxis, hypersensitivity, vasculitis. 
Analysis of Deaths 
The following deaths summaries will be generated: 
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• Number (%) of patients who died by study period (TEAE, on-study) and reasons for death 
summarized on the safety population by treatment received 
• Death in nonrandomized patients or randomized and not treated patients   
• TEAE leading to death (death as an outcome on the AE e-CRF page as reported by the 
Investigator) by primary SOC, HLGT, HLT and PT showing number (%) of patients 
sorted by internationally agreed order of SOC and alphabetic order of HLGT, HLT, and 
PT. 
Analysis of the laboratory data 
The summary statistics (including number, mean, median, standard deviation, minimum and 
maximum) of all laboratory variables will be calculated for each visit or study assessment 
(baseline, each post-baseline time point, endpoint) by treatment group. Listings will be provided 
with flags indicating the out of range values as well as the PCSA values. 
The incidence of PCSA at any time will be summarized by treatment group for each laboratory 
parameter. Shift tables showing changes with respect to the baseline status will be provided. 
Analysis of the vital signs data 
The summary statistics (including number, mean, median, standard deviation, minimum and 
maximum) of all vital signs variables will be calculated for each visit or study assessment 
(baseline, each post-baseline time point, endpoint) by treatment group. 
The incidence of PCSA at any time will be summarized by treatment group for each vital signs 
variable. Shift tables showing changes with respect to the baseline status will be provided. 
Listings will be provided with flags indicating the out of range values as well as the PCSA values. 
Assessment of potential drug-induced liver injury 
The liver function tests, namely ALT, AST, alkaline phosphatase and total bilirubin, are used to 
assess possible drug induced liver toxicity. The proportion of patients with PCSA values at any 
post-baseline visit by baseline status will be displayed by treatment group for each parameter. The 
proportion of patients with PCSA values at any post-baseline visit will also be displayed by 
duration of exposure for each treatment group. 
A graph of distribution of peak values of ALT versus peak values of total bilirubin will also be 
presented. Note that the ALT and Total bilirubin values are presented on a logarithmic scale. The 
graph will be divided into 4 quadrants with a vertical line corresponding to 3xULN for ALT and a 
horizontal line corresponding to 2xULN for total bilirubin. 
Summarize the normalization by parameter (to ≤1 ULN or return to baseline) of elevated liver 
function tests by categories of elevation (1-<3x, 3x, 5x, 10x, 20x ULN for ALT and AST, 1.5x 
ULN for Alkaline phosphatase, and 1.5x and 2x ULN for total bilirubin), with following 
categories of normalization: never normalized, normalized after IMP discontinuation. Note that a 
patient will be counted only under the maximum elevation category. 1-3, 3-5, 5-10, 10-20, >20 
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Summarize the incidence of liver related AEs by treatment group. The selection of PTs will be 
based on standardized MedDRA query (SMQ) for drug related hepatic disorders. 
Analysis of the electrocardiogram data 
The summary statistics (including number, mean, median, standard deviation, minimum and 
maximum) of all ECG variables will be calculated for each visit or study assessment (baseline, 
each post baseline time point, endpoint) by treatment group. 
The incidence of PCSA at any during the TEAE period will be summarized by treatment group 
for each ECG variable. Shift tables showing changes with respect to the baseline status will be 
provided. Listings will be provided with flags indicating the PCSA values. 
Analysis of Immunogenicity 
Anti-SAR antibody (ADA) assay results will be described categorically. Descriptive statistics will 
be provided for: 
• Patients with any positive ADA assay response during the study. 
• ADA positive patients during the TEAE period. 
ADA positive patient is defined as patient with at least 1 treatment-induced or treatment-boosted 
ADA positive sample during the TEAE period, where 
• Treatment-induced ADA positive patient is defined as a patient with non-positive assay 
(meaning negative or unevaluable) response at baseline but with a positive assay response 
during the TEAE period. 
• Treatment-boosted ADA positive patient is defined as a patient with a positive ADA assay 
response at baseline and with at least a 4-fold increase in titer during the TEAE period 
The rest will be classified as ADA negative or inconclusive patients. 
Response of treatment-induced ADA positive patient is further classified as transient ADA 
response, persistent ADA response or indeterminate. 
Transient ADA response: 
• Treatment-induced ADA detected only at one sampling time point during the TEAE 
period and at least 16 weeks before the last sample, or   
• Treatment induced ADA detected at 2 or more sampling time points, where the first and 
last ADA positive samples (irrespective of any negative samples in between) are separated 
by a period less than 16 weeks and the first ADA positive sample and last ADA sample 
are separated by a period exceeding 16 weeks or longer.  
Persistent ADA response: 
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• Treatment-induced ADA detected at 2 or more sampling time points during the TEAE 
period, where the first and last ADA positive samples (irrespective of any negative 
samples in between) are separated by a period exceeding 16 weeks or longer 
Descriptive statistics for ADA titers will be provided for patients with positive ADA assay 
response and selected sub-categories. 
11.4.4 Analyses of pharmacokinetic, pharmacodynamics and biomarker variables 
• PK data will summarized by treatment arm and timepoint using descriptive statistics 
(number of patients, arithmetic mean, standard deviation, geometric mean, coefficient of 
variation, minimum and maximum).  
• Biomarkers will be summarized by treatment arm and visit using descriptive statistics. 
Correlation analysis may be conducted to explore the PK/PD relationship.  
11.5 
INTERIM ANALYSIS 
Futility analysis: 
In case of major recruitment issues a futility analysis with non-binding recommendation will be 
performed in order to make further decisions regarding trial continuation/discontinuation. Futility 
analysis will be considered when at least 50% of patients have week 24 evaluation of FVC. All 
futility rules will be described in the statistical analysis plan.  
Two step analysis: 
The analysis will be conducted in two steps: 
• First step: Main efficacy and safety analyses: 
The first analysis will be conducted when all patients have been randomized and have at least all 
their data up to Week 52 collected and validated, and will consist in the final analysis of the 
primary and secondary endpoints up to Week 52. The safety analysis will be performed on all 
safety data collected and validated at the time of the first analysis. The results of the first analysis 
will not be used to change the conduct of the ongoing study in any aspect. 
• Second step will be the final analysis: 
The second analysis will be conducted at the end of the study and will consist in the final analysis 
of Week 64 efficacy endpoints and final safety analysis. 
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12 
ETHICAL AND REGULATORY CONSIDERATIONS 
12.1 
ETHICAL AND REGULATORY STANDARDS 
This clinical trial will be conducted by the Sponsor, the Investigator, delegated Investigator staff 
and Sub-investigator, in accordance with the principles laid down by the 18th World Medical 
Assembly (Helsinki, 1964) and all applicable amendments laid down by the World Medical 
Assemblies, and the ICH guidelines for good clinical practice (GCP), all applicable laws, rules 
and regulations. 
This clinical trial will be recorded in a free, publicly accessible, internet-based registry, no later 
than 21 days after the first patient enrollment, in compliance with applicable regulatory 
requirements and with Sanofi public disclosure commitments.  
12.2 
INFORMED CONSENT 
The Investigator (according to applicable regulatory requirements), or a person designated by the 
Investigator, and under the Investigator's responsibility, should fully inform the patient of all 
pertinent aspects of the clinical trial including the written information giving approval/favorable 
opinion by the Ethics Committee (IRB/IEC). All participants should be informed to the fullest 
extent possible about the study, in language and terms they are able to understand. 
Prior to a patient’s participation in the clinical trial, the written informed consent form should be 
signed, name filled in and personally dated by the patient or by the patient’s legally acceptable 
representative (not applicable for this study as it is not planned to include vulnerable patients), 
and by the person who conducted the informed consent discussion. A copy of the signed and 
dated written informed consent form will be provided to the patient.  
Prior to collection of blood for pharmacogenetics and for potential future markers of interest, the 
optional pharmacogenetic informed consent form (written) and the optional informed consent 
form (written) for future use of samples should be signed, name filled in, and personally dated by 
the patient or by the subject’s legally acceptable representative (not applicable for this study as it 
is not planned to include vulnerable patients), and by the person who conducted the informed 
consent discussion. A copy of the signed and dated written optional informed consent forms will 
be provided to the subject. 
The informed consent form, the optional pharmacogenetic informed consent form and the optional 
informed consent form for future use of samples, used by the Investigator for obtaining the 
patient's informed consent must be reviewed and approved by the Sponsor prior to submission to 
the appropriate Ethics Committee (IRB/IEC) for approval/favorable opinion. 
The scientific justification for collection of race/ethnic origin of the patients during the clinical 
study is specified in Section 14.5.  
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12.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) 
As required by local regulation, the Investigator or the Sponsor must submit this clinical trial 
protocol to the appropriate IRB/IEC, and is required to forward to the respective other party  a 
copy of the written and dated approval/favorable opinion signed by the Chairman with IRB/IEC 
composition. 
The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, informed consent form, Investigator’s Brochure, Investigator’s 
curriculum vitae [CV], etc.) and the date of the review should be clearly stated on the written 
(IRB/IEC) approval/favorable opinion. 
IMP will not be released at the study site and the Investigator will not start the study before the 
written and dated approval/favorable opinion is received by the Investigator and the Sponsor. 
During the clinical trial, any amendment or modification to the clinical trial protocol should be 
submitted to the IRB/IEC before implementation, unless the change is necessary to eliminate an 
immediate hazard to the patients, in which case the IRB/IEC should be informed as soon as 
possible. It should also be informed of any event likely to affect the safety of patients or the 
continued conduct of the clinical trial, in particular any change in safety. All updates to the 
Investigator’s Brochure will be sent to the IRB/IEC. 
A progress report is sent to the IRB/IEC at least annually and a summary of the clinical trial’s 
outcome at the end of the clinical trial.  
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13 
STUDY MONITORING 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) 
The Investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the Sponsor (including security rules). The 
Investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the e-CRF, Discrepancy Resolution Form [DRF] or other appropriate 
instrument) in an accurate and legible manner according to the instructions provided and to ensure 
direct access to source documents by Sponsor representatives. 
If any circuit includes transfer of data particular attention should be paid to the confidentiality of 
the patient's data to be transferred. 
The Investigator may appoint such other individuals as he/she may deem appropriate as Sub-
investigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Sub-investigators shall be appointed and listed in a timely manner. The Sub-
investigators will be supervised by and work under the responsibility of the Investigator. The 
Investigator will provide them with a copy of the clinical trial protocol and all necessary 
information. 
13.2 
RESPONSIBILITIES OF THE SPONSOR 
The Sponsor of this clinical trial is responsible to regulatory authorities for taking all reasonable 
steps to ensure the proper conduct of the clinical trial as regards ethics, clinical trial protocol 
compliance, and integrity and validity of the data recorded on the e-CRFs. Thus, the main duty of 
the monitoring team is to help the Investigator and the Sponsor maintain a high level of ethical, 
scientific, technical and regulatory quality in all aspects of the clinical trial. 
At regular intervals during the clinical trial, the site will be contacted, through monitoring visits, 
letters or telephone calls, by a representative of the monitoring team to review study progress, 
Investigator and patient compliance with clinical trial protocol requirements and any emergent 
problems. These monitoring visits will include but not be limited to review of the following 
aspects: patient informed consent, patient recruitment and follow-up, SAE documentation and 
reporting, AESI documentation and reporting, AE documentation, IMP allocation, patient 
compliance with the IMP regimen, IMP accountability, concomitant therapy use and quality of 
data. 
13.3 
SOURCE DOCUMENT REQUIREMENTS 
According to the ICH GCP, the monitoring team must check the CRF entries against the source 
documents, except for the pre-identified source data directly recorded in the CRF. The informed 
consent form will include a statement by which the patient allows the Sponsor’s duly authorized 
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personnel, the Ethics Committee (IRB/IEC), and the regulatory authorities to have direct access to 
original medical records  which support the data on the CRFs (e.g. patient's medical file, 
appointment books, original laboratory records, etc.). These personnel, bound by professional 
secrecy, must maintain the confidentiality of all personal identity or personal medical information 
(according to confidentiality and personal data protection rules). 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST 
It is the responsibility of the Investigator to maintain adequate and accurate CRFs (according to 
the technology used) designed by the Sponsor to record (according to Sponsor instructions) all 
observations and other data pertinent to the clinical investigation in a timely manner. All CRFs 
should be completed to ensure accurate interpretation of data. 
Should a correction be made, the corrected information will be entered in the e-CRF overwriting 
the initial information. An audit trail allows identifying the modification.  
Data are available within the system to the Sponsor as soon as they are entered in the e-CRF. 
The computerized handling of the data by the Sponsor may generate additional requests (DRF) to 
which the Investigator is obliged to respond by confirming or modifying the data questioned. The 
requests with their responses will be managed through the e-CRF. 
13.5 
USE OF COMPUTERIZED SYSTEMS 
The complete list of computerized systems used for the study is provided in a separate document 
which is maintained in the Sponsor and Investigator study files. 
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14 
ADDITIONAL REQUIREMENTS 
14.1 
CURRICULUM VITAE 
A current copy of the curriculum vitae describing the experience, qualification and training of 
each Investigator and Sub-investigator will be signed, dated and provided to the Sponsor prior to 
the beginning of the clinical trial. 
14.2 
RECORD RETENTION IN STUDY SITES 
The Investigator must maintain confidential all study documentation, and take measures to 
prevent accidental or premature destruction of these documents. 
The Investigator should retain the study documents at least 15 years after the completion or 
discontinuation of the clinical trial. 
However, applicable regulatory requirements should be taken into account in the event that a 
longer period is required. 
The Investigator must notify the Sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation. 
If the Investigator's personal situation is such that archiving can no longer be ensured by him/her, 
the Investigator shall inform the Sponsor and the relevant records shall be transferred to a 
mutually agreed upon designee.  
14.3 
CONFIDENTIALITY 
All information disclosed or provided by the Sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to, the clinical trial 
protocol, personal data in relation to the patients, the CRFs, the Investigator's Brochure and the 
results obtained during the course of the clinical trial, is confidential, prior to the publication of 
results. The Investigator and any person under his/her authority agree to undertake to keep 
confidential and not to disclose the information to any third party without the prior written 
approval of the Sponsor. 
However, the submission of this clinical trial protocol and other necessary documentation to the 
Ethics committee (IRB/IEC) is expressly permitted, the IRB/IEC members having the same 
obligation of confidentiality. 
The Sub-investigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Sub-investigators of the confidential nature of the clinical trial. 
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The Investigator and the Sub-investigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party's account. 
14.4 
PROPERTY RIGHTS 
All information, documents and IMP provided by the Sponsor or its designee are and remain the 
sole property of the Sponsor. 
The Investigator shall not and shall cause the delegated Investigator staff /Sub-investigator not to 
mention any information or the Product in any application for a patent or for any other intellectual 
property rights. 
All the results, data, documents and inventions, which arise directly or indirectly from the clinical 
trial in any form, shall be the immediate and exclusive property of the Sponsor. 
The Sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, 
develop, market or otherwise use the results of the clinical trial. 
As the case may be, the Investigator and/or the Sub-investigators shall provide all assistance 
required by the Sponsor, at the Sponsor's expense, for obtaining and defending any patent, 
including signature of legal documents. 
14.5 
DATA PROTECTION 
• The patient's personal data, which are included in the Sponsor database shall be treated in 
compliance with all applicable laws and regulations; 
• When archiving or processing personal data pertaining to the Investigator and/or to the 
patients, the Sponsor shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party. 
• The Sponsor also collects specific data regarding Investigator as well as personal data 
from any person involved in the study which may be included in the Sponsor’s databases, 
shall be treated by both the Sponsor and the Investigator in compliance with all applicable 
laws and regulations. 
Subject race or ethnicity will be collected in this study because these data are required by several 
regulatory authorities (e.g. on afro American population for FDA). 
Analyses of Subject genetic data will be conducted as described in the protocol as this is needed 
for pharmacogenetics analyses required for the purpose of the study or by regulatory authorities. 
The data collected in this study will only be used for the purpose(s) of the study and to document 
the evaluation of the benefit/ risk ratio, efficacy and safety of the product(s). They may be further 
processed if they have been anonymized. 
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14.6 
INSURANCE COMPENSATION 
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship.  This insurance policy is in accordance with local laws and requirements. 
The insurance of the Sponsor does not relieve the Investigator and the collaborators from any 
obligation to maintain their own liability insurance policy. An insurance certificate will be 
provided to the IECs/IRBs or regulatory authorities in countries requiring this document.  
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES 
For the purpose of ensuring compliance with the clinical trial protocol, Good Clinical Practice and 
applicable regulatory requirements, the Investigator should permit auditing by or on the behalf of 
the Sponsor and inspection by regulatory authorities. 
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel is bound by professional secrecy, and as 
such will not disclose any personal identity or personal medical information. 
The Investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents. 
As soon as the Investigator is notified of a planned inspection by the authorities, he will inform 
the Sponsor and authorize the Sponsor to participate in this inspection. 
The confidentiality of the data verified and the protection of the patients should be respected 
during these inspections. 
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to the Sponsor. 
The Investigator shall take appropriate measures required by the Sponsor to take corrective 
actions for all problems found during the audit or inspections. 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE 
14.8.1 By the Sponsor  
The Sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including but not limited to the following:  
• The information on the product leads to doubt as to the benefit/risk ratio; 
• Patient enrollment is unsatisfactory; 
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• The Investigator has received from the Sponsor all IMP, means and information necessary 
to perform the clinical trial and has not included any patient after a reasonable period of 
time mutually agreed upon; 
• Non-compliance of the Investigator or Sub-investigator, delegated staff with any provision 
of the clinical trial protocol, and breach of the applicable laws and regulations or breach of 
the ICH GCP; 
• The total number of patients are included earlier than expected; 
In any case the Sponsor will notify the Investigator of its decision by written notice. 
14.8.2 By the Investigator 
The Investigator may terminate his/her participation upon thirty (30) days' prior written notice if 
the study site or the Investigator for any reason becomes unable to perform or complete the 
clinical trial.  
In the event of premature discontinuation of the study or premature close-out of a site, for any 
reason whatsoever, the appropriate IRB/IEC and regulatory authorities should be informed 
according to applicable regulatory requirements. 
14.9 
CLINICAL TRIAL RESULTS 
The Sponsor will be responsible for preparing a clinical study report and to provide a summary of 
study results to the Investigator. 
14.10 PUBLICATIONS AND COMMUNICATIONS 
The Investigator undertakes not to make any publication or release pertaining to the study and/or 
results of the study prior to the Sponsor’s written consent, being understood that the Sponsor will 
not unreasonably withhold its approval. 
As the study is being conducted at multiple sites, the Sponsor agrees that, consistent with 
scientific standards, a primary presentation or publication of the study results based on global 
study outcomes shall be sought. However, if no multicenter publication is submitted, underway or 
planned within twelve (12) months of the completion of this study at all sites, the Investigator 
shall have the right to publish or present independently the results of this study in agreement with 
other Investigators and stakeholders. The Investigator shall provide the Sponsor with a copy of 
any such presentation or publication for review and comment at least 30 days in advance of any 
presentation or submission for publication.  In addition, if requested by the Sponsor, any 
presentation or submission for publication shall be delayed for a limited time, not to exceed 90 
days, to allow for filing of a patent application or such other justified measures as the Sponsor 
deems appropriate to establish and preserve its proprietary rights.  
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The Investigator shall not use the name(s) of the Sponsor and/or its employees in advertising or 
promotional material or publication without the prior written consent of the Sponsor. The Sponsor 
shall not use the name(s) of the Investigator and/or the collaborators in advertising or promotional 
material or publication without having received his/her and/or their prior written consent(s). 
The Sponsor has the right at any time to publish the results of the study. 
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15 
CLINICAL TRIAL PROTOCOL AMENDMENTS 
All appendices attached hereto and referred to herein are made part of this clinical trial protocol. 
The Investigator should not implement any deviation from, or changes of the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) 
to clinical trial patients, or when the change(s) involves only logistical or administrative aspects of 
the trial. Any change agreed upon will be recorded in writing, the written amendment will be 
signed by the Investigator and by the Sponsor and the signed amendment will be filed with this 
clinical trial protocol. 
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
IRB/IEC prior to its implementation, unless there are overriding safety reasons. 
In some instances, an amendment may require a change to the informed consent form. The 
Investigator must receive an IRB/IEC approval/favorable opinion concerning the revised informed 
consent form prior to implementation of the change and patient signature should be re-collected if 
necessary. 
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16 
BIBLIOGRAPHIC REFERENCES 
1. 
Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, et al. An official 
ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for 
diagnosis and management. Am J Respir Crit Care Med. 2011 Mar15;183 (6):788-824. 
2. 
Ley B, Collard HR, King TE Jr. Clinical course and prediction of survival in idiopathic 
pulmonary fibrosis. Am J Respir Crit Care Med. 2011 Feb 15;183 (4):431-40. 
3. 
Gribbin J, Hubbard RB, Le Jeune I, Smith CJ, West J, Tata LJ. Incidence and mortality of 
idiopathic pulmonary fibrosis and sacoidosis in the UK. Thorax 2006 Nov;61 (11):980-5. 
4. 
Navaratnam V, Fleming KM, West J, Smith CJ, Jenkins RG, Fogarty A, et al. The rising 
incidence of idiopathic pulmonary fibrosis in the U.K. Thorax. 2011 Jun;66 (6):462-7. 
5. 
Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G. Incidence and prevalence of 
idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2006 Oct 1;174(7):810-6. 
6. 
Molyneaux PL, Maher TM. The role of infection in the pathogenesis of idiopathic 
pulmonary fibrosis. Eur Respir Rev. 2013 Sep 1;22(129):376-81. 
7. 
Hodgson U, Laitinen T, Tukiainen P. Nationwide prevalence of sporadic and familial 
idiopathic pulmonary fibrosis: evidence of founder effect among multiplex families in Finland. 
Thorax. 2002 Apr;57(4):338-42. 
8. 
Flaherty KR, King TE Jr, Raghu G, Lynch JP 3rd, Colby TV, Travis WD, et al. Idiopathic 
interstitial pneumonia: what is the effect of a multidisciplinary approach to diagnosis? Am J 
Respir Crit Care Med. 2004 Oct 15;170(8):904-10. 
9. 
King TE Jr, Pardo A, Selman M. Idiopathic pulmonary fibrosis. Lancet. 2011Lancet. 2011 
Dec 3;378(9807):1949-61. 
10. 
Thabut G, Christie JD, Ravaud P, Castier Y, Dauriat G, Jebrak G et al. : Survival after 
bilateral versus single-lung transplantation for idiopathic pulmonary fibrosis. Ann intern Med 
2009 Dec 1; 151(11):767-74. 
11. 
Hershey GK. IL-13 receptors and signaling pathways: an evolving web. J Allergy Clin 
Immunol. 2003;111(4):677-90. 
12. 
Oh CK, Geba GP, Molfino N. Investigational therapeutics targeting the IL-4/IL-13/STAT-
6 pathway for the treatment of asthma. Eur Respir Rev. 2010 Mar;19(115):46-54. 
13. 
Jakubzick C, Choi ES, Carpenter KJ, Kunkel SL, Evanoff H, Martinez FJ, et al. Human 
pulmonary fibroblasts exhibit altered interleukin-4 and interleukin-13 receptor subunit expression 
in idiopathic interstitial pneumonia. Am J Pathol. 2004 Jun;164(6):1989-2001. 
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14. 
Murray LA, Argentieri RL, Farrell FX, Bracht M, Sheng H, Whitaker B, et al. 
Hyperresponsiveness of IPF/UIP fibroblasts: interplay between TGFbeta1, IL-13 and CCL2. Int J 
Biochem Cell Biol. 2008;40(10):2174-82. 
15. 
Park SW, Ahn MH, Jang HK, Jang AS, Kim DJ, Koh ES, et al. Interleukin-13 and its 
receptors in idiopathic interstitial pneumonia: clinical implications for lung function. J Korean 
Med Sci. 2009 Aug;24(4):614-20. 
16. 
Singh D, Kane B, Molfino NA, Faggioni R, Roskos L, Woodcock A. A phase 1 study 
evaluating the pharmacokinetics, safety and tolerability of repeat dosing with a human IL-13 
antibody (CAT-354) in subjects with asthma. BMC Pulm Med. 2010 Jan 8;10:3. 
17. 
Collard HR, King TE Jr, Bartelson BB, Vourlekis JS, Schwarz MI, Brown KK. Changes in 
clinical and physiologic variables predict survival in idiopathic pulmonary fibrosis. Am J Respir 
Crit Care Med. 2003 Sep 1;168(5):538-42. 
18. 
Flaherty KR, Andrei AC, Murray S, Fraley C, Colby TV, Travis WD et al. Idiopathic 
Pulmonary Fibrosis: Prognostic Value of Changes in Physiology and Six-Minute-Walk Test. Am 
J Respir Crit Care Med. 2006 Oct 1;174(7):803-9. 
19. 
Battista G, Zompatori M, Fasano L, Pacilli A, Basile B. Progressive worsening of 
idiopathic pulmonary fibrosis. High resolution computed tomography (HRCT) study with 
functional correlations. Radiol Med. 2003 Jan-Feb;105(1-2):2-11. 
20. 
Barr JT, Schumacher GE, Freeman S, LeMoine M, Bakst AW, Jones PW. American 
translation, modification, and validation of the St. George's Respiratory Questionnaire. Clin Ther. 
2000 Sep;22(9):1121-45. 
21. 
Toru H, Kinashi T, Ra C, Nonoyama S, Yatra J, Nakahata T et al. Interleukin-4 induces 
homotypic aggregation of human mast cells by promoting LFA-1/ICAM-1 adhesion molecules. 
Blood. 1997;89:3296-302. 
22. 
Vasakova M, Sterclova M, Matej R, Olejar T, Kolesar L, Skibova J et al. IL-4 
polymorphisms , HRCT score and lung tissue markers in idiopathic pulmonary fibrosis. Hum 
Immunol. 2013 Oct;74(10):1346-51. 
23. 
Walford HH and Doherty TA. STAT6 and lung inflammation. Jakstat. 2013 
Oct;2(4):e25301:1 
24. 
Siebold MA, Wise AL, Speer MC, Steele MP, Brown KK, Loyd JE, et al. A common 
MUC5B promoter polymorphism and pulmonary fibrosis. N Engl J Med. 2011 Apr:364(16):1503-
12. 
25. 
World Health Organization. Guidelines on the management of latent tuberculosis 
infection. http://apps.who.int/iris/bitstream/10665/136471/1/9789241548908_eng.pdf 
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Page 91 
26. 
Du bois R., Weycker D., Albera C, Bradford WZ, Costabel U, Kartashov A et al. Forced 
Vital Capacity in Patients with Idiopathic Pulmonary Fibrosis: Test Properties and Minimal 
Clinically Important Difference. Am J Respir Crit Care Med. 2011 Dec15;184 (12):1382-9. 
27. 
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Bock SA , Branum A, et 
al. Second symposium on the definition and management of anaphylaxis: Summary report—
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol 2006; 117: 391-397) 
28. 
Raghu G, Behr J, Brown KK, Egan JJ, Kawut SM, Flaherty KR et al.Treatment of 
Idiopathic Pulmonary Fibrosis With Ambrisentan. Ann intern Med 2013 May 7; 158(9):641-49. 
 
 
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APPENDICES 
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Appendix A 
Saint George Respiratory Questionnaire 
 
 
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Appendix B 
EuroQol Questionnaire ( EQ-5D-5L) 
 
 
 
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Appendix C 
 
 
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Appendix D 
Clinical criteria for diagnosing anaphylaxis 
H.A. Sampson et al – J Allergy Clin Immunol, 2006; vol 117, n°2: 391-7. 
 
Anaphylaxis is highly likely when any one of the following 3 criteria are fullfilled: 
Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (e.g. generalized hives, pruritus or flushing, swollen lips-tongue-uvula) 
AND AT LEAST ONE OF THE FOLLOWING 
a 
Respiratory compromise (e.g. dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia) 
b 
Reduced BP or associated symptoms of end-organ dysfunction (e.g. hypotonia [collapse], 
syncope, incontinence) 
Two or more of the following that occur rapidly after exposure to a likely allergen for that 
patient (minutes to several hours): 
a. Involvement of the skin-mucosal tissue e.g. generalized hives, pruritus or flushing, swollen 
lips-tongue-uvula 
b. Respiratory compromise (e.g. dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia) 
c. Reduced BP or associated symptoms (e.g. hypotonia [collapse], syncope, incontinence) 
d. Persistent gastrointestinal symptoms (e.g. crampy, abdominal pain, vomiting) 
Reduced BP after exposure to known allergen for that patient (minutes to several hours): 
a. Infants and children: low systolic BP (age specific) or greater than 30% decrease in systolic 
BP* 
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that person's 
baseline 
PEF, peak expiratory flow; BP, blood pressure 
*Low systolic blood pressure for children is defined as less than 70 mm Hg from 1 month to 1 year, less than (70 mm Hg = [2 x age]) from 1 to 10 
years and less than 90 mm Hg from 11 to 17 years. 
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Appendix E 
Assessment of Local Injection Site Reactions 
 
 
 
Reaction to 
Injectable 
Product 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Very Severe 
(Grade 4) 
Pain 
Does not interfere 
with activity 
Interferes with 
activity or repeated 
use of non-narcotic pain 
reliever 
Prevents daily activity or 
repeated use of narcotic 
pain reliever 
Emergency Room 
(ER) visit or 
hospitalization 
Tenderness 
Mild pain to touch 
Pain with movement 
Significant pain at 
 
rest 
ER visit or 
 
hospitalization 
Erythema / Redness * 
2.5 – 5 cm 
5.1 – 10 cm 
>10 cm 
Necrosis or 
exfoliative 
dermatitis 
Swelling ** 
2.5 – 5 cm and does 
not interfere with 
activity 
5.1 – 10 cm or 
interferes with 
activity 
> 10 cm or 
prevents daily 
activity 
Necrosis 
Itching 
Does not interfere 
with activity 
Interferes with 
activity or repeated 
use of topical or systemic 
treatment 
Prevents daily activity or 
leads to other significant 
dermatologic conditions 
(such as infection, 
scarring, etc.) 
Emergency Room 
(ER) visit or 
hospitalization 
Other (Please 
specify)*** 
No modification of 
daily activities and/or 
does not require 
symptomatic 
treatment. 
Hinders normal daily 
activities and/or requires 
symptomatic treatment. 
Prevents daily activities 
and requires 
symptomatic treatment. 
Emergency Room 
(ER) visit or 
hospitalization 
* 
In addition to grading the measured local reaction at the greatest single diameter, the measurement should be recorded as a 
continuous variable. 
** 
Swelling should be evaluated and graded using the functional scale as well as the actual measurement. 
*** 
Please specify the other signs or symptoms (for example, hematoma, discoloration, re-activation, etc.). 
 
ADAPTED from the toxicity grading scale table from the FDA Draft Guidance for Industry: Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials April 2005 
 
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According to template: QSD-002643 VERSION 6.0 (06-JUL-2016) 
Page 1 
STATISTICAL ANALYSIS PLAN 
Efficacy and safety of SAR156597 in the treatment of Idiopathic Pulmonary 
Fibrosis (IPF): A randomized, double-blind, placebo-controlled, 52-week dose-
ranging study 
SAR156597 - DRI11772 
STATISTICIAN: 
 
DATE OF ISSUE: 16-Jun-2017 
Total number of pages: 
82 
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NCT02345070


Statistical Analysis Plan  
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ...................................................................................................................1 
TABLE OF CONTENTS..................................................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..........................................................................5 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................6 
1.1 
STUDY DESIGN AND RANDOMIZATION ......................................................................................6 
1.2 
OBJECTIVES...................................................................................................................................6 
1.2.1 
Primary objectives............................................................................................................................6 
1.2.2 
Secondary objectives.......................................................................................................................6 
1.3 
DETERMINATION OF SAMPLE SIZE.............................................................................................7 
1.4 
STUDY PLAN...................................................................................................................................7 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL..................................9 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN .....................10 
2 
STATISTICAL AND ANALYTICAL PROCEDURES ....................................................................11 
2.1 
ANALYSIS ENDPOINTS ...............................................................................................................11 
2.1.1 
Demographic and baseline characteristics ....................................................................................11 
2.1.2 
Prior or concomitant medications...................................................................................................13 
2.1.3 
Efficacy endpoints..........................................................................................................................14 
2.1.3.1 
Primary efficacy endpoint(s) ..........................................................................................................14 
2.1.3.2 
Secondary efficacy endpoint(s)......................................................................................................14 
2.1.4 
Safety endpoints ............................................................................................................................19 
2.1.4.1 
Adverse events variables...............................................................................................................20 
2.1.4.2 
Deaths............................................................................................................................................21 
2.1.4.3 
Laboratory safety variables............................................................................................................21 
2.1.4.4 
Vital signs variables .......................................................................................................................22 
2.1.4.5 
Electrocardiogram variables ..........................................................................................................22 
2.1.5 
Pharmacokinetic variables .............................................................................................................22 
2.1.6 
Immunogenicity variables ..............................................................................................................23 
2.1.7 
Biomarker endpoints ......................................................................................................................25 
2.1.8 
Health economic endpoints............................................................................................................25 
2.2 
DISPOSITION OF PATIENTS .......................................................................................................25 
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2.2.1 
Randomization and drug dispensing irregularities.........................................................................27 
2.3 
ANALYSIS POPULATIONS...........................................................................................................28 
2.3.1 
Efficacy populations .......................................................................................................................28 
2.3.1.1 
Modified intent-to-treat population .................................................................................................28 
2.3.2 
Safety population ...........................................................................................................................28 
2.3.3 
Pharmacokinetics population.........................................................................................................29 
2.3.4 
Immunogenicity population ............................................................................................................29 
2.3.5 
Biomarker population .....................................................................................................................29 
2.4 
STATISTICAL METHODS .............................................................................................................29 
2.4.1 
Demographics and baseline characteristics ..................................................................................29 
2.4.2 
Prior or concomitant medications...................................................................................................30 
2.4.3 
Extent of investigational medicinal product exposure and compliance .........................................31 
2.4.3.1 
Extent of investigational medicinal product exposure....................................................................31 
2.4.3.2 
Compliance ....................................................................................................................................32 
2.4.4 
Analyses of efficacy endpoints.......................................................................................................33 
2.4.4.1 
Analysis of primary efficacy endpoint(s) ........................................................................................33 
2.4.4.2 
Analyses of secondary efficacy endpoints.....................................................................................42 
2.4.4.3 
Multiplicity issues ...........................................................................................................................48 
2.4.4.4 
Additional efficacy analysis ............................................................................................................49 
2.4.5 
Analyses of safety data..................................................................................................................49 
2.4.5.1 
Analyses of adverse events ...........................................................................................................50 
2.4.5.2 
Deaths............................................................................................................................................55 
2.4.5.3 
Analyses of laboratory variables....................................................................................................56 
2.4.5.4 
Analyses of vital sign variables ......................................................................................................57 
2.4.5.5 
Analyses of electrocardiogram variables .......................................................................................57 
2.4.6 
Analyses of pharmacokinetic variables..........................................................................................58 
2.4.7 
Analyses of immunogenicity data ..................................................................................................58 
2.4.8 
Analyses of Biomarker data...........................................................................................................59 
2.5 
DATA HANDLING CONVENTIONS ..............................................................................................59 
2.5.1 
General conventions ......................................................................................................................59 
2.5.2 
Data handling conventions for secondary efficacy variables.........................................................61 
2.5.2.1 
St George Respiratory Questionnaire (SGRQ) endpoint...............................................................61 
2.5.3 
Missing data...................................................................................................................................61 
2.5.4 
Windows for time points.................................................................................................................63 
2.5.5 
Unscheduled visits .........................................................................................................................64 
2.5.6 
Pooling of centers for statistical analyses......................................................................................64 
2.5.7 
Statistical technical issues .............................................................................................................64 
3 
INTERIM ANALYSIS .....................................................................................................................65 
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4 
DATABASE LOCK........................................................................................................................66 
5 
SOFTWARE DOCUMENTATION .................................................................................................67 
6 
REFERENCES...............................................................................................................................68 
7 
LIST OF APPENDICES.................................................................................................................69 
APPENDIX A 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA ......................70 
APPENDIX B 
SUMMARY OF STATISTICAL ANALYSES ........................................................................75 
APPENDIX C SYSTEMIC CORTICOSTEROIDS ROUTES......................................................................78 
APPENDIX D EQ-5D-5L SCORING...........................................................................................................79 
APPENDIX E 
MEDDRA CODELISTS FOR AESIS AND RELATED HEPATIC DISORDER ....................81 
APPENDIX F WHODD CODELISTS FOR PRIOR AND CONCOMITANT MEDICATIONS......................82 
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Page 5 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
6MWT: 
6-meter walking test 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALP: 
alkaline phosphatase 
ALT: 
alanine aminotransferase 
AST: 
aspartate aminotransferase 
ATC: 
anatomic or therapeutic categories 
BMI: 
body mass idex 
CI: 
confidence interval 
CIR: 
copy increment from reference 
CK: 
creatine kinase 
CMQ: 
Customized MedDRA Query 
DLCO: 
diffusing capacity of the lung for carbon monoxyde 
ESR: 
erythrocyte sedimentation rate 
FEV1: 
forced expiratory volume in 1 second 
FVC: 
forced vital capacity 
GGO: 
Ground Glass Opacification 
hsCRP: 
high-sensitivity C-reactive protein 
ILD: 
Identifiable Causes of Interstitial Lung Disease 
IMP: 
Investigational Medicinal Product 
ITT: 
intent-to-treat 
IVRS: 
interactive voice response system 
IWRS: 
interactive web response system 
PK: 
pharmacokinetics 
PPI: 
proton pump inhibitors 
RV: 
residual volume 
SAE: 
serious adverse event 
SMQ: 
Standardized MedDRA Query 
SpO2: 
peripheral oxygen saturation 
TEAE: 
treatment-emergent adverse event 
TLC: 
total lung capacity 
UIP: 
usual interstitial pneumonitis 
WHO-DD: 
World Health Organization Drug Dictionary 
 
 
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1 
OVERVIEW AND INVESTIGATIONAL PLAN 
1.1 
STUDY DESIGN AND RANDOMIZATION 
This is a phase 2, proof-of-concept, multicenter, multinational, randomized, placebo-controlled, 
double-blind, 3-parallel-arm (placebo qw, SAR156597 200mg qw and SAR156597 200mg q2w 
alternating with placebo every other week), stratified study design. 
After a screening phase of up to 4 weeks, patients will be centrally randomized (using allocation 
from block randomization schedule with stratifying factors) via IRT in a 1:1:1 ratio to 1 of the 3 
treatment groups and treated double-blind for approximately 1 year.  
Randomization will be stratified according to background therapy in authorized countries at the 
moment of randomization (patient with background therapy with either pirfenidone or nintedanib 
versus patient without background therapy). According to protocol amendment No. 10, it is 
planned to include a maximum of 66% of patient with background therapy. 
Only patients with adjudicated IPF status were allowed to be enrolled in the study. 
Approximately 300 patients (100 patients per treatment arm) will be recruited and randomized 
from 109 initiated sites. 
1.2 
OBJECTIVES 
1.2.1 Primary objectives 
The primary objective of this study is to evaluate, in comparison with placebo, the efficacy of 2 
dose regimens of SAR156597 (200 mg qw every week and 200 mg q2w every two weeks 
alternating with placebo every other week) administered subcutaneously during 52 weeks on lung 
function of patients with IPF. 
1.2.2 Secondary objectives 
The secondary objectives of this study are: 
• To evaluate the efficacy of 2 dose levels/regimens of SAR156597 compared to placebo on 
IPF disease progression 
• To evaluate the safety of 2 dose levels/regimens of SAR156597 compared to placebo in 
patients with IPF 
• To evaluate the pharmacokinetics (through plasma concentrations) of SAR156597 200 mg 
administered subcutaneously during 52 weeks 
• To assess the potential immunogenicity of SAR156597 
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• To evaluate the effect of SAR156597 on circulating biomarkers 
• To explore the effect of SAR156597 on quality of life 
1.3 
DETERMINATION OF SAMPLE SIZE 
Approximately 300 patients will be randomized in this study, 100 per treatment arm. Based on the 
enrollment in prior studies of this population approximately half of the patients are expected to be 
older than 65. 
The sample size calculations are based on the primary efficacy variable of % predicted FVC 
change from baseline to week 52, with the following assumptions: 
• A common standard deviation of 12% is assumed based on the data from previous trials 
(26) 
• A 5% mean difference between each dose and placebo in change from baseline in % 
predicted FVC 
• A 2-sided 5% significance level with 80% power 
Ninety two (92) patients per treatment arm will yield 80% power to detect a 5 percentage point 
difference between the treatment groups and placebo. Additional patients will be randomized in 
each regimen to allow for dropouts; therefore, approximately 100 patients will be randomized into 
each treatment arm, for a total sample size of approximately 300 patients for the study. 
As a rank-based method will be used for analysis the actual power may differ from these 
calculations, however, calculations based on the ASCEND study (28), which used the same 
analysis method and endpoint confirm that the planned analysis should have at least 80% power. 
No adjustment is made for multiplicity since a hierarchical testing procedure is proposed. 
Calculations were made using nQuery Advisor 7.0. 
1.4 
STUDY PLAN 
The following figure presents the graphical study design: 
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Figure 1 - Graphical study design (screening period, double-blind period and follow-up period)  
 
Approximately 300 patients will be randomized in a ratio 1:1:1 to the following three treatment 
arms: 
• SAR156597 (qw) arm (n = 100): Patients will receive SAR156597 administered 
subcutaneously in 200 mg doses once every week (qw) 
• SAR156597 (q2w) arm (n = 100): Patients will receive SAR156597 administered 
subcutaneously in 200 mg doses once every 2 weeks (q2w) alternating with placebo 
subcutaneously once every 2 weeks 
• Placebo (qw) arm (n = 100): Patients will receive placebo subcutaneously once every 
week. 
The study population will be stratified at baseline according to a background therapy with 
pirfenidone or nintedanib (standard of care for IPF in authorized countries).  
The study will last up to 68 weeks as follows: 
• Up to 4 weeks of screening 
• 52 weeks of study treatment (from Day 1 dosing to Week 52 dosing) 
• 12 weeks of follow-up 
The total duration will be approximately 64 weeks (excluding screening period) per patient. 
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1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
This section summarizes major changes to the protocol statistical section with emphasis on 
changes after study start (after the first patient was enrolled). The protocol history table below 
gives the timing, rationale, and key details of major changes to the protocol statistical section.  
The first patient was screened on 01-May-2015. 
The first patient was randomized on 27-May-2015. 
Table 1 - Protocol amendment statistical changes 
Amendment 
Number 
Date 
Approved 
Rationale 
Description of statistical 
changes 
10 
21-Jul-2015 
An early analysis of the main efficacy 
endpoints and safety data will be 
performed after the last patient completed 
the End of treatment visit (Visit 9, week 52) 
to allow an evaluation of the benefit/risk for 
the treatment of IPF with SAR156597 and 
take the decision to move to Phase 3 of 
clinical development and prepare for future 
phase 3 studies. 
Not applicable. 
10 
21-Jul-2015 
In case of major recruitment issues, a 
futility analysis could be considered in 
order to make further decisions regarding 
trial continuation/discontinuation. 
No major recruitment issues occurred 
during the enrollment therefore no 
interim analysis was performed. 
10 
21-Jul-2015 
Due to the recent approval of pirfenidone 
(Esbriet®) and nintedanib (Ofev®) and 
thus the availability on the market in 
almost all countries participating in the 
study, the rate of patients with authorized 
background therapy is likely to be higher 
than that initially expected at time of study 
design. In consequence, in order to limit 
the impact of background therapy on 
efficacy and safety assessment of 
SAR156597 for the treatment of IPF, the 
rate of patients in the background therapy 
stratum will be capped to a maximum of 
66% (i.e, 33% in the without background 
therapy stratum). 
In protocol: stratification factor was 
already planned for primary analysis 
but was not described for secondary 
analyses.  
In SAP, description for secondary 
analyses and specification whether 
specific parameters will be described 
by With/Without Background Therapy 
status will be specified. 
NA 
NA 
Duration of IMP exposure is defined as: 
last dose date – first dose date + 14 days, 
however for 200 mg SAR156597 q2w arm, 
there is an IMP injection every two weeks 
alternating with placebo the other week. 
Duration of IMP exposure will be 
defined as: last dose date – first dose 
date + 7 days. 
NA 
NA 
Change in mITT definition due a too low 
selection of patients (more than 5% of 
patients were discarded with the protocol 
definition). 
The new definition is all randomized 
patients who take at least one dose or 
part of a dose of IMP. Patients will be 
analyzed using the treatment arm to 
which they were randomized. This 
results in considering all mITT patients 
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Amendment 
Number 
Date 
Approved 
Rationale 
Description of statistical 
changes 
in efficacy analysis provided that the 
endpoint was measured or could be 
calculated (e.g. at least 1 baseline and 
1 post-baseline values for imputing 
and calculating a change). 
NA 
NA 
Baseline definition has been revised 
because the timeslot between a screening 
and a baseline value is large (up to 4 
weeks) and there will not be several 
assessments at 52 weeks. 
Last available value before first IMP 
administration. 
NA 
NA 
%predicted DLCO analysis is of interest, it 
was missing in protocol. 
Addition of the %predicted DLCO 
exploratory endpoint analysis. 
NA 
NA 
Primary efficacy endpoint - change in 
week 52 missing data (due to death or 
lung-transplant) imputation approach: the 
time-to-death or lung transplant approach 
is more sensitive in ranking patients. For 
example, a patient who dies early will be 
more penalized than a patient who dies 
lately during the study.  
Primary efficacy endpoint - change in 
week 52 missing data (due to reasons 
other death or lung-transplant) imputation 
approach:  
• patients taking treatment at 52 weeks 
will be imputed using a linear 
regression run on their treatment arm 
completers. 
• patients not taking treatment at 52 
weeks will be imputed using a linear 
regression run on the placebo 
completers. 
Time-to-death or lung transplants will 
be used instead of allocating the 
lowest rank for all died and lung 
transplanted patients.  
For patients with a week 52 missing 
data (due to reasons other than death 
or lung transplant), depending on 
treatment intake at 52 weeks, a linear 
regression will be performed on a 
particular set of completers. 
NA 
NA 
Disease progression endpoint - change in 
analysis cut-off date: Day 375 will be used 
instead of superior boundary of week 52 
analysis window (Day 406) in order to 
prevent from non-random censures.  
Patients not meeting the definition for 
disease progression will be considered 
censored at the time of their week 52 
FVC or DLCO assessment provided 
that it was performed before Day 375. 
For patients with a missing week 52 
assessment, the censoring time will be 
the time of the last measured FVC or 
DLCO assessment. For patients with 
week 52 assessment performed after 
Day 375, the censoring time will be 
Day 375. 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN 
Not applicable. 
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2 
STATISTICAL AND ANALYTICAL PROCEDURES 
2.1 
ANALYSIS ENDPOINTS 
2.1.1 Demographic and baseline characteristics 
The baseline value is defined as the last available value obtained before or equal to the date and 
time of the first double-blind Investigation Medicinal Product (IMP) administration. For patients 
randomized and not treated, the baseline value is defined as the last available value obtained 
before or equal to the date and time of randomization. 
All baseline safety and efficacy parameters are presented along with the on-treatment summary 
statistics in the safety and efficacy sections (Section 2.4.4 and Section 2.4.5). 
Demographic characteristics 
Demographic variables at baseline are gender (Male, Female), race (Caucasian/White, Black, 
Asian/Oriental, Other), age in years (quantitative and qualitative variable: <40, ≥40 and >65, ≥65 
and <75, ≥75 years), ethnicity (Hispanic/Latino, Not Hispanic/Latino). 
Medical or surgical history 
Medical (or surgical) history includes (but are not limited to) the following previous relevant 
medical and surgery history collected at baseline: 
• All prior significant medical conditions, and/or hospitalization history: eg. pneumonia, 
asthma, Chronic Obstructive Pulmonary Disease (COPD), diabetes, hypertension, 
pulmonary arterial hypertension, congestive heart failure, esophageal reflux, depression, 
sleep apnea, myocardial infarction or arrhythmias, need for major surgery or surgical 
complications. 
Habits 
Habits includes: 
• smoking habits (never smoke, quit smoking (have smoked regularly in their lifetimes but 
have stopped at least 8 days ago), currently smokes (smoked at least 1 cigarette, as a mean, 
per day during the past 7 days)), pack years (if currently smoking or quit smoking: One 
pack year is smoking 20 cigarettes a day for one year), mean smoking duration for quit 
and current smokers in years. 
• alcohol habits (frequency of alcoholic drinks in the last 12 months (Never/At least 
monthly/At least weekly/At least daily/Occasionally), number of standard drinks (1 or 
2/Greater than 2 where standard drink means 1 pint/bottle of beer, 1 glass of wine, 1 shot 
of hard liquor…) per day when drinking alcohol) 
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Disease characteristics at baseline 
Specific disease history includes:  
• IPF diagnosis algorithm: Identifiable Causes of Interstitial Lung Disease (ILD) (yes, no), 
Diagnosis confirmation by Central review (yes, no), IPF diagnosis based on HRCT alone 
OR HRCT and Surgical Lung biopsy 
• HRCT UIP (usual interstitial pneumonitis) determination during adjudication (Definite 
UIP, Probable UIP, Possible UIP and Definitely not UIP) 
• Lung Biopsy UIP determination during adjudication (Definite UIP, Probable UIP, Possible 
UIP and Definitely not UIP) 
• Time since diagnosis of IPF (in years and by category: <1, 1-≤3 and >3 years) 
• Time since first symptoms of IPF (years) 
• Any acute exacerbation within the past 12 months before enrollment (yes, no) and if yes, 
time from most recent date of acute exacerbation (months and by category (<6 months and 
≥6 months))  
• Family IPF history (yes, no, unknown) 
• Oxygen therapy need (yes, no) and if yes number of hours the patient is on supplemental 
oxygen therapy per day 
• Currently taking pirfenidone or nintedanib for at least 12 weeks prior to enrollment (yes, 
no) and if yes, will continue with pirfenidone or nintedanib during the study (yes, no)  
The following efficacy parameters will be also summarized at baseline (see definition in 
Section 2.1.3):  
• FVC (forced vital capacity): L and % predicted (quantitative and by tercile (≤60, >60 and 
≤75, >75)),  
• FEV1 (forced expiratory volume in 1 second): L and % predicted,  
• FEV1/FVC ratio,  
• % predicted DLCO (diffusing capacity of the lung for carbon monoxide): quantitative and 
by tercile (≤40, >40 and ≤55, >55), 
• residual volume (RV): L, 
• total lung capacity (TLC): L,  
• SpO2 (peripheral oxygen saturation): % under oxygenotherapy and under ambient air,  
• SGRQ total score,  
• EQ-5D-5L total score,  
• 6MWT (6-meter walking test) distance (m),  
• Total Fibrosing ILD score. 
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Other baseline characteristics 
Other baseline characteristics include stratification factor (With/Without Background Therapy) as 
per IVRS/IWRS and e-CRF (patients taking at least a dose or part of a dose of Nintedanib or 
Pirfenidone at randomization (Visit 2/Day 1) will be considered in the With Background Therapy 
stratum). 
Any technical details related to computation, dates and imputation for missing dates are described 
in Section 2.5.  
2.1.2 Prior or concomitant medications  
All medications taken before randomization and until the end of the study are to be reported in 
one of the specific case report form pages: 
• Pirfenidone or Nintedanib (within 12 weeks prior to randomization (baseline) and during 
the course of the study) on the dedicated page using ATC code, 
• Systemic Corticosteroids category will gather the routes described in Appendix C (within 
4 weeks prior to randomization (baseline) and during the course of the study). 
• Other prior and concomitant specific medications (within 30 days before randomization 
(baseline) and during the course of the study) on the dedicated page:  
- 
In particular, N-acetylcysteine (administered at the dosage recommended by Czech 
Republic guidelines) will be selected using a WHO-DD codelist. 
- 
Anti-acids will be selected using a WHO-DD codelist. 
• in particular, H2 receptor blocker will be selected using a WHO-DD codelist 
• proton pump inhibitors (PPI) will be selected using a WHO-DD codelist. 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
using the version currently in effect at Sanofi at the time of database lock. All WHO-DD codelists 
used in this study are detailed in Appendix F. 
• Prior medications are those the patient used from 12 weeks prior screening up to first 
investigational medicinal product (IMP) intake. Prior medications can be discontinued 
before first administration or can be ongoing during treatment phase. 
• Concomitant medications are any treatments received by the patient concomitantly to the 
IMPs, from first IMP administration to the last IMP administration + 84 days. A given 
medication can be classified both as a prior medication and as a concomitant medication. 
Concomitant medications do not include medications started during the post-treatment 
period (as defined in Section 2.1.4).  
• Post-treatment medications are those the patient took in the period running from the day 
after the last IMP administration + 84 days period (ie, 85 days after the day of last dose of 
double-blind IMP injection). 
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Any technical details related to computation, dates, imputation for missing dates are described in 
Section 2.5. 
2.1.3 Efficacy endpoints 
Unless otherwise specified, all efficacy parameters values (scheduled or unscheduled) may be 
used to provide a value for the primary and secondary efficacy endpoints.  
For FVC, FEV1 and FEV1/FVC parameters, a value is considered valid if this is an ATSBEST 
value with a grade “A” or “B” and a status “CLEAN” or “MANUAL”.  
All measurements (scheduled or unscheduled) will be assigned to analysis windows defined in 
Table 6, in order to provide an assessment of the efficacy parameter at each time point planned to 
be collected as per protocol. For all post-baseline time points, the value used for the analyses at a 
given time point (e.g at week 52) is the valid value obtained within the corresponding analysis 
window. If multiple valid values of a variable exist within an analysis window, the nearest from 
the targeted study day will be selected. In case of ties, the best value will be considered. 
The baseline value is the last available and valid measurement obtained before or equal to the date 
and time of the first double-blind IMP injection. For patients randomized and not treated, the 
baseline value is defined as the last available and valid value obtained before or equal to the date 
and time of randomization.  
2.1.3.1 Primary efficacy endpoint(s) 
The pulmonary function test % predicted FVC is planned to be assessed at baseline, Week 12 
(Visit 6), Week 24 (Visit 7), Week 36 (Visit 8), Week 52 (Visit 9/End of treatment) and Week 64 
(Visit 10/End of study).  
The primary efficacy endpoint of the study is the absolute change from baseline in % predicted 
FVC at 52 weeks in the mITT population. 
2.1.3.2 Secondary efficacy endpoint(s) 
2.1.3.2.1 Key secondary efficacy endpoints 
Two key secondary endpoints will evaluate other aspects of the efficacy of SAR156597 in IPF: 
• 
Patients experiencing Disease progression at 52 weeks in the mITT population 
• 
Deaths (all-cause) at 52 weeks in the mITT population 
2.1.3.2.2 Disease progression endpoint 
Disease progression is defined as time from randomization to the first occurrence of any of the 
following events: 
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• decrease in absolute % predicted FVC≥10% (as in Section 2.1.3.1) 
• decrease in absolute % predicted DLCO≥15% (as in Section 2.4.4.2.3) 
• lung transplant (recorded on the dedicated e-CRF page during the study) 
• death (recorded on the dedicated e-CRF page during  the study) 
Disease progression will be analyzed as a time-to-event variable: event date – randomization date 
+ 1 day where the event date is described in Table 2.  
Table 2 - Time-to-event variable definition for disease progression 
Scenarii 
Event status 
Event date 
First event up to Day 375 is decrease in 
absolute % predicted FVC≥10% or 
decrease in absolute % predicted 
DLCO≥15%  
event 
Date of the 1st decrease observed 
First event up to Day 375 is death or lung 
transplant 
event 
Date of death or date or lung transplant 
No event prior to last available and valid 
assessment of %predicted FVC or last 
available assessment of %predicted DLCO 
censored 
Min(date of last available %predicted FVC, 
date of last available %predicted DLCO) 
No event up to Day 375 (last available and 
valid assessment of %predicted FVC and 
last available assessment of %predicted 
DLCO performed after Day 375) 
censored 
Date of Day 375 
2.1.3.2.3 All-cause mortality endpoint 
Deaths are reported during the study on the Death e-CRF page. 
All-cause mortality endpoint will be analyzed as a time-to-event variable: event date - 
randomization date + 1 day where the event date is described in Table 3. 
Table 3 - Time-to-event definition for all-cause mortality 
Scenarii 
Event status 
 
 
Event date 
Death up to Day 375 
event 
 
 
date of death 
Lung transplant  
event 
 
 
Date of transplant  
Study discontinuation 
(according to EOS e-CRF 
page) before Day 375 
censored 
 
 
Min{max(date of last available 
information, SAE recovery date), date of 
Day 375} 
No death up to Day 375 
censored 
 
 
Date of Day 375 
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2.1.3.2.4 Exploratory efficacy endpoints 
The other secondary efficacy endpoints are considered exploratory and include: 
• Rate of acute IPF exacerbations at 52 weeks in the mITT population 
• Rate of respiratory hospitalizations and rate of non-elective hospitalizations at 52 weeks in 
the mITT population 
• Change from baseline in 6-MWT distance at 52 weeks in the mITT population 
• Change from baseline in HRCT lung interstitial score at 52 weeks in the mITT population 
• Change from baseline in the total score of the SGRQ at 52 weeks in the mITT population  
• Change from baseline in the total score of the EQ-5D-5L at 52 weeks in the mITT 
population 
2.1.3.2.5 Acute IPF exacerbations endpoint 
All acute IPF exacerbations events are recorded during the study on the AE e-CRF page. To help 
the investigator in diagnosing an acute IPF exacerbation, an “IPF Exacerbation Complementary” 
e-CRF form has to be completed.  
For efficacy analysis, only acute IPF exacerbations with a confirmed diagnosis on the “IPF 
Exacerbation Complementary” e-CRF form and occurring from randomization to Day 375 will be 
considered. 
In addition, the following information is recorded on this complementary form: 
• Diagnosis of AE,  
• Clinical evaluations  
- 
unexplained worsening or development of dyspnea within 30 days, 
• if no what is the symptom or finding of the patient related to this AE,  
- 
worsening of hypoxemia from a known baseline arterial blood gas,  
- 
pulmonary infection ruled out by endotracheal aspiration or broncho-alveolar lavage 
(BAL),  
• if no, was pulmonary infection ruled out by routine clinical practice and/or 
microbiological studies 
- 
have alternative causes (including left heart failure, P.E., acute lung injury, tec.) been 
excluded 
• Radiology assessment 
- 
HRCT performed 
• If yes, did it show new ground-glass abnormality and/or consolidation consistent 
with a UIP pattern 
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• Final diagnosis 
- 
Based on response provided, do you believe that the patient experienced an acute IPF 
exacerbation 
• Management 
- 
Was corrective treatment/therapy used 
2.1.3.2.6 Respiratory and non-elective hospitalizations endpoints 
All hospitalizations are recorded during the study on the “Hospitalization” e-CRF page. 
The respiratory hospitalizations occurring from randomization to Day 375 will be considered will 
be selected from the “Hospitalization” e-CRF page using reason = “Respiratory”. 
The non-elective hospitalizations occurring from randomization to Day 375 will be considered 
will be selected using the Yes response to the “nonelective hospitalization” item on the 
“Hospitalization” e-CRF page.  
2.1.3.2.7 Change from baseline in 6-MWT distance endpoint 
The total distance covered by the patient over a 6 minute walk is planned to be measured at Visit 
2 (Day 1) predose, Visit 6 (Week 12), Visit 7 (Week 24), Visit 8 (Week 36), Visit 9/EOT (Week 
52), Visit 10/EOS (Week 64), and reported in meters on the “6 Minute Walk Test - 6MWT” e-
CRF page.  
Additional information to assess quality will be reportedusing the “6 Minute Walk Test - 6MWT” 
e-CRF page: 
• the completion of the 6 minute walk test (If No, what was the time patient walked? (in 
seconds)),  
• the need of any pauses or breaks (if Yes, duration of pause (in seconds) and reason for 
pause were recorded). 
Of note: If during visits 6, 7, 8, 9 and 10, oxygen saturation is less than 88% under ambient air at 
rest, the patient should perform 6-MWT under 4L oxygen. 
2.1.3.2.8 Change from baseline in HRCT lung interstitial score endpoint 
The HRCT lung interstitial score is adjudicated in a blinded manner, and planned to be assessed at 
screening (unless already done within 1 year prior to screening) and Visit 9/EOT (Week 52) (in 
Germany, second assessement at 52 weeks based on Investigator’s judgment).  
The Total Fibrosing ILD, Reticular, Ground Glass Opacification (GGO), Honeycomb and 
Emphysema scores are recorded in six lobar regions (namely: RUL, LUL, RML, LML, RLL and 
LLL).  
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For each lobar region: 
• The sum of the 3 patterns (Reticular, GGO and Honeycomb) should be 100%  
• The Total Fibrosing ILD and the Emphysema scores ranges from 0 to 100% 
The score of interest will be the Total Fibrosing ILD score averaged on the 6 lobar regions. 
Each pattern score and Emphysema total score are the mean of values observed in the 6 lobar 
regions.  
In case of image quality issue, a value NE will be recorded. For any other issue, a value NA will 
be recorded. A score will be calculated only if at least 4 of the 6 lobar regions are filled in (other 
than NE or NA). 
2.1.3.2.9 Change from baseline in total score of St George Respiratory Questionnaire (SGRQ) 
endpoint 
Impact of IPF on quality of life health status will be assessed using SGRQ planned to be measured 
at Visit 2 (Day 1) predose, Visit 6 (Week 12), Visit 7 (Week 24), Visit 8 (Week 36), Visit 9/EOT 
(Week 52) and Visit 10/EOS (Week 64).  
Three component scores are calculated for the SGRQ: 
• Symptoms: effect of respiratory symptoms, their frequency and severity 
• Activity: activities that cause or are limited by breathlessness 
• Impacts: range of aspects concerned with social functioning and psychological 
disturbances resulting from airways disease 
A Total score is also calculated which summarizes the impact of the disease on overall health 
status.  
Scores are expressed as a percentage of overall impairment where 100 represents worst possible 
health status and 0 indicates best possible health status (1). 
Data handling conventions and detailed definitions are described in Table 5. 
2.1.3.2.10 Change from baseline in total score of EuroQol Questionnaire, 5 level system 
(EQ-5D-5L) endpoint 
EQ-5D is a generic measure of health status developed by the EuroQol Group in order to provide 
a simple, measure of health for clinical and economic appraisal. It was designed for self-
completion by patients. 
EQ-5D-5L is planned to be measured at Visit 2 (Day 1) predose, Visit 8 (Week 36), Visit 9/EOT 
(Week 52) and Visit 10/EOS (Week 64). 
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EQ-5D-5L is the 5-level system for the 5-dimensional format of the EQ-5D and covers the 
measurement of mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each 
dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and 
extreme problems. Scores on the 5 levels are used to create an index score derived from 
population weights. The United Kingdom population-based scoring will be used to derive an 
index score from -0.594 to 1.0 renamed the EQ-5D-5L total score. 
In addition, the EQ-5D has a single visual analogue scale (VAS) (0-100) to evaluate perceived 
current health. 
Of note: There should be only one response for each dimension. Missing values can be coded as 
‘9’ and ambiguous values (e.g. 2 boxes are ticked for a single dimension) should be treated as 
missing values (2). 
Further explanations are available in Appendix D. 
2.1.4 Safety endpoints 
The safety analysis will be based on: 
•  the reported adverse events (AEs) including serious adverse events (SAEs) and adverse 
events of special interest (AESIs)  
• and other safety information, such as: 
- 
clinical laboratory data,  
- 
vital signs,  
- 
electrocardiogram ECG. 
Observation period  
The observation period will be divided as follows: 
• The pre-treatment period is defined as the time from the signed informed consent date up 
to the first administration of IMP.  
• The treatment-emergent adverse event (TEAE) period is defined as the time from the 
first administration of the IMP to the last administration of the IMP + 84 days. It will 
include both treatment and residual treatment periods: 
- 
The treatment period is defined as the time from the first administration of the IMP to 
the last administration of the IMP + 7 days 
- 
The residual treatment period is defined as the time from the last administration of 
the IMP + 8 days to the last administration of the IMP + 84 days. 
• The post-treatment period is defined as the period of time starting the day after the end of 
the TEAE period (ie, 85 days after the day of last dose of double-blind IMP injection). 
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The on-study observation period is defined as the time from the first administration of IMP until 
the end of the study (defined as last protocol planned visit (end of study visit) or the 
resolution/stabilization of all SAEs and adverse events of special interest (AESIs)).  
2.1.4.1 Adverse events variables 
Adverse event observation period  
• Pre-treatment adverse events are AEs that developed or worsened or became serious 
during the pre-treatment period 
• Treatment-emergent adverse events are AEs that developed or worsened or became 
serious during the TEAE period 
• Post-treatment adverse events are AEs that developed or worsened or became serious 
during the post-treatment period 
All adverse events (including SAEs and AESIs) will be coded to a lower-level term (LLT), 
preferred term (PT), high-level term (HLT), high-level group term (HLGT), and associated 
primary system organ class (SOC) using the version of Medical Dictionary for Regulatory 
Activities (MedDRA) currently in effect at Sanofi at the time of database lock. 
Record the occurrence of AEs (including SAEs and AESIs) from the time of signed informed 
consent until the end of the study. 
Adverse events of special interest (AESIs) include the following terms (their complete 
descriptions are provided in the protocol): 
• Pregnancy of a female subject entered in a study as well as pregnancy occurring in a 
female partner of a male subject entered in a study with IMP selected using the e-CRF 
“Pregnancy” tick box on the AE page. 
• Symptomatic overdose (serious or non-serious) with IMP, selected using the e-CRF 
“Symptomatic overdose of the IP” tick box on the AE.  
• Increase in ALT ≥3·ULN (if baseline ALT <ULN) or ≥2·baseline value (if baseline ALT 
≥ULN), selected using laboratory data.  
• 
 
• Hypersensitivity: 
- 
Anaphylactic reactions or acute allergic reactions that require immediate treatment, 
selected using a CMQ coding list. 
- 
Severe injection site reactions, selected using HLT=”Injection site reaction” and an 
intensity equal to severe.  
• Tuberculosis, selected using a CMQ coding list. 
• Initiation of medications for suspected tuberculosis, selected using a WHODD 
CDG00737 “initiation of medications for suspected tuberculosis”.  
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• Acute renal failure, selected using a CMQ coding list. 
The summary of CMQ coding lists to be used in determining these AESIs is displayed in 
Appendix E. 
2.1.4.2 Deaths 
The deaths observation period are per the observation periods defined above.  
• 
Death on-study: deaths occurring during the on-study observation period 
• 
Death on-treatment: deaths occurring during the TEAE period  
• 
Death post-study: deaths occurring after the end of the study visit  
2.1.4.3 Laboratory safety variables 
Clinical laboratory data consists of blood analysis, including hematology, clinical chemistry, and 
urinalysis. Clinical laboratory values after conversion will be analyzed into standard international 
units and international units will be used in all listings and tables. 
The laboratory parameters will be classified as follows: 
• Hematology  
- 
Red blood cells and platelets and coagulation: hemoglobin, hematocrit, red blood 
cell count (erythrocytes), platelet count, erythrocyte sedimentation rate (ESR) 
- 
White blood cells: white blood cell count with differential (leukocytes, neutrophils, 
lymphocytes, monocytes, basophils, eosinophils) 
- 
Tuberculosis screen: a Quantiferon®-TB gold evaluation. 
• Chemistry  
 
- 
Metabolism: glucose, total protein, albumin, creatine kinase (CK), high-sensitivity C-
reactive protein (hsCRP), Hemoglobin A1C, Cholesterol, Triglycerides 
- 
Electrolytes: sodium, potassium, chloride, calcium, phosphorous, bicarbonate  
- 
Renal function: creatinine, creatinine clearance, blood urea nitrogen, urate 
- 
Liver function: alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
alkaline phosphatase (ALP), bilirubin 
- 
Pregnancy test: (For women of childbearing potential) β-HCG blood test, urine 
pregnancy tests.  
- 
  
• Serology 
- 
Hepatitis screen: hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B 
core antibody and hepatitis C antibodies 
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- 
 
 
 
 
• Cytometry 
- 
 
• Urine samples will be collected as follows:  
- 
Urinalysis (by dipstick): pH, specific gravity, protein, glucose, ketones, occult blood, 
nitrite, leukocyte esterase, urobilinogen and bilirubin. If any parameter on the dipstick 
is abnormal, a urine sample should be sent to the central laboratory for testing. If 
positive for proteins, microscopic analysis is performed by central laboratory. 
Technical formulas are described in Section 2.5.1. 
2.1.4.4 Vital signs variables 
Vital signs include: heart rate (beats per minute), diastolic and systolic blood pressure (mmHg) 
after 5 minutes of resting in sitting position and body weight (kg) and height (cm). body mass 
index (BMI) is calculated automatically at each visit on e-CRF page. 
In addition to quantitative variables, the following qualitative variables will be displayed at 
baseline for weight in kilograms (<50, ≥50 and <100, ≥100), body mass index (BMI) in kg/m² 
(<30, ≥30). 
Moreover, the values and changes from baseline in SPO2 over time will be displayed from the 
“Pulse Oximetry - Oxygenotherapy” e-CRF page and “Pulse Oximetry – Ambient air” e-CRF 
page separately. 
2.1.4.5 Electrocardiogram variables 
A standard 12-lead ECG will be performed and evaluate locally. 
ECG parameters include heart rate (beats per minute), PR interval (msec), QRS duration (msec), 
QT interval (msec), ST deviation (mm), T-wave and U-wave morphologies as normal or 
abnormal. In addition, ECG assessments will be described as normal or abnormal (clinically 
significant or not) according to the Investigator’s interpretation on the ECG eCRF page. The 
corrected QTc (according to Bazett and Fridericia) will be derived afterwards.  
2.1.5 Pharmacokinetic variables  
All measurements (scheduled or unscheduled) will be assigned to analysis windows defined in 
Table 7, in order to provide an assessment of the PK parameter at each time point planned to be 
collected as per protocol. 
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Samples for PK analysis are planned to be collected at pre-dose (within 2 hours before each dose 
administration) during Visits 2 (Day 1), 4 (Week 4), 6 (Week 12), 7 (Week 24), 8 (Week 36) and 
9/EOT (Week 52). Pharmacokinetics samples during Visit 10 will be collected in the morning. An 
additional sample should be taken in a subgroup (at least 30 patients by cohort) between 5 and 10 
days after last dose (i.e. after Visit 9). The possibility to perform this additional sample will be 
discussed between Investigator and patient on a case by case basis. 
Pharmacokinetic variable is the SAR156597 concentration at each time point using the time 
windows defined in Table 8. Depending on the timing of the sample versus the previous injection, 
Ctrough, Ctrough,av, Cmax and CFollow-Up will be defined as follows: 
• 
Cmax: SAR156597 concentration sample taken 5 to 10 days after last injection (week 52);  
• 
Ctrough: SAR156597 concentration sample within 2h before each administration (day 1, 
week 4, week 12, week 24, week 36 and week 52); 
- 
Ctrough,av,ss: SAR156597 average trough concentrations (“Ctrough,av,ss”) will be calculated 
for each patient as the mean of “Ctroughs” considered at steady state (ss). The occurrence 
of steady state will be assessed graphically, by plotting “Ctrough” throughout the study 
visits over all patients.  
• 
CFollow-up: SAR156597 concentration sample taken in week 64, 14 weeks after last 
injection. 
2.1.6 Immunogenicity variables 
All measurements (scheduled or unscheduled) will be assigned to analysis windows defined in 
Table 7, in order to provide an assessment of the ADA parameter at each time point planned to be 
collected as per protocol. 
Anti-SAR156597 antibodies (ADA) samples are planned to be collected at approximately the 
same times as the PK samples, namely: Visit 2 (Day 1), Visit 4 (Week 4), Visit 6 (Week 12), Visit 
7 (Week 24), Visit 8 (Week 36), Visit 9 (EOT visit at Week 52) and Visit 10 (EOS visit at Week 
64). 
ADA positive patients are patients with at least 1 treatment-induced or treatment-boosted ADA 
positive sample during the TEAE period, where 
• 
Treatment induced ADAs: ADAs developed de novo (seroconversion) following 
administration of the biotherapeutic (i.e., formation of ADAs any time after the initial drug 
administration in a subject without pre-existing ADAs). If the baseline ADA sample is 
missing or non-reportable and at least one reportable ADA sample is available during the 
treatment (including follow-up period) the baseline sample will be considered as 
“negative” for data analysis. This is considered being a conservative approach for ADA 
assessment. 
• Treatment boosted ADA: Pre-existing ADAs that were boosted to a higher level following 
administration of biotherapeutic (i.e., any time after the initial drug administration) the 
ADA titer is significantly higher than the baseline titer. A low serial dilution schema (2-
fold or 3 fold) should be applied during titration. A difference in titer values of two titer 
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steps between an on treatment or follow-up sample and its baseline sample is considered 
significant. For examples, at least a 4-fold increase in titers for 2-fold serial dilution 
schema (or 9-fold increase in titers for 3- fold serial dilution schema). If no titer could be 
determined for a positive sample, the titer will be reported as the MRD of the assay. 
The rest will be classified as ADA negative or inconclusive patients. 
The following variables will be described: 
• 
ADA response (Positive, Negative or inconclusive). For ADA positive: 
- 
Titer levels  
- 
Neutralizing status (Positive or inconclusive) 
• 
Pre-existing positive ADA defined as patients with positive ADA response at baseline 
with less than a specific increase (depending on titer calculation, e.g. 4-fold increase in 
titer for 2-fold serial dilution schema, 9–fold increase in titer for 3-fold serial dilution 
schema) in the post-baseline period 
• Treatment-emergent positive ADA response defined as 1) Patients with no ADA positive 
response at baseline but with any positive response in the post-baseline period (up to 
follow-up visit) or 2) Patients with a positive ADA response at baseline and at least a 
specific increase (depending on titer calculation, e.g. 4-fold increase in titer for 2-fold 
serial dilution schema, 9–fold increase in titer for 3-fold serial dilution schema) in titer in 
the post-baseline period (up to follow-up visit). For treatment-emergent positive ADA, the 
following categories for ADA duration will be applied: 
- 
A persistent positive response is a treatment-emergent ADA positive response detected 
in at least 2 or more post-baseline samples separated by at least a 16-week period 
(irrespective of any negative sample in between) 
- 
An indeterminate duration positive response is defined as ADA present only at the last 
sampling time point (and all previous samples negative) or with two last samples are 
positives but separated by a period less than 16 weeks. 
• 
A transient positive response is defined as 
- 
Treatment induced ADA detected only at one sampling time during treatment or 
follow-up observation period (excluding last sampling time) 
- 
Treatment induced ADA detected at two or more sampling time during treatment 
where the first and last ADA positive sample are separated by a period less than 16 
weeks and last sampling time is negative. 
• 
Duration of ADA defined as longevity of treatment induced ADA (in days): date of last 
treatment induced ADA sample minus date of first treatment induced or treatment boosted 
ADA sample + 1. This will be calculated only for subjects with at least 2 positive ADA 
samples.  
• Time to onset of treatment-emergent ADA positive response (in days): date of first ADA 
positive – date of first IMP administration.  
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2.1.7 Biomarker endpoints  
All measurements (scheduled or unscheduled) will be assigned to efficacy analysis windows 
defined in Table 6, in order to describe all BM assessments by time points even in case of 
premature treatment discontinuation. 
Peripheral blood are planned to be collected for measurement of protein biomarkers in serum or 
plasma at the study visits 2 (Day 1), 7 (Week 24) and 9/EOT (Week 52). 
The protein biomarkers include, but are not limited to:  
• Inter-cellular adhesion molecule 1 (ICAM1), 
• TARC,  
• Periostin,  
• Human Epipidymis protein 4 (HE4). 
• IL-6 
2.1.8 Health economic endpoints  
Health economic endpoints other than quality of life will not be assessed.  
2.2 
DISPOSITION OF PATIENTS 
This section describes patient disposition for both patient study status and the patient analysis 
populations. 
Screened patients are defined as any patients who signed the informed consent.  
Randomized patients consist of all patients with a signed informed consent form who have had a 
treatment kit number allocated and recorded in the IVRS/IWRS database, regardless of whether 
the treatment kit was used.  
For patient study status, the total number of patients in each of the following categories will be 
presented in the clinical study report using a flowchart diagram or summary table by treatment 
arm and overall: 
• Screened patients 
• Screen failure patients and reasons for screen failure 
• Non-randomized but treated patients 
• Randomized patients 
• Randomized but not treated patients and reason for not being treated 
• Randomized and treated patients 
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• Patients who complete and did not complete the study treatment period as per protocol 
• Patients who discontinued study treatment by main reason for permanent treatment 
discontinuation 
• Patients who complete and did not complete the study follow-up period as per protocol 
• Patients who discontinued study by main reason for study discontinuation 
• Status at last study contact and patient ongoing at the moment of the early analysis 
This table will be duplicated for background therapy status. 
For all categories of patients (except for the screened and non-randomized categories) percentages 
will be calculated using the number of randomized patients as the denominator. Reasons for 
treatment discontinuation will be supplied in tables giving numbers and percentages by treatment 
arm. This summary will be provided by treatment arm. 
The incidence of premature treatment discontinuation (irrespective of the reason) and premature 
treatment discontinuation due to AEs will be presented graphically by treatment arm, background 
therapy status on randomized and treated patients (as randomized), using Kaplan-Meier method. 
The time-to-event variable is defined as: event date – randomization date + 7 days, where an event 
could be: 
• a permanent treatment discontinuation recorded on the “End of Treatment” eCRF page 
with a No answer to “Did the subject complete treatment period per protocol?”. 
• a death before week 52 (without previous EOT) recorded on the “Death” eCRF page.  
In case of a complete treatment period (with a Yes answer to “Did the subject complete treatment 
period per protocol?” recorded on the End of Treatment” eCRF page), the patient will be censored 
at the completion date.  
The incidence of premature study discontinuation will be presented graphically by treatment arm, 
background therapy status on randomized patients, using Kaplan-Meier method. The time-to-
event variable is defined as: event date – randomization date + 1 day, where an event could be: 
• a study discontinuation without a 12-week follow-up. 
• a study discontinuation with a 12-week follow-up but occurring before week 52. 
• a death occurring before week 52 (without previous EOS) recorded on the “Death” eCRF 
page. 
In case of a complete study period (i.e. with at least 12 weeks of follow-up ending after week 52), 
the patient will be censored at the completion date. 
A patient is considered lost to follow-up at the end of the study if he/she is not assessed at the last 
protocol planned visit and if the time from the last successful contact (from the vital patient status 
case report form) to the last protocol planned visit is greater than 2 days, unless died before. 
Patient with insufficient follow-up will be described. 
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A patient is considered with insufficient follow-up or without follow-up at the end of the study in 
the following cases: 
• If the patient is not assessed at the scheduled follow-up visit, or any post-treatment visit, 
unless patient died before; 
• If the follow-up visit is less than 12 weeks after the last double-blind IMP injection. 
All critical or major quantitative deviations potentially impacting efficacy, randomization and 
drug-dispensing irregularities, and other important deviations will be summarized in tables giving 
numbers and percentages of deviations by treatment arm. These deviations are listed in the data 
review and surveillance plan. All critical or major qualitative deviations will be described. 
Additionally, the analysis populations for safety, efficacy, pharmacokinetics, immunology and 
biomarkers will be summarized in a table by number of patients on the randomized population.  
• Efficacy population: modified intent-to-treat (mITT) population  
• Safety population 
• Pharmacokinetics population 
• Anti-Drug Antibody population 
• Pharmacodynamics biomarker populations: Biomarker TARC population,  Biomarker 
ICAM1 population, Biomarker HE4 population, Biomarker Periostin population, 
Biomarker IL-6 population. 
Definitions of the study populations are provided in Section 2.3. 
2.2.1 Randomization and drug dispensing irregularities 
Randomization and drug-dispensing irregularities occur whenever: 
1. A randomization is not in accordance with the protocol-defined randomization method, 
such as  
a) an ineligible patient is randomized,  
b) a patient is randomized based on an incorrect stratum,  
c) a patient is randomized twice.  
OR 
2. A patient is dispensed an IMP kit not allocated by the protocol-defined randomization, 
such as  
a) a patient at any time in the study is dispensed a different treatment kit than as 
randomized (which may or may not contain the correct-as-randomized IMP), or  
b) a non-randomized patient is treated with IMP reserved for randomized patients. 
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Randomization and drug-dispensing irregularities will be monitored throughout the study and 
reviewed on an ongoing basis.  
All randomization and drug-dispensing irregularities will be documented in the clinical study 
report. If the number of irregularities is large enough to make a tabular summary useful, the 
irregularities will be categorized and summarized among randomized patients (number and 
percentages). Non-randomized, treated patients will be described separately.  
Randomization and drug-dispensing irregularities to be prospectively identified include but are 
not limited to:  
Randomization and drug allocation irregularities 
Kit dispensation without IRT transaction 
Erroneous kit dispensation 
Kit not available 
Randomization by error 
Patient randomized twice 
Stratification error 
Patient switched to another site 
2.3 
ANALYSIS POPULATIONS 
Patients treated without or before being randomized will not be considered randomized and will 
not be included in any analysis population. The safety experience of these patients will be 
reported separately. 
The randomized population includes any patient who has been allocated to a randomized 
treatment regardless of whether the treatment kit was used. 
For any patient randomized more than once, only the data associated with the first randomization 
will be used in any analysis population. The safety experience associated with any later 
randomization will be assessed separately. 
2.3.1 Efficacy populations 
2.3.1.1 Modified intent-to-treat population  
The modified intent-to-treat (mITT) population is defined as all randomized patients who received 
at least 1 dose or part of a dose of the IMP. Patients in the mITT population will be analyzed 
according to the treatment arm to which they are randomized. 
2.3.2 Safety population 
The safety population is defined as randomized population who actually received at least 1 dose 
or part of a dose of the IMP, analyzed according to the treatment actually received. 
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In addition:  
• Non-randomized but treated patients will not be part of the safety population; however, 
their safety data will be presented separately 
• Randomized patients for whom it is unclear whether they took the IMP will be included in 
the safety population as randomized 
• For patients receiving more than 1 IMP during the trial, the treatment arm allocation for 
as-treated analysis will be the one received at the majority of injections during the first 52 
weeks of treatment in terms of kits. 
2.3.3 Pharmacokinetics population 
The PK analysis will be performed on all randomized and treated patients (safety population) with 
at least one available PK sample post first double-blind IMP injection. 
2.3.4 Immunogenicity population 
The anti-SAR156597 antibody analysis will be performed on all randomized and treated patients 
(safety population) with at least one available ADA sample post first double-blind IMP injection. 
2.3.5 Biomarker population 
Baseline biomarker population includes the randomized and treated patients with a baseline 
sample successfully analyzed.  
Pharmacodynamics biomarker population includes the randomized and treated patients with a 
baseline sample and at least one post first double-blind IMP injection sample successfully 
analyzed.  
2.4 
STATISTICAL METHODS 
Continuous data will be summarized using the number of available data, mean, standard 
deviation (SD), median, minimum and maximum for each treatment arm. Categorical and ordinal 
data will be summarized using the number and percentage of patients in each treatment arm. 
2.4.1 Demographics and baseline characteristics 
Parameters will be summarized on the randomized population analyzed in the treatment arm to 
which they were randomized and according to background therapy status. 
Parameters described in Section 2.1.1 will be summarized by treatment arm and overall treatment 
groups using descriptive statistics.  
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Medical/surgical history will be summarized in each treatment arm by primary SOC, HLT and 
PT. Events will be sorted by SOC internationally agreed order and decreasing frequency of PT 
based on the incidence in the overall treatment arm. 
P-values on demographic and baseline characteristic data will not be calculated.  
A specific quantitative description of the efficacy parameters will be provided at baseline by 
treatment arm and by background therapy status. In particular, Q1 and Q3 will be described for 
PFTs. In addition, the terciles categories at baseline will be displayed for % predicted FVC and % 
predicted DLCO parameters.  
2.4.2 Prior or concomitant medications  
Specific prior medications (Nintedanib, Pirfenidone, Systemic Corticosteroids, N-Acetylcysteine, 
Anti-acid (including PPI and H2 receptor blocker)) and other prior medications will be presented 
separately for the randomized population. 
Specific concomitant medications (Nintedanib, Pirfenidone, Systemic Corticosteroids, N-
Acetylcysteine, Anti-acid (including PPI and H2 receptor blocker)) and other concomitant 
medications will be presented separately for the randomized population. 
Specific post-treatment medications (Nintedanib, Pirfenidone, Systemic Corticosteroids, N-
Acetylcysteine, Anti-acid (including PPI and H2 receptor blocker)) and other concomitant 
medications will be presented separately for the randomized population. 
Specific prior, concomitant, post-treatment medications will be summarized by treatment arm 
according to the WHO-DD dictionary, considering the first digit of the anatomic category (ATC) 
class (anatomic category) and standardized medication names. 
Other prior, concomitant, post-treatment medications will be summarized by treatment arm 
according to the WHO-DD dictionary, considering the first digit of the anatomic category (ATC) 
class (anatomic category) and the first 3 digits of the ATC class (therapeutic category). All ATC 
codes corresponding to a medication will be summarized, and patients will be counted once in 
each ATC category (anatomic or therapeutic) linked to the medication. Therefore patients may be 
counted several times for the same medication.  
The table for prior specific medications will be sorted by decreasing frequency of ATC followed 
by the standardized medication names based on the overall incidence across treatment groups. The 
table for other prior medications will be sorted by decreasing frequency of ATC followed by all 
other therapeutic classes based on the overall incidence across treatment groups. In case of equal 
frequency regarding ATCs (anatomic or therapeutic categories or standardized medication 
names), alphabetical order will be used.  
The tables for specific concomitant and post-treatment medications will be sorted by decreasing 
frequency of ATC followed by standardized medication names based on the incidence on the 
column all. The tables for other concomitant and post-treatment medications will be sorted by 
decreasing frequency of ATC followed by all other therapeutic classes based on the incidence on 
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the column all. In case of equal frequency regarding ATCs (anatomic or therapeutic categories or 
standardized medication names), alphabetical order will be used.  
In addition, the following specific medications will be summarized on the randomized population:  
• The prohibited medications will be presented in the deviations table. 
• For the specific concomitant medications (Pirfenidone, Nintedanib, Systemic 
Corsticosteroids, NAC and Anti-acid therapy (combined anti-acid, PPI and H2 receptor 
blocker)), the number of patients taking at least one dose at randomization will be 
summarized. For Pirfenidone, Nintedanib and Systemic Corsticosteroids only, the mean, 
median, standard deviation (SD), minimum and maximum dose will be summarized (use 
of the standard prednisone equivalent dose for Systemic Corticosteroids). If several doses 
for a given medication were taken by patient at this timepoint, the sum of the doses will be 
used.  
• The change in dose for Nintedanib and Pirfenidone medications will be described by visit 
and treatment arm according to the “Status of IPF Background Therapy” eCRF page: Has 
the dose of the background therapy changed since the previous visit? (Yes, No). 
A list of ATC codes to be used in determining these specific medications is displayed in Appendix 
F. 
2.4.3 Extent of investigational medicinal product exposure and compliance  
The extent of IMP exposure and compliance will be assessed and summarized by actual treatment 
within the safety population (Section 2.3.2). 
2.4.3.1 Extent of investigational medicinal product exposure 
The extent of IMP exposure will be assessed by the duration of IMP exposure. 
Duration of IMP exposure is defined as last dose date – first dose date + 7 days, regardless of 
unplanned intermittent discontinuations (see Section 2.5.3 for calculation in case of missing or 
incomplete data). 
Duration of IMP exposure will be summarized descriptively as a quantitative variable (number, 
mean, SD, median, minimum, and maximum) in weeks. In addition, duration of treatment 
exposure will also be summarized categorically by numbers and percentages for each of the 
following categories and cumulatively according to these categories: ≥1 day and <2 weeks, ≥2 
weeks and <4 weeks, ≥4 weeks and <6 weeks, ≥6 weeks and <12 weeks, ≥12 weeks and <24 
weeks, ≥24 weeks and <36 weeks, ≥36 weeks and <44 weeks, ≥44 weeks and <53 weeks and ≥53 
weeks. Non-integer values will be rounded to 1 decimal place. 
Additionally, the cumulative duration of treatment exposure will be provided, defined as the sum 
of the duration of treatment exposure for all patients, and will be expressed in patient years. 
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The graphical representation of exposure to investigational product and time since randomization 
will also be displayed by treatment arm. 
2.4.3.2 Compliance  
A given administration will be considered noncompliant if the patient did not take the planned 
dose of treatment as required by the protocol. No imputation will be made for patients with 
missing or incomplete data.  
Overall percentage of compliance for a patient will be defined as 100-(% day with below-
planned dosing + % days with above-planned dosing), considering that injection should be 
performed every week +/- 2 days as per protocol. 
Above-planned dosing percentage for a patient will be defined as the number of days with more 
than 1 injection administration within the 5 days before divided by the duration of IMP injection 
exposure in days.  
Below-planned dosing percentage for a patient will be defined as the number of days with no 
injection administration within the previous 9 days divided by the duration of IMP injection 
exposure in days.  
These parameters will be summarized descriptively as quantitative variables (number, mean, SD, 
median, minimum, and maximum). 
The overall percentage of patients whose compliance is ≥80% will be summarized. In addition, 
numbers and percentages of patients with >0 and ≤5, >5 and ≤10, >10 and ≤20 and >20% days 
with above-planned dose administrations will also be provided, as well as numbers and 
percentages of patients with >0 and ≤5, >5 and ≤10, >10 and ≤20 and >20% days with below-
planned dose administrations. 
In addition, the following parameters will be summarized by treatment arm: 
• The number of IMP injections (mean (SD), median, Min:Max description).  
• The number of advanced injections (less than 5 days between two consecutive injections) 
and the number of delayed injections (more than 9 days between two consecutive 
injections).  
• The number of patients with at least one advanced injection and the number of patients 
with at least one delayed injection. A patient could be counted in several categories.  
• The frequency of IMP injections (mean (SD), median, Min:Max description) will be 
defined for each patient as the average number of days between two consecutive 
injections: (last injection date – first injection date)/(number of injections -1) for patients 
with at least 2 injections. 
Cases of overdose are reported in the AE e-CRF pages as AESI if symptomatic or AE if 
asymptomatic. The reported cases of overdose will be described in the AE analysis (see 
Section 2.1.4 and Section 2.4.5.1). 
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2.4.4 Analyses of efficacy endpoints 
All visits will be re-allocated as given in Table 6, and re-allocated visits measurements will be 
included in the by-time point summaries unless otherwise specified. 
2.4.4.1 Analysis of primary efficacy endpoint(s) 
The primary efficacy endpoint will be analyzed on the mITT population. In the primary analysis, 
assessments at week 52 will be used regardless of whether the patient has previously discontinued 
treatment.  
Due to the non-normality of the endpoint distribution, the absolute change from baseline in % 
predicted FVC at week 52 as defined in Section 2.1.3.1 will be analyzed in the mITT population 
using a rank ANCOVA model adjusted on the stratification factor (with/without background 
therapy). This model will use the ranks of absolute change from baseline to week 52 in % 
predicted FVC as the outcome and the ranks of baseline % predicted FVC as a covariate. In case 
of ties, the mean of the corresponding ranks will be assigned.  
To summarize, the following steps will be performed: 
A) On the pool of arms SAR156597 200mg qw and placebo: 
1. Imputation of missing data at 52 weeks 
a) Week 52 missing values due to reasons other than death or lung transplant 
i. 
Patients in active arm and taking treatment at 52 weeks: Missing values at 52 
weeks will be imputed using a model estimated from the subset of patients in 
the active arm who completed the 52-week treatment period and with a week 
52 value. The imputation model will be based on a Mixed Model with 
Repeated Measures (MMRM) with fixed categorical effect of stratification 
factor (with/without Background Therapy) and repeated categorical effect for 
time point (baseline, week 12, week 24, week 36, week 52). Parameters will be 
estimated with the Newton-Raphson algorithm, an unstructured covariance 
matrix will model the within-patient errors, and the denominator degrees of 
freedom will be estimated using Satterthwaite’s approximation. Missing values 
at 52 weeks will be imputed using the empirical best linear unbiased prediction 
(EBLUP). 
ii. 
Other patients (patients in active arm and not taking treatment at 52 weeks; or 
patients in placebo arm): Missing values at 52 weeks will be imputed using a 
model estimated from the subset of patients in the placebo arm who completed 
the 52-week treatment period and with a week 52 value. The imputation model 
will be based on a Mixed Model with Repeated Measures (MMRM) with fixed 
categorical effect of stratification factor (with/without Background Therapy) 
and repeated categorical effect for time point (baseline, week 12, week 24, 
week 36, week 52). Parameters will be estimated with the Newton-Raphson 
algorithm, an unstructured covariance matrix will model the within-patient 
errors, and the denominator degrees of freedom will be estimated using 
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Satterthwaite’s approximation. Missing values at 52 weeks will be imputed 
using the empirical best linear unbiased prediction (EBLUP). 
iii. 
When running the imputation model, if the predicted absolute change from 
baseline calculated from the predicted week 52 value is greater than zero 
(increases above baseline), it will be set to zero. 
iv. 
The non-monotone missing patterns with a week 52 value available will not be 
imputed.  
b) Week 52 missing values due to lung transplant: 
i. 
Any % predicted FVC value assessed after a lung transplant will be considered 
as missing. 
ii. 
No imputation of a week 52 value for % predicted FVC. In step 2, patients will 
be ranked worse than missing data due to reasons other than death or lung 
transplant. 
c) Week 52 missing values due to death : 
i. 
No imputation of a week 52 value for % predicted FVC. In step 2, patients will 
be ranked worse than missing data due to lung transplant. 
2. Rank ANCOVA 
a) Ranking within each stratum of the stratification factor (with/without Background 
Therapy) 
i. 
Death: Missing data due to death will be ranked based on a time-to-death, with 
shortest time until death as the worst (lowest) rank (from 1 to nstratum,death). 
ii. 
Lung transplant: Missing data due to lung transplant will be ranked based on a 
time-to-lung transplant, with shortest time until lung transplant as the worst 
(lowest) rank (from nstratum,death+1 to nstratum,death+nstratum,lungtransplant). So, missing 
data due to lung transplant will less penalized than deaths. 
iii. 
Other: Absolute change from baseline at 52 weeks in % predicted FVC values 
will be calculated from observed and imputed week 52 % predicted FVC 
values and then ranked (from nstratum,death+nstratum,lungtransplant + 1 to nstratum). 
iv. 
Standardization of ranks using the NPLUS1 option of PROC RANK on SAS 
with the by statement for the stratification factor (with/without Background 
Therapy). 
b) Adjustment on baseline % predicted FVC covariate 
i. 
The residuals from the linear regression of response ranks on baseline ranks 
will be calculated within each stratum of the stratification factor (with/without 
Background Therapy) using the following PROC GLM on SAS: 
proc GLM data=xx; 
by stratification_factor; 
model chg_Rank=base_Rank; 
output out=residual r=resid; 
run; 
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c) Test of treatment effect using the CMH2 option of PROC FREQ on SAS and the 
residuals as scores 
i. 
The qw arm will be compared to placebo using a Mantel-Haenszel mean score 
chi-square test at a two-sided type-I error level of 5%. This test will be 
stratified on the stratification factor. 
B) On the pool of arms SAR156597 200mg q2w and placebo: 
Same steps as A except for 2c: the q2w arm will be compared to placebo using a Mantel-
Haenszel mean score chi-square test at a two-sided type-I error level of 5% only if the qw 
arm versus placebo comparison was significant. This test will be stratified on the 
stratification factor. 
Descriptive statistics for values and changes from baseline will be presented by treatment arm and 
background therapy status for each time point. The mean (SD) % predicted FVC values and the 
mean (SD) absolute change from baseline in % predicted FVC over time will be graphically 
represented by treatment arm and by background therapy status without any imputation. 
A specific table will describe the following items by treatment arm and background therapy: 
• The number (%) of patients with an observed week 52 value for % predicted FVC 
- 
The mean (SD) and median (Q1:Q3) of baseline and week 52 values of % predicted 
FVC for those patients 
- 
The mean (SD) and median (Q1:Q3) of absolute change from baseline at 52 weeks in 
% predicted FVC for those patients 
• The number (%) of patients having a missing data due to death at week 52,  
• The number (%) of patients having a missing data due to lung transplant at week 52,  
• The number (%) of patients having a missing data due to reasons other than death or lung 
transplant, 
• The mean (SD) of baseline % predicted FVC value for all patients included in the analysis 
• The p-values versus placebo of rank ANCOVA (only by treatment arm). 
The magnitude of treatment effect will be assessed as follows: 
• For each quartile of ranks per pool (A then B) of treatment arms, the following items will 
be displayed: 
- 
The number (%) of patients with death 
- 
The number (%) of patients with lung transplant 
- 
The number (%) of patients with an observed or imputed week 52 value for % 
predicted FVC 
• The median (Q1:Q3) absolute change from baseline at 52 weeks in % predicted 
FVC for those patients 
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This will allow to compare across treatment arms the distribution of deaths, lung transplants and 
absolute change from baseline at 52 weeks within each quartile (first quartile corresponding to the 
worst ranks). As ranks will be performed by background therapy status, one table will be provided 
on patients with background therapy status and another one will be provided on patients without 
background therapy status.  
• The worsening of the change from baseline at 24 weeks and 52 weeks (imputed and 
observed values) will be described thanks to the number (%) of patients by treatment arm 
and by background therapy status in following categories:  
- 
Stability or improvement (decrease ≤0%) 
- 
Decrease >0 % to ≤5% 
- 
Decrease >5% to ≤10% 
- 
Decrease >10% or death or lung transplant  
Supportive analysis 
The cumulative distribution of decline from baseline at 24 weeks and at 52 weeks in % predicted 
FVC will be graphically represented by treatment arm and by background therapy status without 
any imputation. 
2.4.4.1.1 Sensitivity analyses 
The description of all sensitivity analyses is available on the below Table 4: 
Table 4 - primary efficacy outcome algorithm in case of missing data 
Type of missing data 
Sensitivity 1 
Sensitivity 2 
Missing data at week 52 due to reasons 
other than death or lung transplant 
Multiple imputation of week 52 value 
using copy increment from reference 
(CIR) approach (assuming normality) 
No imputation 
Missing data at week 52 due to death 
Multiple imputation of week 52 value 
using the distribution of the last 
available % Predicted FVC 
assessment of dead and lung 
transplanted patients 
No imputation 
Missing data at week 52 due to lung 
transplant 
Multiple imputation of week 52 value 
using the distribution of the last 
available % Predicted FVC 
assessment of dead and lung 
transplanted patients 
No imputation 
Sensitivity analysis 1: Assessments at week 52 will be used regardless of whether the patient has 
previously discontinued treatment. 
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The absolute change from baseline to week 52 in %predicted FVC will be analyzed on the mITT 
population using a Mixed Model with Repeated Measures (MMRM) with the fixed categorical 
effects of treatment arm, stratification factor (with/without Background Therapy), time point, 
treatment-by-time point interaction, stratification factor-by-treatment-by-time point interaction, as 
well as the continuous fixed covariate of % predicted FVC baseline. Parameters will be estimated 
with the Newton-Raphson algorithm, an unstructured covariance matrix will model the within-
patient errors, and the denominator degrees of freedom will be estimated using Satterthwaite’s 
approximation.  
As for primary analysis, the non-monotone missing patterns with a week 52 value available will 
not be imputed.  
Week 52 missing values (due to reasons other than death or lung transplant) will be imputed using 
the CIR multiple imputation approach (3). The CIR approach is a multiple imputation 
methodology based on a Gaussian repeated-measures model: 
• First, a large number of datasets will be imputed using the posterior distribution of a linear 
model containing: 
- 
baseline value,  
- 
week 12, week 24 and week 36 time points values (if occurred before the current time 
point to be imputed),  
- 
stratification factor, 
- 
treatment arm* time point interaction, 
- 
treatment arm.  
This requires a monotone missingness, which is why all time points will be imputed 
sequentially to determine week 52 value. 
• Then, the analysis will be run independently on those imputed datasets to estimate 
parameters. 
• Finally, all the results will be combined thanks to Rubin’s rule.  
• The particularity of this approach is that it will takes into account the disease progression: 
- 
Before withdrawal, all patterns have the same profile. A patient will be assumed to 
have the same mean response as his/her treatment arm. 
- 
After withdrawal (which results in missing values for all subsequent visits): 
• a patient in placebo arm will be imputed as in MAR framework. 
• a patient in active arm will be imputed assuming that the advantage due to past 
treatment is incremented with placebo slope assessed from withdrawal visit to 
imputed visit. 
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• In practice: 
- 
When running the imputation model, if the absolute change from baseline calculated 
from the predicted week 52 value is greater than zero (increases above baseline), it will 
be set to zero. 
- 
The MMRM will be performed on each imputed dataset. 
- 
The Rubin’s rule will be performed using Roger’s macro or MIANALYZE SAS 
procedure as appropriate 
 The number of datasets (1000 if appropriate) will be chosen to achieve p-value 
stability. 
Week 52 missing data due to death or lung transplant will be imputed using the distribution of 
their last available % Predicted FVC assessment. The mean (SD) will be calculated and then, for 
each dead or lung transplanted patient, a value will be drawn several times (same number as for 
CIR methodology) between this mean and 0 (translation of this distribution with mean as maximal 
value achievable and right truncated at 0 if required). If the value drawn is higher than the last 
available patient’s value, the imputed week 52 value will be set to the last available patient’s 
value. 
The SAR156597 qw arm will be tested versus Placebo at a type I error level of 5% first and if 
significant, will the SAR156597 q2w arm be tested versus Placebo at a two-sided type I error 
level of 5% using the appropriate contrast. The adjusted Least Square Means (LSMeans) estimates 
and standard errors (SE) will be provided for each of the 3 arms, adjusted differences of means 
(LSMEAN differences), corresponding standard errors (SE), 90% and 95% CIs will be assessed 
for each active arm versus placebo.  
A specific table will describe the following items by treatment arm: 
• The number (%) of patients with an observed week 52 value for % predicted FVC 
- 
The mean (SD) and median (Q1:Q3) of baseline and week 52 values of % predicted 
FVC for those patients 
- 
The mean (SD) and median (Q1:Q3) of absolute change from baseline at 52 weeks in 
% predicted FVC for those patients 
• The number (%) of patients having a missing data due to death at week 52,  
• The number (%) of patients having a missing data due to lung transplant at week 52,  
• The number (%) of patients having a missing data due to reasons other than death or lung 
transplant, 
• The mean (SD) of baseline % predicted FVC value for all patients included in the analysis, 
• The LSMEANS (SE), the LSMEAN Differences versus placebo (SE, corresponding 90% 
and 95% CIs) and the p-values versus placebo of MMRM. 
The representation of LSmeans (SE) over time will be displayed by treatment arm and 
background therapy status. 
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Sensitivity analysis 2: Only on-treatment data will be analyzed which means that only data 
during the treatment period (from randomization to last IMP administration date + 7 days) will be 
considered. Post-treatment data will be considered missing. Only patients having a baseline and a 
post-baseline (during the treatment period) % predicted FVC values in at least one time point 
analysis window will be considered in the analysis. 
The absolute change from baseline to week 52 in %predicted FVC will be analyzed on the mITT 
population using a Mixed Model with Repeated Measures (MMRM) with the fixed categorical 
effects of treatment arm, stratification factor (with/without Background Therapy), time point, 
treatment-by-time point interaction, stratification factor-by-treatment-by-time point interaction, as 
well as the continuous fixed covariate of % predicted FVC baseline. Parameters will be estimated 
with the Newton-Raphson algorithm, an unstructured covariance matrix will model the within-
patient errors, and the denominator degrees of freedom will be estimated using Satterthwaite’s 
approximation.  
No imputation of week 52 missing data due to death, lung transplant or reasons other than death 
or lung transplant will be performed. 
The SAR156597 qw arm will be tested versus Placebo at a type I error level of 5% first and if 
significant, will the SAR156597 q2w arm be tested versus Placebo at a two-sided type I error 
level of 5% using the appropriate contrast. The adjusted Least Square Means (LSMeans) estimates 
and standard errors (SE) will be provided for each of the 3 arms, adjusted differences of means 
(LSMEAN differences), corresponding standard errors (SE), 90% and 95% CIs will be assessed 
for each active arm versus placebo.  
A specific table will describe the following items by treatment arm: 
• The number (%) of patients with an observed week 52 value for % predicted FVC 
- 
The mean (SD) and median (Q1:Q3) of baseline and week 52 values of % predicted 
FVC for those patients 
- 
The mean (SD) and median (Q1:Q3) of absolute change from baseline at 52 weeks in 
% predicted FVC for those patients 
• The number (%) of patients having a missing data due to death at week 52,  
• The number (%) of patients having a missing data due to lung transplant at week 52,  
• The number (%) of patients having a missing data due to reasons other than death or lung 
transplant, 
• The mean (SD) of baseline % predicted FVC value for all patients included in the analysis, 
• The LSMEANS (SE), the LSMEAN differences versus placebo (SEs, corresponding 90% 
and 95% CIs) and the p-values versus placebo of MMRM. 
The representation of LSmeans (SE) over time will be displayed by treatment arm and 
background therapy status. 
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2.4.4.1.2 Subgroups analyses 
The following subgroups will be explored: 
• Smoking status: Smoke / Never Smoke 
• Gender: Male / Female  
• Age: Age ≤65 / Age >65  
• Stratification factor: With / Without background therapy 
• % predicted FVC categories at baseline (using terciles: (≤60, >60 and ≤75, >75)) 
• ANA at baseline: Positive / Negative where a Positive ANA titer is defined as titer ≥1:40 
For each subgroup, the change from baseline at 52 weeks in % Predicted FVC will be analyzed 
using a rank ANCOVA model. For each pool of active arm vs placebo (A and B), the subgroup-
by-treatment interaction will be tested as follows: 
A) For Smoking status, Gender, Age subgroups: rank ANCOVA model with covariate 
baseline and terms of treatment, stratification factor, subgroup, treatment-by-subgroup 
i. 
First, compute ranks of baseline and response as in the primary analysis 
proc rank data=xxx nplus1 ties=mean out=rankdata; 
by stratum; 
var base ranks; 
ranks base_Rank ranks_Rank; 
run; 
ii. 
Then, calculate the residuals as in the primary analysis 
proc glm data=xx; 
by stratum; 
model ranks_Rank=base_Rank; 
output out=residual r=resid; 
run; 
iii. 
Finally, the subgroup-by-treatment interaction will be tested using residuals with 
PROC GLM 
proc glm data=residual; 
class armn subgroup stratum; 
model resid=stratum armn subgroup subgroup*armn; 
run; 
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B) For Stratification factor subgroup: rank ANCOVA model with covariate baseline and 
terms of treatment, stratification factor, treatment-by-stratification factor 
i. 
First, compute ranks of baseline and response without by stratum statement 
proc rank data=xxx nplus1 ties=mean out=rankdata; 
var base ranks; 
ranks base_Rank ranks_Rank; 
run; 
ii. 
Then, calculate the residuals without by stratum statement 
proc glm data=xx; 
model ranks_Rank=base_Rank; 
output out=residual r=resid; 
run; 
iii. 
Finally, the subgroup-by-treatment interaction will be tested using residuals with 
PROC GLM 
proc glm data=residual; 
class armn stratum; 
model resid=stratum armn stratum*armn; 
run; 
C) For % predicted FVC baseline categories: rank ANCOVA model with terms of treatment, 
stratification factor, subgroup, treatment-by-subgroup 
i. 
First, compute ranks of response as in the primary analysis 
proc rank data=xxx nplus1 ties=mean out=rankdata; 
by stratum; 
var ranks; 
ranks ranks_Rank; 
run; 
ii. 
Second, the subgroup-by-treatment interaction will be tested using response ranks 
with PROC GLM 
proc glm data=residual; 
class armn subgroup stratum; 
model ranks_Rank=stratum armn subgroup subgroup*armn; 
run; 
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Descriptive statistics of baseline values, week 52 values and change from baseline at 52 weeks in 
%predicted FVC including number (%) of patients, mean, SD, median, Q1, Q3, Min, Max by 
subgroup will be reported by treatment arm without any imputation. 
Supportive analysis 
The MMRM of Sensitivity analysis 1 will also be performed in order to provide the LSMEANS 
(SE) by treatment arm in each subgroup and test the subgroup-by-treatment-by-time point 
interaction in each pool (A and B) of active arm versus placebo. The MMRM will contain in 
addition the subgroup variable and the subgroup-by-treatment-by-time point interaction to be 
tested. When the stratification factor or the % predicted FVC baseline terciles are the subgroups to 
be tested, the model will not be adjusted on those variables. 
In addition, a forest plot will resume the adjusted differences of means (LSMEAN differences) 
and corresponding 95% CIs of each active arm versus placebo by subgroup. 
2.4.4.2 Analyses of secondary efficacy endpoints 
Secondary efficacy endpoints are described in Section 2.1.3.2 and will be analyzed using the 
mITT population.  
2.4.4.2.1 Disease progression endpoint 
The disease progression will be analyzed on the mITT population. Assessments at week 52 
(performed before Day 375) will be used regardless of whether the patient has previously 
discontinued treatment. Only patients having a baseline and a post-baseline values in at least one 
time points analysis window for both the % predicted FVC and the % predicted DLCO parameters 
will be considered in the analysis. No week 52 missing data will be imputed for the disease 
progression. 
The cumulative incidence of disease progression at 52 weeks will be presented graphically by 
treatment arm and background therapy status, using Kaplan-Meier method. The Kaplan Meier 
survival estimates (number of patients at risk, number of patients censored, number of disease 
progression events and probability of surviving without event  (95% CI)) will be summarized by 
time points and overall (number of patients censored, number of events, median time to event).  
The censoring reasons will be described by treatment arm and background therapy status. 
The time to disease progression at 52 weeks will be tested comparing SAR156597 200 mg qw 
dose versus placebo using a log-rank test stratified on stratification factor (with/without 
Background Therapy) at a two-sided type I error level of 5%; and only if this comparison is 
significant will the SAR156597 200 mg q2w dose be tested versus placebo using a log-rank test 
stratified on stratification factor (with/without Background Therapy) at a two-sided type I error 
level of 5%. 
The event rates for each of the 3 treatment arms, the hazard ratio and its 90 and 95% confidence 
interval (CI) compared to placebo for each active arm versus Placebo will be estimated from a 
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Cox model containing the treatment and the stratification factor variables. The underlying 
assumption of proportional hazards for Cox model will be checked by visual inspection. 
In order to assess the significance, the magnitude and the repartition within components of the 
treatment effect of disease progression at 52 weeks, the following items will be described by 
treatment arm and by background therapy status: 
• Summary of the disease progression at 52 weeks: number of events, event rates, p-values 
(only by treatment arm), estimated hazard ratios and their 90 and 95% CIs 
• Description of each component as part of the disease progression: their number of events, 
event rates and their estimated hazard ratios 
• Description of each component as individual (all events will be considered meaning that a 
patient could be represented several times per component): their number of events, event 
rates, their estimated hazard ratios and their 90 and 95% CIs 
In addition, the maximal absolute decrease in % predicted FVC and the maximal absolute 
decrease in %predicted DLCO will be described by categories (≥0 and <5%, ≥5% and <10%, 
≥10% and <15%, ≥15% and <20%, ≥20%) at 52 weeks.Decomposition of events and maximal 
events will be explored at 24 weeks as well. 
Subgroup analyses 
The following subgroups will be explored: 
• Smoking status: Smoke / Never Smoke 
• Gender: Male / Female  
• Age: Age ≤65 / Age >65  
• Stratification factor: With / Without background therapy 
• % predicted FVC categories at baseline (using terciles (≤60, >60 and ≤75, >75)) 
• ANA at baseline: Positive / Negative where a Positive ANA titer is defined as titer ≥1:40 
For each pool of active arm vs placebo (A and B), the subgroup-by-treatment interaction will be 
tested using a Cox model containing in addition the subgroup variable and the subgroup-by-
treatment interaction to be tested. When the stratification factor is the subgroup to be tested, the 
model should not be stratified by this stratification factor. 
Descriptive statistics including number (%) of patients, number of events, event rates, HR, 95% 
CI by subgroup will be reported by treatment arm. 
In addition, a forest plot will resume the HR and corresponding 95% CIs of each active arm 
versus placebo by subgroup.  
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2.4.4.2.2 All-cause mortality endpoint 
The all-cause mortality will be analyzed on the mITT population. Deaths from baseline to week 
52 (performed before Day 375) will be used regardless of whether the patient has previously 
discontinued treatment. 
The cumulative incidence of all-cause mortality will be presented graphically by treatment arm 
and background therapy status, using Kaplan-Meier method. The Kaplan Meier survival estimates 
(number of patients at risk, number of patients censored, number of death events and probability 
of surviving without event  (95% CI)) will be summarized by time points and overall (number of 
patients censored, number of events, median time to event).  
The censoring reasons will be described by treatment arm and background therapy status. 
The event rates for each of the 3 treatment arms, the hazard ratio and its 90% and 95% CIs 
compared to placebo for each active arm versus Placebo will be estimated from a Cox model 
containing the treatment and the stratification factor variables. The underlying assumption of 
proportional hazards for Cox model will be checked by visual inspection. 
No hypothesis testing will be performed as per protocol. 
The same time-to-event analysis with IPF-related deaths only will be explored on the mITT 
population. 
2.4.4.2.3 Exploratory endpoints 
2.4.4.2.3.1 Acute IPF exacerbations endpoint 
The number of acute IPF exacerbations and the number of patients having one, two or more than 
two acute IPF exacerbations will be described in the mITT population by treatment arm and 
background therapy status. 
The annual rate in patient-year by treatment arm, the rate ratio and its 90% CI for each active arm 
versus placebo will be determined using a negative binomial model adjusted on the stratification 
factor variable and containing the stratification factor-by-treatment interaction. The SAR156597 
qw arm will be tested versus Placebo at a type I error level of 10% first and if significant, will the 
SAR156597 q2w arm be tested versus Placebo at a two-sided type I error level of 10%.  
In addition, a description of the following items will be performed by treatment arm and by 
background therapy status for events occurring between randomization and Day 375: 
• the number (%) of patients with any IPF event (complementary form filled whatever the 
final diagnosis question answer),  
• the number (%) of patients with acute IPF exacerbation (final diagnosis question is equal 
to “yes”),  
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• the other diagnoses (final diagnosis question is equal to “no”, with associated PT term and 
verbatim),  
• the clinical evaluation,  
• the radiology assessment  
• and any corrective treatment/therapy used. 
2.4.4.2.3.2 Respiratory and non-elective hospitalizations endpoints 
The numbers of respiratory and non-elective hospitalizations and the numbers of patients having 
at least one respiratory or at least one non-elective hospitalization will be described in the mITT 
population by treatment arm and background therapy status separately. 
The annual rates for respiratory and non-elective hospitalizations in patient-year by treatment arm, 
the rate ratio and its 90% CI for each active arm versus placebo will be determined separately 
using a negative binomial model adjusted on the stratification factor variable and containing the 
stratification factor-by-treatment interaction. The SAR156597 qw arm will be tested versus 
Placebo at a type I error level of 10% first and if significant, will the SAR156597 q2w arm be 
tested versus Placebo at a two-sided type I error level of 10%. 
The number (%) of patients with any hospitalization, the type of hospitalization (elective, non-
elective) and the reason (respiratory, other reason) will be provided by treatment arm and 
background therapy status for hospitalization occurring between randomization and Day 375. 
Furthermore, a listing with details of reasons (respiratory and other reason) will be displayed.  
2.4.4.2.3.3 Change from baseline in 6-MWT distance endpoint 
The absolute change from baseline in 6-MWT distance endpoint will be analyzed on the mITT 
population. Assessments at week 52 will be used regardless of whether the patient has previously 
discontinued treatment. No imputation will be performed for the week 52 missing values of 6-
MWT distance. Only patients having a baseline and a post-baseline 6-MWT distance values in at 
least one time points analysis window will be considered in the analysis. 
The absolute change from baseline in 6-MWT distance at 52 weeks will be analysed using a 
Mixed Model with Repeated Measures (MMRM) with the fixed categorical effects of treatment 
arm, stratification factor (with/without Background Therapy), time point, treatment-by-time point 
interaction, stratification factor-by-treatment-by-time point interaction, supplemental oxygen use 
(Yes/No answer to the “Does the subject need oxygen therapy” question on the “Idiopathic 
Pulmonary Fibrosis History“ e-CRF page) recorded at baseline, as well as the continuous fixed 
covariate of 6-MWT distance at baseline will be used. Parameters will be estimated with the 
Newton-Raphson algorithm, an unstructured covariance matrix will model the within-patient 
errors, and the denominator degrees of freedom will be estimated using Satterthwaite’s 
approximation. 
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The SAR156597 qw arm will be tested versus Placebo at a type I error level of 10% first and if 
significant, will the SAR156597 q2w arm be tested versus Placebo at a two-sided type I error 
level of 10% using the appropriate contrast. The adjusted Least Square Means (LSMeans) 
estimates and standard errors (SE) will be provided for each of the 3 arms, adjusted differences of 
means (LSMEAN differences), corresponding standard errors (SE) and 90% CIs will be assessed 
for each active arm versus placebo.  
Descriptive statistics for values and changes from baseline in 6-MWT distance in the mITT 
population will be presented by treatment arm and background therapy status for each time point. 
The mean (SD) 6-MWT distance values and the mean (SD) absolute change from baseline in 
6MWT distance over time will be graphically represented by treatment arm and by background 
therapy status. 
The representation of LSmeans (SE) over time will be displayed by treatment arm and 
background therapy status. 
In addition, to assess the quality of data: 
• the number (%) of patients having a completed 6 minute walking test,  
• the distribution of the time walked (in seconds) for those who did not complete 6-MWT,  
• the number (%) of patients with any pause or break 
• the distribution of the duration of pause (in seconds)  
will be resumed by time point. 
2.4.4.2.3.4 Change from baseline in HRCT lung interstitial score endpoint 
The absolute change from baseline in HRCT lung interstitial score endpoint will be analyzed on 
the mITT population. Assessments at week 52 will be used regardless of whether the patient has 
previously discontinued treatment. No imputation will be performed for the week 52 missing 
values of HRCT lung interstitial scores. Only patients having both the baseline and week 52 Total 
Fibrosing ILD score assessments available will be considered in the analysis. 
The change from baseline at 52 weeks in Total Fibrosing ILD score will be analyzed using an 
ANCOVA model with fixed effect for treatment arm, adjusted on baseline Total Fibrosing ILD 
score, Emphysema total score at baseline, and the stratification factor (with/without Background 
Therapy) covariates, with a stratification factor-by-treatment interaction will be performed. The 
SAR156597 qw arm will be tested versus Placebo at a two-sided type I error level of 10% first 
and if significant, will the SAR156597 q2w arm be tested versus Placebo at a two-sided type I 
error level of 10% using the appropriate contrast.  The adjusted Least Square Means (LSMeans) 
and their 90% CIs will be assessed for each treatment arm. 
Descriptive statistics for values and changes from baseline in Total Fibrosing ILD score will be 
described over time by treatment arm and by background therapy status. The mean (SD) Total 
Fibrosing ILD score values and the mean (SD) absolute change from baseline in Total Fibrosing 
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ILD score over time will be graphically represented by treatment arm and by background therapy 
status. 
The representation of LSmeans (SE) over time will be displayed by treatment arm and 
background therapy status for the Total Fibrosing ILD score. 
In addition, descriptive statistics for values and changes from baseline in pattern score and the 
Emphysema total score will be described over time by treatment arm and by background therapy 
status. The mean (SD) scores values and the mean (SD) absolute change from baseline in scores 
over time will be graphically represented by treatment arm and by background therapy status. 
2.4.4.2.3.5 Change from baseline in total score of St George Respiratory Questionnaire (SGRQ) 
endpoint 
The absolute change from baseline in SGRQ total score endpoint will be analyzed on the mITT 
population. Assessments at week 52 will be used regardless of whether the patient has previously 
discontinued treatment. No imputation will be performed for the week 52 missing values of 
SGRQ total score. Only patients having a baseline and a post-baseline total SGRQ score values in 
at least one time points analysis window will be considered in the analysis. 
The absolute change from baseline in SGRQ total score at 52 weeks will be analysed using a 
Mixed Model with Repeated Measures (MMRM) with the fixed categorical effects of treatment 
arm, stratification factor (with/without Background Therapy), time point, treatment-by-time point 
interaction, stratification factor-by-treatment-by-time point interaction, as well as the continuous 
fixed covariate of SGRQ total score at baseline will be used. Parameters will be estimated with 
the Newton-Raphson algorithm, an unstructured covariance matrix will model the within-patient 
errors, and the denominator degrees of freedom will be estimated using Satterthwaite’s 
approximation. 
The SAR156597 qw arm will be tested versus Placebo at a type I error level of 10% first and if 
significant, will the SAR156597 q2w arm be tested versus Placebo at a two-sided type I error 
level of 10% using the appropriate contrast. The adjusted Least Square Means (LSMeans) 
estimates and standard errors (SE) will be provided for each of the 3 arms, adjusted differences of 
means (LSMEAN differences), corresponding standard errors (SE) and 90% CIs will be assessed 
for each active arm versus placebo.  
For each component score (Symptoms, Activity, Impacts) and the SGRQ total score, descriptive 
statistics for values and changes from baseline will be described  over time by treatment arm and 
by background therapy status. The mean (SD) of each score values and the mean (SD) absolute 
change from baseline in each score over time will be graphically represented by treatment arm 
and by background therapy status. 
The representation of LSmeans (SE) over time will be displayed by treatment arm and 
background therapy status for the SGRQ total score. 
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2.4.4.2.3.6 Change from baseline in total score of EuroQol Questionnaire, 5 level system 
(EQ-5D-5L) endpoint 
The absolute change from baseline in EQ-5D-5L total score endpoint will be analyzed on the 
mITT population. Assessments at week 52 will be used regardless of whether the patient has 
previously discontinued treatment. No imputation will be performed for the week 52 missing 
values of EQ-5D-5L total score. Only patients having a baseline and a post-baseline EQ-5D-5L 
total score values in at least one time points analysis window will be considered in the analysis. 
The absolute change from baseline in EQ-5D-5L  total score at 52 weeks will be analysed using a 
Mixed Model with Repeated Measures (MMRM) with the fixed categorical effects of treatment 
arm, stratification factor (with/without Background Therapy), time point, treatment-by-time point 
interaction, stratification factor-by-treatment-by-time point interaction, as well as the continuous 
fixed covariate of EQ-5D-5L total score at baseline will be used. Parameters will be estimated 
with the Newton-Raphson algorithm, an unstructured covariance matrix will model the within-
patient errors, and the denominator degrees of freedom will be estimated using Satterthwaite’s 
approximation. 
The SAR156597 qw arm will be tested versus Placebo at a type I error level of 10% first and if 
significant, will the SAR156597 q2w arm be tested versus Placebo at a two-sided type I error 
level of 10% using the appropriate contrast. The adjusted Least Square Means (LSMeans) 
estimates and standard errors (SE) will be provided for each of the 3 arms, adjusted differences of 
means (LSMEAN differences), corresponding standard errors (SE) and 90% CIs will be assessed 
for each active arm versus placebo.  
For EQ-5D-5L VAS and the EQ-5D-5L total score, descriptive statistics for values and changes 
from baseline will be described  over time by treatment arm and by background therapy status. 
The mean (SD) of each score values and the mean (SD) absolute change from baseline in each 
score over time will be graphically represented by treatment arm and by background therapy 
status. 
The representation of LSmeans (SE) over time will be displayed by treatment arm and 
background therapy status for the EQ-5D-5L total score. 
2.4.4.3 Multiplicity issues 
The overall type I error rate for this study is 5%. For the primary endpoint, a hierarchical testing 
procedure will be used to control the type I error over the two doses. The SAR156597 qw arm 
will be compared to placebo first, and only if this comparison is significant will the SAR156597 
q2w arm be compared to placebo. 
The same procedure will be used for the disease progression endpoint if significance is achieved 
for both doses on the primary endpoint. 
For other secondary endpoints considered exploratory, a hierarchical testing procedure will be 
used to control the type I error over the two doses. The SAR156597 qw arm will be compared to 
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placebo first at a two-sided type I error level of 10%, and only if this comparison is significant 
will the SAR156597 q2w arm be compared to placebo at a two-sided error level of 10%. 
2.4.4.4 Additional efficacy analysis 
2.4.4.4.1 Absolute change from baseline in % predicted DLCO 
The absolute change from baseline in % predicted DLCO endpoint will be analyzed on the mITT 
population. Assessments at week 52 will be used regardless of whether the patient has previously 
discontinued treatment. No imputation will be performed for the week 52 missing values of 
%predicted DLCO. Only patients having a baseline and a post-baseline % predicted DLCO values 
in at least one time points analysis window will be considered in the analysis. 
The absolute change from baseline in % predicted DLCO at 52 weeks will be analyzed using a 
Mixed Model with Repeated Measures (MMRM) with the fixed categorical effects of treatment 
arm, stratification factor (with/without Background Therapy), time point, treatment-by-time point 
interaction, stratification factor-by-treatment-by-time point interaction, as well as the continuous 
fixed covariate of % predicted DLCO baseline. Parameters will be estimated with the Newton-
Raphson algorithm, an unstructured covariance matrix will model the within-patient errors, and 
the denominator degrees of freedom will be estimated using Satterthwaite’s approximation.  
The SAR156597 qw arm will be tested versus Placebo at a type I error level of 10% first and if 
significant, will the SAR156597 q2w arm be tested versus Placebo at a two-sided type I error 
level of 10% using the appropriate contrast. The adjusted Least Square Means (LSMeans) 
estimates and standard errors (SE) will be provided for each of the 3 arms, adjusted differences of 
means (LSMEAN differences), corresponding standard errors (SE) and 90% CIs will be assessed 
for each active arm versus placebo.  
Descriptive statistics for values and changes from baseline will be presented by treatment arm and 
background therapy status for each time point. The mean (SD) % predicted DLCO values and the 
mean (SD) absolute change from baseline in % predicted DLCO over time will be graphically 
represented by treatment arm and by background therapy status. 
The representation of LSmeans (SE) over time will be displayed by treatment arm and 
background therapy status. 
2.4.4.4.2 Absolute change from baseline in FEV1 (% Predicted and L), FEV1/FVC, FCV (% 
Predicted and L), 
Descriptive statistics for values and changes from baseline in FEV1 (% Predicted and L), 
FEV1/FVC, FCV (% Predicted and L) will be presented by treatment arm and background 
therapy status for each time point.  
2.4.5 Analyses of safety data 
The summary of safety results will be presented by treatment arm on the basis of the safety 
population.  
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General common rules 
All safety analyses will be performed on the safety population as defined in Section 2.3.2, unless 
otherwise specified, using the following common rules: 
• Safety data in patients who do not belong to the safety population (eg, exposed but not 
randomized) will be listed separately. The baseline value is defined in Section 2.1.4. 
• The potentially clinically significant abnormality (PCSA) values are defined as abnormal 
values considered medically important by the Sponsor according to predefined 
criteria/thresholds based on literature review and defined by the Sponsor for clinical 
laboratory tests, vital signs, and ECG (PCSA version dated March 2014  [Appendix A]). 
• PCSA criteria will determine which patients had at least 1 PCSA during the TEAE period, 
taking into account all evaluations performed during the TEAE period, including 
unscheduled or repeated evaluations. The number of all such patients will be the 
numerator for the on-treatment PCSA percentage.  
• The treatment-emergent PCSA denominator by arm for a given parameter will be based on 
the number of patients assessed for that given parameter in the TEAE period by treatment 
arm on the safety population. 
• For quantitative safety parameters based on central laboratory/reading measurements, 
descriptive statistics will be used to summarize results and change from baseline values by 
time point and treatment arm. Summaries will include the endpoint baseline value, the last 
on-treatment value and change from baseline, the worst on-treatment value and change 
from baseline. The last on-treatment value is commonly defined as the last value collected 
during the treatment period (see Section 2.1.4). The worst on-treatment value is defined as 
the nadir and /or the peak post-baseline during the treatment period according to the 
direction (minimum or maximum) of the abnormality as defined in the PCSA list.  
• All measurements (scheduled or unscheduled) will be re-allocated as given in 
Section 2.5.4 and re-allocated visits measurements will be included in the by-time point 
summary. 
• The analysis of the safety variables will be essentially descriptive and no systematic 
testing is planned. Relative risks versus placebo and their 95% CIs may be provided, if 
relevant. 
2.4.5.1 Analyses of adverse events 
Generalities 
The primary focus of AE reporting will be on TEAE as defined in Section 2.3.2. Pre-treatment 
and post-treatment adverse events will be described separately.  
If an AE date/time of onset (occurrence, worsening, or becoming serious) is incomplete, an 
imputation algorithm will be used to classify the AE as pre-treatment, treatment-emergent, or 
post-treatment. The algorithm for imputing date/time of onset will be conservative and will 
classify an AE as treatment emergent unless there is definitive information to determine it is pre-
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treatment or post-treatment. Details on classification of AEs with missing or partial onset dates 
are provided in Section 2.1.4.1. 
Adverse event incidence tables will present by SOC, HLGT, HLT, and PT, for each treatment 
arm, the number (n) and percentage (%) of patients experiencing an AE sorting based on results of 
column all. Multiple occurrences of the same event in the same patient will be counted only once 
in the tables within a treatment period. The denominator for computation of percentages is the 
safety population within each treatment arm.  
Sorting within tables ensures the same presentation for the set of all AEs within the observation 
period (pre-treatment, treatment-emergent, and post-treatment). For that purpose, the table of all 
TEAEs presented by SOC and PT sorted by the internationally agreed SOC order and decreasing 
frequency of PTs within SOCs will define the presentation order for all other tables unless 
otherwise specified. Sorting will be based on results of column all.  
Analysis of all treatment-emergent adverse events 
The following TEAE summaries will be generated for the safety population. 
• Overview of TEAEs by treatment arm and by background therapy status, summarizing 
number (%) of patients with any 
- 
Treatment-emergent adverse event 
- 
Serious treatment-emergent adverse event 
- 
Treatment-emergent adverse event leading to death 
- 
Treatment-emergent adverse event leading to permanent treatment discontinuation 
• All TEAES by primary SOC, HLGT, HLT, and PT, showing number (%) of patients with 
at least 1 TEAE sorted by the SOC internationally agreed order. The other levels (HLGT, 
HLT, and PT) will be presented in alphabetical order. This table will be presented by 
treatment arm. 
• All TEAEs by primary SOC and PT, showing the number (%) of patients with at least 1 
TEAE, sorted by the internationally agreed SOC order and by decreasing incidence of PTs 
within each SOC. This sorting order will be applied to all other tables, unless otherwise 
specified. This table will be presented by treatment arm and by background therapy status. 
• All TEAEs regardless of relationship and related by primary SOC, HLGT, HLT and PT, 
showing the number (%) of patients with at least 1 TEAE, sorted by the internationally 
agreed SOC order. The other levels (HLGT, HLT, and PT) will be presented in 
alphabetical order. This table will be presented by treatment arm and by background 
therapy status. 
• All TEAEs by primary SOC and PT, showing the number (%) of patients with at least 1 
TEAE, sorted by the internationally agreed SOC order and by decreasing incidence of PTs 
within each SOC. This table will be presented by treatment arm and by background 
therapy status. 
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• All TEAEs by maximal severity, presented by primary SOC and PT, showing the number 
(%) of patients with at least 1 TEAE by severity (ie, mild, moderate, or severe), sorted by 
the sorting order defined above. This table will be presented by treatment arm. 
Analysis of all treatment emergent serious adverse event(s) 
• 
All treatment-emergent serious adverse events by primary SOC, HLGT, HLT, and PT, 
showing the number (%) of patients with at least 1 serious TEAE, sorted by the 
internationally agreed SOC order. The other levels (HLGT, HLT, and PT) will be 
presented in alphabetical order. This table will be presented by treatment arm. 
• 
All treatment-emergent serious adverse events by primary SOC and PT, showing the 
number (%) of patients with at least 1 serious TEAE, sorted by the internationally 
agreed SOC order and by decreasing incidence of PTs within each SOC. This table 
will be presented by treatment arm and by background therapy status. 
• 
All treatment-emergent serious adverse events regardless of relationship and related to 
IMP, by primary SOC, HLGT, HLT, and PT, showing the number (%) of patients with 
at least 1 treatment-emergent serious adverse event, sorted by the internationally 
agreed SOC order. The other levels (HLGT, HLT, and PT) will be presented in 
alphabetical order. This table will be presented by treatment arm. 
• 
All treatment-emergent serious adverse events regardless of relationship and related to 
IMP, by primary SOC and PT, showing the number (%) of patients with at least 1 
serious TEAE, sorted by the internationally agreed SOC order and by decreasing 
incidence of PTs within each SOC. This table will be presented by treatment arm and 
by background therapy status. 
• 
Listings will be provided for all SAEs by treatment arm during on-treatment period. 
Analysis of all treatment-emergent adverse event(s) leading to permanent treatment 
discontinuation 
• All TEAEs leading to treatment discontinuation, by primary SOC, HLGT, HLT, and PT, 
showing the number (%) of patients sorted by the internationally agreed SOC order 
(column “All”). The other levels (HLGT, HLT, and PT) will be presented in alphabetical 
order. Listings will be provided for all TEAEs leading to permanent treatment 
discontinuation by treatment arm and patient. This table will be presented by treatment 
arm.  
• All TEAEs leading to treatment discontinuation, by primary SOC and PT, showing the 
number (%) of patients with at least 1 TEAE, sorted by the internationally agreed SOC 
order and by decreasing incidence of PTs within each SOC. This table will be presented by 
treatment arm and by background therapy status. 
Analysis of treatment-emergent AESIs 
All treatment emergent AESIs, by AESI category and PT, showing the number (%) of patients by 
treatment arm and overall, sorted by decreasing incidence of PT within each AESI category. This 
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table will be presented by background therapy. The AESIs categories and details of the MedDRA 
coding are provided in Section 2.1.4.1. 
• Listing of all Treatment emergent AESIs experienced per patient and by treatment arm: 
Patient ID, AESI category, PT, date of onset (day of onset), date of recovery (day of end), 
duration, intensity, corrective treatment, seriousness, relationship to SAR, relationship to 
BTs. 
• Kaplan-Meier cumulative incidence curve for time to first treatment emergent local 
injection site reaction. The time to first treatment emergent local injection site reaction will 
be derived as follows: date of randomization minus date of last IMP injection. Patients are 
censored at cut-off date or date of last injection in case of study drug discontinuation. 
• Kaplan-Meir cumulative incidence curve for number of injections to first treatment 
emergent local injection site reaction. The number of injections to first treatment emergent 
local injection site reaction will be derived as follows: sum of injections from baseline to 
event. Patients are censored at cut-off date or date of last injection in case of study drug 
discontinuation. 
• Number (%) of patients with at least one TEAE in local injection site reaction category by 
primary SOC/PT. 
In addition, the following variables will be tabulated for the local injection site reactions TEAEs: 
• Number (%) of patients with at least one local injection site reaction TEAE  
• Local injection site reaction per patient (1, >1) 
• Highest intensity of the event (Mild, Moderate, Severe, Very Severe) 
• Mean duration (in days) 
• Number of events divided by the number of double-blind IMP injections received 
• Time from first double-blind IMP injection to first injection site reaction (in days) 
• Time from most recent IMP injection before first injection site reaction (in days) 
• Description of the highest intensity (and size) of each symptom (using pre-specified 
eCRF-terms: Erythema, Swelling, Itch, Pain, Tenderness; or using MedDRA coding if 
Other) from “Reaction at Injection Site” eCRF complementary form. Number will 
correspond to the count of patients with treatment emergent local injection site reaction 
and the corresponding symptom. More than one symptom may be reported for each 
injection site reaction. In case of several occurrences of a symptom, the maximal intensity 
is used 
• Number of double-blind IMP injections received up to the first event (1, 2, 3, 4, ≥5 to <10, 
≥10 to <20, ≥20) 
In addition, the following variables will be tabulated for the ALT increase TEAEs: 
• Number (%) of patients with at least one ALT increase TEAE 
• Number (%) of patients who met the following symptoms: 
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- 
Asthenia 
- 
Nausea 
- 
Fever 
- 
Pruritus 
- 
Jaundice  
- 
Joint pain 
- 
Abdominal pain  
- 
Vomiting  
- 
Skin eruption 
- 
Purpura 
- 
Hepatomegaly 
- 
Splenomegaly 
- 
Lymph nodes enlarged 
- 
Ascites 
- 
Asterixis 
- 
Confusion  
In addition, the following variables will be tabulated for the ALT increase – Trigger Factors 
TEAEs: 
• Number (%) of patients with at least one ALT increase – Trigger factors TEAE 
• Number (%) of patients with: 
- 
Any blood transfusion within the last 12 months 
- 
Exposure to potential hepatotoxic environmental or occupational agent within the last 
12 months  
• Duration of exposure 
- 
Alcohol consumption within the last 7 days prior to increase 
• Number of standard drinks 
- 
Traveled in country at risk of viral hepatitis within the last 6 months 
- 
Used addictive drug within the last 12 months 
• Details of addictive drug 
• IV administration intake 
• Time to first administration (in weeks) 
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In addition, the following variables will be tabulated for the other event TEAEs: 
• 
 
• Number (%) of patients with at least one tuberculosis event TEAE 
• Number (%) of patients with at least one anaphylaxis event TEAE 
Analysis of pre-treatment and post-treatment adverse events  
An overview presenting number of patients with any pre-/post-treatment adverse events, serious 
pre-/post-treatment adverse events, pre-/post-treatment adverse events leading to death, 
pretreatment adverse events leading to permanent treatment discontinuation will be displayed by 
treatment arm. If only few patients (<10% of randomized patients) are concerned, a global listing 
will be provided.  
2.4.5.2 Deaths 
The following summaries of deaths will be generated for the safety population by treatment arm. 
• Number (%) of patients who died by study period (on-study, on TEAE period, post-study) 
and reasons for death summarized on the safety population by treatment received and by 
background therapy. 
• Deaths in nonrandomized patients or randomized but not treated patients 
• Treatment-emergent adverse events leading to death (death as an outcome on the AE case 
report form page as reported by the Investigator) by primary SOC, HLGT, HLT, and PT 
showing number (%) of patients sorted by internationally agreed SOC order, with HLGT, 
HLT, and PT presented in alphabetical order within each SOC. This table will be 
presented by treatment received and by background therapy. 
• Treatment-emergent adverse events leading to death (death as an outcome on the AE case 
report form page as reported by the Investigator) by primary SOC and PT showing number 
(%) of patients with at least 1 TEAE leading to death, sorted by internationally agreed 
SOC order and by decreasing incidence of PTs within each SOC. This table will be 
presented by treatment received and by background therapy. 
• All pre-treatment adverse events leading to death by primary SOC and PT, showing the 
number (%) of patients, sorted by the internationally agreed SOC order and decreasing 
incidence of PTs within each SOC 
• All post-treatment adverse events leading to death by primary SOC and PT, showing the 
number (%) of patients, sorted by the internationally agreed SOC order and decreasing 
incidence of PTs within each SOC 
• Listings of deaths will be provided. For deaths in non-randomized patients or randomized 
and not treated patients, a distinct listing will be provided. 
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2.4.5.3 Analyses of laboratory variables  
The summary statistics (including number, mean, median, standard deviation, minimum and 
maximum) of all laboratory variables (central laboratory values and changes from baseline) will 
be calculated for each time point or study assessment (baseline, each post-baseline time point, 
endpoint) by treatment arm. This section will be organized by biological function as specified in 
Section 2.1.4.3 (except for pregnancy test). 
For parameters glucose, monocytes, basophils, eosinophils and bicarbonate, the last on-treatment 
and worst on-treatment value will also be provided. 
The pH parameter will be described by category: ≤4.6, >4.6 and <8, ≥8. 
 
 
A specific description of the following parameters will be provided at baseline by treatment arm 
and overall treatment groups: 
• Tuberculosis information using MedDRA CMQ and the specific “Tuberculosis 
Assessment” eCRF page (signs and symptoms at screening (Yes, No), treated for 
tuberculosis in the past (Yes, No), receiving Active Anti-TB Therapy at screening (Yes, 
No)) and Quantiferon®-TB Gold test result (Positive, Negative, Indeterminate). 
• Serology tests: hepatitis B surface antigen (Positive, Negative, Borderline), hepatitis B 
surface antibody (Positive, Negative, Borderline), hepatitis B core antibody (Positive, 
Negative, Borderline) and hepatitis C antibodies (Reactive, Unreactive, Borderline). 
• 
 connective tissue disorders using MedDRA CMQs. 
The incidence of PCSAs (list provided in Appendix A) at any time during the TEAE period will 
be summarized by biological function and treatment arm whatever the baseline level and 
according to the following baseline status categories:  
• 
Normal/missing 
• Abnormal according to PCSA criterion or criteria 
For parameters for which no PCSA criteria are defined, similar table(s) using the normal range 
will be provided. 
Listings will be provided with flags indicating the out of range values as well as PCSA values. 
Drug-induced liver injury 
The liver function tests, namely AST, ALT, alkaline phosphatase, and total bilirubin, are used to 
assess possible drug-induced liver toxicity. The proportion of patients with PCSA values at any 
post-baseline visit by baseline status will be displayed by treatment arm for each parameter. The 
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proportion of patients with PCSA values at any post-baseline visit will also be displayed by 
duration of exposure for each treatment arm.  
A graph of distribution of peak values of ALT versus peak values of total bilirubin will also be 
presented. Note that the ALT and total bilirubin values are presented on a logarithmic scale. The 
graph will be divided into 4 quadrants with a vertical line corresponding to 3 x ULN for ALT and 
a horizontal line corresponding to 2 x ULN for total bilirubin. 
Summarize the normalization by parameter (to ≤1 x ULN or return to baseline) of elevated liver 
function tests by categories of elevation (1-<3 x, 3 x, 5 x, 10 x, 20 x ULN for ALT and AST, 1.5 x 
ULN for alkaline phosphatase, and 1.5 x and 2 x ULN for total bilirubin), with the following 
categories of normalization: never normalized, normalized after IMP discontinuation. Note that a 
patient will be counted only under the maximum elevation category: 1-3, 3-5, 5-10, 10-20, >20. 
Summarize the incidence of liver-related AEs by treatment arm. The selection of preferred terms 
will be based on the drug related hepatic disorder SMQ.  
2.4.5.4 Analyses of vital sign variables 
The summary statistics (including number, mean, median, standard deviation, minimum and 
maximum) of all vital signs variables (central laboratory values and changes from baseline) will 
be calculated for each time point or study assessment (baseline, each post-baseline time point, 
endpoint) by treatment arm. For parameters heart rate, systolic and diastolic blood pressures, the 
last on-treatment and worst on-treatment value will also be provided. 
The incidence of PCSAs at any time during the TEAE period will be summarized by treatment 
arm irrespective of the baseline level and according to the following baseline status categories:  
• Normal/missing 
• Abnormal according to PCSA criterion or criteria 
Listings will be provided with flags indicating the out of range values as well as PCSA values. 
2.4.5.5 Analyses of electrocardiogram variables 
The summary statistics (including number, mean, median, standard deviation, minimum and 
maximum) of all ECG variables (central laboratory values and changes from baseline) will be 
calculated for each time point or study assessment (baseline, each post-baseline time point, 
endpoints) by treatment arm.  
The incidence of PCSAs at any time during the TEAE period will be summarized by treatment 
arm irrespective of the baseline level and according to the following baseline status categories:  
• Normal/missing 
• Abnormal according to PCSA criterion or criteria 
Listings will be provided with flags indicating the out of range values as well as PCSA values. 
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2.4.6 Analyses of pharmacokinetic variables 
Ctrough Concentrations of SAR156597 in plasma will be described on the PK population for each 
time point by treatment arm and by background therapy status using descriptive statistics (number 
of patients, arithmetic mean (SD), geometric mean, coefficient of variation, minimum and 
maximum).  
In a separate table, Ctrough,av,ss, Cmax and CFollow-up will be described on the PK population by 
treatment arm and background therapy status using descriptive statistics (number of patients, 
arithmetic mean (SD), geometric mean, coefficient of variation, minimum and maximum). 
The representation of time profiles for Ctrough concentration (mean ± SD or Median, as 
appropriate) will be also provided by treatment arm and by background therapy status. Average 
steady state achievement will be performed by visual inspection of mean plots. 
According to study results, additional plots will be prepared, as deemed necessary (eg, to explore 
the relationship with some safety or efficacy endpoints of interest).  
The results of population PK modeling will be reported separately from the study report. 
2.4.7 Analyses of immunogenicity data 
The following summaries will be performed on the ADA population, taking into account all 
samples regardless of timing in relation to injections: 
• 
ADA results (negative, positive or inconclusive) by time point and by treatment arm  
• Neutralizing status (inconclusive or positive) for positive ADA by time point and by 
treatment arm 
• ADA titers using descriptive statistics (median, Q1, Q3, minimum and maximum) for 
positive ADA by time point and by treatment arm  
• Number (%) of patients with pre-existing ADA and number (%) of patients with 
treatment-emergent ADA positive response by treatment arm  
• Number (%) of patients with persistent/transient/indeterminate treatment-emergent ADA 
positive response by treatment arm  
• Time to onset of treatment-emergent ADA positive response (in days) using descriptive 
statistics by treatment arm and also according to peack titer. 
• Duration of ADA (in days, only for subjects with at least 2 positive ADA samples) using 
descriptive statistics by treatment arm. 
Correlations between ADA parameters (eg, titers, treatment-emergent ADA positive status, 
neutralizing status) and PK, safety and/or main efficacy endpoint(s) will be explored (eg, scatter 
plot) according to the study results. 
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2.4.8 Analyses of Biomarker data 
Biomarkers will be summarized on the Pharmacodynamics population using descriptive statistics 
by treatment arm and time point. 
Time profile of biomarkers will be explored and link between biomarkers and treatment arm will 
be investigated. 
Correlation between each biomarker and the main efficacy endpoint(s) will be assessed taking 
into account the dose and the background therapy status.  
According to study results, correlation between each biomarker at baseline and Ctrough,av,ss will be 
explored. 
In addition, transcriptomic (mRNA) and genomic (DNA) properties will be explored. 
A detailed description of the analyses will be provided apart of this SAP. The results of 
biomarker, transcriptomic and genomic analyses will be reported separately from the study report. 
2.5 
DATA HANDLING CONVENTIONS 
2.5.1 General conventions 
The following formulas will be used for computation of parameters. 
Study day 
Study day = assessment date - first IMP injection date + 1 (if assessment date ≥first IMP injection 
date),  otherwise study day = assessment date - first IMP injection date, the day of first IMP 
injection being Day 1. For randomized but not treated patients, Day 1 is the day of randomization.  
Demographic formulas 
• Age (years) = (date of informed consent – date of birth)/365.25 
Disease characteristics formulas 
• Time since diagnosis of IPF (years) = (date of randomization - date of first 
diagnosis)/365.25 
• Time since first symptoms of IPF (years) = (date of randomization - date of first IPF 
symptoms)/365.25 
• Time from most recent date of acute exacerbation (months) = (date of randomization – 
date of most recent acute exacerbation)/30.4375 
• Mean smoking duration: 
• for quit smokers: smoking duration = end year – start year. In case of missing end year, no 
imputation with analysis year. 
• for current smokers: smoking duration = analysis year - start year 
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ECG formulas 
Bazett (QTcB (ms)): 
)
(
60
 
(ms)
 
QT
bpm
HR
  
Fridericia (QTcF (ms)): 
3
)
(
60
 
(ms)
 
QT
bpm
HR
 
Renal function formulas  
Creatinine clearance value will be derived using the equation of Cockroft and Gault: 
For Male: 
CLCR (mL/min) = 
)
/
(
*
814
.0
)
(
*
))
(
140
(
L
mol
inine
serumcreat
kg
weight
years
age
µ
−
 
For Female: result above multiplied by 0.85.  
Date of last dose of investigational medicinal product 
The date of the last dose of IMP is equal to the last date of administration reported on the IMP 
administration case report form page, or missing if the last administration date is unknown.  
Lipids variables, laboratory safety variables, hs-CRP 
For data below the lower limit of quantification (LLOQ)/limit of linearity, half of the lower limit 
value (i.e; LLOQ/2) will be used for quantitative analyses. For data above the upper limit of 
quantification (ULOQ) / limit of linearity, the upper limit value (i.e., ULOQ) will be used for 
quantitative analyses. 
For ANCA parameter: values '<1:20' are considered as negative; other results are considered as 
positive.  
The above rules won’t be applied for the calculated LDL-C and non-HDL-C when HDL-C value 
is below the LLOQ. The value of LLOQ/2 for HDL-C will be used to obtain the non-HDL-C and 
calculated LDL-C used for quantitative analyses. 
ADA 
Missing baseline ADA will be considered as negative  
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2.5.2 Data handling conventions for secondary efficacy variables 
2.5.2.1 St George Respiratory Questionnaire (SGRQ) endpoint  
Table 5 - Data handling convention for the SGRQ variable from scales 
Secondary 
Efficacy 
variable 
Short Description 
Data Collection 
Derivation rules/Missing data 
handling 
SGQRT: 
“Symptoms 
component” score 
100 x (Sum of weights for the positive 
responses to questions 1 to 8) / Sum 
of weights for all items in Symptoms 
component 
Self-administration 
questionnaire on site, 
entered in the 
database 
In case of more than 2 missing items, the 
sum will not be calculated. 
The weight for the missed item is 
subtracted from the total possible weight 
for the Symptoms component (662.5) 
and from the Total weight (3989.4) 
SGQRT: “Activity 
component” score 
100 x (‘Sum of weights for the positive 
responses to questions 11 and 15) / 
Sum of weights for all items in Activity 
component 
Self-administration 
questionnaire on site, 
entered in the 
database 
In case of more than 4 missing items, the 
sum will not be calculated. 
The weight for the missed item is 
subtracted from the total possible weight 
for the Symptoms component (1209.1) 
and from the Total weight (3989.4). 
SGQRT: “Impacts 
component” score 
100 x (Sum of weights for the positive 
responses to questions 9 to 10, 12 to 
14 and 16 to 17)/ Sum of weights for 
all items in Impacts component 
Self-administration 
questionnaire on site, 
entered in the 
database 
In case of more than 6 missing items, the 
sum will not be calculated. 
The weight for the missed item is 
subtracted from the total possible weight 
for the Symptoms component (2117.8) 
and from the Total weight (3989.4). 
SGQRT total 
score 
100 x (Sum of weights for all positive 
responses in the questionnaire)/ Sum 
of total weights for the questionnaire 
Self-administration 
questionnaire on site, 
entered in the 
database 
If more than 24% of items are missing in 
the questionnaire, the total score will not 
be calculated. 
It will be noted that the questionnaire requests a single response to questions 1-7, 9-10 and 17. If 
multiple responses are given to one of these questions then averaging the weights for the positive 
responses for that question are acceptable. We feel that this is a better approach than losing an 
entire data set and have used this technique in calculating the results used in our validation 
studies. (Clearly a better approach is to prevent such multiple responses occurring, but it is 
difficult to prevent occasional accidents). 
2.5.3 Missing data 
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified. When relevant, the number of patients with missing data 
is presented. 
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Handling of computation of time since diagnosis of IPF if the date of first diagnosis is 
incomplete  
If the day is missing, the date is imputed to first day of the month. If the month is missing, the 
date is imputed to first month of the year  
Handling of computation of time since first symptoms of IPF if the date of first symptoms of 
IPF is incomplete  
If the day is missing, the date is imputed to first day of the month. If the month is missing, the 
date is imputed to first month of the year  
Handling of computation of treatment duration if investigational medicinal product end of 
treatment date is missing  
For the calculation of the treatment duration, the date of the last dose of IMP is equal to the date 
of last administration reported on the Investigational Product Administration case report form 
page.  
The last dose intake should be clearly identified in the case report form and should not be 
approximated by the last returned package date. 
Handling of medication missing/partial dates 
No imputation of medication start/end dates or times will be performed. If a medication date or 
time is missing or partially missing and it cannot be determined whether it was taken prior or 
concomitantly, it will be considered a prior, concomitant, and post-treatment medication. 
Handling of adverse events with missing or partial date/time of onset 
Missing or partial AE onset dates and times will be imputed so that if the partial AE onset 
date/time information does not indicate that the AE started prior to treatment or after the TEAE 
period, the AE will be classified as treatment-emergent. No imputation of AE end dates/times will 
be performed. These data imputations are for categorization purpose only and will not be used in 
listings. No imputation is planned for date/time of AE resolution. 
Handling of adverse events when date and time of first investigational medicinal product 
administration is missing 
When the date and time of the first IMP administration is missing, all AEs that occurred on or 
after the day of randomization should be considered as TEAE. The exposure duration should be 
kept as missing. 
The last dose intake should be clearly identified in the case report form and should not be 
approximated by the last returned package date. 
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Handling of missing assessment of relationship of adverse events to investigational medicinal 
product  
If the assessment of the relationship to IMP is missing, then the relationship to IMP has to be 
assumed and the AE considered as such in the frequency tables of possibly related AE, but no 
imputation should be done at the data level. 
Handling of missing severity of adverse events 
If the severity is missing for 1 of the treatment-emergent occurrences of an AE, the maximal 
severity on the remaining occurrences will be considered. If the severity is missing for all the 
occurrences, a “missing” category will be added in the summary table. 
Handling of potentially clinically significant abnormalities  
If a patient has a missing baseline he will be grouped in the category “normal/missing at 
baseline.” 
For PCSAs with 2 conditions, one based on a change from baseline value or a normal range and 
the other on a threshold value, with the first condition being missing, the PCSA will be based only 
on the second condition. 
For a PCSA defined on a threshold and/or a normal range, this PCSA will be derived using this 
threshold if the normal range is missing; eg, for eosinophils the PCSA is >0.5 GIGA/L or >ULN 
if ULN ≥0.5 GIGA/L. When ULN is missing, the value 0.5 should be used. 
Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSA values. 
2.5.4 Windows for time points 
Data analyzed by time point (including efficacy, PK, BM, ADA, safety) will be summarized using 
the analysis windows given in Table 6, Table 7 and Table 8. The analysis windows will be 
exhaustive so that data recorded at any time point (including unscheduled visits) has the potential 
to be summarized. These analysis windows will be applicable for all analyses (except for disease 
progression, all-cause mortality, IPF-related cause mortality, acute IPF exacerbations, respiratory 
hospitalizations, non-elective hospitalizations), and they are defined to provide more 
homogeneous data for time point-specific analyses. For efficacy, PK, BM, ADA, if multiple valid 
values of a variable exist within an analysis window, the nearest from the targeted study day will 
be selected. In case of ties, the maximum value will be displayed. For safety, if multiple valid 
values of a variable exist within an analysis window, the nearest from the targeted study day will 
be selected. In case of ties, the mean will be displayed. 
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Table 6 - Analysis windows definition for efficacy 
Time point 
Targeted study day 
Efficacy analysis window  
(in study days) 
Week 12 
85 
2 to 126 
Week 24 
169 
127 to 210 
Week 36 
253 
 211 to 308 
Week 52 
365 
309 to 406 
Week 64 
449 
>406 
Note: Safety and BM will follow the same analysis windows. 
Table 7 - Analysis windows definition for PK and ADA 
Time point 
Targeted study 
day 
Analysis window 
(in study days) 
Week 4 
29 
27 to 31 
Week 12 
85 
83 to 87 
Week 24 
169 
167 to 171 
Week 36 
253 
251 to 255 
Week 52 
365 
363 to 367 
Optional: Week 52+ 5 to 10 days 
370 
370 to 375 
Week 64 
449 
447 to 451 
PK concentrations will be analyzed following time windows as defined below in Table 8. If the 
date of the previous injection is unknown, the SAR156597 concentration will not be considered 
for the analysis. 
Table 8 - Time windows for PK variables definition 
PK variables 
Time 
Cmax 
W52 + 5 to 10 days 
Ctrough 
-2h (day 1, Weeks 12,24,36,52) 
Cfollow-up 
Week 64 
2.5.5 Unscheduled visits 
For all analyses, unscheduled visit measurements may be used to provide a measurement for a 
time point, a baseline, if appropriate according to their definitions. 
2.5.6 Pooling of centers for statistical analyses 
Not applicable. 
2.5.7 Statistical technical issues 
Not applicable. 
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3 
INTERIM ANALYSIS 
As there was no major enrollment issue, no futility analysis was performed. 
Early analysis: 
The primary analysis of efficacy and safety will be performed on the data collected during the 
52-week treatment period. The results of this analysis will not be used to change the conduct of 
the follow-up in any aspect. The 52-week data will not be reanalyzed at the end of the study. 
Individuals who have access to patients’ source documents will remain blinded with regards to the 
treatment arm of individual patients throughout the study. Treatment arm will not be disclosed on 
Data review and Surveillance report.  
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4 
DATABASE LOCK 
There are two database locks planned for this study as follows: 
• First database lock (for early analysis of the main efficacy and safety analyses evaluation 
at Week 52): 4 weeks after last patient last efficacy visit (Visit 9 Week 52). 
• Final database lock (for final analysis of efficacy endpoints and final safety analysis at 
Week 64): 4 weeks after last patient last visit (Visit 10 Week 64). 
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5 
SOFTWARE DOCUMENTATION 
All summaries and statistical analyses will be generated using SAS version 9.4. 
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6 
REFERENCES 
 
1. Jones P. St George's Respiratory Questionnaire. University of London. (June 2009) 
2. van Reenen M. and Janssen B. EQ-5D-5L User Guide. EQ-5D. (April 2015) 
3. Roger, J. A tool to fit Bayesian Gaussian Repeated Measures models within SAS proc MCM 
using conjugate priors. DIA working group on Missing Data. (2015) 
 
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7 
LIST OF APPENDICES 
 
Appendix A: 
Potentially clinically significant abnormalities (PCSA) criteria 
Appendix B: 
Summary of statistical analyses  
Appendix C: 
Systemic corticosteroids routes 
Appendix D: 
 EQ-5D-5L scoring 
Appendix E: 
 MedDRA codelists for AESIs 
Appendix F: 
 WHODD codelists for prior and concomitant medications 
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Appendix A 
Potentially clinically significant abnormalities criteria  
 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES – March 2014 
for phase 2/3 studies (oncology excepted) 
Parameter 
PCSA 
Comments 
Clinical Chemistry 
ALT 
By distribution analysis : 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be expressed in ULN, not in 
IU/L. 
Concept paper on DILI – FDA draft Guidance Oct 2007.
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning 
zero can be deleted. 
AST 
By distribution analysis : 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be expressed in ULN, not in 
IU/L. 
Concept paper on DILI – FDA draft Guidance Oct 2007.
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning 
zero can be deleted. 
Alkaline 
Phosphatase 
>1.5 ULN 
Enzymes activities must be expressed in ULN, not in 
IU/L. 
Concept paper on DILI – FDA draft Guidance Oct 2007.
Internal DILI WG Oct 2008. 
Total Bilirubin 
>1.5 ULN 
>2 ULN 
Must be expressed in ULN, not in µmol/L or mg/L. 
Categories are cumulative. 
Concept paper on DILI – FDA draft Guidance Oct 2007.
Internal DILI WG Oct 2008. 
Conjugated Bilirubin >35% Total Bilirubin and TBILI>1.5 ULN 
Conjugated bilirubin dosed on a case-by-case basis. 
ALT and Total 
Bilirubin 
ALT>3 ULN and TBILI>2 ULN 
Concept paper on DILI – FDA draft Guidance Oct 2007.
Internal DILI WG Oct 2008. 
To be counted within a same treatment phase, 
whatever the interval between measurement. 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES – March 2014 
for phase 2/3 studies (oncology excepted) 
Parameter 
PCSA 
Comments 
CPK 
>3 ULN 
>10 ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning 
zero can be deleted. 
CLcr (mL/min) 
(Estimated 
creatinine clearance 
based on the 
Cokcroft-Gault 
equation)  
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - <60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with impaired renal 
function-study design, data analysis, and impact on 
dosing and labeling 
eGFR 
(mL/min/1.73m2) 
(Estimate of GFR 
based on an MDRD 
equation) 
 
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - <60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with impaired renal 
function-study design, data analysis, and impact on 
dosing and labeling 
Creatinine 
≥150 µmol/L (Adults) 
≥30% change from baseline 
≥100% change from baseline 
Benichou C., 1994. 
 
Uric Acid 
Hyperuricemia 
Hypouricemia  
 
>408 µmol/L 
<120 µmol/L  
Harrison- Principles of internal Medicine 17th Ed., 2008. 
Blood Urea 
Nitrogen 
≥17 mmol/L 
 
Chloride 
<80 mmol/L 
>115 mmol/L 
 
Sodium 
≤129 mmol/L 
≥160 mmol/L 
 
Potassium 
<3 mmol/L 
≥5.5 mmol/L 
FDA Feb 2005. 
Total Cholesterol 
≥7.74 mmol/L  
Threshold for therapeutic intervention. 
Triglycerides 
≥4.6 mmol/L 
Threshold for therapeutic intervention. 
Lipasemia 
≥3 ULN 
 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES – March 2014 
for phase 2/3 studies (oncology excepted) 
Parameter 
PCSA 
Comments 
Amylasemia 
≥3 ULN 
 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
≤3.9 mmol/L and <LLN 
≥11.1 mmol/L (unfasted); ≥7 mmol/L (fasted) 
 
ADA May 2005. 
ADA Jan 2008. 
HbA1c 
>8% 
 
Albumin 
≤25 g/L 
 
CRP 
>2 ULN or >10 mg/L (if ULN not provided) 
 FDA Sept 2005. 
Hematology 
WBC 
<3.0 Giga/L (Non-Black); <2.0 Giga/L (Black) 
≥16.0 Giga/L 
Increase in WBC: not relevant. 
To be interpreted only if no differential count available. 
Lymphocytes 
>4.0 Giga/L 
 
Neutrophils 
<1.5 Giga/L (Non-Black);<1.0 Giga/L (Black) 
International Consensus meeting on drug-induced 
blood cytopenias, 1991. 
FDA criteria. 
Monocytes 
>0.7 Giga/L 
 
Basophils 
>0.1 Giga/L 
 
Eosinophils 
>0.5 Giga/L or >ULN (if ULN≥0.5 Giga/L) 
Harrison- Principles of internal Medicine 17th Ed., 2008. 
Hemoglobin 
≤115 g/L (Male); ≤95 g/L (Female) 
≥185 g/L (Male); ≥165 g/L (Female) 
 
Decrease from Baseline ≥20 g/L 
Criteria based upon decrease from baseline are more 
relevant than based on absolute value. Other 
categories for decrease from baseline can be used 
(≥30 g/L, ≥40 g/L, ≥50 g/L). 
Hematocrit 
≤0.37 v/v (Male) ; ≤0.32 v/v (Female) 
≥0.55 v/v (Male) ; ≥0.5 v/v (Female) 
 
RBC 
≥6 Tera/L 
Unless specifically required for particular drug 
development, the analysis is redundant with that of Hb. 
Otherwise, consider FDA criteria. 
Platelets 
<100 Giga/L 
≥700 Giga/L 
International Consensus meeting on drug-induced 
blood cytopenias, 1991. 
Urinalysis 
pH 
≤4.6 
≥8 
 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES – March 2014 
for phase 2/3 studies (oncology excepted) 
Parameter 
PCSA 
Comments 
Vital signs 
HR 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline≥20 bpm 
To be applied for all positions (including missing) 
except STANDING. 
SBP 
≤95 mmHg and decrease from baseline ≥20mmHg 
≥160 mmHg and increase from baseline ≥20 mmHg 
To be applied for all positions (including missing) 
except STANDING. 
DBP 
≤45 mmHg and decrease from baseline ≥10 mmHg 
≥110 mmHg and increase from baseline ≥10 mmHg 
To be applied for all positions (including missing) 
except STANDING. 
Orthostatic 
Hypotension 
Orthostatic SDB 
Orthostatic DBP 
 
 
≤-20 mmHg 
≤-10 mmHg 
 
Weight 
≥5% increase from baseline 
≥5% decrease from baseline 
FDA Feb 2007. 
ECG 
Ref.: ICH E14 guidance (2005) and E14 Q&A (2012), 
and Cardiac Safety Research Consortium White Paper 
on PR and QRS (Nada et al. Am Heart J. 2013; 165(4) 
: 489-500) 
HR 
<50 bpm 
<50 bpm and decrease from baseline ≥20 bpm 
<40 bpm 
<40 bpm and decrease from baseline ≥20 bpm 
<30 bpm 
<30 bpm and decrease from baseline ≥20 bpm 
>90 bpm 
>90 bpm and increase from baseline ≥20bpm 
>100 bpm 
>100 bpm and increase from baseline ≥20bpm 
>120 bpm 
>120 bpm and increase from baseline ≥20 bpm 
Categories are cumulative 
 
 
 
 
 
Categories are cumulative 
 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES – March 2014 
for phase 2/3 studies (oncology excepted) 
Parameter 
PCSA 
Comments 
PR 
>200 ms 
>200 ms and increase from baseline ≥25% 
>220 ms 
>220 ms and increase from baseline ≥25% 
>240 ms 
>240 ms and increase from baseline ≥25% 
Categories are cumulative 
 
QRS 
>110 ms 
>110 msec and increase from baseline ≥25% 
>120 ms 
>120 ms and increase from baseline ≥25% 
Categories are cumulative 
QT 
>500 ms 
 
QTc 
 
Absolute values (ms) 
 
 
>450 ms 
>480 ms 
>500 ms 
 
Increase from baseline 
Increase from baseline ]30-60] ms 
Increase from baseline >60 ms 
To be applied to any kind of QT correction formula. 
Absolute values categories are cumulative 
 
QTc >480 ms and ∆QTc>60 ms are the 2 PCSA 
categories to be identified in individual subjects/patients 
listings. 
 
 
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Appendix B 
Summary of statistical analyses 
 
EFFICACY ANALYSIS 
Endpoint 
Analysis 
population 
Primary 
analysis 
Supportive 
analysis 
Subgroup 
analysis 
Other 
analyses 
Primary endpoint 
%predicted FVC: Change 
from baseline at week 52 
mITT 
Rank ANCOVA with adjustment 
covariates: stratification factor 
(with/without Background Therapy), 
%predicted FVC baseline; and a 
treatment fixed effect. 
Imputation of W52 values using linear 
regression (according to treatment 
arm and treated status 52 weeks), 
time-to-death for ranking deaths and 
time-to-lung transplants for ranking 
lung transplants. 
MMRM with treatment 
arm, stratification 
factor, % predicted 
FVC baseline, time 
point, treatment-by-
time point interaction, 
stratification factor-by-
treatment-by-time point 
interaction.  Multiple 
imputation of W52 
values using CIR 
(other) and translated 
distribution of their last 
available assessments 
(death or lung 
transplant).  
Subgroups: Gender, 
age ≤65 or <65, 
Smoking status, 
with/without 
Background 
Therapy, Baseline 
%predicted FVC% 
categories, ANA at 
baseline 
(Positive/Negative) 
using both rank 
ANCOVA model and 
MMRM. 
 
MMRM on-treatment data with treatment arm, 
stratification factor, % predicted FVC baseline, time 
point, treatment-by-time point interaction, 
stratification factor-by-treatment-by-time point 
interaction.  No imputation.  
Cumulative distribution of decline from baseline at 
24 weeks and at 52 weeks in % predicted FVC 
Secondary endpoints 
Time-to-disease progression 
at 52 weeks: time-to-first 
event between a decrease 
in change from baseline in 
%predicted FVC≥10%, a 
decrease in change from 
baseline in %predicted 
DLCO≥15%, death and lung 
transplant. 
mITT 
Log-rank stratified on stratification 
factor (with/without Background 
Therapy); Kaplan-Meier 
representation and Hazard Ratio 
using a Cox model with treatment, 
stratification factor,. No imputation. 
No 
Subgroups: Gender, 
age≤65 or <65, 
Smoking status, 
with/without 
Background 
Therapy, Baseline 
%predicted FVC% 
categories, ANA at 
baseline 
(Positive/Negative). 
Time-to-disease progression at 24 weeks: Hazard 
Ratio using a Cox model with treatment, 
stratification factor , stratification factor-by-
treatment. No imputation. 
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Endpoint 
Analysis 
population 
Primary 
analysis 
Supportive 
analysis 
Subgroup 
analysis 
Other 
analyses 
Cumulative incidence of all-
cause mortality 
mITT 
Kaplan-Meier representation and 
Hazard Ratio using a Cox model with 
treatment, stratification factor ,. No 
imputation. 
No 
No 
IPF-related deaths: Kaplan-Meier representation 
and Hazard Ratio using a Cox model with 
treatment, stratification factor , stratification factor-
by-treatment. No imputation. 
Exploratory 
endpoints 
 
 
 
 
 
Change from baseline to 
week 52 in %predicted 
DLCO 
mITT 
MMRM with treatment arm, 
stratification factor, time point, 
treatment-by-time point interaction, 
stratification factor-by-treatment-by-
time point interaction, % predicted 
DLCO baseline.No imputation. 
No 
No 
No 
Annual rate of acute IPF 
exacerbations 
mITT 
Annual rate from negative binomial 
model adjusted on stratification factor 
(with/without Background Therapy) 
and stratification factor-by-treatment 
interaction. No imputation. 
No 
No 
No 
Annual rates of respiratory 
and non-elective 
hospitalizations 
mITT 
Annual rates from negative binomial 
model adjusted on stratification factor 
(with/without Background Therapy) 
and stratification factor-by-treatment 
interaction. No imputation. 
No 
No 
No 
Change from baseline to 
week 52 in 6-MWT distance 
mITT 
MMRM with the fixed categorical 
effects of treatment arm, stratification 
factor, time point, treatment-by-time 
point interaction, stratification factor-
by-treatment-by-time point interaction, 
supplemental oxygen use at baseline, 
6-MWT distance at baseline. No 
imputation. 
No 
No 
No 
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Endpoint 
Analysis 
population 
Primary 
analysis 
Supportive 
analysis 
Subgroup 
analysis 
Other 
analyses 
Change from baseline to 
week 52 in HRCT lung 
interstitial score (Total 
Fibrosing ILD score) 
mITT 
Ancova with baseline value, 
emphysema score at baseline, 
stratification factor, treatment, 
stratification factor-by-treatment 
interaction. No imputation. 
No 
No 
No 
Change from baseline to 
week 52 in SGRQ 
mITT 
MMRM with treatment arm, 
stratification factor, time point, 
treatment-by-time point interaction, 
stratification factor-by-treatment-by-
time point interaction, SGRQ total 
score at baseline. No imputation. 
No 
No 
No 
Change from baseline to 
week 52 in EQ-5D-5L 
mITT 
MMRM with treatment arm, 
stratification factor, time point, 
treatment-by-time point interaction, 
stratification factor-by-treatment-by-
time point interaction, as EQ-5D-5L 
total score at baseline . No 
imputation. 
No 
No 
No 
 
 
(electronic 
 
 
1.0)


Statistical Analysis Plan  
16-Jun-2017 
SAR156597 - DRI11772 -   
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 78 
Appendix C 
Systemic corticosteroids routes 
 
Route 
Buccal 
Enteral 
Administration Via Hemodialysis 
Intraarterial 
Intraduodenal 
Intraesophageal 
Intragastric 
Intraileal 
Intrajejunal 
Intraluminal 
Intralymphatic 
Intramuscular 
Intramuscular or Subcutaneous 
Intravascular 
Intravenous 
Intravenous Bolus 
Intravenous Drip 
Intraventricular 
Nasogastric 
Oral 
Oral Gavage 
Oromucosal 
Oropharyngeal 
Parenteral 
Percutaneous 
Rectal 
Subcutaneous 
Sublingual 
Submucosal 
Transdermal 
Mucosal 
(electronic 
 
 
 
1.0)


Statistical Analysis Plan  
16-Jun-2017 
SAR156597 - DRI11772 -   
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 79 
Appendix D 
EQ-5D-5L Scoring 
 
 
 
* Creation of variable :qsstresn ; 
data qs1; 
   
set adsd.QS_all; 
 
where QSSTAT ne 'NOT DONE'; 
   
if index(qsorres,"NO")>0 or index (qsorres,"NOT")>0 
 
then qsstresn=1; 
 
else if index(qsorres,"SOME") or index(qsorres,"MODERATE") or index(qsorres,"MODERATELY") 
 
 
 then qsstresn=2; 
 
 
 else if index(qsorres,"CONFINED") or index(qsorres,"UNABLE") or index(qsorres, "EXTREME") or 
index(qsorres, "EXTREMELY") 
 
 
  
  then qsstresn=3; 
 
 
 
  else qsstresn=.; 
run; 
 
proc sort data=qs1 out=qs2; 
 
by usubjid visit QSTESTCD; 
run; 
 
data qs3; 
 
set qs2; 
 
by usubjid visit QSTESTCD; 
 
retain qsstreni profil; 
 
**********Mobility*********; 
 
if QSTESTCD="QS1" and qsstresn=1 then qsstreni=1; 
 
if QSTESTCD="QS1" and qsstresn=2 then qsstreni=1-0.069; 
 
if QSTESTCD="QS1" and qsstresn=3 then qsstreni=1-0.314; 
 
if QSTESTCD="QS1" then if qsstresn=. then profil=0; else profil=qsstresn; 
 
********Self-care**********; 
 
if QSTESTCD="QS2" and qsstresn=1 then qsstreni=qsstreni; 
 
if QSTESTCD="QS2" and qsstresn=2 then qsstreni=qsstreni-0.104; 
(electronic 
 
 
1.0)


Statistical Analysis Plan  
16-Jun-2017 
SAR156597 - DRI11772 -   
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 80 
 
if QSTESTCD="QS2" and qsstresn=3 then qsstreni=qsstreni-0.214; 
 
if QSTESTCD="QS2" then if qsstresn=. then profil=compress(profil!!0); else 
profil=compress(profil!!qsstresn); 
 
******Usual activities*****; 
 
if QSTESTCD="QS3" and qsstresn=1 then qsstreni=qsstreni; 
 
if QSTESTCD="QS3" and qsstresn=2 then qsstreni=qsstreni-0.036; 
 
if QSTESTCD="QS3" and qsstresn=3 then qsstreni=qsstreni-0.094; 
 
if QSTESTCD="QS3" then if qsstresn=. then profil=compress(profil!!0); else 
profil=compress(profil!!qsstresn); 
 
*****Pain/discomfort******; 
 
if QSTESTCD="QS4" and qsstresn=1 then qsstreni=qsstreni; 
 
if QSTESTCD="QS4" and qsstresn=2 then qsstreni=qsstreni-0.123; 
 
if QSTESTCD="QS4" and qsstresn=3 then qsstreni=qsstreni-0.386; 
 
if QSTESTCD="QS4" then if qsstresn=. then profil=compress(profil!!0); else 
profil=compress(profil!!qsstresn); 
 
*****Anxiety/depression*****; 
 
if QSTESTCD="QS5" and qsstresn=1 then qsstreni=qsstreni; 
 
if QSTESTCD="QS5" and qsstresn=2 then qsstreni=qsstreni-0.071; 
 
if QSTESTCD="QS5" and qsstresn=3 then qsstreni=qsstreni-0.236; 
 
if QSTESTCD="QS5" then if qsstresn=. then profil=compress(profil!!0); else 
profil=compress(profil!!qsstresn); 
 
output; 
 
if last.visit then do; 
 
 
qsstresn=profil; 
 
 
 
 
 
if index(profil,'3') ne 0 then qsstreni=qsstreni-0.269; 
 
 
if index(profil,'2') ne 0 or index(profil,'3') ne 0 then qsstreni=qsstreni-0.081;  
 
 
 
 else if profil=0 then qsstreni=.; 
 
 
 
  
  else qsstreni=qsstreni; 
 
 
QSTESTCD='QS6'; 
 
 
QSTEST='Total score'; 
 
 
QSORRES=''; 
 
 
QSSTRESC=''; 
 
 
output; 
 
end; 
run; 
(electronic 
 
 
1.0)


Statistical Analysis Plan  
16-Jun-2017 
SAR156597 - DRI11772 -   
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 81 
Appendix E 
MedDRA codelists for AESIs and related hepatic disorder 
 
requested list 
type (cmq, 
smq, others) 
name or code (cmqname, smqcd, others) description (cmqdesc or 
SMQ_ShortName, others) 
scope (smq) / 
prim_sec (soc) 
reqlist 
type 
Codename 
desc 
scope 
Acute renal failure  CMQ 
GLB_ACUTE RENAL FAILURE NARROW 
Acute renal failure Narrow 
Narrow 
Tuberculosis 
CMQ 
GZ402673_TUBERCULOSIS 
Tuberculosis 
Anaphylactic 
reactions or acute 
allergic reactions 
that require 
immediate 
treatment 
CMQ 
GLB_ANAPHYLACTIC REACTION 
NARROW 
Anaphylactic reaction Narrow Narrow 
Hepatic disorder 
CMQ 
GLB_HEPATIC 
DISORDERS 
NARROW 
Hepatic 
disorders 
Narrow 
Narrow 
 
Hepatic disorders Narrow 
Narrow 
(electronic 
 
 
 
1.0)


Statistical Analysis Plan  
16-Jun-2017 
SAR156597 - DRI11772 -   
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 82 
Appendix F 
WHODD codelists for prior and concomitant medications 
 
requested lists 
cdgname 
cdgdesc 
 
Use of any cytotoxic/immunosuppressive agent including but not 
limited to azathioprine, cyclophosphamide, methotrexate, and 
cyclosporine 
CDG00696 
Cytotoxic_or_immunosuppressive_agent 
 
Use of any cytokine modulators (alefacept, etanercept, 
adalimumab, efalizumab, infliximab, golimumab, certolizumab, 
rituximab) 
CDG00697 
Cytokine modulators 
Prohibited concomitant biologic agents  
CDGSn073 
Biologicals NARROW 
Prohibited concomitant Alefacept  
CDG00736 
Alefacept_mono_and_multi_ingredients 
Initiation of medications for suspected tuberculosis  
CDG00737 
Medications for suspected tuberculosis  
ORAL CORTICOSTEROIDS 
CDGSn010 
Corticosteroids NARROW 
acetylcystein 
CDG20006 
ACETYLCYSTEIN_mono_and_multi_ingredients
n-acetylcystein 
CDG20006 
ACETYLCYSTEIN_mono_and_multi_ingredients
NAC 
CDG20006 
ACETYLCYSTEIN_mono_and_multi_ingredients
Anti-Acids 
CDG00592 
ANTACIDS 
Proton pump inhibitors (PPI) 
CDG00593 
PROTON PUMP INHIBITORS 
H2-receptor blockers 
CDGSn292 
H2 receptor antagonists Narrow 
 
(electronic 
 
 
 
1.0)


 
 
 
 
 
 
 
 
 
ELECTRONIC SIGNATURES 
 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DRI11772 16.1.9 Statistical analysis plan
Clinical Approval
16-Jun-2017 22:13 GMT+0200
Clinical Approval
19-Jun-2017 16:20 GMT+0200