Efficacy and Safety of SAR156597 in the Treatment of Idiopathic Pulmonary Fibrosis (IPF): A Randomized, Double-blind, Placebo-controlled, 52-week Dose-ranging Study
Phase: PHASE2
Conditions: Idiopathic Pulmonary Fibrosis
Sponsor: Sanofi



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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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15 
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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4 
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 
patient. 
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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 
necessary. 
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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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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. 
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idiopathic pulmonary fibrosis and sacoidosis in the UK. Thorax 2006 Nov;61 (11):980-5. 
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idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2006 Oct 1;174(7):810-6. 
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idiopathic pulmonary fibrosis: evidence of founder effect among multiplex families in Finland. 
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interstitial pneumonia: what is the effect of a multidisciplinary approach to diagnosis? Am J 
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Dec 3;378(9807):1949-61. 
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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 
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Oh CK, Geba GP, Molfino N. Investigational therapeutics targeting the IL-4/IL-13/STAT-
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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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17 
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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