Clinical trial NCT02921971
Conditions: Systemic Sclerosis
Sponsor: Sanofi
Start date: 2016-12-21; Completion date: 2019-04-01
Enrollment: 97 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objective:

To evaluate, in comparison with placebo, the efficacy of SAR156597 administered subcutaneously for 24 weeks on skin fibrosis in participants with diffuse cutaneous systemic sclerosis (dcSSc).

Secondary Objectives:

* To evaluate the efficacy of SAR156597 compared to placebo on physical/functional disability in participants with dcSSc.
* To evaluate the efficacy of SAR156597 compared to placebo on respiratory function of participants with dcSSc.
* To evaluate the safety profile of SAR156597 compared to placebo in participants with dcSSc.
* To evaluate the potential for immunogenicity (anti-drug antibodies response) of SAR156597 in participants with dcSSc.
* To evaluate the pharmacokinetics (trough plasma concentrations) of SAR156597 administered subcutaneously for 24 weeks.

Detailed description:
The total study duration per participant was 39 weeks; consisting of a 4-week screening, a 24-week of study treatment period, and an 11-week follow-up with no study drug treatment.

Arms: arm 1: Placebo (for SAR156597), single subcutaneous (SC) injection once in a week (QW) up to Week 24. arm 2: SAR156597 200 milligram (mg), single SC injection QW up to Week 24.
Interventions: intervention 1: SAR156597 intervention 2: Placebo
Intervention descriptions: intervention 1: Pharmaceutical form: Solution Route of administration: Subcutaneous intervention 2: Pharmaceutical form: Solution Route of administration: Subcutaneous

Protocol documents:
Prot_000.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: QSD-003152 VERSION N°3.0 (04-FEB-2016) 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL NO. 01 
Protocol Amendment 01 
Version number: 1 (electronic 1.0) 
Date : 09-Aug-2017 
Clinical Trial Protocol 
Version number: 1 (electronic 3.0) 
Date : 09-Jun-2016 
EudraCT
2016-001028-80
IND Number(s) 
129312 
Version Number: 
1 
WHO universal trial number: 
U1111 1179 4690 
Date: 
09-Aug-2017
Total number of pages: 
115 
(electronic 1.0)
COMPOUND: SAR156597  
Efficacy and safety of SAR156597 in the treatment of diffuse cutaneous Systemic 
Sclerosis (dcSSc): A randomized, double blind, placebo controlled, 24 week, proof 
of concept study 
STUDY NUMBER: ACT14604 
VERSION DATE / STATUS: Approval date (09-Aug-2017) / Approved 
NCT02921971


Amended Clinical Trial Protocol NO. 01  
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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.: ACT14604  
TITLE 
Efficacy and safety of SAR156597 in the treatment of dcSSc: A 
randomized, double-blind, placebo-controlled, 24-week, proof of 
concept study 
INVESTIGATOR/TRIAL LOCATION 
International 
PHASE OF DEVELOPMENT 
2 
STUDY OBJECTIVES 
Primary objective: 
• 
To evaluate, in comparison with placebo, the efficacy of 
SAR156597 administered subcutaneously for 24 weeks on 
skin fibrosis in patients with dcSSc. 
Secondary objectives: 
• 
To evaluate the efficacy of SAR156597 compared to placebo 
on physical/functional disability in patients with dcSSc. 
• 
To evaluate the efficacy of SAR156597 compared to placebo 
on respiratory function in patients with dcSSc. 
• 
To evaluate the safety profile of SAR156597 compared to 
placebo in patients with dcSSc. 
• 
To evaluate the potential for immunogenicity anti-drug 
antibodies (ADA) response of SAR156597 in patients with 
dcSSc. 
• 
To evaluate the pharmacokinetics (PK) (trough plasma 
concentrations) of SAR156597 administered subcutaneously 
for 24 weeks. 
Exploratory objectives: 
• 
To explore the efficacy of SAR156597 compared to placebo 
on other manifestations of Systemic Sclerosis (SSc) 
(gastrointestinal, joint pain, cardiovascular, and renal 
manifestations) in patients with dcSSc. 
• 
To explore the effect of SAR156597 on the Quality Of Life in 
patients with dcSSc. 
• 
To measure the effect of SAR156597 on biomarkers of the 
disease activity and the interlukin-4/interlukin-13 pathway (IL-
4/IL-13) pathway. 
STUDY DESIGN 
• 
Multinational, randomized, double-blind, placebo-control, 
2 parallel groups 
• 
Patients will be randomized in a 1:1 ratio to receive 
subcutaneous (SC) administrations of either: 
- 
SAR156597 200 mg every week (qw) 
- 
Placebo qw 
• 
Randomization will be stratified based upon the patients’ 
medical history of SSc-Interstitial Lung Disease (SSc-ILD) 
(yes or no). 
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STUDY POPULATION 
Main selection criteria 
Inclusion criteria: 
I 01. 
Systemic Sclerosis according to the American college of 
Rheumatology/The European League against Rheumatism 
(ACR/EULAR) 2013 criteria. 
I 02. 
Diffuse cutaneous form of SSc according to Leroy’s criteria. 
I 03. 
Able and willing to sign the written informed consent form 
with comprehension of its contents and comply with the 
requirements of the study protocol. 
Key exclusion criteria: 
E 01. 
Age <18 years. 
E 02. 
Disease duration of >36 months from time of first 
non-Raynaud’s phenomenon manifestation. 
E 03. 
Modified Rodnan Skin Score (mRSS) <10 or >35 at screening 
and baseline visits. 
E 04. 
History of vasculitis, active or in remission. 
E 05. 
Diagnosis of connective tissue disease (other than SSc) or 
overlap syndrome (eg, polymyositis/SSc). 
Total expected number of patients 
Approximately 94 randomized patients (47 patients per group) 
STUDY TREATMENT(s) 
 
Investigational medicinal products (IMPs) 
SAR156597 or placebo 
Formulation: 
• 
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 in lyophilized form (each vial containing excipients, 
to be reconstituted with 1.1 mL of sterile water in order to 
achieve at least 1 mL of placebo for injection). 
Route of administration: 
SC 
Dose regimen: 
qw 
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ENDPOINTS 
Efficacy 
Primary endpoint: 
• 
Change in mRSS from baseline to Week 24. 
Secondary endpoints: 
• 
Change in Health Assessment Questionnaire Disability Index 
(HAQ-DI), assessed with Scleroderma health assessment 
questionnaire (SHAQ), from baseline to Week 24. 
• 
Change in respiratory function as measured by observed 
Forced Vital Capacity (FVC) and observed Carbon Monoxide 
Diffusing Lung Capacity (DLco [corrected for hemoglobin]) 
from baseline to Week 24. 
Exploratory endpoints: 
• 
Proportion of patients with improvement in mRSS of at least 
20%, 40% and 60% from baseline to Week 24.  
• 
Change in Visual Analog Scales (VAS) for pain, breathing 
function, vascular function (Raynaud's phenomenon), 
gastrointestinal function, digital ulcers, and global 
assessment from SHAQ from baseline to Week 24.  
• 
Change in respiratory function as measured by % predicted 
FVC and % predicted DLco (corrected for hemoglobin) from 
baseline to Week 24.  
• 
Change in UCLA Scleroderma Clinical Trial Consortium 
Gastrointestinal Tract 2.0 (UCLA SCTC GIT 2.0) score from 
baseline to Week 24. 
• 
Change in Tender Joint Count 28 (TJC28) from baseline to 
Week 24. 
• 
Change in digital ulcer count from baseline to Week 24. 
• 
Composite Response Index for diffuse cutaneous Systemic 
Sclerosis (CRISS) from baseline to Week 24. 
• 
Change in EQ-5D-5L index from baseline to Week 24. 
• 
Change in efficacy endpoints (mRSS, HAQ-DI, VAS from 
SHAQ, observed FVC, % predicted FVC, observed DLco 
[corrected for hemoglobin], % predicted DLco [corrected for 
hemoglobin], UCLA SCTC GIT 2.0, TJC28, digital ulcer count, 
CRISS, and European Quality of Life-5 Dimension-5 Level [EQ-
5D-5L]) from baseline to Week 35 (up to end of follow-up 
period) and proportion of patients with improvement in mRSS 
of at least 20%, 40% and 60% from baseline to Week 35. 
• 
Proportion of patients with improvement in SHAQ (HAQ-DI 
and VAS) and EQ-5D-5L (index value and VAS) based upon 
Minimally Important Change (MIC) at Week 24. 
Safety: 
• 
Adverse events (AEs)/treatment-emergent adverse events 
(TEAEs) 
• 
Physical examination and body weight 
• 
Vital signs and 12-lead electrocardiogram (ECG) 
• 
Clinical laboratory evaluations including hematology, 
biochemistry and urinalysis 
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• 
Tolerability at the IMP injection site: 
- 
Erythema/redness (diameter and graded severity) 
- 
Swelling/induration/edema (diameter and graded 
severity) 
- 
Pain assessment. 
Immunogenicity: 
• 
Testing for ADA 
Pharmacokinetics: 
• 
SAR156597 plasma concentrations 
Biomarkers: 
• 
Measurement of protein biomarkers associated with the 
activity of the disease (COMP, CCL2) and the IL-4/IL-13 
pathway (TARC, periostin, and eotaxin-3). 
• 
Archived blood samples for future assays of protein and 
mRNA biomarkers related to the disease and the response to 
therapy (requires separate informed consent).  
ASSESSMENT SCHEDULE 
The study will comprise 8 on-site visits AND 4 phone calls: 
• 
Visits: 
- 
V1 (screening visit) between Day -28 and Day -1. 
- 
V2 (baseline visit) at Day 1 (first dosing). 
- 
Treatment period*: V3 at Week 2, V4 at Week 4, V5 at 
Week 8, V6 at Week 12, V7 at Week 24. 
- 
V8 (End-of-Study [EOS] visit) at Week 35. 
- 
A time window of ±2 days will be allowed for each visit. 
• 
Phone calls: 
- 
For safety considerations phone calls will be made at 
Week 6, 16 and 20 during the treatment period, and at 
Week 30 during the follow-up period. 
*IMP administration given qw starting at V2 with the last dose given at 
Week 23. 
STATISTICAL CONSIDERATIONS 
Sample size determination: 
Ninety-four (94) patients (47 patients per group) will yield 80% 
power to detect a difference versus placebo group of 3.6 in the 
mean change from baseline in mRSS at 24 weeks, assuming a 
standard deviation (SD) of 7 and using a 1-sided alpha of 5% 
(type I error). 
The impact of treatment discontinuations in the context of an 
intent-to-treat (ITT) analysis where all mRSS data will be included in 
the analysis (regardless of adherence to treatment) was evaluated. 
Assuming that 10% of patients will discontinue the treatment, the 
estimated treatment effect at 24 weeks will be decreased from 4 
(targeted treatment effect if all patients adhered to treatment) to 3.6 
(targeted treatment effect in all randomized patients). 
Analysis population: 
The efficacy population will be the ITT population, which includes all 
randomized patients. 
Patients in the ITT population will be analyzed according to the 
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treatment group allocated by randomization. 
The safety population will include all randomized patients who 
received at least 1 dose or part of a dose of the IMP. 
Patients in the safety population will be analyzed in the treatment 
group as actually received. Patients receiving more than 1 study 
treatment during the trial will be analyzed in the treatment group 
from which they received the majority of injections. 
Primary efficacy analysis: 
All measurements are assigned to analysis windows in order to 
provide an assessment for Week 4 to Week 24 time points. 
With regards to the primary efficacy analysis, the change in mRSS 
from baseline to Week 24 will be analyzed using a mixed-effect 
model with repeated measures (MMRM) approach. All post-baseline 
data available from Week 4 to Week 24 analysis windows will be 
used and missing data will be accounted for by the MMRM. The 
model includes the fixed categorical effects of treatment group, 
randomization strata, time points (Week 4 to Week 24), 
randomization strata-by-time point interaction and treatment-by-time 
point interaction, as well as the continuous fixed covariates of 
baseline mRSS value and baseline value-by-time point interaction. 
This model will provide baseline adjusted least-squares means 
(LSmeans) estimates at Week 24 for both treatment groups with their 
corresponding 95% confidence interval. To compare SAR156597 to 
the placebo group, an appropriate statement will be used to test the 
differences of these estimates at the 5% one sided alpha level. The 
95% and 90% confidence intervals of the difference will be provided. 
Analysis of secondary efficacy endpoints: 
Continuous secondary efficacy endpoints will be analyzed using the 
same MMRM model as for the primary endpoint with the continuous 
fixed covariates of corresponding baseline value and baseline 
value-by-time point interaction. 
Safety: 
Safety analyses will be descriptive, based on the safety population. 
The safety analysis will focus on the TEAE period. This period is 
defined as the time from the first administration of the IMP to the last 
administration of the IMP + 12 weeks. 
DURATION OF STUDY PERIOD (per patient)
The study can last up to 39 weeks per patient as follows: 
• 
4 weeks of screening. 
• 
24 weeks of study treatment. 
• 
11 weeks of follow-up with no study treatment. 
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1 
FLOW CHARTS 
1.1 
GRAPHICAL STUDY DESIGN 
 
R
D-28
D1
W2   W4     (W6)    W8              W12     (W16)   (W18)      (W20)
W24                  (W30)              W35      
SAR156597 200 mg SC qw
Placebo SC qw
No studydrug
No study drug
Screening period
Treatment period
Follow-up period
R: randomization
SC: subcutaneous
D: day
W: week
qw: once a week
 
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1.2 
STUDY FLOW CHART 
Period 
Screening 
Baseline visit 
Treatment period 
FU 
Visits/phone calls 
V1 
V2a,b 
V3 
V4 
Phone call 
V5 
V6r 
Phone call 
IVRS callr 
Phone call 
V7s 
(EOT) 
Phone call 
V8 (EOS) 
Day/Week 
D-28 to D-1 
D1 
W2 
W4 
W6 
W8 
W12 
W16 
W18 
W20 
W24 
W30 
W35 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Call IVRS 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
Study treatment 
administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAR156597 or placeboc 
 
Å------------------------------------------------------------------------------------------------------------------------------------------------------Æ 
 
 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationd 
X 
X 
X 
X 
 
X 
X 
 
 
 
X 
 
X 
Vital signse 
X 
X 
X 
X 
 
X 
X 
 
 
 
X 
 
X 
ECGf 
X 
X 
 
X 
 
X 
X 
 
 
 
X 
 
X 
Echocardiogramg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology, biochemistry, 
urinalysish 
X 
X 
 
X 
 
X 
X 
 
 
 
X 
 
X 
Serology testsi 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Tuberculosis screenk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
β-HCG blood testl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy testl 
 
X 
 
X 
 
X 
X 
X 
 
X 
X 
 
X 
Review patient booklet 
(Local tolerability of SC 
 
X (post-dose)--------------------------------------------------------------------------------------------------------------------------------------/E 
 
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injections/IMP compliance)m 
Period 
Screening 
Baseline visit 
Treatment period 
FU 
Visits/phone calls 
V1 
V2a,b 
V3 
V4 
Phone call 
V5 
V6r 
Phone call 
IVRS callr 
Phone call 
V7s 
(EOT) 
Phone call 
V8 (EOS) 
Day/Week 
D-28 to D-1 
D1 
W2 
W4 
W6 
W8 
W12 
W16 
W18 
W20 
W24 
W30 
W35 
Adverse event reporting 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Pharmacokinetics 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood samples for PK 
 
X 
 
X 
 
X 
X 
 
 
 
X 
 
X 
Blood samples for ADA 
X 
X 
 
X 
 
X 
X 
 
 
 
X 
 
X 
Efficacy 
 
 
 
 
 
 
 
 
 
 
 
 
 
mRSS 
X 
X 
 
X 
 
X 
X 
 
 
 
X 
 
X 
SHAQ 
 
X 
 
X 
 
X 
X 
 
 
 
X 
 
X 
PFTs (FVC & DLco) 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
UCLA SCTC GIT 2.0 
 
X 
 
X 
 
X 
X 
 
 
 
X 
 
X 
Digital Ulcer Count 
 
X 
 
X 
 
X 
X 
 
 
 
X 
 
X 
Tender Joint Count 28 
 
X 
 
X 
 
X 
X 
 
 
 
X 
 
X 
CRISSn 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
Patient Global Assessmento 
 
X 
 
X 
 
X 
X 
 
 
 
X 
 
X 
Physician Global Assessmentp 
 
X 
 
X 
 
X 
X 
 
 
 
X 
 
X 
EQ-5D-5L 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
Resource Utilizationq 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
Blood samples for protein 
biomarkers analysis 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
Future Use of Sample: 
Archived blood samples for 
future protein assays and 
mRNA (Optional and requires 
signing of separate ICF) 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
a Randomization/baseline Visit is defined as Day 1. Visit windows for subsequent visits are ±2 days 
b All assessments at Visit 2 (Day 1) are to be conducted pre dose with the exception of the assessment of local tolerability of SC injections 
c Study treatment is to be administered once a week, either at the site or at home by a qualified healthcare professional – Last dose will be given at Week 23 
d Complete physical examinations will include skin, nasal cavities, eyes, ears, respiratory, cardiovascular, gastrointestinal, neurological, lymphatic, and musculoskeletal systems. For the dermatological examination 
the Investigator should evaluate for SSc related skin changes and some specific findings that may indicate vasculitis including, but not limited to: purpura, papules or non-blanching rashes. Nail beds (periungual 
areas) should be examined for “splinter lesions” and digital tuft for tuft purpura or ischemia. Gynecological and urogenital examinations will not be done in this study unless for cause 
e Vital signs, including blood pressure (mmHg), heart rate (beats per minute) and body weight (kg) will be measured at screening, baseline and every subsequent visit. Height (cm) will be measured at screening 
(Visit 1) only. BMI will be calculated automatically at all visits 
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f 
All abnormal ECG interpretation will be reviewed and confirmed by a local cardiologist. 
g Previous echocardiogram may be used if obtained within 6 months of V1 (screening visit). 
h Hematology: Hemoglobin, hematocrit, red blood cell count, erythrocyte sedimentation rate (ESR), white blood cell count with differential and platelet count. Biochemistry: Fasting glucose, blood urea nitrogen, 
creatinine, sodium, potassium, chloride, bicarbonate, calcium, phosphorous, total protein, albumin, total bilirubin, alkaline phosphatase, ALT, AST, CPK, hs CRP. Urinalysis (dipstick) to include: specific gravity, pH, 
glucose, ketones, blood, protein, nitrate, leukocyte esterase, urobilinogen and bilirubin. If any parameter on the dipstick is abnormal, a urine sample should be sent to the central laboratory for testing. If positive for 
protein and/or red blood cells, microscopic analysis will be performed by the central laboratory 
i 
Serology testing includes HIV-1/HIV-2 antibody, hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B core antibody, hepatitis B DNA (reflex to a positive hepatitis B core antibody), hepatitis C 
antibody and hepatitis C RNA (reflex to a positive hepatitis C antibody) 
j 
k Tuberculosis screen: history and QuantiFERON-TB Gold test. If the result of the initial QuantiFERON-TB Gold test is indeterminate, the test should be repeated one time 
l 
In women of child-bearing potential. After Visit 6 (W12) and until subsequent study visit the patient will have a urine pregnancy test at home on a monthly basis. Patients will be given sufficient urine pregnancy kits 
to take home for monthly testing up until the end-of-study visit. When the testing coincides with a study visit as indicated in the flow chart, the results should be reported in the e-CRF. When the testing is done at 
home between study visits, the results should be collected by the Investigator during the monthly phone calls (Week 16 and Week 20) and reported in the electronic case report form (e-CRF). If any interim urine 
pregnancy test performed by the patient is positive, the patient should immediately report to the investigator for appropriate follow-up and pregnancy reporting as appropriate 
m Local tolerability of SC injections will be assessed by the study nurse either at patient’s place or at the site for the inter-visit SC injection given once a week. One patient booklet to record information on injections 
administered at home will be provided to the patient at baseline and will be reviewed at each visit by Investigator 
n Step 1 of CRISS will be assessed based upon available data and individual components of Step 2 of CRISS will be captured through other efficacy procedures (eg, Change in mRSS, HAQ-DI, patient and 
physician global assessments and FVC) 
o This will be assessed using a Likert scale for CRISS calculations and will be a separate assessment from the global assessment conducted for the SHAQ using a VAS. 
p This will be assessed using a Likert scale for CRISS calculations. 
q Health care resources will include hospitalizations (reason, number of days per hospital admission, date of entry, date of discharge from hospital), number of out-patients visits by type (gastroenterologist, 
pulmonologist, occupational therapist, psychiatrist, physiotherapist, other), sick leaves (number of day off from work) and caregiver support (time spent per day to take care of the patient, number of days off from 
work to take care of the patient) 
r 
An additional IVRS call will need to be made at Week 18 for IMP dispensation. Only 6 weeks of IMP will be dispensed with the IVRS call made at Visit 6 (W12) 
s If a patient discontinues treatment before Week 24, a Premature/Early End-of-Treatment Visit (as labelled in the e-CRF) will be performed employing all assessments and procedures associated with EOT (V7). 
Irrespective of the timing of early treatment discontinuation, every effort should be undertaken to continue the patient in the study by conducting all the remaining scheduled visits on time including Week 24 
(V7), and the End-of-Study visit at Week 35 (V8). 
Abbreviations: ADA = anti-drug antibodies; ALT = Alanine transaminase; ANA = anti-nuclear antibodies; ANCA = anti-neutrophil cytoplasmic antibodies; AST = aspartate transaminase; β-HCG = beta-human 
chorionic gonadotropin; CD4 = T helper cells; CD8 = T suppressor cells; CD19 = total B cells; CPK = creatinine phosphokinase; CRISS = Composite Response Index for diffuse cutaneous Systemic Sclerosis; 
D = day; DLco = Carbon Monoxide Diffusing Lung Capacity; ECG = electrocardiogram; e-CRF = electronic case report form; EOT = end-of-treatment; EOS = end-of-study; EQ-5D-5L = European Quality of 
Life-5 Dimension-5 Level; ESR = erythrocyte sedimentation rate; FVC = forced vital capacity; FU = follow-up; HAQ-DI = Health Assessment Questionnaire Disability Index; HIV = Human Immunodeficiency Virus; 
hsCRP = high-sensitivity C-reactive protein; ICF = informed consent form; IVRS = interactive voice response system; Mrss = modified Rodnan Skin Score; PFTs = Pulmonary function tests; 
PK = pharmacokinetics; RF = rheumatoid factor; SC = subcutaneous; SHAQ = Scleroderma Health Assessment Questionnaire; UCLA SCTC GIT 2.0 = University of California at Los Angeles Scleroderma Clinical 
Trial Consortium Gastrointestinal Tract 2.0; V = Visit; VAS = visual analog scale; W = week. 
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2 
TABLE OF CONTENTS 
1 
FLOW CHARTS...............................................................................................................................8 
1.1 
GRAPHICAL STUDY DESIGN ........................................................................................................8 
1.2 
STUDY FLOW CHART ....................................................................................................................9 
2 
TABLE OF CONTENTS ................................................................................................................12 
2.1 
LIST OF TABLES...........................................................................................................................18 
2.2 
LIST OF FIGURES.........................................................................................................................18 
3 
LIST OF ABBREVIATIONS ..........................................................................................................19 
4 
INTRODUCTION AND RATIONALE.............................................................................................22 
5 
STUDY OBJECTIVES ...................................................................................................................25 
5.1 
PRIMARY.......................................................................................................................................25 
5.2 
SECONDARY ................................................................................................................................25 
5.3 
EXPLORATORY ............................................................................................................................25 
6 
STUDY DESIGN ............................................................................................................................26 
6.1 
DESCRIPTION OF THE STUDY...................................................................................................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 
INTERIM ANALYSIS......................................................................................................................26 
6.4 
STUDY COMMITTEES..................................................................................................................27 
7 
SELECTION OF PATIENTS..........................................................................................................28 
7.1 
INCLUSION CRITERIA..................................................................................................................28 
7.2 
EXCLUSION CRITERIA ................................................................................................................28 
8 
STUDY TREATMENTS .................................................................................................................31 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCTS.............................................................................31 
8.1.1 
Pharmaceutical Form.....................................................................................................................31 
8.1.2 
Dose of drug per administration.....................................................................................................31 
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8.1.3 
Method of preparation....................................................................................................................31 
8.1.4 
Route and method of administration..............................................................................................32 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) ..................................................................32 
8.3 
BLINDING PROCEDURES............................................................................................................33 
8.3.1 
Methods of blinding........................................................................................................................33 
8.3.2 
Randomization code breaking during the study.............................................................................33 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................33 
8.5 
PACKAGING AND LABELING ......................................................................................................34 
8.6 
STORAGE CONDITIONS AND SHELF LIFE................................................................................34 
8.7 
RESPONSIBILITIES ......................................................................................................................35 
8.7.1 
Treatment accountability and compliance......................................................................................35 
8.7.2 
Return and/or destruction of treatments ........................................................................................36 
8.8 
CONCOMITANT MEDICATION.....................................................................................................36 
8.8.1 
Prohibited concomitant medications ..............................................................................................36 
8.8.2 
Key Authorized Concomitant Medications .....................................................................................37 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................38 
9.1 
EFFICACY ENDPOINT..................................................................................................................38 
9.1.1 
Primary efficacy endpoint...............................................................................................................38 
9.1.2 
Secondary efficacy endpoints........................................................................................................38 
9.1.3 
Exploratory endpoints ....................................................................................................................38 
9.1.4 
Assessment methods and activity parameters ..............................................................................39 
9.1.4.1 
Modified Rodnan Skin Score .........................................................................................................39 
9.1.4.2 
Respiratory Function......................................................................................................................39 
9.1.4.3 
Gastrointestinal Manifestations......................................................................................................39 
9.1.4.4 
Renal Function...............................................................................................................................40 
9.1.4.5 
Cardiac Manifestations ..................................................................................................................40 
9.1.4.6 
Joint Pain Assessment...................................................................................................................40 
9.1.4.7 
Digital Ulcer Count .........................................................................................................................40 
9.1.4.8 
Scleroderma Health Assessment Questionnaire...........................................................................40 
9.1.4.9 
Euro-QOL-5D-5L............................................................................................................................41 
9.1.4.10 Composite response index in diffuse cutaneous systemic sclerosis.............................................41 
9.2 
SAFETY ENDPOINTS ...................................................................................................................42 
9.2.1 
Adverse events ..............................................................................................................................43 
9.2.2 
Laboratory safety variables............................................................................................................43 
9.2.2.1 
Physical examination .....................................................................................................................44 
9.2.2.2 
Vital signs.......................................................................................................................................45 
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9.2.2.3 
Electrocardiogram variables ..........................................................................................................45 
9.2.2.4 
Hypersensitivity/Allergic or anaphylactic reactions ........................................................................45 
9.2.2.5 Echocardiogram ................................................................................................................................46 
9.3 
OTHER ENDPOINTS.....................................................................................................................46 
9.3.1 
Pharmacokinetics and Immunogenicity .........................................................................................46 
9.3.1.1 
Sampling time ................................................................................................................................46 
9.3.1.2 
Pharmacokinetics and Immunogenicity handling procedure .........................................................46 
9.3.1.3 
Bioanalytical method......................................................................................................................47 
9.3.1.4 
Pharmacokinetics parameters .......................................................................................................48 
9.3.2 
Resource utilization........................................................................................................................48 
9.3.3 
Biomarkers.....................................................................................................................................48 
9.4 
FUTURE USE OF SAMPLES ........................................................................................................49 
9.5 
APPROPRIATENESS OF MEASUREMENTS ..............................................................................49 
10 
STUDY PROCEDURES ................................................................................................................50 
10.1 
VISIT SCHEDULE..........................................................................................................................50 
10.1.1 
Visit 1: Screening/Day-28 to Day-1................................................................................................50 
10.1.2 
Visit 2: Baseline visit/Randomization/Day 1...................................................................................52 
10.1.3 
Visit 3: on treatment/Week 2..........................................................................................................53 
10.1.4 
Visit 4: on treatment/Week 4..........................................................................................................53 
10.1.5 
Phone call: on treatment/Week 6, Week 16, and Week 20 ...........................................................54 
10.1.6 
Visit 5: on treatment/Week 8..........................................................................................................55 
10.1.7 
Visit 6: on treatment/Week 12........................................................................................................56 
10.1.8 
Visit 7: End-of-Treatment/Week 24 (or Early Termination)............................................................57 
10.1.9 
Phone call: Follow-up post treatment/Week 30 .............................................................................58 
10.1.10 Visit 8: End-of-study visit/Week 35 ................................................................................................59 
10.2 
DEFINITION OF SOURCE DATA..................................................................................................60 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.......................................60 
10.3.1 
Temporary treatment discontinuation with investigational medicinal products..............................60 
10.3.2 
Permanent treatment discontinuation with investigational medicinal product(s) ...........................60 
10.3.3 
List of criteria for permanent treatment discontinuation.................................................................60 
10.3.4 
Handling of patients after permanent treatment discontinuation ...................................................61 
10.3.5 
Procedure and consequence for patient withdrawal from study....................................................61 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................62 
10.4.1 
Definitions of adverse events.........................................................................................................62 
10.4.1.1 Adverse event ................................................................................................................................62 
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10.4.1.2 Serious adverse event ...................................................................................................................63 
10.4.1.3 Adverse event of special interest...................................................................................................64 
10.4.2 
Serious adverse events waived from expedited regulatory reporting to regulatory 
authorities.......................................................................................................................................65 
10.4.3 
General guidelines for reporting adverse events ...........................................................................65 
10.4.4 
Instructions for reporting serious adverse events ..........................................................................66 
10.4.5 
Guidelines for reporting adverse events of special interest...........................................................66 
10.4.6 
Guidelines for management of specific laboratory abnormalities ..................................................66 
10.5 
OBLIGATIONS OF THE SPONSOR .............................................................................................67 
10.6 
Safety instructions..........................................................................................................................68 
10.6.1 
........................................68 
10.6.2 
Tolerability at the IMP injection ......................................................................................................69 
10.6.2.1 Local injection site reactions..........................................................................................................69 
10.6.3 
Systemic allergy reaction ...............................................................................................................70 
10.6.3.1 Anaphylaxis....................................................................................................................................70 
10.6.3.2 Allergic adverse event with cutaneous involvement ......................................................................70 
10.7 
ADVERSE EVENTS MONITORING..............................................................................................71 
11 
STATISTICAL CONSIDERATIONS..............................................................................................72 
11.1 
DETERMINATION OF SAMPLE SIZE...........................................................................................72 
11.2 
DISPOSITION OF PATIENTS .......................................................................................................72 
11.3 
ANALYSIS POPULATIONS...........................................................................................................73 
11.3.1 
Efficacy populations .......................................................................................................................73 
11.3.1.1 Intent–to-treat population ...............................................................................................................73 
11.3.2 
Safety population ...........................................................................................................................73 
11.3.3 
Anti-SAR156597 antibody (ADA) population .................................................................................73 
11.3.4 
Pharmacokinetics population.........................................................................................................73 
11.4 
STATISTICAL METHODS .............................................................................................................74 
11.4.1 
Extent of study treatment exposure and compliance.....................................................................74 
11.4.1.1 Extent of investigational medicinal product exposure....................................................................74 
11.4.1.2 Compliance ....................................................................................................................................74 
11.4.2 
Analyses of efficacy endpoints.......................................................................................................74 
11.4.2.1 Analysis of primary efficacy endpoints...........................................................................................74 
11.4.2.2 Analyses of secondary efficacy endpoints.....................................................................................75 
11.4.2.3 Multiplicity considerations ..............................................................................................................76 
11.4.3 
Analyses of safety data..................................................................................................................76 
11.4.3.1 Adverse events ..............................................................................................................................77 
11.4.3.2 Laboratory data..............................................................................................................................78 
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11.4.3.3 Potential drug-induced liver injury..................................................................................................78 
11.4.3.4 Vital signs data...............................................................................................................................79 
11.4.3.5 ECG data .......................................................................................................................................79 
11.4.4 
Analysis of immunogenicity............................................................................................................79 
11.4.5 
Analyses of pharmacokinetic and pharmacodynamic variables ....................................................79 
11.4.6 
Analyses of patient reported outcomes (health-related quality of life/health economics 
variables)........................................................................................................................................80 
11.4.7 
Analyses of biomarkers..................................................................................................................80 
11.5 
INTERIM ANALYSIS......................................................................................................................80 
12 
ETHICAL AND REGULATORY CONSIDERATIONS...................................................................81 
12.1 
ETHICAL AND REGULATORY STANDARDS ..............................................................................81 
12.2 
INFORMED CONSENT .................................................................................................................81 
12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC)...................................................................................................82 
13 
STUDY MONITORING...................................................................................................................83 
13.1 
RESPONSIBILITIES OF THE INVESTIGATORS .........................................................................83 
13.2 
RESPONSIBILITIES OF THE SPONSOR.....................................................................................83 
13.3 
SOURCE DOCUMENT REQUIREMENTS....................................................................................83 
13.4 
USE AND COMPLETION OF ELECTRONIC CASE REPORT FORMS (E-CRFS) AND 
ADDITIONAL REQUEST ...............................................................................................................84 
13.5 
USE OF COMPUTERIZED SYSTEMS..........................................................................................84 
14 
ADDITIONAL REQUIREMENTS...................................................................................................85 
14.1 
CURRICULUM VITAE....................................................................................................................85 
14.2 
RECORD RETENTION IN STUDY SITES ....................................................................................85 
14.3 
CONFIDENTIALITY .......................................................................................................................85 
14.4 
PROPERTY RIGHTS.....................................................................................................................86 
14.5 
DATA PROTECTION.....................................................................................................................86 
14.6 
INSURANCE COMPENSATION....................................................................................................87 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES .................................87 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE............................................................................................................................................87 
14.8.1 
By the Sponsor...............................................................................................................................87 
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14.8.2 
By the Investigator .........................................................................................................................88 
14.9 
CLINICAL TRIAL RESULTS ..........................................................................................................88 
14.10 
PUBLICATIONS AND COMMUNICATIONS .................................................................................88 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ..........................................................................90 
16 
BIBLIOGRAPHIC REFERENCES.................................................................................................91 
17 
APPENDICES................................................................................................................................94 
APPENDIX A 
MRSS...................................................................................................................................94 
APPENDIX B 
SHAQ...................................................................................................................................95 
APPENDIX C UCLA SCTC GIT 2.0 QUESTIONNAIRE ............................................................................98 
APPENDIX D : EQ-5D-5L.........................................................................................................................102 
APPENDIX E 
PATIENT AND PHYSICIAN GLOBAL ASSESSMENTS OF OVERALL HEALTH 
USING THE 0-10 LIKERT SCALE...............................................................................................104 
APPENDIX F TJC28.................................................................................................................................105 
APPENDIX G 
GUIDANCE ON CONTRACEPTIVE METHODS FOR UNITED KINGDOM ONLY..........106 
APPENDIX H 
..........................................................................................107 
APPENDIX I 
CLINICAL CRITERIA FOR DIAGNOSING ANAPHYLAXIS ...............................................108 
APPENDIX J 
ASSESSMENT OF LOCAL INJECTION SITE REACTIONS.............................................109 
APPENDIX K 
GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES BY SANOFI....................................................................................................110 
APPENDIX L CLINICALLY SIGNIFICANT ECG......................................................................................115 
 
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2.1 
LIST OF TABLES 
Table 1 - Plasma samples handling for immunogenicity (anti-SAR156597) at screening............................46 
Table 2 - Plasma samples handling for PK (SAR156597) and immunogenicity (anti-SAR156597).............47 
Table 3 - Summary of adverse event reporting instructions..........................................................................67 
Table 4 - Power calculations for mRSS, depending on treatment effect and standard deviation, using a 
1-sided alpha of 0.05.....................................................................................................................................72 
 
2.2 
LIST OF FIGURES 
Not Applicable. 
 
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3 
LIST OF ABBREVIATIONS 
 
ACE: 
angiotensin-converting enzyme  
ACR/EULAR: 
American college of Rheumatology/European League against Rheumatism 
ADA: 
anti-drug antibodies 
AEs: 
adverse events 
AESI: 
adverse event of special interest 
ALP: 
alkaline phosphatase 
ALT: 
alanine transaminase 
ANA: 
anti-nuclear antibodies 
ANCA: 
anti-neutrophil cytoplasmic antibodies 
ANCOVA: 
analysis of covariance 
AST: 
aspartate transaminase 
AUC: 
area under curve 
BCG: 
bacillus Calmette-Guérin 
BMI: 
body mass index 
BP: 
blood pressure 
CD19: 
total B cells 
CD4: 
T helper cells 
CD8: 
T suppressor cells  
CIRs: 
clinically important responders 
Cmax: 
peak plasma concentrations 
CNS: 
central nervous system 
CPK: 
creatinine phosphokinase 
CRISS: 
composite response index for diffuse cutaneous systemic sclerosis 
CRP: 
C-reactive protein 
CV: 
curriculum vitae 
CV%: 
coefficient of variation 
dcSSc: 
diffuse cutaneous Systemic Sclerosis 
DLco: 
carbon monoxide diffusing lung capacity 
DMC: 
data monitoring committee 
DRF: 
discrepancy resolution form 
DTP: 
duties and taxes paid 
ECG: 
electrocardiogram 
e-CRF: 
electronic case report form 
ELISA: 
enzyme-linked immunosorbent assay 
EOS: 
end-of-study 
EOT: 
end-of-treatment 
EQ-5D-5L: 
European Quality of Life-5 Dimension-5 Level  
ESR: 
erythrocyte sedimentation rate 
FVC: 
forced vital capacity  
GCP: 
good clinical practice 
HAQ-DI: 
health assessment questionnaire disability index  
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HBcAb: 
hepatitis B core antibody 
HBsAb: 
hepatitis B surface antibody 
HBsAg: 
hepatitis B surface antigen 
HBV DNA: 
hepatitis B DNA 
HCV Ab: 
hepatitis C virus antibody 
HEOR: 
health economics and outcome research 
HIV: 
human immunodeficiency virus 
HLGT: 
high-level group term 
HLT: 
high level term 
HRCT: 
high resolution computer tomography 
hsCRP: 
high-sensitivity C-reactive protein 
IB: 
investigator’s brochure 
IEC: 
independent ethics committee 
Ig-G4: 
immunoglobulin-G4 
IL-13: 
interleukin-13 
IL-4: 
interleukin-4 
IL-4/IL-13 pathway: 
interlukin-4/interlukin-13 pathway 
ILD: 
interstitial lung disease 
IMPs: 
investigational medicinal products 
IPF: 
idiopathic pulmonary fibrosis 
IRB: 
institutional review board 
ITT: 
intent to treat 
IUD: 
intrauterine device 
IUS: 
intrauterine hormone-releasing system 
IVIG: 
intravenous immunoglobulin 
IVRS: 
interactive voice response system 
lcSSc: 
limited cutaneous systemic sclerosis 
LSmeans: 
least-squares means 
MAD: 
maximal administered doses 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MIC: 
minimally important change 
MMRM: 
mixed-effect model with repeated measures 
mRSS: 
modified Rodnan Skin Score 
MTD: 
maximal tolerated dose 
NK: 
natural killer 
NOAEL: 
no observed adverse effect level 
PAH: 
pulmonary arterial hypertension 
PCSA: 
potentially clinically significant abnormality 
PFTs: 
pulmonary function tests , pulmonary function tests  
PK: 
pharmacokinetics 
PNS: 
peripheral nervous system 
PROs: 
patient reported outcome 
PT: 
preferred term 
QALYs: 
quality adjusted life years 
qw: 
every week 
RF: 
rheumatoid factor 
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SAEs: 
serious adverse events 
SC: 
subcutaneous 
SD: 
standard deviation 
SEM: 
standard error of measurement 
SHAQ: 
scleroderma health assessment questionnaire  
SMQ: 
standardized MedDRA query 
SOC: 
system organ class 
SSc: 
systemic sclerosis  
SSc-ILD: 
SSc-Interstitial Lung Disease 
SUSAR: 
suspected unexpected adverse drug reaction 
t1/2z: 
terminal elimination half-life 
TBILI: 
total bilirubin 
TEAEs: 
treatment emergent adverse events 
TH2: 
T helper type 2 
TJC28: 
tender joint count 28 
UCLA SCTC GIT 2.0: 
UCLA Scleroderma Clinical Trial Consortium Gastrointestinal 
Tract 2.0 
ULN: 
upper limit of normal range 
VAS: 
visual analog scales 
WBC: 
white blood cell 
β-HCG: 
beta-human chorionic gonadotropin 
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4 
INTRODUCTION AND RATIONALE 
Systemic sclerosis (or scleroderma) is a chronic disabling condition characterized by three pivotal 
features: immune dysregulation, small vessel vasculopathy, and fibrosis. There are two major 
subgroups in the commonly accepted classification of SSc: limited cutaneous SSc (lcSSc) and 
diffuse cutaneous SSc (dcSSc) (1). In lcSSc, fibrosis is restricted to the distal upper and lower 
extremities, with possible facial involvement. While the fibrosis will tend to stabilize within the first 
several years of development, the condition may continue to evolve in the internal organs particularly 
in the lungs resulting in the development of pulmonary arterial hypertension (PAH) which is the 
leading cause of mortality associated with lcSSc in its later stages. In contrast, dcSSc is a rapidly 
progressive disorder that affects a larger area of the skin beyond the limited form with truncal 
manifestation likely. These patients will often have early internal organ involvement and more 
significant systemic symptoms such as arthralgia, tendon friction rubs and weight loss. Although 
skin fibrosis is the distinguishing hallmark, the pathological changes in the lungs, gastrointestinal 
tract, kidneys and heart ultimately determine the clinical outcome. The extent of skin involvement 
and its rate of progression, however, may reflect the severity of the visceral organ complications 
(2), outcome and survival (3). Survival in patients with dcSSc has improved over the last several 
decades; currently the average 10-year survival is estimated to be approximately 70% to 80%. 
Mortality associated with renal crisis has significantly declined during the last couple of decades 
with the use of angiotensin-converting enzyme (ACE) inhibitors while pulmonary involvement is 
the leading cause of death in these patients (4, 5, 6, 7). 
The prevalence of SSc in 2014 is estimated to be around 120 000 persons in the US and EU5 
nations combined with over 60% of the cases being of the diffuse form. The prevalence may 
increase by as much as 20% in the future using the new ACR/EULAR 2013 (8) classification 
criteria which is more sensitive than the previous ACR 1980 criteria. Overall, the disease is more 
frequent in women (3-6:1) and in certain races (eg, black). 
Currently, there is no approved therapy for SSc. The general therapeutic strategy is to address 
specific SSc manifestations (eg, Raynaud’s phenomenon, digital ulcers, gastrointestinal 
involvement, PAH) while controlling any underlying inflammatory process of the skin or internal 
organs with the use of potent immunosuppressive therapies (eg, cyclophosphamide, 
mycophenolate mofetil, azathioprine, methotrexate, rituximab). Because these immunosuppressive 
therapies do not target specific pathways related to the fibrotic process, they are not particularly 
effective and are often fraught with significant side effects. Thus, there is an unmet need to find 
effective targeted therapies with limited side effect profile for this disease population. 
T helper type 2 (TH2) cytokines, including interleukin-4 (IL-4) and interleukin-13 (IL-13), have 
prominent roles in the pathogenesis of SSc and are promising targets. The levels of TH2 cytokines 
are increased in the serum and fibrotic tissues, and they stimulate fibroblast proliferation and 
extracellular matrix synthesis in cell cultures (9). These findings are supported by studies in animal 
models, as illustrated by the attenuation of fibrosis in mice with the genetic deletion of IL-13, 
whereas targeted overexpression of IL-13 results in pulmonary fibrosis (10). Similarly, increased 
IL-4 activity has been described in the fibrotic pathway (11, 12). 
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SAR156597 is an engineered humanized bispecific immunoglobulin-G4 (Ig-G4) 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. SAR156597 has the potential to provide benefits to patients with SSc by 
targeting these pro fibrotic pathways. 
Clinical Studies 
A placebo-controlled first time in man study (TDU11325 study) has shown that single SC doses 
ranging from 10 to 300 mg were safe and well tolerated in healthy subjects. After single SC 
administration of SAR156597 at doses of 10 to 300 mg, peak concentrations of SAR156597 in 
plasma (Cmax) occurred, on average, 4 to 7 days after administration. SAR156597 exposure 
increased with dose but in a less than dose proportional manner. The overall terminal elimination 
half-life (t1/2z) was about 15 days and was independent of dose over the dose range of 10 to 
300 mg. Low titers of ADA were detected and confirmed in post-dose plasmas from 4 of 
36 subjects who received SAR156597. 
The repeated ascending dose study (TDR11326) was conducted in patients with Idiopathic 
Pulmonary Fibrosis (IPF) to evaluate the safety, tolerability, PK and pharmacodynamics of 3 dose 
levels of SAR156597 (50, 100, and 200 mg) administered SC once a week over a 6-week period 
(7 administrations) according to a double-blind, randomized, placebo-controlled, sequential 
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design. A total of 24 patients with IPF were randomized (6 in the placebo group and 18 in the 
SAR156597 groups). SAR156597 was generally safe and well tolerated. The most commonly 
reported AEs were infections with a comparable incidence across treatment groups. No significant 
emergent ADA reactivity developed as a consequence of treatment with SAR156597. Steady state 
of SAR156597 was achieved on Day 43 for all doses. The results of pharmacodynamic data 
showed that SAR156597 reduced, in an apparent dose-dependent manner from 50 to 200 mg once 
a week, the plasma level of TARC (or CCL17), a protein directly induced by IL-4 and IL-13 
receptor activation. SAR156597 is currently in Phase 2b of clinical development for the treatment 
of IPF. 
More detailed information is provided in the Investigator’s Brochure (IB). 
ACT14604 Study 
The ACT14604 study will evaluate the efficacy and safety of SAR156597 administered 
subcutaneously over a 24-week period for the treatment of patients with dcSSc. It will be a 
multinational, randomized, double-blind, placebo-controlled, 2 parallel group study conducted in 
patients diagnosed with dcSSc. 
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5 
STUDY OBJECTIVES 
5.1 
PRIMARY 
To evaluate, in comparison with placebo, the efficacy of SAR156597 administered subcutaneously 
for 24 weeks on skin fibrosis in patients with dcSSc. 
5.2 
SECONDARY 
• 
To evaluate the efficacy of SAR156597 compared to placebo on physical/functional 
disability in patients with dcSSc. 
• 
To evaluate the efficacy of SAR156597 compared to placebo on respiratory function of 
patients with dcSSc. 
• 
To evaluate the safety profile of SAR156597 compared to placebo in patients with dcSSc. 
• 
To evaluate the potential for immunogenicity (ADA response) of SAR156597 in patients 
with dcSSc. 
• 
To evaluate the PK (trough plasma concentrations) of SAR156597 administered 
subcutaneously for 24 weeks. 
5.3 
EXPLORATORY 
• 
To explore the efficacy of SAR156597 compared to placebo on other manifestations of 
SSc (gastrointestinal, joint pain, cardiovascular and renal manifestations) in patients with 
dcSSc. 
• 
To explore the effect of SAR156597 on the Quality Of Life in patients with dcSSc. 
• 
To measure the effect of SAR156597 on biomarkers of the disease activity and the 
IL-4/IL-13 pathway. 
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6 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE STUDY 
This study will be a multinational, randomized, double-blind, placebo-controlled, 2 parallel 
groups, proof of concept Phase 2 study to assess the efficacy and safety of SAR156597 200 mg 
administered subcutaneously once a week over a 24 week period to patients with diffuse SSc. 
Approximately 94 patients will be randomized in a ratio 1:1 to the following two treatment 
groups: 
• 
SAR156597 group (n = 47): Patients will receive SAR156597 administered 
subcutaneously in 200 mg doses qw 
• 
Placebo group (n = 47): Patients will receive placebo subcutaneously qw. 
Randomization will be stratified based upon the patients’ medical history of SSc-ILD (yes or no). 
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 can last up to 39 weeks as follows: 
• 
4 weeks of screening 
• 
24 weeks of study treatment 
• 
11 weeks of follow-up with no study treatment. 
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. 
6.3 
INTERIM ANALYSIS 
A futility analysis will be conducted, if needed. A two-step analysis will be performed. Please 
refer to Section 11.5. 
 
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6.4 
STUDY COMMITTEES 
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 in 
patients with SSc. 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. 
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7 
SELECTION OF PATIENTS 
7.1 
INCLUSION CRITERIA 
I 01. Systemic Sclerosis according to the ACR/EULAR 2013 criteria (8). 
I 02. Diffuse cutaneous form of SSc according to Leroy’s criteria. 
I 03. Able and willing to sign the written informed consent form with comprehension of its 
contents and comply with the requirements of the study protocol. 
7.2 
EXCLUSION CRITERIA 
E 01. Age <18 years of age. 
E 02. Disease duration of >36 months from time of first non-Raynaud’s phenomenon 
manifestation. 
E 03. mRSS <10 or >35 at screening and baseline visits. 
E 04. History of vasculitis, active or in remission. 
E 05. Diagnosis of connective tissue disease (other than SSc) or overlap syndrome 
(eg, polymyositis/SSc). 
E 06. Positive Human Immunodeficiency Virus (HIV) serology or a known history of HIV 
infection, active or in remission. 
E 07. Abnormal hepatitis B and/or hepatitis C tests indicative of active or chronic infection: 
- 
Abnormal Hepatitis B tests: Positive hepatitis B surface antigen (HBsAg) OR positive 
total hepatitis B core antibody (HBcAb) with negative hepatitis B surface antibody 
(HBsAb) OR positive total HBcAb with positive HBsAb and presence of hepatitis B 
DNA (HBV DNA). 
- 
Abnormal Hepatitis C tests: Positive anti-hepatitis C virus antibody (HCV Ab) and 
positive HCV RNA. 
E 08. Positive or 2 confirmed indeterminate Quantiferon-TB Gold tests at screening (regardless 
of prior treatment status). 
E 09. Serious infection (eg, pneumonia, pyelonephritis) within 4 weeks of screening, infection 
requiring hospitalization or intravenous antibiotics within 4 weeks of screening or chronic 
bacterial infection (eg, osteomyelitis). 
E 10. History of anaphylaxis to any biologic therapy. 
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E 11. Evidence of any clinically significant, severe or unstable, acute or chronically progressive, 
uncontrolled infection or medical condition (eg, cerebral, cardiac, pulmonary, renal, 
hepatic, gastrointestinal or neurologic other than SSc or SSc-ILD) or previous, active or 
pending surgical disorder, or any condition that may affect patient safety in the judgment 
of the investigator. 
E 12. At screening, the % predicted forced vital capacity (FVC) is ≤75% AND % predicted 
carbon monoxide diffusing lung capacity (DLCO) after hemoglobin correction is ≤40% 
E 13. History of heart failure (including acutely decompensated in the setting of preserved 
ejection fraction), Left Ventricular Ejection Fraction (LVEF) ≤ 45%, coronary artery 
disease, angina, myocardial infarction, ischemic cardiomyopathy and/or hypertrophic 
cardiomyopathy 
E 14. Any prior history of malignancy or active malignancy, including lymphoproliferative 
diseases (except successfully-treated carcinoma in-situ of the cervix, non-metastatic 
squamous cell or basal cell carcinoma of the skin) within 5 years prior to baseline. 
E 15. Ischemic ECG changes (except those NOT supported by the findings of a left heart 
catheterization performed in the last year within screening) and/or other clinically 
significant ECG findings (Appendix L) at screening.  (All abnormal ECG finding will be 
reviewed and confirmed by a local cardiologist.) 
E 16. High dose steroids (>10 mg/day prednisone equivalent); or a change in steroid dose within 
4 weeks prior to randomization (or baseline visit); or expected changes during the course 
of the study. 
E 17. Previous treatment with rituximab within 12 months prior to screening. 
E 18. Previous treatment with bone marrow transplantation, total lymphoid irradiation or ablative 
ultra-high dose cyclophosphamide. 
E 19. Treatment with high dose immunosuppressive drug (eg, cyclophosphamide 
>1 mg/kg oral/day or >750 mg IV/month; azathioprine >100 mg/day; methotrexate 
>15 mg/week; mycophenolate mofetil >2 g/day) within 3 months of screening or a change 
in dose within 4 weeks prior to randomization (or baseline visit); or expected changes in 
dose during the course of the study. 
E 20. Treatment with etanercept, cyclosporine A, intravenous immunoglobulin (IVIG), 
rapamycin, D-penicillamine, tyrosine kinase inhibitors within 4 weeks of screening or 
antithymocyte globulin within 6 months of screening. 
E 21. Treatment with infliximab, certolizumab, golimumab, abatacept, or adalimumab, 
tocilizumab within 8 weeks of screening or anakinra within 1 week of screening. 
E 22. Treatment with any investigational drug within 1 month of screening, or 5 half-lives, if 
known (whichever is longer). 
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E 23. Abnormal laboratory test(s) 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. 
Note: Laboratory parameters may be repeated once during the screening period if felt to be 
spurious or due to technical error in order to determine eligibility. 
E 24. Current history of substance and/or alcohol abuse 
E 25. Current employee of Sanofi or has an immediate family member (eg, spouse, parents, child 
or sibling) who is a current employee of Sanofi. 
E 26. Currently incarcerated or anticipated/scheduled to be incarcerated during the course of the 
study. 
E 27. Any condition or circumstance that will preclude the patient from following and 
completing protocol requirements, in the opinion of the Investigator. 
E 28. Pregnant or breastfeeding woman 
E 29. Women who are of childbearing potential not protected by highly-effective contraceptive 
method(s) of birth control (defined in the informed consent form and/or Appendix G for 
United Kingdom), and/or who are unwilling or unable to be tested for pregnancy. 
Note: Women of childbearing potential must have a confirmed negative pregnancy test at 
screening and randomization visits. They must use an effective contraceptive method 
throughout the entire duration of the study treatment, and for at least 12 weeks after the last 
administration of IMP. Postmenopausal women must be amenorrheic for at least 
12 months. 
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8 
STUDY TREATMENTS 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCTS 
A complete description of the IMP and its proper handling will be provided in a pharmacy 
manual. 
8.1.1 Pharmaceutical Form 
• 
SAR156597 solution for injection at 100 mg/mL: SAR156597 is supplied as a sterile 
freeze-dried powder for solution for injection, in a glass vial. Each vial is filled 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 sterile water for injection, 
leading to an amount of 125 mg of SAR156597 drug substance in a total volume of 
1.25 mL equating to a concentration of 100 mg/mL of SAR156597 solution. One (1) mL 
of this 100 mg/mL SAR156597 solution can then be withdrawn for dose administration. 
Two (2) drug product vials are thus needed to reach a 200 mg dose and to prepare a 2 mL 
SAR156597 solution syringe. 
• 
Placebo in lyophilized form: each vial containing excipients, is to be reconstituted with 
1.1 mL of sterile water resulting in a total volume of 1.25 mL. Two (2) placebo product 
vials are required with 1 mL to be taken from each vial to prepare a 2 mL placebo solution 
syringe. 
8.1.2 Dose of drug per administration 
• 
SAR156597 group: 1 injection of SAR156597 200 mg administered subcutaneously qw. 
• 
Placebo group: 1 injection of placebo administered subcutaneously qw. 
8.1.3 Method of preparation 
The SAR156597 and the placebo must be reconstituted prior to injection. The description of the 
reconstitution from lyophilizate vials will be provided in a pharmacy manual. 
Once reconstituted, the placebo and the active vials are subtlety distinguishable. Thus, in order to 
maintain blinding at the study site, the reconstitution of the IMP and the preparation of the syringe 
must be done by an unmasked personnel (eg, pharmacist) other than those administering the drug 
and making clinical observations (Refer to Section 8.3). 
At the patient’s home, reconstitution must be prepared and administered by healthcare 
professionals (eg, visiting nurse). 
The IMP should be reconstituted the day of dosing (no more than 3 hours prior to SC injection), at 
room temperature. 
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8.1.4 Route and method of administration  
The route and method of administration are SC in the abdomen. SC 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. The exact site of each injection will be 
documented on the source document. It is recommended that the injection occur at a site free of 
SSc involvement, if possible. 
The IMP is administered every 7 days ±2 days from initial IMP administration. This window is 
permitted per protocol to accommodate various circumstances (eg, pending laboratory results, 
management of AE, visit scheduling difficulty). The IMP administration should be performed by 
other site personnel, blinded from the person in charge of the preparation of the solutions and 
syringes. 
If IMP administration is missed or temporarily discontinued, the initial schedule of injections may 
be resumed upon the investigator’s medical judgment and discretion while the missed dose(s) will 
not be administered. 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 (eg, visiting nurse service). 
Patients should be monitored by site personnel/visiting nurse for at least 30 minutes or up to 
2 hours as per country specific requirements after each administration for potential signs and 
symptoms that may suggest a hypersensitivity reaction. 
For doses not given at the 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. 
Between the protocol-scheduled on-site visits, interim visits to the site may be required for IMP 
dispensing. As an alternative to these 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. 
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 list of treatment kit numbers will be generated by 
Sanofi. A patient randomization list will be generated by the interactive voice response system 
(IVRS). Both the randomization and treatment kit lists will be loaded into IVRS. 
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 
code except under circumstances described in Section 8.3.2. 
Before the reconstitution, the lyophilized SAR156597 and lyophilized placebo are similar. Once 
reconstituted, the active solution differs subtly in its appearance from the placebo solution. In 
order to maintain blinding conditions, the personnel involved with dose and syringe preparation 
will be required not to reveal to other study personnel the type or characteristics of IMP solution 
(SAR156597 versus placebo) in the vials and syringes. 
Please refer to Section 10.4 for unblinding by the Sponsor related to suspected unexpected serious 
adverse drug reaction. 
8.3.2 Randomization code breaking during the study 
In case of an AE, the code should only be broken in circumstances when knowledge of the IMP is 
required for treating the patient.  
Code breaking can be performed at any time by using the proper module of the IVRS 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 the day, and reason for code breaking.  
If the blind is broken by the Investigator, the patient must withdraw from IMP administration. 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP 
Patient will be randomized following a 1:1 ratio to one of the two treatment groups via a 
centralized randomization system using IVRS. 
Randomization will be stratified based upon the patients’ medical history of SSc-ILD (yes or no). 
A randomized treatment kit number list will be generated centrally by Sanofi. The IMP 
(SAR156597 or placebo) will be packaged in accordance with this list. 
At Visit 1 (screening), the study staff will contact the IVRS to obtain a patient number for each 
patient who signs the informed consent. Each patient will be allocated a patient number associated 
with the center and allocated in chronological order in each site. 
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At Visit 2 (baseline), after confirming that the patient is eligible for entry into the treatment 
period, the site coordinator will contact IVRS in order to receive the first treatment allocation kit 
numbers. Patients will be randomized to 1 of the 2 treatment groups at the ratio of 1:1. At 
subsequent visits during the treatment period, the site coordinator will call IVRS to obtain the next 
treatment kit numbers. A confirmation fax/e-mail will be sent to the site after each assignment. 
A patient cannot be randomized more than once in the clinical trial.  
Patients who meet exclusion criteria may be rescreened once during the open screening period of 
study; a different patient number will be assigned by IVRS. 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-screen date. The IVRS report will flag re-screened patients. Patients 
who are re-screened must sign a new informed consent and all Visit 1 procedures must be 
repeated.  
One (1) treatment kit is sufficient for 1 week of treatment. As the treatment duration is 24 weeks, 
a patient will be allocated by IVRS to several treatment kit numbers corresponding to the same 
treatment group 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 in a 1 week treatment kit containing 2 vials per kit. 
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 IMPs should be stored between 2°C and 8°C (36°F and 46°F), and should be kept upright. The 
Investigators or other authorized persons (eg, 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 (eg, 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 are dispensed to the 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, if home injections are permitted under local laws and regulations. As an alternative to 
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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. 
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 IMPs 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 reported 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 the IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party (except for duties and 
taxes paid [DTP] shipment, for which a courier company has been approved by the Sponsor), 
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 
The patient will be injected the study drug subcutaneously once a week during the treatment 
period. The patient will be injected the study drug at the trial site on the scheduled visits, and at 
weekly intervals in between scheduled visits. A home visiting nurse will administer the study drug 
at the patient’s place during the inter-visit period, should the patient choose this option and if 
permitted by local laws and regulations.  
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 or it is the End of Treatment visit. In 
case of Direct-To-Patient process, the treatment units can be returned by the carrier (if 
defined in the contract). 
• 
The site 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. 
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• 
The 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, or unused IMP will be destroyed on site according to the 
standard practices of the site after reconciliation and verification by the monitor. 
A detailed treatment log of the destroyed IMP will be established with the Investigator (or the 
pharmacist) and countersigned by the Investigator and the monitoring team. 
The Investigator will not destroy any IMP 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 MEDICATION 
A concomitant medication is any treatment received by the patient concomitantly to any IMP(s). 
8.8.1 Prohibited concomitant medications 
• 
High dose immunosuppressive drugs will be prohibited 
(eg, cyclophosphamide >1 mg/kg oral/day or >750 mg IV/month; 
azathioprine >100 mg/day; methotrexate >15 mg/week, mycophenolate mofetil >2 g/day) 
within 3 months prior to screening and during the course of the trial, a change in dose 
within 4 weeks prior to randomization (or baseline visit) or expected changes in dose 
during the course of the study will be prohibited. 
• 
High dose steroids (>10 mg/day prednisone equivalent); or a change in steroid dose within 
4 weeks prior to randomization (or baseline visit) or expected changes in dose during the 
course of the study will be prohibited. 
• 
Treatment with etanercept, cyclosporine A, IVIG, rapamycin, D-penicillamine, tyrosine 
kinase inhibitors within 4 weeks of screening, antithymocyte globulin within 6 months of 
screening and during the course of the study will be prohibited. 
• 
Treatment with infliximab, certolizumab, golimumab, abatacept, or adalimumab, 
tocilizumab within 8 weeks of screening, anakinra with 1 week of screening and during 
the course of the study will be prohibited. 
• 
Treatment with rituximab within 12 months prior to screening and during the course of the 
study will be prohibited. 
• 
Treatment with any investigational drug for SSc during the course of the study will be 
prohibited. 
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8.8.2 Key Authorized Concomitant Medications 
• 
Oral corticosteroids are permitted if dose ≤10 mg/day of oral prednisone or equivalent and 
at a stable dose for at least 4 weeks prior to the randomization (or baseline visit). No 
change in dose is permitted during the study unless for the management of an AE. Dose 
and any change will be recorded on the patient e-CRF. Oral corticosteroids cannot be 
started during the course of the study. 
• 
Low dose immunosuppressive drugs (cyclophosphamide ≤1 mg/kg oral/day or 
≤750 mg IV/month; azathioprine ≤100 mg/day; methotrexate ≤15 mg/week, 
mycophenolate mofetil ≤2 g/day) are permitted if at stable dose for at least 4 weeks prior 
to randomization (or baseline visit). No change in dose is permitted unless for the 
management of an AE. Dose and any change will be recorded on the patient e-CRF. Low 
dose immunosuppressive drugs cannot be started during the course of the study. 
• 
Calcium channel blockers, alpha blockers, prostaglandins, endothelin receptor antagonists, 
phosphodiesterase inhibitors, angiotensin receptor blockers, nitrate therapy, other 
vasodilators, and anti-platelets/anticoagulants for the treatment of Raynaud’s phenomenon 
and/or digital ulcers are permitted during the course of the study. 
• 
Vasodilators, endothelin receptor antagonists, phosphodiesterase inhibitors, calcium 
channel blockers, soluble guanylate cyclase stimulators (eg, riociguat) and anticoagulants 
for the treatment of controlled PAH are permitted during the course of the study. 
• 
Angiotensin-converting enzyme inhibitors for prevention of scleroderma renal crisis are 
permitted during the course of the study. 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 
9.1 
EFFICACY ENDPOINT 
9.1.1 Primary efficacy endpoint 
The primary efficacy endpoint will evaluate the efficacy of SAR156597 on skin fibrosis of 
patients with dcSSc by assessing: 
• 
Change in mRSS from baseline to Week 24. 
9.1.2 Secondary efficacy endpoints 
Two secondary endpoints will evaluate the efficacy of SAR156597 on other aspects of dcSSc: 
• 
Change in HAQ-DI, assessed with SHAQ, from baseline to Week 24. 
• 
Change in respiratory function as measured by observed FVC and observed DLco 
(corrected for hemoglobin) from baseline to Week 24. 
9.1.3 Exploratory endpoints 
• 
Proportion of patients with improvement in mRSS of at least 20%, 40% and 60% from 
baseline to Week 24. 
• 
Change in VAS for pain, breathing function, vascular function (Raynaud's phenomenon), 
gastrointestinal function, digital ulcers, and global assessment from SHAQ from baseline 
to Week 24. 
• 
Change in respiratory function as measured by % predicted FVC and % predicted DLco 
(corrected for hemoglobin) from baseline to Week 24. 
• 
Change in UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract 2.0 
(UCLA SCTC GIT 2.0) score from baseline to Week 24. 
• 
Change in TJC28 from baseline to Week 24. 
• 
Change in digital ulcer count from baseline to Week 24. 
• 
CRISS from baseline to Week 24. 
• 
Change in EQ-5D-5L index from baseline to Week 24. 
• 
Change in efficacy endpoints (mRSS, HAQ-DI, VAS from SHAQ, observed FVC, % 
predicted FVC, observed DLco [corrected for hemoglobin], % predicted DLco [corrected 
for hemoglobin], UCLA SCTC GIT 2.0, TJC28, digital ulcer count, CRISS, and 
EQ-5D-5L) from baseline to Week 35 (up to end of follow-up period) and proportion of 
patients with improvement in mRSS of at least 20%, 40% and 60% from baseline to 
Week 35. 
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• 
Proportion of patients with improvement in SHAQ (HAQ-DI and VAS) and EQ-5D-5L 
(index value and VAS) based upon MIC at Week 24. 
9.1.4 Assessment methods and activity parameters 
9.1.4.1 Modified Rodnan Skin Score  
The fibrosis of the skin will be assessed using the mRSS which is conducted by palpation of the 
skin in 17 areas of the body (fingers, hands, forearms, arms, feet, legs and thighs, face, chest and 
abdomen) using a 0–3 scale, where 0 = normal, 1 = mild thickness, 2 = moderate thickness and 
3 = severe thickness. Total skin score can range from 0 (no thickening) to 51 (severe thickening in 
all 17 areas). Only those physicians or qualified medical personnel who have undergone a 
standardized training will be permitted to evaluate the skin thickening. Every effort will be 
undertaken for the same medical personnel to evaluate a given patient from baseline to EOS 
participation in order to minimize any inter-rater variability. In the unlikely event of the 
evaluation being carried out by different personnel, the reason will be documented. The baseline 
and Week 24/Visit 7 mRSS assessment must be conducted by the same medical personnel. 
9.1.4.2 Respiratory Function 
The pulmonary function test is a secondary endpoint that will assess the change in respiratory 
function as measured by observed FVC and observed DLco (corrected for hemoglobin) from 
baseline to Week 24. The absolute change in observed and % predicted change in FVC and DLco 
from baseline to Week 24 and/or Week 35 will also be assessed as exploratory endpoints. The 
manual correction of DLco for hemoglobin will be based upon the following equation unless it is 
automatically corrected during measurement: 
1. For male patients: DLcoobserved/(factor), where factor is = (1.7 x Hb)/(10.22 + Hb) 
2. For female patients: DLcoobserved/(factor), where factor is = (1.7 x Hb)/(9.38 + Hb) 
Note: Hb = Hemoglobin. The value of hemoglobin will be taken from the same visit where 
the DLco is conducted. 
The spirometry should be performed in compliance with the 2005 ATS/ERS guideline (13) while 
the DLco should be performed in compliance with standard guidance (14). 
9.1.4.3 Gastrointestinal Manifestations  
The UCLA SCTC GIT 2.0 instrument is a validated self-reported questionnaire used to assess 
QOL related to gastrointestinal function in patients with SSc (15). It employs a 7-multi-item scale 
with areas of reflux, distention/bloating, diarrhea, fecal soilage, constipation, emotional 
well-being, and social functioning. This will be captured at all visits except V1 and V3. 
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9.1.4.4 Renal Function 
Renal function will be assessed through the measurement of blood urea nitrogen, creatinine and 
urinalysis (dipstick) at all visits except V3. The urinalysis (dipstick) will capture specific gravity, 
pH, glucose, ketones, blood, protein, nitrate, leukocyte esterase, urobilinogen and bilirubin. If any 
parameter on the dipstick is abnormal, a urine sample will be sent to the central laboratory for 
testing. If the dipstick is positive for protein and/or red blood cells, microscopic analysis will be 
performed by the central laboratory.  
9.1.4.5 Cardiac Manifestations 
Systemic sclerosis associated cardiac manifestations will be assessed by physical examination and 
ECG which is an established method of monitoring for cardiac conduction and potential coronary 
and myocardial diseases. Electrocardiogram will be captured at all scheduled visits except Visit 3. 
Cardiovascular events will be reported as AEs. 
9.1.4.6 Joint Pain Assessment 
The TJC28 is an assessment of the overall joint pain based upon the examination of 28 key joints. 
It is a reliable and validated method of assessing general joint pain and will be captured at all 
visits except V1 and V3. The 28 joints that are part of the assessments include: shoulders (2), 
elbows (2), wrists (2), metacarpophalangeals (10), proximal interphalangeals (10), and knees (2). 
9.1.4.7 Digital Ulcer Count 
The digital ulcer count captures the number of active open sores (or digital ulcers) on fingertips 
secondary to SSc (and not secondary to localized trauma or injury). Cracks, fissures or even skin 
breakdown related to calcinosis should not be included. The digital ulcer count will be conducted 
at all visits except V1 and V3. 
9.1.4.8 Scleroderma Health Assessment Questionnaire 
The SHAQ, which includes the standard HAQ-DI to measure the functional disability and 
5 SSc-specific VAS assessments will be completed by patients at baseline and throughout the 
study, except V1 and V3 (16). The SHAQ is the standard, validated, and accepted health 
assessment questionnaire in patients with SSc to assess the physical/functional disability related to 
skin and systemic fibrosis. 
The HAQ DI contains 8 domains of activity (dressing, arising, eating, walking, hygiene, reach, 
grip, and common daily activities) each of which has at least 2 questions, for a total of 20 items. 
For each item, patients report the amount of difficulty experienced performing the activity. There 
are 4 possible responses for each item ranging from 0 (without any difficulty) to 3 (unable to do). 
For each of the 8 domains included in the HAQ-DI, the score is the single response within the 
domain with the highest score. If aids or devices are used, and if the highest score is 0 or 1, then 
the score is raised to 2; if the highest score is 2 or 3, the score is kept as it is. The HAQ-DI 
composite score is then calculated as the average of the scores of the 8 domains. If 1 or 2 of the 
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domains are missing, the HAQ-DI composite score is obtained by dividing the sum of the 
domains by the number of answered domains. If three or more of the domains are missing, then 
the HAQ-DI composite score is missing. The composite score is reported, falling between 0 and 3 
on an ordinal scale. The scores are interpreted as 0 (no impairment in function) to 3 (maximal 
impairment of function). 
The HAQ-DI also contains a VAS that patients use to report the amount of pain experienced in 
the past week. The VAS is a 10-cm line that is converted to a continuous scale from 0 to 3 where 
1 cm is equivalent to 0.3 points. The anchors of the VAS are 0 (no pain) to 100 (very severe pain). 
To obtain the patient score, a metric ruler is used to measure the distance in centimeters from the 
left anchor to the patient’s mark, and then multiplied by 0.3. The VAS pain score is not 
incorporated into the HAQ DI composite score.  
For the other 5 VAS, the patients will rate breathing, vascular (Raynaud’s phenomenon), 
gastrointestinal function, digital ulcers, and global assessment. They will be asked to make a mark 
on a 10 cm line to indicate the severity from 0-100 where 0 indicates no severity and 100 indicates 
the worst severity. 
9.1.4.9 Euro-QOL-5D-5L 
The EQ-5D-5L questionnaire is a standardized measure of health status developed by the EuroQol 
Group in order to provide a simple, generic measure of health for clinical and economic appraisal. 
The EQ-5D-5L is designed for self-completion by patients. 
The EQ-5D comprises 2 discrete scales: the EQ-5D descriptive system and the EQ VAS. The 
EQ-5D descriptive system has 5 items, each measuring one dimension of health: mobility, 
self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension/item has a 
5 level Likert-type response scale: no problems, slight problems, moderate problems, severe 
problems, and extreme problems. Responses for the 5 dimensions can be combined in a single 
5-digit number describing the respondent’s health profile and can be converted into a single index 
value for the calculation of quality-adjusted life years (QALYs) to inform economic evaluations 
of health care interventions. The EQ VAS provides a quantitative measure of health as judged by 
the individual respondents on a vertical visual analogue scale. The EQ VAS ‘thermometer’ has 
endpoints of 100 (“The best health you can imagine”) at the top and 0 (“The worst health you can 
imagine”) at the bottom. 
In the analysis the index value will be considered as a continuous variable. 
9.1.4.10 Composite response index in diffuse cutaneous systemic sclerosis 
The CRISS tool summarizes the changes in the clinical and patient-reported outcomes using a 
single composite score that reflects the probability that the patient with dcSSc has improved (17). 
For an effective therapeutic agent of dcSSc, CRISS will be able to summarize the higher 
probability of improvement in a subject treated with the IMP versus an ineffective agent (or 
placebo). 
CRISS is a 2-step process as described below. 
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Step 1: Patients who develop new or worsening of cardiopulmonary and/or renal involvement due 
to SSc are considered as not improved (irrespective of improvement in other core items) and 
assigned a probability of improving equal to 0.0. Specifically if a subject develops any of the 
following: 
• 
New scleroderma renal crisis 
• 
Decline in FVC % predicted ≥15% (relative), confirmed by another FVC% within a 
month, high resolution computer tomography (HRCT) to confirm ILD (if previous HRCT 
of chest did not show ILD) and FVC % predicted below 80% predicted*  
• 
New onset of left ventricular failure (defined as left ventricular ejection fraction ≤45%) 
requiring treatment*  
• 
New onset of PAH on right heart catheterization requiring treatment*. PAH is defined as 
mean pulmonary artery pressure ≥25 mm Hg at rest and an end-expiratory pulmonary 
artery wedge pressure ≤15 mm Hg and a pulmonary vascular resistance >3 Wood units. 
* Attributable to SSc 
Step 2: For the remaining patients, Step 2 involves computing the predicted probability of 
improving for each subject using the following equation (equation to derive predicted 
probabilities from a logistic regression model): 
 
 
∆mRSS indicates the change in mRSS from baseline, ∆FVC denotes the change in FVC% predicted from 
baseline, ∆Pt-glob indicates the change in patient global assessment, ∆MD-glob denotes the change in 
physician global assessment, and ∆HAQ-DI is the change in HAQ-DI. All changes are absolute change 
(Time2–Timebaseline). 
Patient and physician global assessments of overall health will be used in the Step 2 calculation of 
CRISS. These two assessments are based upon a Likert scale ranging from 0 (Excellent) to 10 
(Extremely Poor) (see Appendix E) (17). 
9.2 
SAFETY ENDPOINTS 
The same safety assessments will be applied across all phases of the study and across both 
treatment groups. Adverse events, including serious adverse events (SAEs), and adverse events of 
special interest (AESI), will be collected at every visit. The Investigator will ask the patient how 
he/she has felt since the last study visit. The study specific and general safety criteria 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 6.4. 
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9.2.1 Adverse events 
Refer to Section 10.4 to Section 10.7 for details. 
9.2.2 Laboratory safety variables 
The clinical laboratory data consist of blood analysis (including but not limited to hematology, 
clinical chemistry) and urinalysis. Clinical laboratory values will be analyzed after conversion 
into standard international units. International units will be used in all listings and tables. 
The clinical laboratory tests will be conducted by an accredited (college of American Pathologists 
or equivalent) central laboratory with national and regional clinical licenses as required for 
diagnostic testing and must provide evidence of participation in proficiency testing, as 
appropriate. After reviewing the laboratory report and evaluating any results that are outside the 
normal range, the Investigator must sign and date the laboratory report. Laboratory parameters 
with abnormal values that are considered to be clinically significant by the Investigator must be 
retested as soon as possible after receiving the laboratory report to rule out laboratory error. 
Persistent abnormal laboratory values should be retested until they return to normal, to baseline 
values, or to values no longer considered as clinically significant by the Investigator. If 
abnormalities are part of a determined disease/etiology, they should be monitored as per standard 
of care for the corresponding etiology/disease. 
Samples will be taken at the study site before administration of the IMP. The following 
parameters will be measured as per study flowchart (Section 1.2) and description of study 
procedures in Section 10. 
• 
Hematology 
- 
Hemoglobin, hematocrit, red blood cell count, erythrocyte sedimentation rate (ESR), 
WBC count with differential and platelet count. 
• 
Biochemistry 
- 
Fasting glucose, blood urea nitrogen, creatinine, sodium, potassium, chloride, 
bicarbonate, calcium, phosphorous, total protein, albumin, TBILI, alkaline phosphatase 
(ALP), ALT, AST, creatinine phosphokinase (CPK), high-sensitivity C-reactive 
protein (hsCRP). (Fasting is defined as a period of at least 8 hours since the last 
consumption of any food or liquid. Minor water intake is permitted during this fasting 
period).  
• 
Urinalysis 
- 
Specific gravity, pH, glucose, ketones, blood, protein, nitrate, leukocyte esterase, 
urobilinogen and bilirubin (by dipstick). If any parameter on the dipstick is abnormal, 
a urine sample should be sent to the central laboratory for testing. If positive for 
protein and/or red blood cells, microscopic analysis will be performed by the central 
laboratory to assess for cellular casts. 
 
 
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• 
Pregnancy Testing 
- 
For women of childbearing potential, a serum pregnancy test (β-human chorionic 
gonadotrophin) and urine pregnancy tests will be performed as per study flow chart in 
Section 1.2. From Visit 6, the site will dispense urine pregnancy kits to the patients 
who will perform the test at home on a monthly basis. If any interim urine pregnancy 
test performed by the patient is positive, the patient should immediately report to the 
investigator for appropriate follow-up and pregnancy reporting as appropriate. 
• 
Serology and TB Testing  
- 
Clinical laboratory testing performed at Visit 1 will also include: hepatitis screen 
(HBsAg, HBsAb, HBcAb, HBV DNA [reflex testing if HBcAb is positive], hepatitis C 
antibody, hepatitis C RNA [reflex testing if hepatitis C antibody is positive]), 
HIV-1/HIV-2 antibody, and tuberculosis screen (Quantiferon®-TB gold evaluation), in 
addition to other testing as per the study flow chart (Section 1.2). 
Decision trees for the management of some laboratory abnormalities are provided in Appendix K. 
9.2.2.1 Physical examination 
A complete physical examination will be performed at each site-visit as per study flow chart 
(Section 1.2) and description of study procedures in Section 10. Gynecological and urogenital 
examinations will not be done in this study unless for cause. 
Specific attention will be paid to the skin, nasal cavities, eyes, ears, respiratory, cardiovascular, 
gastrointestinal, neurological, lymphatic, and musculoskeletal systems. For the dermatological 
examination, it is recommended that the patient only wears undergarments. 
 
 
 
 
 
 
Clinically significant abnormalities should be reported in the patient’s e-CRF as medical history, 
if observed at the screening visit (Visit 1) or as an AE if observed during subsequent visits. 
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9.2.2.2 Vital signs 
Vital signs include blood pressure (BP) (mmHg), heart rate (beats per minute), body weight (kg) 
and height (cm).  
Blood pressure will be measured at each study site visit in the sitting position. Both systolic and 
diastolic BP should be recorded. BP should be checked after 5 minutes of resting in the sitting 
position.  
Weight should be taken with the patient wearing undergarments (or very light clothing), no shoes, 
and with an empty bladder. The same scale should be used throughout the study.  
Height will be measured at screening (Visit 1) only.  
Body mass index (BMI) will be calculated automatically at each visit. 
9.2.2.3 Electrocardiogram variables 
A standard 12-lead ECG will be performed at all the on-site visits (except Visit 3) as per the study 
flow chart (Section 1.2) and description of study procedures in Section 10. Electrocardiogram 
parameters will be based upon the automatic reading of the device. If the device does not provide 
automatic reading, then the ECG parameters will need to be determined and interpreted by the 
Investigator.  
At Visit 1, all abnormal ECG interpretation will need to be confirmed by a local cardiologist.  All 
findings of ischemic ECG changes will result in exclusion unless there is a left heart 
catheterization performed in the last year within screening that is not supportive of the current 
ECG finding.  All other clinically significant ECG findings per guidance provided in Appendix L 
will result in exclusion.     
At the post randomization visits, ECGs will be performed prior to IMP 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 U-wave morphology. 
9.2.2.4 Hypersensitivity/Allergic or anaphylactic reactions 
Assessment, categorization and treatment of systemic allergic reactions including anaphylactic 
reactions (18) will be specifically performed as detailed in Section 10.6.3.1 and Appendix I as 
appropriate. 
Local injection site reactions will be assessed to determine if it is of an allergic origin as described 
in Section 10.6.2 and Section 10.6.3.2 (see also Appendix I and Appendix J). 
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9.2.2.5 Echocardiogram 
A standard 2-Dimensional transthoracic echocardiogram will be obtained at Visit 1 (unless one 
had been previously obtained within 6 months of Visit 1) to help determine patient’s eligibility 
with regards to Exclusion criterion 13 [E 13].   
 
At a minimum, the echocardiogram should be able to assess for the left ventricular ejection 
fraction (LVEF) and the status and function of the four cardiac chambers, myocardium and 
valves. 
9.3 
OTHER ENDPOINTS 
9.3.1 Pharmacokinetics and Immunogenicity 
9.3.1.1 Sampling time 
Samples for PK analysis will be collected pre dose (within 2 hours before each dose 
administration) during Visits 2, 4, 5, 6 and 7.  
Pharmacokinetics samples during Visit 8 will be collected in the morning.  
Anti-SAR156597 antibodies (ADA) samples will be collected at approximately the same times as 
the PK samples. An additional ADA sample will be collected at Visit 1. 
9.3.1.2 Pharmacokinetics and Immunogenicity handling procedure 
Detailed procedures of sample preparation, storage and shipment are described in the specific 
laboratory manual. A total of five (5) mL blood volume is to be collected at screening for ADA 
samples (Table 1). A total of five (5) mL blood volume is to be collected at each subsequent visit 
for the PK (3 mL) and ADA (2 mL) samples combined (Table 2). 
Table 1 - Plasma samples handling for immunogenicity (anti-SAR156597) at screening 
Sample type 
anti-SAR156597 
Matrix 
 Plasma 
Blood sample volume 
5mL (4 aliquots) 
Anticoagulant 
CPD (Citrate Phosphate Dextrose) 
Storage conditions 
≤-20°C 
 
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Table 2 - 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 (2 aliquots) 
Anticoagulant 
CPD (Citrate Phosphate Dextrose) 
Storage conditions 
≤-20°C 
Abbreviation: PK =  pharmacokinetics 
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 enzyme-linked immunosorbent assay (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 0.05 µg/mL. 
9.3.1.3.2 Anti-drug antibodies 
All ADA samples will be analyzed by the Bioanalysis and Biomarkers domain in DSAR OC 
Montpellier (France). 
For the analysis of potential ADAs 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 ADAs 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. 
Placebo samples will only be analyzed at baseline, and will continue to be followed if the baseline 
time point results positive for ADA. 
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In the interim, the Sponsor will store frozen specific aliquots for neutralizing activity testing if 
necessary. 
9.3.1.3.3 Half-arm exchange molecule assessment 
If necessary, half-arm exchange of SAR156597 with endogenous hIgG4 may be assessed on 
specific PK sample aliquots. 
9.3.1.4 Pharmacokinetics parameters 
SAR156597 concentrations at selected time points 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. 
9.3.2 Resource utilization 
To assess the economic benefit of SAR156597, health care resources will be collected 
retrospectively at baseline, Week 12, Week 24 and Week 35. These resources will include the 
following information: 
• 
Hospitalizations (reason, number of days per ward, date of entry, date of discharge from 
hospital) 
• 
Number of out-patients visits by type (gastroenterologist, pulmonologist, occupational 
therapist, psychiatrist, physiotherapist, other) 
• 
Sick leaves (number of day off from work) 
• 
Caregiver support (time spent per day to care of the patient, number of days off from work 
to take care of the patient). 
9.3.3 Biomarkers 
Blood samples will be collected for protein biomarker analyses. There will be measurement of 
protein biomarkers associated with the activity of the disease (COMP, CCL2) and the IL-4/IL-13 
pathway (TARC, periostin, and eotaxin-3). 
Additionally, archived blood samples may be used for future assays of protein and mRNA 
biomarkers related to the disease and the response to therapy. Participation is voluntary and will 
require the signing of a separate Future Use of Samples informed consent form. (Refer to 
Section 9.4) 
Of note, safety biomarkers, if any, will be analyzed as necessary. 
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9.4 
FUTURE USE OF SAMPLES 
This is a voluntary procedure which requires the patient to sign a separate informed consent 
document should he/she agree to participate. If agreed to participate, the patient will have blood 
samples collected at Visit 2, Visit 6 and Visit 8. The archived samples may be used to potentially 
assess for protein and mRNA biomarkers in the future. Additionally,  
• 
Stored samples may also be used to explore safety concerns that may have arisen during or 
after study completion 
• 
Stored samples may also be used for other research purposes (excluding genetic analysis) 
related to SSc than those defined in the present protocol. These other research purposes 
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 used during the study (ie, 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  
The primary endpoint will be the change in mRSS from baseline to Week 24. The mRSS is a 
widely used endpoint in SSc clinical trials as it is the only validated measure of cutaneous 
involvement in patients with SSc and it correlates with patient function and mortality. Because of 
the challenges related to inter-rater variability, it is imperative that all raters are to be trained and 
certified and one rater is to be used to assess the same patient throughout the course of the study. 
The secondary endpoints will assess the change from baseline to Week 24 in HAQ-DI and in 
respiratory function as measured by observed FVC and observed DLco (corrected for 
hemoglobin). Both the FVC and DLco are widely used measures of pulmonary function 
particularly related to the disease status of an underlying interstitial lung disease (ILD). Lastly, 
because it is a multisystem disease, SSc can significantly impact a patient’s function and quality 
of life. Thus, patient reported outcomes (PROs) such as HAQ-DI (assessed with the SHAQ) 
which is both reliable and validated are vital information to be captured in this study (19). 
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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 randomization date), 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 
informed consent form (including voluntary participation in 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 who fail screening for 
certain exclusion criteria (eg, 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). 
In general, PRO assessments should be completed at the study site as part of the visit (per study 
flow chart) but prior to any meaningful communication with a health care professional or any 
other study procedures, unless noted otherwise in the suggested order of the study procedures for 
each individual visit described below. 
10.1.1 Visit 1: Screening/Day-28 to Day-1 
Following a discussion of participation in the clinical trial, informed consent must be obtained and 
documented which must precede any study procedures. 
The following procedures will then be performed: 
• 
Call IVRS to assign a patient number 
• 
Commence AE reporting 
• 
Record patient demographic information 
• 
IVRS Interview to collect: 
- 
SSc history 
- 
SSc characteristics and manifestations (including SSc-ILD to be used for 
stratification should the patient be enrolled) 
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- 
Disease duration from the time of the first non-Raynaud’s phenomenon 
manifestation 
- 
Treatment history including current therapies 
- 
other medical/surgical history 
• 
Record vital signs including BP, heart rate, weight (kg) and height (cm) (collected for BMI 
calculation) 
• 
Perform a complete physical examination (Refer to Section 9.2.2.1), including:  
- 
Assess the mRSS 
• 
Assess eligibility by review of Inclusion/Exclusion Criteria. This includes the review of 
prior and concomitant medications, SSc history and physical examination findings. 
Patients who fail to meet the eligibility criteria based on this preliminary review should not 
continue the screening process (eg, ECG or blood work) and a screen failure call should be 
done in the IVRS 
• 
Perform 12-lead ECG (All abnormal ECG interpretations will need to be reviewed and 
confirmed by a local cardiologist) 
• 
Perform Pulmonary function tests (PFTs): observed and % predicted FVC and observed 
and % predicted Carbon Monoxide DLco (corrected for hemoglobin) 
• 
Perform echocardiogram unless one had been previously obtained within 6 months of 
Visit 1 (screening visit). 
• 
Obtain blood samples for screening laboratory determinations: hematology, biochemistry, 
serology tests (HBsAg, HBsAb, HBcAb, HBV DNA (reflex to a positive HBcAb), 
hepatitis C antibody, hepatitis C RNA (reflex to a positive hepatitis C antibody), 
HIV-1/HIV-2 antibody), and serum beta-human chorionic gonadotropin (β-HCG) plasma 
test if female of childbearing potential. 
• 
Obtain blood samples for anti-SAR156597 ADA  
• 
Obtain urine for urinalysis (dipstick). If any parameter on the dipstick is abnormal, a urine 
sample should be sent to the central laboratory for testing. If positive for protein and/or red 
blood cells, microscopic analysis will be performed by central laboratory 
• 
Complete all remaining assessments for tuberculosis screen: history and 
QuantiFERON-TB Gold test: 
- 
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 
2 confirmed indeterminate QuantiFERON TB Gold tests are excluded. 
• 
Schedule a visit within a maximum of 28 days (Visit 2, Day 1) 
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10.1.2 Visit 2: Baseline visit/Randomization/Day 1 
• 
Record all concomitant medication use with start date and dose in e-CRF 
• 
Inquire about AEs/SAEs 
• 
Record vital signs including BP, heart rate and weight 
• 
Perform a complete physical examination (Refer to Section 9.2.2.1), including: 
- 
Perform the mRSS (confirm eligibility based upon Exclusion Criteria 03 [E 03]) 
- 
Perform a TJC28 
- 
Perform a digital ulcer count 
• 
Confirm eligibility by review of Inclusion/Exclusion Criteria 
If the patient meets all inclusion criteria and does not meet any exclusion criteria, please 
conduct the following procedures in the recommended order, if possible. 
• 
Call IVRS to randomize the patient and receive a treatment kit allocation. 
• 
Questionnaires/forms to be completed: 
- 
SHAQ (by patient) 
- 
UCLA SCTC GIT 2.0 (by patient) 
- 
EQ-5D-5L (by patient) 
- 
Patient Global Assessment (by patient) 
- 
Physician Global Assessment (by Investigator) 
• 
Inquire about Resource Utilization (Refer to Section 9.3.2)  
• 
Blood and Urine Testing 
- 
Obtain blood samples for complete clinical laboratory determinations including 
hematology, biochemistry profile 
- 
Obtain urine for urinalysis (dipstick) 
- 
Perform urine pregnancy test for women of childbearing potential 
- 
Obtain blood samples for serum SAR156597 level (PK) and for anti-SAR156597 
antibody (ADA) 
- 
Obtain blood samples for protein biomarkers assessment 
- 
Obtain blood samples for supplementary tests for vasculitis (Refer to Section 9.2.2)  
- 
Obtain blood samples for archiving (potential future protein and mRNA biomarkers of 
interest); only for patients who signed a Future Use of Samples informed consent form. 
• 
Other Tests and Procedures  
- 
Perform 12-lead ECG 
- 
Perform Pulmonary function tests (PFTs): observed and % predicted FVC and 
observed and % predicted Carbon Monoxide DLco (corrected for hemoglobin). 
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• 
Dispense and administer IMP 
- 
Patients will be monitored for at least 30 minutes or up to 2 hours as per country 
specific requirements after dosing for any signs or symptoms of a hypersensitivity 
reaction. An assessment of local tolerability at the injection site (present pain, 
erythema/redness, swelling/induration/edema and other related observations) will be 
conducted 
- 
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 
• 
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 
• 
Record vital signs including BP, heart rate and weight 
Perform a complete physical examination (Refer to Section 9.2.2.1) 
• 
Call IVRS to dispense a 2 week treatment kit allocation  
• 
Administer IMP for Week 2 
- 
Patients will be monitored for at least 30 minutes or up to 2 hours as per country 
specific requirements after dosing for any signs or symptoms of a hypersensitivity 
reaction. An assessment of local tolerability at the injection site (present pain, 
erythema/redness, swelling/induration/edema and other related observations) will be 
conducted 
• 
Provide treatment kit to be administered at Week 3 
• 
Schedule an appointment for Visit 4 
10.1.4 Visit 4: on treatment/Week 4 
• 
Questionnaires/forms to be completed:  
- 
SHAQ (by patient) 
- 
UCLA SCTC GIT 2.0 (by patient) 
- 
Patient Global Assessment (by patient) 
- 
Physician Global Assessment (by Investigator) 
• 
Record all concomitant medication use 
• 
Inquire about AEs/SAEs 
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• 
Review patient booklet to assess local tolerability at the injection site and treatment 
compliance 
• 
Record vital signs including BP, heart rate and weight 
• 
Perform a complete physical examination (Refer to Section 9.2.2.1), including: 
- 
Perform the mRSS 
- 
Perform a TJC28 
- 
Perform a digital ulcer count 
• 
Perform 12-lead ECG 
• 
Blood and Urine Testing 
- 
Obtain 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 
- 
Obtain blood sample for serum SAR156597 level (PK) and for anti-SAR156597 
antibody (ADA) 
- 
Obtain blood sample for ANCA and complements (C3, C4 and CH50) 
• 
Call IVRS to dispense a 4 week treatment kit allocation  
• 
Administer IMP for Week 4 
- 
Patients will be monitored for at least 30 minutes or up to 2 hours as per country 
specific requirements after dosing for any signs or symptoms of a hypersensitivity 
reaction. An assessment of local tolerability at the injection site (present pain, 
erythema/redness, swelling/induration/edema and other related observations) will be 
conducted 
• 
Provide treatment kits to be administered at Weeks 5, 6 and 7 
• 
Schedule an appointment for phone call at Week 6 
• 
Schedule an appointment for Visit 5 (Week 8) 
10.1.5 Phone call: on treatment/Week 6, Week 16, and Week 20 
• 
Record all concomitant medication use 
• 
Inquire about AEs/SAEs 
• 
Ask about the result of urine pregnancy test (for phone calls made at Week 16 and 
Week 20 only) 
• 
Assess local tolerability at the injection site by reviewing the patient booklet. 
 
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10.1.6 Visit 5: on treatment/Week 8 
• 
Questionnaires/forms to be completed:  
- 
SHAQ (by patient) 
- 
UCLA SCTC GIT 2.0 (by patient) 
- 
Patient Global Assessment (by patient) 
- 
Physician Global Assessment (by Investigator) 
• 
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 BP, heart rate and weight 
• 
Perform a complete physical examination (Refer to Section 9.2.2.1), including: 
- 
Perform the mRSS 
- 
Perform a TJC28 
- 
Perform a digital ulcer count 
• 
Perform a 12-lead ECG 
• 
Blood and Urine Testing 
- 
Obtain blood samples for evaluating laboratory determinations including hematology 
and biochemistry 
- 
Obtain a urine sample for urinalysis (dipstick) 
- 
Perform urine pregnancy test for women of childbearing potential 
- 
Obtain blood sample for serum SAR156597 level (PK) and for anti-SAR156597 
antibody (ADA) 
• 
Call IVRS to dispense a 4 week treatment kit allocation  
• 
Administer IMP for Week 8 
- 
Patients will be monitored for at least 30 minutes or up to 2 hours as per country 
specific requirements after dosing for any signs or symptoms of a hypersensitivity 
reaction. An assessment of local tolerability at the injection site (present pain, 
erythema/redness, swelling/induration/edema and other related observations) will be 
conducted 
• 
Provide treatment kits to be administered at Weeks 9, 10 and 11 
• 
Schedule an appointment for the next visit, Visit 6 (Week 12) 
 
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10.1.7 Visit 6: on treatment/Week 12 
• 
Questionnaires/forms to be completed:  
- 
SHAQ (by patient) 
- 
UCLA SCTC GIT 2.0 (by patient) 
- 
EQ-5D-5L (by patient) 
- 
Patient Global Assessment (by patient) 
- 
Physician Global Assessment (by Investigator) 
• 
Record all concomitant medication use 
• 
Inquire about AEs/SAEs 
• 
Inquire Resource Utilization (Refer to Section 9.3.2) 
• 
Assess for Step 1 of CRISS (cardiopulmonary and/or renal involvement) 
• 
Review patient booklet to assess local tolerability at the injection site and treatment 
compliance 
• 
Record vital signs including BP, heart rate and weight 
• 
Perform a complete physical examination (Refer to Section 9.2.2.1), including: 
- 
Perform the mRSS 
- 
Perform a TJC28 
- 
Perform a digital ulcer count 
• 
Perform 12-lead ECG 
• 
Blood and Urine Testing 
- 
Obtain blood samples for complete clinical laboratory determinations including 
hematology and biochemistry profile 
- 
Obtain urine for urinalysis (dipstick) 
- 
For women of childbearing potential: 
- 
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. 
- 
Dispense urine pregnancy test kits for monthly urine pregnancy tests (sufficient 
monthly supplies to last until the next scheduled on-site visit). 
- 
Obtain blood sample for serum SAR156597 level (PK) and for anti-SAR156597 
antibody (ADA) 
- 
Obtain blood sample for ANCA and complements (C3, C4 and CH50) 
- 
Obtain blood samples for protein biomarkers analysis  
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- 
Obtain blood samples for archiving for future protein assays and mRNA analysis (only 
for those patients who have signed a separate Future Use of Samples informed consent 
form) 
• 
Perform PFTs: observed and % predicted FVC, and observed and % predicted DLco 
(corrected for hemoglobin) 
• 
Call IVRS to dispense a 6 week treatment kit allocation (Weeks 12, 13 ,14, 15, 16, and 17) 
- 
Reminder: Make an additional IVRS call (as per study flow chart [Section 1.2]) at 
Week 18 to dispense an additional 6 week supply of IMP which will be required for 
Weeks 18, 19, 20, 21, 22 and 23. 
• 
Administer IMP for Week 12 
- 
Patients will be monitored for at least 30 minutes or up to 2 hours as per country 
specific requirements after dosing for any signs or symptoms of a hypersensitivity 
reaction. An assessment of local tolerability at the injection site (present pain, 
erythema/redness, swelling/induration/edema and other related observations) will be 
conducted 
• 
Provide treatment kits to be administered at Weeks 13, 14, 15, 16 and 17 
• 
Schedule appointment for phone calls at Weeks 16 and 20 and for the End-of-Treatment 
(EOT) visit. 
10.1.8 Visit 7: End-of-Treatment/Week 24 (or Early Termination) 
The End of treatment visit is scheduled for Week 24. If a patient discontinues treatment before 
Week 24, a premature EOT (as noted in the e-CRF) visit will be performed employing all 
assessments and procedures associated with Visit 7/EOT.  
• 
Questionnaires/forms to be completed: 
- 
SHAQ (by patient) 
- 
UCLA SCTC GIT 2.0 (by patient) 
- 
EQ-5D-5L (by patient) 
- 
Patient Global Assessment (by patient) 
- 
Physician Global Assessment (by Investigator) 
• 
Record all concomitant medication use 
• 
Inquire about AEs/SAEs 
• 
Inquire about Resource Utilization (Refer to Section 9.3.2) 
• 
Assess for Step 1 of CRISS (cardiopulmonary and/or renal involvement) 
• 
Review patient booklet to assess local tolerability at the injection site and treatment 
compliance 
• 
Record vital signs including BP, heart rate and weight 
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• 
Perform a complete physical examination (Refer to Section 9.2.2.1), including: 
- 
Perform the mRSS 
- 
Perform a TJC28 
- 
Perform a digital ulcer count 
• 
Perform 12-lead ECG 
• 
Blood and Urine Testing 
- 
Obtain blood samples for complete clinical laboratory determinations including 
hematology and biochemistry profile 
- 
Obtain urine for urinalysis (dipstick) 
- 
For women of child bearing potential: 
- 
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 
- 
Dispense urine pregnancy test kits for monthly urine pregnancy tests (2 months 
supply) 
- 
Obtain blood sample for serum SAR156597 level (PK) and for anti-SAR156597 
antibody (ADA) 
- 
Obtain blood sample for ANCA and complements (C3, C4 and CH50) 
- 
Obtain blood samples for protein biomarkers analysis  
• 
Perform PFTs: observed and % predicted FVC, and observed and % predicted DLco 
(corrected for hemoglobin) 
• 
Call IVRS to update the patient’s status (EOT) 
• 
Schedule an appointment for a phone call for Week 30 
• 
Schedule an appointment for next visit, Visit 8 (EOS visit). 
Post treatment, the patients will be observed for 11 weeks in a follow-up period. It will consist on 
one follow-up phone call at Week 30 and EOS visit at Week 35 (Visit 8). 
10.1.9 Phone call: Follow-up post treatment/Week 30 
The patient will be contacted over phone to: 
• 
Record all concomitant medications 
• 
Inquire about AEs/SAEs 
• 
Ask about the result of pregnancy test from Week 28. 
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10.1.10 Visit 8: End-of-study visit/Week 35 
• 
Questionnaires/forms to be completed: 
- 
SHAQ (by patient) 
- 
UCLA SCTC GIT 2.0 (by patient) 
- 
EQ-5D-5L (by patient) 
- 
Patient Global Assessment (by patient) 
- 
Physician Global Assessment (by Investigator) 
• 
Record all concomitant medication use 
• 
Inquire about AEs/SAEs 
• 
Ask about the result of pregnancy test from Week 32 
• 
Inquire about Resource Utilization (Refer to Section 9.3.2) 
• 
Assess for Step 1 of CRISS (cardiopulmonary and/or renal involvement) 
• 
Record vital signs including BP, heart rate and weight 
• 
Perform a complete physical examination (Refer to Section 9.2.2.1), including: 
- 
Perform the mRSS 
- 
Perform a TJC28 
- 
Perform a digital ulcer count 
• 
Perform 12-lead ECG 
• 
Blood and Urine Testing 
- 
Obtain 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 
- 
Obtain blood sample for serum SAR156597 level (PK) and for anti-SAR156597 
antibody (ADA) 
- 
Obtain blood sample for ANCA and complements (C3, C4 and CH50) 
- 
Obtain blood samples for protein biomarkers analysis 
- 
Obtain blood samples for future protein assays and mRNA analysis (only for those 
patients who have signed a separate Future Use of Samples informed consent form) 
• 
Perform PFTs: observed and % predicted FVC, and observed and % predicted DLco 
(corrected for hemoglobin) 
• 
Call IVRS to update the patient’s status (study completion). 
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10.2 
DEFINITION OF SOURCE DATA 
All evaluations that are reported in the e-CRF and in the patient booklet (completed by the nurse) 
must be supported by appropriately identified source documentation. 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION  
The IMP should be continued whenever possible. In case the IMP is stopped, it should be 
determined whether the stop is temporary; permanent IMP discontinuation should be considered 
as the last resort. Any IMP discontinuation should be fully documented in the e-CRF. In any case, 
the patient should remain in the study as long as possible. 
10.3.1 Temporary treatment discontinuation with investigational medicinal products 
Temporary treatment discontinuation may be considered by the Investigator because of suspected 
AE(s). Re-initiation of treatment with the IMP will be considered with close and appropriate 
clinical and/or laboratory monitoring after the Investigator has determined according to his/her 
best medical judgment that the causality of the event was unlikely related to the IMP(s) and if the 
selection criteria for the study are still met (refer to Section 7.1 and Section 7.2). 
For example, suspicion of vasculitis should lead to a temporary discontinuation to allow for a 
thorough diagnostic work-up and evaluation. 
A discontinuation of IMP greater than 30 days will be considered permanent and relevant e-CRF 
sections should be populated. 
10.3.2 Permanent treatment discontinuation with investigational medicinal product(s) 
Permanent treatment discontinuation is any treatment discontinuation associated with the 
definitive decision from the Investigator, Sponsor or the patient not to re-expose the patient to the 
IMP at any time. 
10.3.3 List of criteria for permanent treatment discontinuation 
The patients may decide to permanently withdraw from treatment with the IMP at any time and 
for any reason; this decision may also rest with the Investigator or Sponsor. All efforts should be 
made to document the reason(s) for treatment discontinuation in the e-CRF. 
IMP will be permanently discontinued in case of the following events (refer to Section 10.6 for 
details). The list is a guide and not intended to be exhaustive: 
• 
 
• 
Symptoms of severe hypersensitivity or anaphylactic reactions (see Appendix I for 
definition) 
• 
Severe skin reactions local to the site of IMP injection (see Appendix J) 
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• 
Pregnancy 
• 
Any AEs, per Investigator’s judgment, that may jeopardize the patient’s safety 
• 
Any code breaking requested by the Investigator will lead to permanent treatment 
discontinuation. 
• 
Any laboratory abnormalities per the algorithms of Appendix K 
• 
At the specific request of the Sponsor 
Any abnormal laboratory value or ECG parameter will be immediately rechecked for 
confirmation before making a decision regarding of possible permanent IMP discontinuation for 
the concerned patient. 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. 
10.3.4 Handling of patients after permanent treatment discontinuation 
Patients will be followed according to the study procedures as specified in this protocol through 
the scheduled date of study completion, or through the recovery or stabilization of any AE to be 
followed as specified in this protocol, whichever comes last. 
After permanent discontinuation of treatment, the patients will be assessed using the procedures 
normally planned for EOT visit/Visit 7 (labeled as Premature/Early EOT in the e-CRF), and then 
will be asked to come for the remaining on-site visits per schedule (including Visit 7 at Week 24 
and EOS at Week 35 for safety monitoring and efficacy assessments, particularly mRSS, SHAQ, 
FVC and DLco (corrected for hemoglobin) up to Week 24 as these are the primary and secondary 
endpoints. Other procedures associated with the remaining visits will also be conducted per study 
flow chart. 
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 for any reason. Withdrawal of consent for treatment should be distinguished from 
withdrawal of consent for ongoing study participation with scheduled visits and from withdrawal 
of consent for non-patient contact follow-up (eg, medical records check). Patients requesting 
withdrawal of consent for ongoing study participation with follow-up may jeopardize the public 
health value of the study. 
If possible, and prior to the withdrawal of consent for ongoing study participation, the patients 
will be assessed using the procedure normally planned for the EOS visit (Visit 8). Then, patients 
will receive a phone call from Investigators at Week 30 for vital status assessment. 
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Patients who withdraw from the study should be explicitly asked about the reason and the 
contribution of any possible AE(s) that led to their decision, and any AE information elicited 
should be documented. The patient may withdraw consent verbally or in writing. If the consent is 
withdrawn verbally, the site should document it appropriately. Preferably the patient should 
withdraw consent in writing and, if the patient or the patient’s representative refuses or is 
physically unavailable, the site should document and sign the reason for the patient’s failure to 
withdraw consent in writing. 
All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
e-CRF and in the patient’s medical records when considered as confirmed. In the medical record, 
at least the date of the withdrawal and the reason should be documented. 
For patients who did not withdraw consent for ongoing study participation but fail to return to the 
site, the Investigator should make the best effort to contact the patient (eg, contacting patient’s 
family or private physician, reviewing available registries or health care databases), and to 
determine his/her health status, particularly vital status. Attempts to contact such patients must be 
documented in the patient’s records (eg, number of attempts and dates of attempted telephone 
contact and 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. 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING 
10.4.1 Definitions of adverse events  
10.4.1.1 Adverse event 
An 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 
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10.4.1.2 Serious adverse event 
A 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. 
Note: The following list of medically important events is intended to serve as a guideline for 
determining which condition has to be considered a medically important event. The list is not 
intended to be exhaustive: 
• 
Intensive treatment in an ER or at home for: 
- 
Severe hypersensitivity reactions ( anaphylaxis, allergic bronchospasm [see  
Appendix I for the clinical criteria for diagnosing anaphylaxis]) 
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia),  
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc). 
• 
ALT >3 x ULN + TBILI >2 x ULN or asymptomatic ALT increase >10 x ULN. See 
Appendix K. 
• 
Suicide attempt or any event suggestive of suicidality. 
• 
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling) 
• 
Bullous cutaneous eruptions. 
• 
Cancers diagnosed during the study or recurs during the study 
• 
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). 
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• 
Suspected transmission of an infectious agent via a medicinal product (eg, product 
contamination). 
10.4.1.3 Adverse event of special interest 
An 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 investigation in order to 
characterize and understand them. Adverse events of special interest may be added, modified 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. 
• 
Symptomatic overdose (serious or non-serious) with IMP: 
- 
An overdose (accidental or intentional) with the IMP is an event suspected by the 
Investigator or spontaneously notified by the patient and defined as at least twice the 
intended dose given during a 4 day period. 
Of note, asymptomatic overdose has to be reported as a standard AE. 
• 
ALT > 3 x ULN:   If increase in ALT >3 x ULN, see the “Increase in ALT” flow chart in 
Appendix K of the protocol.   
- 
However, if the increase in ALT is ≥ 2 x the baseline value (with baseline ALT ≥ 
ULN) but ≤ 3 x ULN, then ALT should be re-tested within 72 hours of initial sample 
to determine if the retest value meets the AESI criterion of ALT > 3 x ULN. If so, 
proceed as above and follow the guidelines of Appendix K. If not, monitoring of the 
laboratory findings will be up to the medical judgment of the Investigator. 
• 
Other project specific AESI(s): 
- 
- 
Anaphylactic reactions or acute allergic reactions that require immediate treatment 
(refer to Appendix I for definition of Anaphylaxis) 
- 
Severe injection site reactions (see Appendix J)  
- 
Tuberculosis or initiation of medications for suspected tuberculosis 
- 
Acute renal failure (see Appendix K). 
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10.4.2 Serious adverse events waived from expedited regulatory reporting to regulatory 
authorities 
Disease progression is anticipated for the disease being treated (ie, dcSSc) and will be considered 
expected for the purpose of regulatory reporting. Conversely, an event more severe than the 
anticipated course of usual disease progression is to be considered unexpected and should be 
reported. 
If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal 
relationship between the drug and the event (SUSAR), the event must be reported, even if it is a 
component of the study endpoint. 
10.4.3 General guidelines for reporting adverse events 
• 
All AEs, regardless of seriousness or relationship to IMP, spanning from the signature of 
the informed consent form until the end of the study as defined by the protocol for that 
patient, are to be recorded on the corresponding screen(s) of the e-CRF. 
• 
Whenever possible, diagnosis or single syndrome should be reported instead of symptoms. 
The Investigator should specify the date of onset, intensity, action taken with respect to 
IMP, corrective treatment/therapy given, additional investigations performed, outcome, 
and his/her opinion as to whether there is a reasonable possibility that the AE was caused 
by the IMP or by the study procedure(s).  
• 
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, or until death, in order to ensure the safety of the patients. 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:  
- 
Symptomatic and/or  
- 
Requiring either corrective treatment or consultation, and/or  
- 
Leading to IMP discontinuation or modification of dosing, and/or  
- 
Fulfilling a seriousness criterion, and/or  
- 
Defined as an AESI 
Instructions for AE reporting are summarized in Table 3. 
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10.4.4 Instructions for reporting serious adverse events 
In the case of occurrence of an SAE, the Investigator or any designees 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. 
10.4.5 Guidelines for reporting adverse events of special interest  
For AESIs, the Sponsor must be informed immediately (ie, within 24 hours), as per SAE 
notification guidelines described in Section 10.4.4, even if not fulfilling a seriousness criterion, 
using the corresponding screens in the e-CRF. 
Instructions for AE reporting are summarized in Table 3. 
10.4.6 Guidelines for management of specific laboratory abnormalities 
A decision tree for the management of laboratory abnormalities suggestive of vasculitis (including 
but not limited to hematuria, proteinuria, increased ESR and/or hsCRP, etc) is provided in 
Appendix H. 
Decision trees for the management of certain laboratory abnormalities by Sanofi are provided in    
Appendix K. 
The following laboratory abnormalities should be monitored, documented, and managed 
according to the related flow chart in protocol appendices. 
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• 
Neutropenia 
• 
Thrombocytopenia 
• 
Increase in ALT 
• 
Acute renal insufficiency 
• 
Suspicion of rhabdomyolysis 
NOTE: However, if a seriousness criterion is met, the Sponsor is informed immediately 
(ie, within 1 working day) using the corresponding screens in the e-CRF, following the same 
process as described for the SAEs. 
Table 3 - Summary of adverse event reporting instructions 
Case Report Form completion 
Event 
category 
Reporting 
timeframe 
Specific events in this category 
AE form 
Safety  
Complementary 
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  
Expedited (within 
24 hours) 
Any AE meeting seriousness criterion per 
Section 10.4.1.2 
Yes 
Yes 
No 
Serious Adverse 
Event AESI 
Expedited (within 
24 hours) 
Any AE meeting seriousness criterion per 
Section 10.4.1.2 
Yes 
Yes 
As 
applicable 
Adverse Event of 
Special Interest  
Expedited (within 
24 hours) 
Pregnancy 
Yes 
Yes 
No 
 
 
Symptomatic overdose 
Yes 
Yes 
No 
 
 
ALT >3 x ULN 
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 
10.5 
OBLIGATIONS OF THE SPONSOR 
During the course of the study, the Sponsor will report in an expedited manner: 
• All SAEs that are both unexpected and at least reasonably related to the IMP (SUSAR), to 
the regulatory authorities, Independent Ethics Committee/ Institutional Review Board 
(IECs/IRBs) as appropriate and to the Investigators. 
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• All SAEs that are expected and at least reasonably related to the IMPs to the regulatory 
authorities, according to local regulations. 
Adverse events that are considered expected will be specified by the reference safety information 
(IB).  
Unblinding of SUSARs by the Sponsor is described in this section. 
In this study, progression of the underlying condition is anticipated and thus will be considered as 
expected for the purpose of regulatory reporting. Please refer to the IB. 
Any other AE not listed as an expected event in the IB or in this protocol will be considered 
unexpected. 
For regulatory purposes, the treatment code will be unblinded at Sponsor Pharmacovigilance 
department level for reporting to the Health Authorities of any suspected unexpected adverse drug 
reaction (SUSAR) and reasonably associated with the use of the IMP according to either the 
judgment of the Investigator and/or the Sponsor. Apart from Sponsor Pharmacovigilance 
department, within the company and associated organizations, the results of this unblinding 
should remain undisclosed. 
The Sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report and in the development safety update report. 
10.6 
Safety instructions 
 
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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 J). Special e-CRF screens will need to be completed. If such an AE were 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. 
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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 an allergic reaction. Allergic reactions may 
begin within few hours and persist up to 24 hours post dosing. Refer to Appendix I "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 is performed at the 
patient's home) for at least 30 minutes or up to 2 hours as per country specific requirements after 
each administration of investigational product for any signs or symptoms of a hypersensitivity 
reaction. 
Patients should be treated as medically appropriate 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. 
The IMP should be temporarily discontinued immediately 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 
Allergic AEs with cutaneous involvement or injection site reactions that progress (expand, 
worsen, etc.) should be evaluated by a dermatologist as soon as possible, and preferably within 
1 week of the site first becoming aware of the event. 
The Investigator should evaluate the patient for possible etiologies (eg, new medications) and 
extra-cutaneous symptoms and signs. An unscheduled Central Laboratory assessment for 
hematology, chemistry, liver panel, PK, and ADA should be obtained. If at all possible, the site 
will take pictures of the cutaneous lesions for them to be seen during the evaluation with the 
dermatologist. If the photos are taken, then the copies should be kept as source documents which 
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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, a detailed description of the skin reaction (such as the morphology 
[lesion type], shape of individual lesions, arrangement of multiple lesions [eg, scattered, grouped, 
linear], distribution, color, consistency and presence of pruritus or pain, and other clinical signs). 
If a skin biopsy is done based on the dermatologist's or Investigator's medical judgment, the 
results of this investigation (including histopathology and immunofluorescence), should be 
reported. 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 
The targeted treatment benefit is a difference of 4 points between treatment groups in the mean 
change in mRSS from baseline to Week 24.  
The impact of treatment discontinuations in the context of an ITT analysis where all mRSS data 
will be included in the analysis (regardless of adherence to treatment) was evaluated. Assuming 
that 10% of patients will discontinue the treatment, the estimated treatment effect at 24 weeks will 
be decreased from 4 (targeted treatment effect if all patients adhered to treatment) to 3.6 (targeted 
treatment effect in all randomized patients). 
Ninety-four (94) patients (47 patients each in SAR156597 and placebo groups) will yield 80% 
power to detect a difference between SAR156597 and placebo groups of 3.6 in the mean change 
from baseline in mRSS at 24 weeks, assuming a SD of 7 and using a 1-sided alpha of 5% (type I 
error).  
Table 4 provides power calculations depending on several assumptions for treatment effect 
(difference between treatment groups in the mean change in mRSS from baseline to Week 24) and 
SD of the response (18) (assumed to be the same in both groups) (20, 21). 
Table 4 - Power calculations for mRSS, depending on treatment effect and standard deviation, 
using a 1-sided alpha of 0.05 
Treatment effect 
SD 
Power 
∆=3 
8 
7 
6 
57% 
67% 
78% 
∆=3.6 
8 
7 
6 
70% 
80% 
90% 
∆=4 
8 
7 
6 
78% 
87% 
94% 
 
Calculations were made using East 6.3 software. 
11.2 
DISPOSITION OF PATIENTS 
Screened patients are defined as any patient who met the inclusion criteria and signed the 
informed consent.  
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Randomized patients consist of all screened patients with a treatment kit number allocated and 
recorded in the IVRS database, regardless of whether the treatment kit was used or not. 
Patients treated without being randomized will not be considered as randomized and will not be 
included in any efficacy population. The safety experience of patients treated and not randomized 
will be reported separately, and these patients will not be in the safety population. 
Although not permitted per the protocol, 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. 
11.3 
ANALYSIS POPULATIONS 
11.3.1 Efficacy populations 
The primary efficacy population will be the ITT population as defined below. 
11.3.1.1 Intent–to-treat population 
The ITT population is defined as all randomized patients. Patients in the ITT population will be 
analyzed according to the treatment group allocated by randomization. 
11.3.2 Safety population 
The safety population considered for the safety analyses will include all randomized patients who 
did actually receive at least 1 dose or part of a dose of the IMP. Patients in the safety population 
will be analyzed according to the treatment actually received. 
In addition: 
• 
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 in the majority of injections. 
11.3.3 Anti-SAR156597 antibody (ADA) population 
The anti-SAR156597 antibody analysis will be performed on all randomized and treated patients 
(safety population) with at least 1 post dose ADA sample with a reportable result. Patients will be 
analyzed according to the treatment actually received. 
11.3.4 Pharmacokinetics population 
The PK population will include all randomized and treated patients (safety population) with at 
least 1 post-dose, non-missing plasma concentration value. 
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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. 
11.4.1.1 Extent of investigational medicinal product exposure 
The duration of IMP exposure in weeks is defined as: (last dose date + 7 – first dose date)/7, 
regardless of 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 endpoints 
The change in mRSS from baseline to Week 24 will be analyzed in the ITT population using a 
MMRM approach. All post-baseline data available from Week 4 to Week 24 analysis windows 
will be included in the analysis, regardless of adherence to treatment. Missing data will be 
accounted for by the MMRM. The model includes the fixed categorical effects of treatment group 
(placebo, SAR156597), randomization strata (SSc-ILD: Yes/No), time point (Week 4, Week 8, 
Week 12, Week 24), randomization strata-by-time point interaction and treatment-by-time point 
interaction, as well as the continuous fixed covariates of baseline mRSS value and baseline 
value-by-time point interaction. Model assumptions for normality will be explored prior to the 
analysis testing.  
The repeated-measures analysis will be based on the restricted maximum likelihood method 
assuming an unstructured correlation matrix to model the within-patient errors. Denominator 
degrees of freedom will be estimated using Kenward-Roger approximation. This model will 
provide baseline adjusted LSmeans estimates at Week 24 for both treatment groups with their 
corresponding 95% confidence intervals. To compare SAR156597 to the placebo group, an 
appropriate contrast statement will be used to test the difference of these estimates at the 5% 
one-sided alpha level. The 95% and 90% confidence intervals of the difference will be provided. 
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Let µ0 and µ1 be the population means of the change from baseline in mRSS at Week 24 under 
placebo and SAR156597, respectively. The null hypothesis that will be tested is “
1
0
0 :
µ
µ =
H
” 
versus “
1
0
1:
µ
µ ≠
H
”. 
As a sensitivity analysis, the change in mRSS from baseline to Week 24 will also be analyzed in 
the safety population using the same MMRM model as described above, including only 
post-baseline data measured during the TEAE period. 
Please refer to Section 9.1.1 for the primary efficacy endpoint. 
11.4.2.2 Analyses of secondary efficacy endpoints 
All secondary endpoints will be analyzed using the ITT population. 
Change in continuous secondary efficacy endpoints (HAQ-DI, observed FVC, observed DLco 
[corrected for hemoglobin]) from baseline to Week 24 will be analyzed using the same MMRM 
model as for the primary endpoint. Specifically, the model will contain fixed categorical effects of 
treatment group, randomization strata, time point (Week 4 to Week 24), randomization 
strata-by-time point interaction and treatment-by-time point interaction, as well as the continuous 
fixed covariates of corresponding baseline value and baseline-by-time point interaction. This 
model will provide baseline adjusted LSmeans estimates at Week 24 for both treatment groups 
with their corresponding 95% confidence intervals. The SAR156597 to placebo difference of 
these estimates will be provided with its corresponding 95% and 90% confidence intervals and 
p-value.  
Exploratory endpoints 
Responder rates (proportion of patients with an improvement from baseline in mRSS of at least 
20%, 40% and 60%) at Week 24 and Week 35 will be analyzed using a logistic regression with 
the categorical effects of treatment group and randomization strata and the continuous covariate of 
corresponding baseline value. This model will provide the SAR156597 to placebo odds ratio 
estimate and its 95% and 90% confidence intervals. The p-value will be obtained from the Wald 
Chi-square test. Patients with missing value at Week 24, respectively Week 35, will be considered 
as non-responders.  
Change in continuous efficacy endpoints from baseline to Week 24 (VAS from SHAQ, UCLA 
SCTC GIT 2.0, TJC28, digital ulcer count, EQ-5D-5L index) and from baseline to Week 35 
(mRSS, HAQ-DI, VAS from SHAQ, observed FVC, observed DLco [corrected for hemoglobin], 
UCLA SCTC GIT 2.0, TJC28, digital ulcer count, EQ-5D-5L index) will be analyzed using the 
same MMRM model as for the primary and continuous secondary efficacy endpoints. 
Due to the non-normality of the distribution of % predicted FVC and % predicted DLco 
(corrected for hemoglobin), their change from baseline at Week 24 and Week 35 will be analyzed 
using a rank-based analysis of covariance (rank analysis of covariance [ANCOVA]) model 
adjusted for baseline. 
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The distribution of the predicted probability of improving obtained using the CRISS at Week 24 
and Week 35 will be compared between SAR156597 and the placebo group using a Van Elteren’s 
test stratified on randomization strata. Methods to handle missing data will be described in the 
SAP. In addition, rate of patients for whom the predicted probability of improving obtained using 
the CRISS at Week 24 and Week 35 is ≥60% will be provided. To assist in interpreting the 
clinical meaningfulness of any differences in group-level mean change for SHAQ (HAQ-DI and 
VAS) and EQ-5D-5L (index value and VAS), individual-level change will be assessed. For this, 
patients will be categorized as “responders” and “non-responders” according to whether they have 
achieved a threshold of change considered to be meaningful (the MIC). Patients who improve 
by ≥ the MIC will be considered as clinically important responders (CIRs). As there is little data 
to support an accepted MIC value for HAQ-DI (20) and the SHAQ VAS assessments in dcSSc, 
estimates will be empirically-derived from within this study using both distribution-based and 
anchor-based methods. Distribution-based methods will include one-half a SD and 1 standard 
error of measurement (SEM) of the baseline score (22, 23, 24). Anchor-based methods will use 
the EQ-5D index value in which the magnitude of change in the HAQ-DI and the SHAQ VASs 
among patients who noted at least a 0.08 improvement in their current health status (0-1 scale) 
will define the MIC (25, 26, 27). 
For the EQ-5D-5L, CIRs will be defined by an MIC of ≥0.08 in the index value. CIRs on the 
EQ-5D VAS will be defined using the same methods as for the HAQ-DI and SHAQ VASs 
(ie, 0.5SD, 1SEM, EQ-5D index value as an anchor). 
The proportion of patients classified as CIRs will be assessed within the ITT sample. Patients 
without data at the relevant time point will be classified as non-responders. Comparison between 
groups on responder rates will be performed as described above using a logistic regression. 
Please refer to Section 9.1.2 for the secondary efficacy endpoints. 
11.4.2.3 Multiplicity considerations 
No adjustment will be made. For secondary and exploratory efficacy endpoints, p-values will be 
provided for descriptive purpose only. 
11.4.3 Analyses of safety data 
The summary of safety results will be presented by treatment group actually received. 
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 the first 
administration of the IMP. 
• 
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 descriptive and no hypothesis testing is 
planned. 
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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.  
• 
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 TEAE PCSA percentage. 
The TEAE period is defined as the time from the first administration of the IMP up to 12 weeks 
(84 days) from the last dose of IMP. 
Please refer to Section 9.2 for the safety endpoints. 
11.4.3.1 Adverse events 
Adverse event incidence tables will be provided by treatment group for all types of TEAEs: all 
TEAEs, all treatment emergent SAEs, all TEAEs leading to permanent treatment discontinuation, 
treatment-emergent AESI and TEAEs leading to death. 
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 1 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. A listing 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. A listing will be provided for all TEAE leading to 
permanent treatment discontinuation by treatment group and patient. 
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Analysis of treatment-emergent AESI 
Treatment-emergent AESI will be presented by AESI category and PT, showing number (%) of 
patients with at least 1 treatment-emergent AESI, sorted by decreasing incidence of PT within 
each AESI category. The AESIs include, but are not limited to, the following categories and 
complete list of AESI categories will be provided in the statistical analysis plan: tuberculosis, 
anaphylaxis, hypersensitivity, and vasculitis. 
Analysis of Deaths 
The following deaths summaries will be generated: 
• 
Number (%) of patients who died by study period (TEAE, on-study) summarized on the 
safety population by treatment received. 
• 
Death in non-randomized 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. 
11.4.3.2 Laboratory data 
The summary statistics (including number, mean, median, SD, minimum and maximum) of all 
laboratory variables (laboratory values and changes from baseline), will be calculated for each 
visit (baseline and post-baseline time points), last and worst on-treatment value assessed and 
presented by treatment group. Only data sampled before or on the day of the last IMP 
administration will be included in this analysis. 
The incidence of PCSAs at any time during the TEAE period will be summarized by treatment 
group whatever the baseline level and/or according to the baseline status. 
For laboratory parameters for which PCSA criterion is not defined, similar table(s) using the 
normal range could be provided. 
11.4.3.3 Potential drug-induced liver injury 
The liver function tests, namely ALT, AST, ALP and total bilirubin (TBILI), 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. 
A graph of distribution of peak values of ALT versus peak values of TBILI will be presented. 
Note that the ALT and TBILI values are presented on a logarithmic scale. The graph will be 
divided into 4 quadrants with a vertical line corresponding to 3 x ULN for ALT and a horizontal 
line corresponding to 2 x ULN for TBILI. 
The normalization (to ≤1 x ULN or return to baseline if baseline > ULN) of elevated liver 
function tests will be summarized by categories of elevation (3 x ULN, 5 x ULN, 10 x ULN, 
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20 x ULN for ALT and AST, 1.5 x ULN for ALP, and 1.5 x ULN and 2 x ULN for TBILI), with 
the following categories of normalization: never normalized, normalized after permanent 
discontinuation of study drug. Note that a patient will be counted only under the maximum 
elevation category (1-3 x ULN, 3-5 x ULN, 5-10 x ULN, 10-20 x ULN, >20 x ULN).  
The incidence of liver-related AEs will be summarized by treatment group. The selection of PTs 
will be based on standardized Medical Dictionary for Regulatory Activities (MedDRA) query 
(SMQ) Hepatic disorder. 
11.4.3.4 Vital signs data 
The summary statistics (including number, mean, median, SD, minimum and maximum) of all 
vital signs variables (values and changes from baseline), will be calculated for each visit (baseline 
and post-baseline time points), last and worst on-treatment value and presented by treatment 
group. Only data measured before or on the day of the last IMP administration will be included in 
this analysis. 
The incidence of PCSAs at any time during the TEAE period will be summarized by treatment 
group whatever the baseline level and/or according to the baseline status. 
11.4.3.5 ECG data 
The summary statistics (including number, mean, median, SD, minimum and maximum) of all 
ECG variables (values and changes from baseline), will be calculated for each visit (baseline and 
post-baseline time points), last and worst on-treatment value and presented by treatment group. 
Only data measured before or on the day of the last IMP administration will be included in this 
analysis. 
The incidence of PCSAs at any time during the TEAE period will be summarized by treatment 
group whatever the baseline level and/or according to the baseline status. 
11.4.4 Analysis of immunogenicity 
The analysis of immunogenicity will be performed on the ADA population. It will include 
summaries for ADA prevalence, treatment-boosted ADA incidence, treatment-induced ADA 
incidence and kinetics of the immune response in patients with treatment-induced ADAs. Impact 
on PK, efficacy and safety will be assessed. Further details will be provided in the SAP. 
Please refer to Section 9.3 for the detection of ADA. 
11.4.5 Analyses of pharmacokinetic and pharmacodynamic variables 
The plasma concentrations of SAR156597 will be summarized by treatment group and visit using 
descriptive statistics, including number of available observations, arithmetic and geometric 
means, SD, coefficient of variation (CV%), median, minimum and maximum. 
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Please refer to Section 9.3 for pharmacokinetic and pharmacodynamics variables. 
Further details will be provided in the SAP. 
11.4.6 Analyses of patient reported outcomes (health-related quality of life/health 
economics variables) 
Analysis of SHAQ and EQ-5D-5L is already described in Section 11.4.2.2 (Analysis of secondary 
efficacy endpoints). 
Statistical analyses of resource use will be described in a separate dedicated health economics and 
outcome research (HEOR) statistical analysis plan. 
Please refer to Section 9.1.4.8 and Section 9.1.4.9 for details on SHAQ and EQ-5D-5L. 
11.4.7 Analyses of biomarkers 
The analysis of biomarkers will be exploratory in nature, with the aim to measure the effect of 
SAR156597 on biomarkers of the IL-4/IL-13 pathway and biomarkers of the disease. 
Please refer to Section 9.3.3 for details on biomarkers. 
Details will be provided in the SAP. 
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. 
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 24 collected and validated, and will consist in the final analysis of the 
efficacy endpoints up to Week 24. 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: Final analysis 
The second analysis will be conducted at the end of the study and will consist in the final analysis 
of Week 35 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, and delegated Investigator 
staff and Sub-Investigator, in accordance with consensus ethics principles derived from 
international ethics guidelines, including the Declaration of Helsinki, 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, 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 archiving for potential future protein assays and mRNA analysis, 
the optional Future Use of Samples informed consent form (written) should be signed, name filled 
in, and personally dated by the patient or by the subject’s legally acceptable representative, and by 
the person who conducted the informed consent discussion. A copy of the signed and dated 
written optional informed consent form will be provided to the subject. 
The informed consent form and the optional Future Use of Samples informed consent form 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 
HEALTH AUTHORITIES AND 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 health authorities (competent regulatory authority) and 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, IB, Investigator’s curriculum vitae 
[CV], etc) and the date of the review should be clearly stated on the written (IRB/IEC) 
approval/favorable opinion. 
The 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 health authorities (competent regulatory authority), as required by local 
regulation, in addition to the IRB/IEC before implementation, unless the change is necessary to 
eliminate an immediate hazard to the patients, in which case the health authorities (competent 
regulatory authority) and the IRB/IEC should be informed as soon as possible. They 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 IB will be sent to the IRB/IEC 
and to health authorities (competent regulatory authority), as required by local regulation. 
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 INVESTIGATORS 
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 e-CRF entries against the source 
documents, except for the pre-identified source data directly recorded in the e-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 e-CRFs (eg, patient's medical file, 
appointment books, original laboratory records). 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 ELECTRONIC CASE REPORT FORMS (E-CRFS) AND 
ADDITIONAL REQUEST 
It is the responsibility of the Investigator to maintain adequate and accurate e-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 e-CRFs 
should be completed in their entirety 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 CV 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 e-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 (eg, 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 purposes 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, GCP, 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. 
• Noncompliance 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 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 consents. 
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 to the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC and/or notification/approval of health authorities (competent regulatory 
authority) of an amendment, as required by local regulation, 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 case of substantial amendment to the clinical trial protocol, approval from the health authorities 
(competent regulatory authority) will be sought before implementation. 
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 
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BIBLIOGRAPHIC REFERENCES 
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25. FDA Guidance for Industry Patient-Reported Outcome Measures: Use in Medical Product 
Development to Support Labeling Claims 2009 
26. Wyrwich KW, Norquist JM, Lenderking WR, Acaster S. Methods for interpreting change over 
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APPENDICES 
Appendix A 
mRSS 
 
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Appendix B 
SHAQ 
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Appendix C 
UCLA SCTC GIT 2.0 Questionnaire 
 
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Appendix D 
: EQ-5D-5L 
 
 
 
Health Questionnaire 
English version for the USA 
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A m e n d e d Cli ni c al Tri al Pr ot o c ol N O. 0 1  
0 9- A u g- 2 0 1 7 
S A R 1 5 6 5 9 7- A C T 1 4 6 0 4 
V er si o n n u m b er: 1 
Pr o pert y of t he Sa n ofi Gr o u p - strictl y c o nfi de ntial   
P a g e 1 0 4  
A p p e n di x E  
P ati e nt a n d p h y si ci a n gl o b al a s s e s s m e nt s of o v er all h e alt h u si n g 
t h e 0- 1 0 Li k ert s c al e 
 
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Appendix F 
TJC28 
Tender Joint Count 28 (TJC28) 
 
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Appendix G 
Guidance on contraceptive methods for United Kingdom only 
 
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). 
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Appendix H 
 
 
 
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Appendix I 
Clinical criteria for diagnosing anaphylaxis 
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: summary report-Second 
National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network 
symposium. J Allergy Clin Immunol. 2006 Feb;117(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 (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia) 
B) Reduced BP or associated symptoms of end-organ dysfunction (eg, 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 eg, generalized hives, pruritus or flushing, swollen 
lips-tongue-uvula 
B) Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia) 
C) Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, incontinence) 
D) Persistent gastrointestinal symptoms (eg, 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 
. 
Abbreviations: PEF = peak expiratory flow; BP = blood pressure 
*Low systolic BP 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 J 
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.) 
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. 
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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Appendix K 
General guidance for the follow-up of laboratory abnormalities by 
Sanofi 
Neutrophils < 1500/mm3 or according to ethnic 
group
NEUTROPENIA
Repeat immediately a full blood count if value 
close to 1500/mm3
Neutrophils < 1500/mm3 confirmed 
with signs of infection  
Neutrophils < 1500/mm3 confirmed 
with no signs of infection  
1.
DISCONTINUE
Investigational Medicinal 
Product, hospitalization 
should be considered
2.
PERFORM biological 
investigations for infection
1.
DISCONTINUE
Investigational 
Medicinal Product
2.
INVESTIGATE for 
infection
In both situations
3.
INFORM the local monitor
4.
INVESTIGATE previous treatments particularly long-term, even a long time ago, 
exposure to toxic agents, e.g., benzene, X-rays, etc.
5.
PERFORM and collect the following investigations (results): 
•
RBC and platelet counts
•
Serology: EBV, (HIV), mumps, measles, rubella
6.
DECISION for bone marrow aspiration: to be taken in specialized unit
7.
COLLECT/STORE one sample following handling procedures described in PK 
sections (for studies with PK sampling) and freeze one serum sample (5 mL) on 
Day 1 (cessation of investigational medicinal product) and Day 5 (for further 
investigations)
8.
MONITOR the leukocyte count 3 times per week for at least one  week, then twice a 
month until it returns to normal
Note: 
•The procedures described in the above flowchart are to be discussed with the patient only in case 
the event occurs. If applicable (according to local regulations), an additional consent (e.g., for 
HIV testing) will only be obtained in the case the event actually occurs.
•For individuals of African descent, the relevant value of concern is <1000/mm3
 
Neutropenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting AEs in Section 10.4.3 is met. 
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Platelets < 100 000/mm3 (rule out EDTA – induced 
pseudo-thrombocytopenia)
THROMBOCYTOPENIA
Repeat immediately the count (rule out EDTA 
anticoagulant in the sample)
Platelets  < 100 000/mm3 confirmed 
with bleeding  
Platelets  < 100 000/mm3 confirmed 
with no bleeding
1.
DISCONTINUE
Investigational Medicinal 
Product
2.
HOSPITALIZATION
should be considered
1.
DISCONTINUE
Investigational Medicinal 
Product
2.
INVESTIGATE for 
bleeding
In both situations
3.
INFORM the local Monitor
4.
QUESTION about last intake of quinine (drinks), alcoholism, heparin administration
5.
PERFORM or collect the following investigations: 
•
Complete blood count, schizocytes, creatinine
•
Bleeding time and coagulation test (fibrinogen, INR or PT, aPTT), Fibrin 
Degradation Product
•
Viral serology: EBV, HIV, mumps, measles, rubella
6.
COLLECT/STORE one sample following handling procedures described in PK 
sections (for studies with PK sampling) and freeze one serum sample (5 mL) on 
Day 1 (cessation of investigational medicinal product) and Day 5 (for further 
investigations)
7.
DECISION for bone marrow aspiration: to be taken in specialized unit
•
On Day 1 in the case of associated anemia and/or leukopenia
•
On Day 8 if platelets remain < 50 000/mm3
8.
MONITOR the platelet count every day for at least one week and then regularly 
until it returns to normal
Note: 
The procedures above flowchart are to be discussed with the patient only in case described in the 
the event occurs. If applicable (according to local regulations), an additional consent (e.g., for 
HIV testing) will only be obtained in the case the event actually occurs.
 
Thrombocytopenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting AEs in Section 10.4.3 is met. 
 
 
 
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ALT > 3 ULN
Monitor LFTs every 72 hours
ALT ≤ 5 ULN
ALT > 3 ULN &
Total Bilirubin > 2 ULN 
Permanent Discontinuation of IMP
ALT > 5 ULN 
In ANY CASE, FOLLOW the instructions listed in the box below: 
1.
INFORM the Site Monitor who will forward the information to the Study Manager
2.
INVESTIGATE specifically for malaise with or without loss of consciousness, dizziness, and/or 
hypotension and/or episode of arrhythmia in the previous 72 hours; rule out muscular injury
3.
PERFORM the following tests:
- LFTs: AST, ALT, alkaline phosphatase, total and conjugated bilirubin and prothrombin time / INR
- CPK, serum creatinine, complete blood count
- Anti-HAV IgM, anti-HBc IgM, (HBV-DNA if clinically indicated), anti-HCV and HCV RNA, anti-
CMV IgM and anti-HEV IgM antibodies
- Depending on the clinical context, check for recent infection with EBV, herpes viruses, and toxoplasma
- Hepatobiliary ultrasonography (or other imaging investigations if needed)
4.
CONSIDER Auto-antibodies: antinuclear, anti-DNA, anti-smooth muscle, anti-LKM
5.
CONSIDER consulting with hepatologist
6.
CONSIDER patient hospitalisation if INR>2 (or PT<50%) and/or central nervous system disburbances 
suggesting hepatic encephalopathy
7.
MONITOR LFTs after discontinuation of IMP:
- As closely as possible (or every 48 hours) until stabilization, then every 2 weeks until return to 
normal/baseline or clinical resolution.
8.
FREEZE serum sample (5ml x 2)
9.
In case of SUSPICION of GILBERT Syndrome, a DNA diagnostic test should be done
COMPLETE the specific CRF forms 
for „ALT Increase” and inform the 
Monitoring Team within 24 hours
Confirm ALT > 3 ULN
Retest within 72 hours of initial sample*
IMP administration can be continued as 
long as – under close monitoring –
conditions for permanent 
discontinuation or temporary 
interruption per protocol are not met
INCREASE IN ALT
 
• *If unable to retest in 72 hours, use original lab results to decide on further reporting/monitoring/discontinuation.  
• Note: 
• “Baseline” refers to ALT sampled at baseline visit; or if baseline value unavailable, to the latest ALT sampled before the 
baseline visit. The algorithm does not apply to the instances of increase in ALT during screening. 
See Section 10.4 for guidance on safety reporting. 
• Normalization is defined as ≤ ULN or baseline value, if baseline value is >ULN. 
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Rapid increase in serum creatinine over 150 µmol/L 
or rapid decrease in creatinine clearance below
50 mL/mn
ACUTE RENAL FAILURE
Can be rapidly reversed:
• By volume repletion
• Or relief of urinary tract 
obstruction (according to etiology)
Cannot be rapidly reversed: 
• Occurrence/aggravation of life 
threatening symptoms of ARF: anemia, 
hyperkalemia, hyperuricemia, metabolic 
acidosis, cardiac insufficiency, 
pulmonary edema, arrhythmia, DIC, etc.
• And/or predominant elimination of 
Investigational Medicinal Product by 
renal route
1.
Investigational Medicinal 
Product may be continued
2.
MONITOR serum creatinine 
until return to baseline level
1.
INFORM the local monitor
2.
DISCONTINUE
Investigational Medicinal Product 
administration
3.
HOSPITALIZATION should be 
considered and seek for nephrologic  
advice
4.
PERFORM the following 
examinations: 
•
BP, HR, hydration status, ECG
•
Blood count
•
Liver function tests + CPK
•
Biochemistry, including urea
•
Urinalysis
5.
COLLECT/STORE one sample 
following handling procedures 
described in PK sections (for studies 
with PK sampling) and freeze one 
serum sample (5 mL) on Day 1 
(cessation of investigational 
medicinal product)
6.
MONITOR renal function until 
return to baseline level (every day at 
the beginning, then every week)
 
Acute renal failure is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting AEs in Section 10.4.3 is met. 
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If Increase in CPK (expressed in ULN)
> 3 ULN
Repeat immediately the count.
If confirmed, inform the local monitor and
INVESTIGATE for the origin:
- PERFORM:
•
ECG
•
CPK-MB -MM 
•
Troponin
•
Creatinine
•
Iono (k+, Ca2+)
•
Transaminases + Total and conjugated bilirubin
•
Myoglobin (serum and urines)
- COLLECT/STORE one sample following handling procedures described in PK sections (for 
studies with PK sampling) and freeze one serum sample (5 mL) on Day 1 (cessation of 
investigational medicinal product). 
- INTERVIEW the patient about a recent intensive muscular effort, trauma, convulsions, electrical 
injury, injury or stress to the skeletal muscle, multiple intramuscular injections, recent surgery, 
concomitant medications, consumption of alcohol, morphine, cocaine.
- SEARCH for alternative causes to cardiac or muscular toxicity, ie: stroke, pulmonary infarction, 
dermatomyositis or polymyositis, convulsions, hypothyroidism, delirium tremens, muscular 
dystrophies.
If either the cardiac origin or the 
rhabdomyolysis is confirmed or if CPK 
> 10 ULN:
1. DISCONTINUE Investigational 
Medicinal Product administration
2. MONITOR CPK every 3 days for the 
first week then once weekly until return 
to normal or for at least 3 months
3. HOSPITALIZATION should be 
considered
If the cardiac origin or the rhabdomyolysis is 
ruled out and if CPK ≤10 ULN:
MONITOR CPK every 3 days for the first week 
then once weekly until return to normal or for 
at least 3 months
Muscular symptoms (myalgia, pain, weakness, 
dark urines)
Systematic CPK assessment as per 
protocol
Perform CPK
SUSPICION OF RHABDOMYOLYSIS
 
Suspicion of rhabdomyolysis is to be recorded as an AE only if at least 1 of the criteria in the 
general guidelines for reporting AEs in Section 10.4.3 is met. 
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Appendix L 
Clinically significant ECG 
The following list of ECG findings is considered to be clinically significant and would result in 
the exclusion of the patient from the study based upon Exclusion criterion 15 [E 15].  This list is 
not exhaustive in nature but serves as a guide to help determine clinical significance with regards 
to ECG for the safety of the patient who is being considered for this study.   
 
If there is a question pertaining to another clinically significant finding not described below, it 
must be brought to the attention of Sanofi before consideration of enrollment.  Sanofi will then 
provide timely recommendation after internal review regarding the patient’s eligibility associated 
with this exclusion criterion.   
 
Clinically significant ECG finding that would meet Exclusion criterion 15 [E 15]: 
• 
Second-degree heart block 
• 
Third-degree heart block 
• 
QT prolongation (symptomatic) 
• 
Sick sinus syndrome 
• 
Left bundle branch block (complete) 
• 
Right bundle branch block (complete) 
• 
Atrial fibrillation (uncontrolled) 
• 
Atrial flutter (uncontrolled) 
• 
Wolff-Parkinson-White syndrome 
• 
Atrioventricular nodal reentry tachycardia 
• 
Ventricular Arrhythmias  
- 
Ventricular Tachycardia 
- 
Ventricular Fibrillation 
- 
Torsades de Pointes 
- 
Bradyarrhythmias 
 
(electronic 
 
 
 
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ELECTRONIC SIGNATURES 
 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ACT14604 Amended Protocol01
Clinical Approval
09-Aug-2017 13:53 GMT+0200
Clinical Approval
09-Aug-2017 16:48 GMT+0200

SAP_001.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: QSD-002643 VERSION 6.0 (06-JUL-2016) 
Page 1 
STATISTICAL ANALYSIS PLAN 
Efficacy and safety of SAR156597 in the treatment of diffuse cutaneous Systemic 
Sclerosis (dcSSc): A randomized, double blind, placebo controlled, 24 week,  
proof of concept study  
SAR156597-ACT14604 
STATISTICIAN: 
  
Statistical Project Leader: 
 
DATE OF ISSUE: 21-Feb-2019 
Total number of pages: 
78 
VV-CLIN-0196174 2.0
NCT02921971


Statistical Analysis Plan  
21-Feb-2019 
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Page 2 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................................................... 5 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................ 7 
1.1 
STUDY DESIGN AND RANDOMIZATION ...................................................................................... 7 
1.2 
OBJECTIVES ................................................................................................................................... 7 
1.2.1 
Primary objectives ............................................................................................................................ 7 
1.2.2 
Secondary objectives ....................................................................................................................... 7 
1.2.3 
Exploratory objectives ...................................................................................................................... 8 
1.3 
DETERMINATION OF SAMPLE SIZE............................................................................................. 8 
1.4 
STUDY PLAN ................................................................................................................................... 9 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL.................................. 9 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN ....................... 9 
2 
STATISTICAL AND ANALYTICAL PROCEDURES .................................................................... 11 
2.1 
ANALYSIS ENDPOINTS ............................................................................................................... 11 
2.1.1 
Demographic and baseline characteristics .................................................................................... 11 
2.1.2 
Prior or concomitant medications ................................................................................................... 12 
2.1.3 
Efficacy endpoints .......................................................................................................................... 12 
2.1.3.1 
Primary efficacy endpoint(s) .......................................................................................................... 13 
2.1.3.2 
Secondary efficacy endpoints ........................................................................................................ 13 
2.1.4 
Exploratory endpoints .................................................................................................................... 14 
2.1.5 
Safety endpoints ............................................................................................................................ 17 
2.1.5.1 
Adverse events variables ............................................................................................................... 17 
2.1.5.2 
Deaths ............................................................................................................................................ 18 
2.1.5.3 
Laboratory safety variables ............................................................................................................ 18 
2.1.5.4 
Vital signs variables ....................................................................................................................... 20 
2.1.5.5 
Electrocardiogram variables .......................................................................................................... 20 
2.1.6 
Pharmacokinetic variables ............................................................................................................. 20 
2.1.7 
Immunogenicity variables .............................................................................................................. 20 
2.1.8 
Biomarker endpoints ...................................................................................................................... 22 
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Page 3 
2.1.9 
Quality-of-life endpoints ................................................................................................................. 22 
2.1.10 
Health economic endpoints ............................................................................................................ 22 
2.2 
DISPOSITION OF PATIENTS ....................................................................................................... 22 
2.2.1 
Randomization and drug dispensing irregularities ......................................................................... 24 
2.3 
ANALYSIS POPULATIONS ........................................................................................................... 25 
2.3.1 
Efficacy populations ....................................................................................................................... 25 
2.3.1.1 
Intent–to-treat population ............................................................................................................... 25 
2.3.2 
Safety population ........................................................................................................................... 25 
2.3.3 
Anti-SAR156597 antibody (ADA) population ................................................................................. 26 
2.3.4 
Pharmacokinetics population ......................................................................................................... 26 
2.3.5 
Biomarker population ..................................................................................................................... 26 
2.4 
STATISTICAL METHODS ............................................................................................................. 26 
2.4.1 
Demographics and baseline characteristics .................................................................................. 26 
2.4.2 
Prior or concomitant medications ................................................................................................... 27 
2.4.3 
Extent of investigational medicinal product exposure and compliance ......................................... 27 
2.4.3.1 
Extent of investigational medicinal product exposure .................................................................... 27 
2.4.3.2 
Compliance .................................................................................................................................... 28 
2.4.4 
Analyses of efficacy endpoints ....................................................................................................... 29 
2.4.4.1 
Analysis of primary efficacy endpoint(s) ........................................................................................ 29 
2.4.4.2 
Analyses of secondary efficacy endpoints ..................................................................................... 33 
2.4.4.3 
Multiplicity issues ........................................................................................................................... 34 
2.4.4.4 
Analyses of exploratory efficacy endpoints .................................................................................... 34 
2.4.5 
Analyses of safety data .................................................................................................................. 37 
2.4.5.1 
Analyses of adverse events ........................................................................................................... 38 
2.4.5.2 
Deaths ............................................................................................................................................ 40 
2.4.5.3 
Analyses of laboratory variables .................................................................................................... 40 
2.4.5.4 
Analyses of vital sign variables ...................................................................................................... 41 
2.4.5.5 
Analyses of electrocardiogram variables ....................................................................................... 42 
2.4.6 
Analyses of pharmacokinetic variables .......................................................................................... 42 
2.4.7 
Analyses of immunogenicity data .................................................................................................. 42 
2.4.8 
Analyses of Biomarker data ........................................................................................................... 43 
2.4.9 
Analyses of quality of life/health economics variables ................................................................... 43 
2.5 
DATA HANDLING CONVENTIONS .............................................................................................. 44 
2.5.1 
General conventions ...................................................................................................................... 44 
2.5.2 
Data handling conventions for efficacy variables ........................................................................... 44 
2.5.3 
Missing data ................................................................................................................................... 46 
2.5.4 
Windows for time points ................................................................................................................. 47 
2.5.5 
Unscheduled visits ......................................................................................................................... 48 
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2.5.6 
Pooling of centers for statistical analyses ...................................................................................... 48 
2.5.7 
Statistical technical issues ............................................................................................................. 48 
3 
INTERIM ANALYSIS ..................................................................................................................... 49 
4 
DATABASE LOCK ........................................................................................................................ 50 
5 
SOFTWARE DOCUMENTATION ................................................................................................. 51 
6 
REFERENCES............................................................................................................................... 52 
7 
LIST OF APPENDICES ................................................................................................................. 53 
APPENDIX A 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA ...................... 54 
APPENDIX B 
SUMMARY OF STATISTICAL ANALYSES ........................................................................ 59 
APPENDIX C 
MRSS .................................................................................................................................. 64 
APPENDIX D 
SHAQ ................................................................................................................................... 65 
APPENDIX E 
UCLA SCTC GIT 2.0 QUESTIONNAIRE ............................................................................ 68 
APPENDIX F 
EQ-5D-5L QUESTIONNAIRE (UK VERSION) .................................................................... 72 
APPENDIX G 
PATIENT AND PHYSICIAN GLOBAL ASSESSMENTS OF OVERALL HEALTH 
USING THE 0-10 LIKERT SCALE ................................................................................................. 74 
APPENDIX H 
TJC28 .................................................................................................................................. 75 
APPENDIX I 
DIGITAL ULCER COUNT ..................................................................................................... 76 
APPENDIX J 
CODELISTS FOR BACKGROUND THERAPY DEFINITIONS, AESIS AND 
RELATED HEPATIC DISORDER .................................................................................................. 78 
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Page 5 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ADA: 
anti-drug antibodies 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALP: 
alkaline phosphate 
ALT: 
alanine transaminase 
ANCA: 
anti-neutrophil cytoplasmic antibodies 
AST: 
aspartate transaminase 
ATC: 
anatomic or therapeutic categories 
AUC: 
area under the curve 
BM: 
biomarker 
BMI: 
body mass index 
CCL2: 
chemokine (C-C motif) ligand 2 
CMQ: 
customized MedDRA query 
COMP: 
cartilage oligomeric matrix Protein 
cpk: 
creatinine phosphokinase 
CRISS: 
composite response index for diffuse cutaneous systemic sclerosis 
dcSSc: 
diffuse cutenous systemic sclerosis  
EBLUP: 
empirical best linear unbiaised prediction  
ECL: 
electrochemiluminescence 
e-CRF: 
electronic case report form 
ELISA: 
enzyme linked immuno sorbent assay 
ESR: 
erythrocyte sedimentation rate 
FVC: 
forced vital capacity 
HEVA: 
health economics and value assessment  
HLGT: 
high-level group term 
HLT: 
high-level term 
HRCT: 
high resolution computer tomography 
hsCRP: 
high-sensitivity C-reactive protein 
ILD: 
interstitial lung disease 
IMP: 
investigational medicinal product 
IRT: 
interactive response technology 
ITT: 
intent-to-treat 
LLT: 
lower level term 
MAR: 
missing at random 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MMRM: 
mixte model with repeated measures 
mRSS: 
modified Rodnan skin score 
NMAR: 
not missing at random 
PAH: 
pulmonary arterial hypertension  
PK: 
pharmacokinetics 
PT: 
preferred term 
VV-CLIN-0196174 2.0


Statistical Analysis Plan  
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QOL: 
quality of life 
QQ: 
quantile 
SAE: 
serious adverse event 
SD: 
standard deviation 
SHAQ: 
scleroderma health assessment questionnaire 
SMQ: 
standardized MedDRA query 
SOC: 
sytemic organ class 
SSc: 
systemic sclerosis 
TBILI: 
total bilirubine 
TJC28: 
tender joint count 28 
UCLA SCTC GIT 2.0: 
 UCLA scleroderma clinical trial consortium gastrointestinal 
tract 2.0 
WHO-DD: 
World Health Organization Drug Dictionnary 
 
 
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1 
OVERVIEW AND INVESTIGATIONAL PLAN 
1.1 
STUDY DESIGN AND RANDOMIZATION 
This study will be a multinational, randomized, double blind, placebo controlled, 2 parallel 
groups, proof of concept Phase 2 study to assess the efficacy and safety of SAR156597 200 mg 
administered subcutaneously once a week over a 24 week period to patients with diffuse  
Systemic Sclerosis (SSc).  
After a screening phase of up to 4 weeks, patients will be centrally randomized (using allocation 
from block randomization schedule with stratifying factors) via Interactive Response  
Technology (IRT) in a 1:1 ratio to 1 of the 2 treatment groups and treated double-blind for 
approximately 6 months. 
Randomization will be stratified based upon the patients’ medical history of SSc ILD (yes or no). 
1.2 
OBJECTIVES 
1.2.1 Primary objectives 
To evaluate, in comparison with placebo, the efficacy of SAR156597 administered 
subcutaneously for 24 weeks on skin fibrosis in patients with diffuse cutaneous SSc (dcSSc). 
1.2.2 Secondary objectives 
The secondary objectives are: 
 To evaluate the efficacy of SAR156597 compared to placebo on physical/functional 
disability in patients with dcSSc. 
  To evaluate the efficacy of SAR156597 compared to placebo on respiratory function of 
patients with dcSSc. 
 To evaluate the safety profile of SAR156597 compared to placebo in patients with dcSSc. 
 To evaluate the potential for immunogenicity (Anti-drug antibodies (ADA) response) of 
SAR156597 in patients with dcSSc. 
 To evaluate the Pharmacokinetics (PK) (trough plasma concentrations) of SAR156597 
administered subcutaneously for 24 weeks. 
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1.2.3 Exploratory objectives 
The exploratory objectives are: 
 To explore the efficacy of SAR156597 compared to placebo on other manifestations of 
SSc (gastrointestinal, joint pain, cardiovascular and renal manifestations) in patients with 
dcSSc. 
 To explore the effect of SAR156597 on the Quality Of Life in patients with dcSSc. 
 To measure the effect of SAR156597 on biomarkers of the disease activity and the  
IL 4/IL 13 pathway. 
 To identify biomarkers predictive of response to treatment as defined by mRSS endpoints.  
1.3 
DETERMINATION OF SAMPLE SIZE 
The targeted treatment benefit is a difference of 4 points between treatment groups in the mean 
change in mRSS from baseline to Week 24.  
The impact of treatment discontinuations in the context of an ITT analysis where all modified 
Rodnan Skin Score (mRSS) data will be included in the analysis (regardless of adherence to 
treatment) was evaluated. Assuming that 10% of patients will discontinue the treatment, the 
estimated treatment effect at 24 weeks will be decreased from 4 (targeted treatment effect if all 
patients adhered to treatment) to 3.6 (targeted treatment effect in all randomized patients). 
Ninety four (94) patients (47 patients each in SAR156597 and placebo groups) will yield  
80% power to detect a difference between SAR156597 and placebo groups of 3.6 in the mean 
change from baseline in mRSS at 24 weeks, assuming a Standard Deviation (SD) of 7 and using a 
1 sided alpha of 5% (Type I error). 
Table 1 provides power calculations depending on several assumptions for treatment effect 
(difference between treatment groups in the mean change in mRSS from baseline to Week 24) and 
SD of the response (1) (assumed to be the same in both groups (2, 3).  
Table 1 - Power calculations for mRSS, depending on treatment effect and standard deviation, 
using a 1-sided alpha of 0.05 
Treatment effect 
SD 
Power 
Δ=3 
8 
7 
6 
57% 
67% 
78% 
Δ=3.6 
8 
7 
6 
70% 
80% 
90% 
Δ=4 
8 
7 
6 
78% 
87% 
94% 
Calculations were made using East 6.3 software.  
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1.4 
STUDY PLAN 
Approximately 94 patients will be randomized in a ratio 1:1 to the following two treatment 
groups: 
 SAR156597 group (n=47): Patients will receive SAR156597 administered subcutaneously 
in 200 mg doses qw. 
 Placebo group (n=47): Patients will receive placebo subcutaneously qw. 
Randomization will be stratified based upon the patients’ medical history of SSc-ILD  
(yes or no). 
The following figure presents the graphical study design.  
Figure 1 - Graphical study design (screening period, double-blind period and follow-up period) 
R
D-28
D1
W2   W4     (W6)    W8              W12     (W16)   (W18)      (W20)
W24                  (W30)              W35                                 
SAR156597 200 mg SC qw
Placebo SC qw
No study drug
No study drug
Screening period
Treatment period
Follow-up period
R: randomization
SC: subcutaneous
D: day
W: week
qw: once a week
 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
The statistical section of the protocol was never changed in an amendment.  
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN 
Some minor modifications were done in this new version: 
 A second definition of background therapy was added (Section 2.4.2). 
 The description of all efficacy endpoints at each visit was added (Section 2.4.4). 
 One sensitivity analysis on high mRSS was added (Section 2.4.4.1.6). 
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 Three subgroups were added to analyze the primary criteria: second definition of 
background therapy, geographical region and ANA staining pattern (Section 2.4.4.1.8). 
 The Section 2.4.4.4.8 and Section 2.4.4.4.9 were updated according to the Appendix B 
from SAP. 
 The observed FVC at Week 24 will be analyzed instead of the change in observed FVC 
from baseline to Week 24 in the linear mixed model (Section 2.4.4.4.2). 
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2 
STATISTICAL AND ANALYTICAL PROCEDURES 
2.1 
ANALYSIS ENDPOINTS 
2.1.1 Demographic and baseline characteristics 
The baseline value is defined as the last available value before the first administration of the 
Investigation Medicinal Product (IMP).  
All baseline safety and efficacy parameters are presented along with the on-treatment summary 
statistics in the safety and efficacy sections (Section 2.4.4 and Section 2.4.5). 
Demographic characteristics 
Demographic variables are gender (Male, Female), ethnicity (Hispanic or Latino, Not Hispanic or 
Latino, Not reported, Unknown), race (American Indian or Alaska Native, Asian, Black or 
African American, Native Hawaiian or other Pacific Islander, White, Not reported, Unknown), 
age in years (quantitative and qualitative variable: <45, [45-65[, [65-75[ and ≥75 years) and  
Body Mass Index (BMI) in kg/m² (quantitative variable and qualitative variable: <30 and ≥30). 
Medical or surgical history 
Medical (or surgical) history includes previous relevant medical and surgery history collected at 
baseline. 
This information will be coded using the version of Medical Dictionary for Regulatory Activities 
(MedDRA) currently in effect at Sanofi at the time of database lock. 
Disease characteristics at baseline 
Specific disease history includes disease duration from the time of first non-Raynaud’s 
phenomenon manifestation (months), any systemic sclerosis history and mRSS at baseline. The 
auto-antibodies specific to systemic sclerosis (centromere antibodies, RNA polymerase III 
antibody, Scl-70 antibody and ANA staining pattern) and stratification factor (with/without 
medical history of SSc-ILD) as per IRT and as per electronic case report form (e-CRF) will be 
also presented.  
Alcohol habits at baseline 
Alcohol habits (frequency of alcoholic drinks in the last 12 months (Never/At least monthly/ 
At least weekly/At least daily/Occasionally), number of standard drinks (1 or 2/Greater than 2 
where standard drink means 1 pint/bottle of beer, 1 glass of wine, 1 shot of hard liquor…) per day 
when drinking alcohol. 
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Other baseline characteristics 
Other baseline characteristics include weight in kilograms (quantitative variable and qualitative 
variable: <50, [50-100[, ≥100). 
Any technical details related to computation, dates, and imputations for missing dates are 
described in Section 2.5.  
2.1.2 Prior or concomitant medications 
All immunosuppressive and investigational drugs taken within 3 months before screening visit, all 
antibiotics taken within 1 month before screening visit, and all medications taken within 28 days 
prior to baseline visit and until the end of the study are to be reported in the case report form 
pages. 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
using the version currently in effect at Sanofi at the time of database lock. 
 Prior medications are those the patient used prior (from 3 months before screening visit) to 
first investigational medicinal product (IMP) intake. Prior medications can be discontinued 
before first administration or can be ongoing during treatment phase. 
 Concomitant medications are any treatments received by the patient concomitantly to the 
IMP, from randomization to the end of treatment + 84 days. A given medication can be 
classified both as a prior medication and as a concomitant medication. Concomitant 
medications do not include medications started during the post-treatment period (as 
defined in the observation period in Section 2.1.5).  
 Post-treatment medications are those the patient took in the period running from the day 
after last administration of IMP + 84 days up to the end of the study. 
Any technical details related to computation, dates, imputation for missing dates are described in 
Section 2.5. 
2.1.3 Efficacy endpoints 
All measurements, scheduled or unscheduled, will be assigned to analysis windows defined in 
Section 2.5.4 in order to provide an assessment of the efficacy parameter at each time point 
planned to be collected as per protocol. For all post-baseline time points, the value used for the 
analyses at a given time point (eg, at Week 24) is the valid value obtained within the 
corresponding analysis window. If multiple valid values of a variable exist within an analysis 
window, the nearest from the targeted study day will be selected. In case of ties, the best value 
will be considered. The baseline value is the last available and valid measurement obtained up to 
the date and time of the first double-blind IMP injection. For patients randomized and not treated, 
the baseline value is defined as the last available and valid value obtained up to the date and time 
of randomization. All efficacy endpoints will be analyzed using the ITT population.  
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2.1.3.1 Primary efficacy endpoint(s) 
The primary efficacy endpoint will evaluate the efficacy of SAR156597 on skin thickening  
(ie, fibrosis) of patients with dcSSc by measuring: 
 Change in mRSS from baseline to Week 24. 
The mRSS assesses skin thickness in 17 body surface areas (face, chest, abdomen, right and left 
fingers, hands, forearms, upper arms, thighs, lower legs and feet). Each area is assessed for 
thickness on a 0 to 3 scale (0 = normal, 1 = mild but definite thickening, 2 = moderate skin 
thickening and 3 = severe skin thickening). The total mRSS score (the sum of score from all 
17 body areas) ranges from 0 (no thickening) to 51 (severe thickening in all 17 areas). If one or 
more the scores from the 17 body areas is missing, then the mRSS is missing (see Appendix C). 
The lower the mRSS is, the better it is for the patient.  
2.1.3.2 Secondary efficacy endpoints 
Two secondary endpoints will evaluate the efficacy of SAR156597 on other aspects of dcSSc: 
 Change in HAQ-DI, assessed with SHAQ, from baseline to Week 24. 
 Change in respiratory function as measured by observed Forced Vital Capacity (FVC) and 
observed DLco (corrected for hemoglobin) from baseline to Week 24. 
The HAQ-DI assesses the extent of the patient’s functional ability; specifically their usual abilities 
using their usual equipment over the past week. It contains 8 domains of activity (dressing and 
grooming, arising, eating, walking, hygiene, reach, grip, and common daily activities) each of 
which has at least 2 questions, for a total of 20 items (see Appendix D). For each item, patients 
report the amount of difficulty experienced performing the activity. There are 4 possible responses 
for each item ranging from 0 (without any difficulty) to 3 (unable to do).  
Each domain is scored separately. A domain score is determined from the highest score of the 
items in that domain. For example, if there are two items (as in the domain “arising”), and the 
patient responds with a 1 and 2, respectively, to the two items, the score for the “arising” domain 
will be a 2. If a question is left blank or is confusing, then the score for that category is determined 
by the remaining completed question(s). 
For each of the eight domains there is an “aids or devices” companion variable(s) that is used to 
record the type of assistance, if any, a patient uses for his/her usual activities. The relationship 
between aids and devices and the domains (disability categories) is presented in Table 2. Use of 
aids or devices, or requirement of help from another person impacts on the scoring of the 
domains. When there are no aids or devices or help indicated for a domain, the category’s score is 
not modified. When aids or devices or help are indicated by the patient, the score for the domain 
is raised from a 0 or a 1 to a 2, but if the patient’s highest score for that domain is a 2 or 3, the 
score is kept as it is. 
No adjustment is made if the patient indicated only “other” under aids or devices, without any 
other aid, device or help. The data entered at field “Other specify” will not be used for score 
adjustment. 
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Table 2 - Relationship between aids or devices and the domains (disability categories) 
Disability Category 
Aids or devices 
Dressing & Grooming  
Devices used for dressing (button hook, zipper pull, long handled shoe 
horn, etc.)  
Arising  
Built up or special chair  
Eating  
Built up or special utensils  
Walking  
Cane, walker, crutches, wheelchair 
Hygiene  
Raised toilet seat, bathtub seat, bathtub bar  
Long handled appliances in bathroom  
Reach  
Long handled appliances for reach  
Grip  
Jar opener (for jars previously opened)  
 
The HAQ-DI composite score is calculated as the average of the scores of the domains. The 
patient must have a score for at least 6 of the 8 domains for the composite score to be calculated. 
The HAQ-DI composite score is obtained by dividing the sum of the domains by the number of 
answered domains. This gives a score between 0 (no impairment in function) and 3 (maximal 
impairment of function).  
If less than 6 domains have been scored then the HAQ-DI composite score is missing. 
2.1.4 Exploratory endpoints 
 Proportion of patients with improvement in mRSS of at least 20%, 40% and 60% from 
baseline to Week 24. 
 Change in VAS for pain, breathing function, vascular function (Raynaud's phenomenon), 
gastrointestinal function, digital ulcers, and global assessment from SHAQ from baseline 
to Week 24 (see Appendix D). 
Each VAS is scored between 0 and 100 measuring (using a ruler) how many mm from 0 the 
patient has placed their mark on the VAS (ie, where the mark crosses the VAS line). Each VAS is 
scored independently; no total score is calculated. Missing data is considered missing, and not 
imputed. 
 Change in respiratory function as measured by % predicted FVC and % predicted DLco 
(corrected for hemoglobin) from baseline to Week 24. 
 Change in UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract 2.0 
(UCLA SCTC GIT 2.0) score from baseline to Week 24. 
The UCLA SCTC GIT 2.0 Questionnaire includes 34 items and 7 multi-item scales (reflux, 
distention/bloating, diarrhea, fecal soilage, constipation, emotional well-being, and social 
functioning) to assess quality of life (QOL) related to gastrointestinal function in patients with 
SSc. All scales are scored from 0.00 (better QOL) to 3.00 (worse QOL) except the diarrhea and 
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constipation (range from 0.00-2.00 and 0.00-2.50, respectively). The UCLA SCTC GIT 2.0 
questionnaire provides a total score of GIT severity: it is calculated as the average of all scales 
(except constipation) and ranges from 0.00 to 2.83 (see Appendix E). If one item is missing, the 
UCLA SCTC GIT 2.0 score will be considered missing. 
 Change in Tender Joint Count 28 (TJC28) from baseline to Week 24. 
The TJC28 is an assessment of the overall joint pain based upon the examination of 28 key joints 
(see Appendix H). With the individual missing joint score (the “replaced or fused” joints are not 
taken into consideration with regards to tenderness) imputed as the mean of the scored joints, the 
tender joint count calculation after imputation is as follows: 
 TJC28 = sum (scored tender joints) * (number of joints in the full joint set/number of 
scored tender joints). 
The number of joints in the full joint set is defined as (28 - number of replaced or fused joints) and 
the scored joints refer to those with an answer (0 - no pain, 1 - pain). 
 Change in digital ulcer count from baseline to Week 24. 
The digital ulcer count corresponds to the sum of active or new plus indeterminate/healing digital 
ulcers secondary to SSc (see Appendix I).  
 
CRISS. 
The Composite Response Index for Diffuse Cutaneous Systemic Sclerosis (CRISS) tool 
summarizes the changes in the clinical and patient-reported outcomes using a single composite 
score that reflects the probability that the patient with dcSSc has improved.  
CRISS is obtained in a 2-step process as described below. 
Step 1: Patients who develop new or worsening of cardiopulmonary and/or renal involvement due 
to SSc are considered as not improved (irrespective of improvement in other core items) and 
assigned a probability of improving equal to 0.0. Specifically if a subject develops any of the 
following: 
 New scleroderma renal crisis. 
 Decline in FVC% predicted ≥15% (relative), confirmed by another FVC% within a month, 
high resolution computer tomography (HRCT) to confirm ILD (if previous HRCT of chest 
did not show ILD) and FVC% predicted below 80% predicted*.  
 New onset of left ventricular failure (defined as left ventricular ejection fraction ≤45%) 
requiring treatment*.  
 New onset of Pulmonary Arterial Hypertension (PAH) on right heart catheterization 
requiring treatment*. PAH is defined as mean pulmonary artery pressure ≥25 mm Hg at 
rest and an end-expiratory pulmonary artery wedge pressure ≤15 mm Hg and a pulmonary 
vascular resistance >3 Wood units. 
*Attributable to SSc 
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Step 2: For the remaining patients, Step 2 involves computing the predicted probability of 
improving for each subject using the following equation (equation to derive predicted 
probabilities from a logistic regression model): 
 
ΔmRSS indicates the change in mRSS from baseline, ΔFVC denotes the change in FVC% 
predicted from baseline, ΔPt-glob indicates the change in patient global assessment (as per  
Likert scale), ΔMD-glob denotes the change in physician global assessment (as per Likert scale) 
(see Appendix G), and ΔHAQ-DI is the change in HAQ-DI. All changes are absolute change 
(Time2 - Timebaseline). 
 Change in EQ-5D-5L index from baseline to Week 24. 
EQ-5D-5L (see Appendix F) is a generic measure of health status developed by the EuroQol 
Group in order to provide a simple measure of health for clinical and economic appraisal. It 
measures 5 dimensions: mobility, self-care, usual activities, pain/discomfort and 
anxiety/depression. Each of the dimensions is divided into 5 levels of perceived problems ranging 
from 1 (no problem) to 5 (extreme problem). 
For each patient, a 5-digit score is obtained by combining each of the 5 dimensions. For example, 
score 11111 indicates no problems on any of the 5 dimensions, while score 12345 indicates no 
problems with mobility, slight problems with washing or dressing, moderate problems with doing 
usual activities, severe pain or discomfort and extreme anxiety or depression. For each patient, the 
EQ-5D-5L index, ranging from -0.594 to 1.0 is derived from this score using the United Kingdom 
population-based scoring (4, 5).  
In addition, the EQ-5D has a single VAS to evaluate perceived current health. The VAS is scored 
between 0 and 100 by using the values indicated on the VAS where the patient has placed their 
mark, or by using the value written by the patient.  
For index and VAS, missing data will not be imputed. Ambiguous values (eg, 2 boxes are ticked 
for a single dimension) on the health state/index score are treated as missing.  
 Change in efficacy endpoints (mRSS, HAQ-DI, VAS from SHAQ, observed FVC, 
% predicted FVC, observed DLco [corrected for hemoglobin], % predicted DLco 
[corrected for hemoglobin], UCLA SCTC GIT 2.0 score, TJC28, digital ulcer count, 
CRISS, and EQ-5D-5L index and VAS) from baseline to Week 35 (up to end of follow-up 
period) and proportion of patients with improvement in mRSS of at least 20%, 40% and 
60% from baseline to Week 35. 
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2.1.5 Safety endpoints 
The safety analysis will be based on the reported adverse events and other safety information, 
such as clinical laboratory data, vital signs, ECG. 
Observation period  
The observation period will be divided into 4 epochs: 
 The pre-treatment epoch is defined as the time from the signed informed consent date up 
to the first administration of IMP.  
 The treatment epoch is defined as the time from the first administration of the IMP to the 
last administration of the IMP + 7 days. 
 The residual treatment epoch is defined as the time from the last administration of the 
IMP + 8 days to the last administration of the IMP + 84 days. 
The treatment-emergent adverse event (TEAE) period will include both treatment and residual 
treatment epochs. 
 The post-treatment epoch is defined as the period of time starting the day after the end of 
the TEAE period up to the end of the study (defined as last protocol-planned visit or last 
study assessment). 
The on-study observation period is defined as the time from the first administration of IMP until 
the end of the study (defined as last protocol planned visit or last study assessment).  
2.1.5.1 Adverse events variables 
Adverse event observation period  
 Pre-treatment adverse events are adverse events that developed or worsened or became 
serious from the signed informed consent date up to first administration of IMP. 
 Treatment-emergent adverse events are adverse events that developed or worsened or 
became serious during the treatment-emergent adverse event period. 
 Post-treatment adverse events are adverse events that developed or worsened or became 
serious during the post-treatment period. 
All adverse events (including serious adverse events and adverse events of special interest 
(AESIs)) will be coded to a lower-level term (LLT), preferred term (PT), high-level term (HLT), 
high-level group term (HLGT), and associated primary system organ class (SOC) using the 
version of MedDRA currently in effect at Sanofi at the time of database lock. 
Occurrence of adverse events (including Serious Adverse Events (SAEs) and Adverse Event of 
Special Interest (AESIs)) are recorded from the time of signed informed consent until the end of 
the study. 
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Adverse events of special interest (AESIs) include the following terms (their complete 
descriptions are provided in the protocol): 
 Pregnancy of a female subject entered in a study as well as pregnancy occurring in a 
female partner of a male subject entered in a study with IMP, selected using the e-CRF 
“Pregnancy” tick box on the AE page.  
 Symptomatic overdose (serious or non-serious) with IMP, selected using the e-CRF 
“symptomatic overdose of the IMP” tick box on the AE page. 
 Alanine transferase (ALT) >3 ULN, selected using laboratory data. 
 
 
  
 Anaphylactic reactions or acute allergic reactions that require immediate treatment, 
selected using a CMQ coding list (see Appendix J). 
 Severe injection site reactions, selected using HLT = ”Injection site reaction” and an 
intensity equal to severe. 
 Tuberculosis, selected using a CMQ coding list and/or Initiation of medications for 
suspected tuberculosis, selected using a WHO-DD CDG00737 “initiation of medications 
for suspected tuberculosis” (see Appendix J). 
 Acute renal failure, selected using a CMQ coding list (see Appendix J) or using the e-CRF 
“Acute renal failure” tick box on the AE page.  
2.1.5.2 Deaths 
The deaths observation period are per the observation periods defined above.  
 Death on-study: deaths occurring during the on-study observation period. 
 Death on-treatment: deaths occurring during the treatment-emergent adverse event period.  
 Death post-study: deaths occurring after the end of the study.  
2.1.5.3 Laboratory safety variables 
Clinical laboratory data consists of blood analysis, including hematology, clinical chemistry, and 
urinalysis. Clinical laboratory values after conversion will be analyzed into standard international 
units and international units will be used in all listings and tables. 
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Blood samples for clinical laboratories will be taken at Visit 1 (Screening), Visit 2 (Day 1),  
Visit 4 (Week 4), Visit 5 (Week 8), Visit 6 (Week 12), Visit 7/EOT (Week 24), early termination 
and Visit 8/EOS (Week 35) unless otherwise specified. The laboratory parameters will be 
classified as follows:  
 Hematology  
- 
Red blood cells and platelets and coagulation: Hemoglobin, hematocrit, red blood 
cell count, erythrocyte sedimentation rate (ESR) and platelet count, 
- 
White blood cells: white blood cell count with differential blood count (neutrophils, 
lymphocytes, monocytes, basophils, eosinophils), 
- 
Tuberculosis screen: a Quantiferon®-TB gold evaluation. 
 Biochemistry  
- 
Metabolism: Fasting glucose, total protein, albumin, high-sensitivity C-reactive 
protein (hsCRP), 
- 
Electrolytes: sodium, potassium, chloride, calcium, phosphorous, bicarbonate, 
- 
Renal function: serum creatinine, creatinine phosphokinase (CPK), blood urea 
nitrogen, clearance of creatinine according to Cockroft and Grault formula (mL per 
minute) (qualitative variable: <30, [30-50[, [50-80], >80), 
- 
Pregnancy test: (For women of childbearing potential) β-HCG blood test and urine 
pregnancy tests will be performed, 
- 
Liver function: alkaline phosphate (ALP), Alanine transaminase (ALT), Aspartate 
transaminase (AST), total bilirubine (TBILI), 
- 
 
 
 Serology  
- 
Hepatitis screen: hepatitis B surface antigen, hepatitis B surface antibody, 
HBV DNA, hepatitis C antibody, hepatitis C RNA, HIV-1/HIV-2 antibody, 
- 
 
 
 Urine sample 
- 
Urinalysis (by dipstick): specific gravity, pH, glucose, ketones, occult blood, protein, 
nitrate, leukocyte esterase, urobilinogen and bilirubin.  
Technical formulas are described in Section 2.5.1. 
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2.1.5.4 Vital signs variables 
Vital signs include: systolic and diastolic blood pressure in sitting position (mmHg),  
weight (kg) and heart rate (beats per minute). 
2.1.5.5 Electrocardiogram variables 
ECGs were recorded automatically by the device at the Investigator site.  
ECG parameters include heart rate (beats per minute), PR interval (msec), QRS duration (msec), 
QT interval (msec) and corrected QTc (according to Bazett and Fridericia, see Section 2.5.1),  
ST deviation (mm), T-wave and U-wave morphologies (category as normal or abnormal).  
2.1.6 Pharmacokinetic variables 
All measurements (scheduled or unscheduled) will be assigned to analysis windows, as defined in 
Section 2.5.4, in order to provide an assessment of the PK parameter at each time point planned to 
be collected as per protocol. 
Ctrough, Ctrough,av,ss) and CFollow-Up will be defined as follows: 
 Ctrough: SAR156597 concentration sample within 2h before each administration (Day 1, 
Week 4, Week 8, Week 12 and Week 24). 
 Ctrough,av,ss: SAR156597 average trough concentrations (“Ctrough,av,ss”) will be calculated for 
each patient as the mean of “Ctroughs” considered at steady state (ss). The occurrence of 
steady state will be assessed graphically, by plotting “Ctrough” throughout the study visits 
over all patients.  
 CFollow-up: SAR156597 concentration sample taken in Week 35, 12 weeks after last 
injection. 
2.1.7 Immunogenicity variables 
All measurements (scheduled or unscheduled) will be assigned to analysis windows defined in 
Section 2.5.4, in order to provide an assessment of the Anti-SAR156597 antibodies (ADA) 
parameter at each time point planned to be collected as per protocol. 
ADA positive patients are patients with at least 1 treatment-induced or treatment-boosted ADA 
positive sample during the TEAE period, where: 
 Treatment induced ADAs: ADAs developed de novo (seroconversion) following 
administration of the biotherapeutic (ie, formation of ADAs any time after the initial drug 
administration in a subject without pre-existing ADAs). If the baseline ADA sample is 
missing or non-reportable and at least one reportable ADA sample is available during the 
treatment (including follow-up period) the baseline sample will be considered as 
“negative” for data analysis. This is considered being a conservative approach for ADA 
assessment. 
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 Treatment boosted ADA: Pre-existing ADAs that were boosted to a higher level following 
administration of biotherapeutic (ie, any time after the initial drug administration) the 
ADA titer is significantly higher than the baseline titer. A low serial dilution schema 
(2-fold or 3 fold) should be applied during titration. A difference in titer values of two titer 
steps between an on treatment or follow-up sample and its baseline sample is considered 
significant. For examples, at least a 4-fold increase in titers for 2-fold serial dilution 
schema (or 9–fold increase in titers for 3- fold serial dilution schema). If no titer could be 
determined for a positive sample, the titer will be reported as the MRD of the assay. 
The rest will be classified as ADA negative or inconclusive patients. 
The following variables will be described: 
 ADA response (Positive, Negative or inconclusive). For ADA positive: 
- 
Titer levels,  
- 
Neutralizing status (Positive or inconclusive). 
 
Pre-existing positive ADA defined as patients with positive ADA response at baseline 
with less than a specific increase (depending on titer calculation, eg, 4-fold increase in titer 
for 2-fold serial dilution schema, 9-fold increase in titer for 3-fold serial dilution schema) 
in the post-baseline period. 
 Treatment-emergent positive ADA response defined as 1) Patients with no ADA positive 
response at baseline but with any positive response in the post-baseline period (up to 
follow-up visit) or 2) Patients with a positive ADA response at baseline and at least a 
specific increase (depending on titer calculation, eg, 4-fold increase in titer for 2-fold 
serial dilution schema, 9-fold increase in titer for 3-fold serial dilution schema) in titer in 
the post-baseline period (up to follow-up visit). For treatment-emergent positive ADA, the 
following categories for ADA duration will be applied: 
- 
A persistent positive response is a treatment-emergent ADA positive response detected 
in at least 2 or more post-baseline samples separated by at least a 16-week period 
(irrespective of any negative sample in between), 
- 
An indeterminate duration positive response is defined as ADA present only at the last 
sampling time point (and all previous samples negative) or with two last samples are 
positives but separated by a period less than 16 weeks. 
 
A transient positive response is defined as 
- 
Treatment induced ADA detected only at one sampling time during treatment or 
follow-up observation period (excluding last sampling time), 
- 
Treatment induced ADA detected at two or more sampling time during treatment 
where the first and last ADA positive sample are separated by a period less than  
16 weeks and last sampling time is negative. 
 
Duration of ADA defined as longevity of treatment induced ADA (in days): date of last 
treatment induced ADA sample minus date of first treatment induced or treatment boosted 
ADA sample + 1. This will be calculated only for subjects with at least  
2 positive ADA samples.  
 Time to onset of treatment-emergent ADA positive response (in days): date of first ADA 
positive - date of first IMP administration.  
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2.1.8 Biomarker endpoints 
All measurements (scheduled or unscheduled) will be assigned to efficacy analysis windows 
defined in Section 2.5.4, in order to describe all biomarkers (BM) assessments by time points even 
in case of premature treatment discontinuation. 
Peripheral blood samples are planned to be collected for measurement of protein biomarkers at the 
study Visits 2 (baseline visit), Visit 6 (Week 12), Visit 7 (Week 24-EOT), Visit 8 
(Week 35-EOS). 
The protein biomarkers include, but are not limited to: 
 Cartilage Oligomeric Matrix Protein (COMP) analyzed by Enzyme Linked Immuno 
Sorbent assay (ELISA) method. 
 Chemokine (C-C Motif) Ligand 2 (CCL2) analyzed by ELISA method. 
 Chemokine (C-C Motif) Ligand 17 - TARC analyzed by ELISA method. 
 Periostin analyzed by ELISA method. 
 Eotaxin-3 analyzed by Electrochemiluminescence (ECL). 
2.1.9 Quality-of-life endpoints 
See Section 2.1.3.2. 
2.1.10 Health economic endpoints  
Health economic endpoints other than quality of life will be described in a separate dedicated 
health economics and value assessment (HEVA) statistical analysis plan. 
2.2 
DISPOSITION OF PATIENTS 
This section describes patient disposition for both patient study status and the patient analysis 
populations. 
Screened patients are defined as any patients who met the inclusion criteria and signed the 
informed consent.  
Randomized patients consist of all patients with a signed informed consent form who have had a 
treatment kit number allocated and recorded in the IRT database, regardless of whether the 
treatment kit was used. 
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For patient study status, the total number of patients in each of the following categories will be 
presented in the clinical study report using a summary table: 
 Screened patients. 
 Screen failure patients and reasons for screen failure. 
 Non-randomized but treated patients. 
 Randomized patients. 
 Randomized but not treated patients and reason for not being treated. 
 Randomized and treated patients. 
 Patients who complete and who did not complete the study treatment period as per 
protocol. 
 Patients who discontinued study treatment sorted by main reason for permanent treatment 
discontinuation. 
 Patients who complete and did not complete the study follow-up period as per protocol. 
 Patients who discontinued study sorted by main reason for study discontinuation. 
 Status at last study contact. 
For all categories of patients (except for the screened and non-randomized categories) percentages 
will be calculated using the number of randomized patients as the denominator. Reasons for 
treatment and study discontinuation will be supplied in tables giving numbers and percentages by 
treatment group. 
The cumulative incidence of premature treatment discontinuation (irrespective of the reason) and 
premature treatment discontinuation due to AEs will be presented graphically by treatment arm 
using Kaplan-Meier method. Not treated patients will be considered with event at Day 1 (day of 
randomization). All completers will be considered as right-censored observations. For randomized 
and treated patients, the time-to-event or censoring variable is defined as: last IMP administration 
date - randomization date + 7 days. 
The cumulative incidence of premature study discontinuation will be presented graphically by 
treatment arm using Kaplan-Meier method. All completers will be considered as right-censored 
observations. The time-to-event of censoring variable is defined as:  
end of study date - randomization date + 1 day, where end of study date is the date of last 
successful contact or visit, whichever comes last, or, for patients who died before this date, the 
date of death. 
A patient is considered lost to follow-up at the end of the study if he/she is not assessed at the last 
protocol-planned visit and if the time from the last successful contact or visit, whichever comes 
last, to the last protocol-planned visit is greater than 2 days. 
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All critical or major deviations potentially impacting efficacy analyses, randomization, and 
drug-dispensing irregularities, and other major or critical deviations will be summarized in tables 
giving numbers and percentages of deviations by treatment group. 
Additionally, the analysis populations for safety, efficacy, anti-SAR156597 antibody (ADA) and 
pharmacokinetics will be summarized in a table by number of patients on the randomized 
population.  
 
Efficacy population: intent-to-treat (ITT) population.  
 
Safety population. 
 
Anti-SAR156597 antibody population. 
 
Pharmacokinetics population. 
 
Biomarkers populations. 
2.2.1 Randomization and drug dispensing irregularities 
Randomization and drug-dispensing irregularities occur whenever: 
1. A randomization is not in accordance with the protocol-defined randomization method, 
such as  
a) An ineligible patient is randomized,  
b) A patient is randomized based on an incorrect stratum, or 
c) A patient is randomized twice. 
OR 
2. A patient is dispensed an IMP kit not allocated by the protocol-defined randomization, 
such as  
a) A patient at any time in the study is dispensed a different treatment kit than as 
randomized (which may or may not contain the correct-as-randomized IMP), or  
b) A non-randomized patient is treated with IMP reserved for randomized patients. 
Randomization and drug-dispensing irregularities will be monitored throughout the study and 
reviewed on an ongoing basis.  
All randomization and drug-dispensing irregularities will be documented in the clinical study 
report. If the number of irregularities is large enough to make a tabular summary useful, the 
irregularities will be categorized and summarized among randomized patients (number and 
percentages). Non-randomized, treated patients will be described separately. 
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Randomization and drug-dispensing irregularities to be prospectively identified include but are 
not limited to:  
 
Randomization and drug allocation irregularities 
Kit dispensation without IRT transaction 
Erroneous kit dispensation (IMP number actually administered to the subject is different from the IMP number allocated by IRT) 
Kit not available 
Stratification error (Wrong stratum of randomization) 
Patient switched to another site 
Randomization of a non-existent subject 
2.3 
ANALYSIS POPULATIONS 
Patients treated without being randomized will not be considered randomized and will not be 
included in any efficacy population. The safety experience of these patients will be reported 
separately, and these patients will not be in the safety population.  
The randomized population includes any patient who has been allocated to a randomized 
treatment regardless of whether the treatment kit was used. 
For any patient randomized more than once, only the data associated with the first randomization 
will be used in any analysis population. The safety experience associated with any later 
randomization will be assessed separately. 
The safety experience of patients treated and not randomized will be reported separately, and 
these patients will not be in the safety population. 
2.3.1 Efficacy populations 
2.3.1.1 Intent–to-treat population 
The intent-to-treat population is defined as all randomized patients. Patients in the ITT population 
will be analyzed according to the treatment group allocated by randomization.  
2.3.2 Safety population 
The safety population is defined as randomized patients who actually received at least 1 dose or 
part of a dose of the IMP, analyzed according to the treatment actually received. 
In addition:  
 Randomized patients for whom it is unclear whether they took the IMP will be included in 
the safety population as randomized. 
 For patients receiving more than 1 IMP during the trial, the treatment group allocation for 
as-treated analysis will be the one received in the majority of injections. 
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2.3.3 Anti-SAR156597 antibody (ADA) population 
The anti-SAR156597 antibody analysis will be performed on all randomized and treated patients 
(safety population) with at least one baseline and post dose ADA sample with a reportable result. 
Patients will be analyzed according to the treatment actually received. 
2.3.4 Pharmacokinetics population 
The PK population will include all randomized and treated patients (safety population) with at 
least one post-dose, non-missing plasma concentration value. 
2.3.5 Biomarker population 
Baseline biomarker population includes the randomized and treated patients with a baseline 
sample successfully analyzed.  
Pharmacodynamics biomarker population includes the randomized and treated patients with a 
baseline sample and at least one post first double-blind IMP injection sample successfully 
analyzed.  
2.4 
STATISTICAL METHODS 
Continuous data will be summarized using the number of available data, mean, SD, median, 
minimum, Q1, Q3 and maximum for each treatment group. Categorical and ordinal data will be 
summarized using the number and percentage of patients in each treatment arm. 
2.4.1 Demographics and baseline characteristics 
Parameters will be summarized on the randomized population analyzed in the treatment arm to 
which they were randomized. Analyses for the safety population will be included in the 
appendices if the size of the safety population is different (>10%) from the size of that in the 
primary analysis population for any treatment group. 
Parameters described in Section 2.1.1 will be summarized by treatment group and overall 
treatment groups using descriptive statistics.  
The disease duration, mRSS, FVC and DLCO at baseline will be also summarized by 
stratification factor (as per IRT).  
Medical/surgical history will be summarized in each treatment arm by primary SOC and PT. 
Events will be sorted by SOC internationally agreed order and decreasing frequency of PT based 
on the incidence in the overall treatment arm. 
P-values on demographic and baseline characteristic data will not be calculated.  
No specific description of the safety parameters will be provided at baseline. If relevant, the 
baseline values will be described along with each safety analysis. 
No specific description of the efficacy parameters will be provided at baseline. If relevant, the 
baseline values will be described along with each efficacy analysis. 
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2.4.2 Prior or concomitant medications  
The prior and concomitant medications will be presented for the randomized population.  
Medications will be summarized by treatment group according to the WHO-DD, considering the 
first digit of the anatomic category (ATC) class (anatomic category) and the first 3 digits of the 
ATC class (therapeutic category). All ATC codes corresponding to a medication will be 
summarized, and patients will be counted once in each ATC category (anatomic or therapeutic) 
linked to the medication. Therefore patients may be counted several times for the same 
medication.  
The table for prior medications will be sorted by decreasing frequency of ATC followed by all 
other therapeutic classes based on the overall incidence across treatment groups. In case of equal 
frequency regarding ATCs (anatomic or therapeutic categories), alphabetical order will be used. 
Patients who received background therapy are defined as all patients who took a medication from 
the anatomic classes of “antineoplastic/immunomodulating agents” and/or “systemic hormonal 
preparations, excl. sex hormones and insulins” (see Appendix J) before and at baseline. 
The second definition of patients who received background therapy is defined as all patients taken 
“methotrexate, mycophenolate mofetil, azathioprine, ciclosporin, and cyclophosphamide”  
(see Appendix J) before and at baseline.  
The tables for concomitant and post-treatment medications will be sorted by decreasing frequency 
of ATC followed by all other therapeutic classes based on the incidence in the SAR156597 group. 
In case of equal frequency regarding ATCs (anatomic or therapeutic categories), alphabetical 
order will be used.  
The patients who took a rescue medication during the study are defined according to the deviation 
“Prohibited use of immunosuppressive therapies as concomitant medications”. 
2.4.3 Extent of investigational medicinal product exposure and compliance  
The extent of IMP exposure and compliance will be assessed and summarized by actual treatment 
within the safety population (Section 2.3.2). 
2.4.3.1 Extent of investigational medicinal product exposure 
The extent of IMP exposure will be assessed by the duration of IMP exposure. 
Duration of IMP exposure in weeks is defined as (last dose date + 7 - first dose date)/7 days, 
regardless of unplanned intermittent discontinuations (see Section 2.5.3 for calculation in case of 
missing or incomplete data). 
Duration of IMP exposure will be summarized descriptively as a quantitative variable (number, 
mean, SD, median, minimum, and maximum) expressed in weeks. In addition, duration of 
treatment exposure will also be summarized categorically by numbers and percentages for each of 
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the following categories and cumulatively according to these categories: ≥1 day and  
<2 weeks, ≥2 weeks and <4 weeks, ≥4 weeks and <6 weeks, ≥6 weeks and <12 weeks, ≥12 weeks 
and <16 weeks, ≥16 weeks and <20 weeks, ≥20 weeks and <24 weeks, ≥24 weeks and <36 weeks. 
Non-integer values will be rounded to 1 decimal place. 
Additionally, the cumulative duration of treatment exposure will be provided, defined as the sum 
of the duration of treatment exposure for all patients, and will be expressed in patient-years. 
2.4.3.2 Compliance 
A given administration will be considered non-compliant if the patient did not take the planned 
dose of treatment as required by the protocol. No imputation will be made for patients with 
missing or incomplete data. 
Overall percentage of compliance for a patient will be defined as 100 - (% days with 
below-planned dosing + % days with above-planned dosing), considering that injections should be 
performed every week ±2 days as per protocol. 
Above-planned dosing percentage for a patient will be defined as 100 * the number of days with 
more than 1 injection administration within the 5 days before divided by the duration of IMP 
injection exposure in days. 
Below-planned dosing percentage for a patient will be defined as 100 * the number of days with 
no injection administration within the previous 9 days divided by the duration of IMP injection 
exposure in days. 
Treatment compliance, above-planned, and under-planned dosing percentages will be summarized 
descriptively as quantitative variables (number, mean, SD, median, minimum, and maximum). 
The percentage of patients whose compliance is <80% will be summarized. In addition, numbers 
and percentages of patients with [0;5], ]5;10], ]10;20], and >20% of days with above or 
under-planned dosing will also be provided. 
In addition, the following parameters will be summarized by treatment arm: 
 The number of advanced injections (≤3 days apart from the previous injection, 4 days 
apart from the previous injection) and the number of delayed injections (more than 9 days 
between two consecutive injections).  
 The number of patients with at least one advanced injection and the number of patients 
with at least one delayed injection. A patient could be counted in several categories.  
 The frequency of IMP injections (mean (SD), median, Min:Max description) will be 
defined for each patient as the average number of days between two consecutive 
injections: (last injection date - first injection date)/(number of injections -1) for patients 
with at least 2 injections. 
Cases of overdose are reported in the AE e-CRF pages as AESI if symptomatic or AE if 
asymptomatic. The reported cases of overdose will be described in the AE analysis  
(see Section 2.1.5 and Section 2.4.5.1). 
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2.4.4 Analyses of efficacy endpoints 
All efficacy measurements, scheduled or unscheduled, will be assigned to time points according 
to analysis windows as defined in Table 3.  
All endpoints will be described at each visit on the ITT population. 
2.4.4.1 Analysis of primary efficacy endpoint(s) 
2.4.4.1.1 Primary efficacy analysis 
The primary estimand will be the difference in mean change from baseline to 24 weeks in mRSS 
in all randomized patients, regardless of whether or not patients completed the treatment period. 
This estimand corresponds to a “treatment policy strategy”.  
A spaghetti plot presentation of individual data by treatment group will be presented.  
The change in mRSS from baseline to Week 24 will be analyzed in the ITT population using 
a MMRM approach. All post-baseline data available from Week 4 to Week 24 analysis windows 
will be included in the analysis, regardless of adherence to treatment. The lower the mRSS is, the 
better it is for the patient.  
Missing data will be accounted for by the MMRM. The model includes the fixed categorical 
effects of treatment group (placebo, SAR156597), randomization strata (as per IRT,  
SSc-ILD: Yes/No), time point (Week 4, Week 8, Week 12, Week 24 as defined in Section 2.5.4), 
randomization strata-by-time point interaction and treatment-by-time point interaction, as well as 
the continuous fixed covariates of baseline mRSS value and baseline value-by-time point 
interaction.  
This model will be run using SAS Mixed procedure. The repeated-measures analysis will be 
based on the restricted maximum likelihood method (Newton-Raphson algorithm) assuming an 
unstructured correlation matrix to model the within-patient errors. Denominator degrees of 
freedom will be estimated using Kenward-Roger approximation. This model will provide baseline 
adjusted LSmeans estimates at Week 24 for both treatment groups with their corresponding 
standard errors (SEs) and 95% confidence intervals (CIs). To compare SAR156597 to the placebo 
group, an appropriate contrast statement will be used to test the difference of these estimates at the 
5% one-sided alpha level. The 95% and 90% confidence intervals of the difference will be 
provided. Let µ0 and µ1 be the population means of the change from baseline in mRSS at  
Week 24 under placebo and SAR156597, respectively. The null hypothesis that will be tested is 
“H0: µ0=µ1” versus “H1: µ0 >µ1”. 
The MMRM model relies on the “missing-at-random” (MAR) assumption. As we can never 
exclude the possibility for a not-missing-at-random (NMAR) missingness mechanism, if more 
than 5 patients have no value for mRSS data at Week 24, a sensitivity analysis to explore the 
impact of non-ignorable missingness on the primary efficacy analysis will be conducted  
(see control-based pattern imputation model defined in Section 2.4.4.1.7). 
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2.4.4.1.2 Analysis of residuals 
The analysis of the residuals of the MMRM will be primarily based on studentized residuals. The 
studentized residuals will be presented graphically using histogram and QQ-plot. 
2.4.4.1.3 On-treatment analysis 
A secondary estimand will be the difference in mean change from baseline to 24 weeks in mRSS 
estimated during the on-treatment period (from the first administration of the IMP to the last 
administration of the IMP + 7 days). This estimand corresponds to a “while on treatment 
strategy”. This estimand will be considered for describing the effect of treatment as long as 
patients adhere to their randomized treatment. 
As a secondary analysis, the change in mRSS from baseline to Week 24 will also be analyzed in 
the randomized and treated population using the same MMRM model as described above, 
including only post-baseline data measured during the on-treatment period (from the first 
administration of the IMP to the last administration of the IMP + 7 days), analyzed according to 
the treatment group allocated by randomization.  
2.4.4.1.4 Sensitivity to error in randomization strata 
In order to assess the robustness of the primary analysis to randomization stratum mistakes  
(ie, the stratum recorded in IRT differs from the actual one), if more than 15% of patients have 
been randomized to the wrong stratum, the MMRM model will be re-run including the actual 
stratum as per the eCRF instead of the stratum recorded in IRT. 
2.4.4.1.5 Sensitivity analysis on rater 
In order to assess the impact of different raters evaluating a same patient from baseline, the 
MMRM model will be re-run using only mRSS values from all visits evaluated by the same rater 
as baseline. All other values evaluated by different rater from baseline will be considered missing 
at random in this sensitivity analysis. 
2.4.4.1.6 Sensitivity analysis on high mRSS 
The MMRM model will be re-run using only patients with mRSS score superior or equal to 15 at 
baseline.  
2.4.4.1.7 Control-based pattern imputation 
In addition to the MMRM method, the control-based pattern imputation method will be used to 
address missing values, in the randomized population, followed by the testing of treatment arms 
using an analysis of covariance (ANCOVA) model, with the intent to evaluate the robustness of 
the primary analysis using a different statistical method.  
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Imputation rules 
The control-based pattern imputation assumes: 
 After treatment discontinuation (defined for this analysis as last injection + 7 days), 
patients from the experimental treatment arm (no longer receiving the experimental 
treatment) will exhibit the same future evolution of the disease as patients on the control 
treatment (who are also not exposed to the experimental treatment). In this experimental 
arm, missing values before treatment discontinuation will be considered missing at random 
and will be imputed using a model estimated using only samples from the experimental 
arm collected before treatment discontinuation.  
 Missing on-treatment mRSS values in the experimental arm will be imputed from other 
on-treatment measurements in the experimental arm assuming MAR, using SAS® MI 
procedure. Only mRSS values collected during the on-treatment period will be included in 
the imputation model. This way, missing mRSS values during the on-treatment period will 
be imputed based solely on observed on-treatment mRSS values. The imputation model 
will include the randomization strata (as per IRT, SSc-ILD: Yes/No), baseline mRSS 
value, and all time points (Week 4, Week 8, Week 12, Week 24). Since the pattern of 
missing data will be non-monotone, a Monte-Carlo Markov Chain (MCMC) method will 
be used. A minimum value of 0 and a maximum value of 51 will be specified in order to 
respect the range value for mRSS.  
 Whatever the timing of treatment discontinuation, patients who discontinue from the 
control arm are assumed to evolve in the same way as control patients who remain in the 
study. Therefore, their missing values will be considered as missing at random and 
imputed using a model estimated using all samples collected from the control arm.  
Imputation method 
To account for the uncertainty, missing values will be imputed 100 times to generate 
100 complete datasets, using the MI SAS procedure. The change from baseline at Week 24 will be 
then derived from observed and imputed mRSS at this time point.  
The 100 complete datasets will be then analyzed using an ANCOVA model with treatment group 
and randomization strata (as per IRT, as defined in Section 1.1) as fixed effects, and the baseline 
mRSS value as continuous covariate, and change in mRSS from baseline to Week 24 as explained 
variable. The MIANALYZE SAS procedure will be used to generate valid statistical inferences by 
combining results from the 100 analyses using Rubin’s formulae. 
The number of imputations (100) will be informally verified by replicating sets of 
100 imputations and checking whether the combined results are stable. If not stable, the number 
of imputations will be increased and informally checked as above, and thus until stable estimates 
are obtained. 
Non continuous variables included in the imputer’s model (ie, treatment group, randomization 
strata) are not expected to be missing. 
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Only imputed values during the on-treatment period will be kept in the final datasets that will be 
analyzed using ANCOVA. Imputed values during the post-treatment period will be discarded and 
replaced by imputed values described in the next paragraph. 
Imputation programming 
In order to implement the control-based pattern imputation, we will break the imputation process 
into a sequence of multiple calls to PROC MI, where each call is intended to impute missing 
values at one time-point only. The general logic of such a strategy is as follows. 
1. With each call to PROC MI, impute only one time-point using a regression-based MI 
method for monotone missingness. Variables included in the regression model are 
randomization strata and mRSS values from previous time-points (including baseline).  
2. When imputing missing values for time-point t, the input dataset should include all control 
patients, but only those patients from the experimental arm who have values at time-point t 
missing (only those who need imputation at time-point t). Since patients from the 
experimental arm with non-missing values at time-point t are not included in the input 
dataset, they will not contribute to the estimation of an imputation model for time-point t. 
The imputation model will then be estimated using control patients only, while this call to 
PROC MI will impute missing data at time-point t for all patients who need imputation at 
that time-point. This way, patients from experimental arm will be imputed based on the 
control patients’ model. Note that treatment arm should not be included as an effect in this 
model.  
3. Repeat (2.) for all other time-points sequentially. Patients whose missing values were 
imputed in the last call to PROC MI will be included in the input dataset for the next call 
to PROC MI except for patients in the experimental arm having non-missing data at 
time-point t+1 (patients with non monotone missingness). Thus data for time-point t, 
imputed during the last call, will be used as predictor variables in the next call to PROC 
MI (for time-point t+1) (6).  
This imputation allows the patient to continue from the level achieved under the active treatment 
as though it had been achieved under the reference treatment. One consequence is that if a patient 
on active is above the reference mean then this positive residual will feed through into subsequent 
observations, to a degree determined by the correlation pattern in the referenced arm. Hence, the 
patient’s profile will slowly decay back toward the mean for reference at later times (7).  
The imputed mRSS data will be between 0 and 51 (range value for mRSS score). 
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2.4.4.1.8 Subgroup analyses 
To assess the homogeneity of the treatment effect across various subgroups, 
treatment-by-subgroup factor and time point-by-subgroup factor interaction terms and a subgroup 
factor term will be added in the primary MMRM model. Within each subgroup, baseline adjusted 
LSmeans estimates at Week 24 will be provided for both treatment groups with their 
corresponding SEs and 95% CIs, as well as their difference with the corresponding 95% and  
90% Cis. Subgroups of interest are: 
 Randomization stratum (as per IRT). 
 Gender (male/female). 
 Both Background therapy (yes/no) definitions defined in Section 2.4.2. 
 Disease duration of non-Raynaud’s phenomenon (<20 months vs ≥20 months). 
 Auto antibodies (Centromere Antibodies, RNA Polymerase III Antibody,  
Scl-70 Antibody, [if size allows] and ANA staining pattern [Centromere vs. 
Non-Centromere staining pattern]). 
 Geographical region (Estonia, Romania, Russia, Poland and Ukraine vs Rest of the 
World). 
2.4.4.2 Analyses of secondary efficacy endpoints 
All secondary endpoints are described in Section 2.1.3.2 and will be analyzed using the ITT 
population.  
Change in continuous secondary efficacy endpoints (HAQ-DI composite score, observed FVC, 
observed DLco [corrected for hemoglobin]) from baseline to Week 24 will be analyzed using the 
same MMRM model as for the primary endpoint. Specifically, the model will contain fixed 
categorical effects of treatment group (placebo, SAR156597), randomization strata (as per IRT, 
SSc-ILD: Yes/No), time point (Week 4 [only for HAQ-DI], Week 8 [only for HAQ-DI], Week 12 
and Week 24), randomization strata-by-time point interaction and treatment-by-time point 
interaction, as well as the continuous fixed covariates of corresponding baseline value and 
baseline-by-time point interaction. All post-baseline data available from Week 4 for HAQ-DI, 
Week 12 for FVC and DLco, to Week 24 analysis windows will be included in the analysis, 
regardless of adherence to treatment. Missing data will be accounted for by the MMRM. The 
studentized residuals of the MMRM will be analyzed as for the primary endpoint. 
This model will provide baseline adjusted LSmeans estimates at Week 24 for both treatment 
groups with their corresponding standard errors (SEs) and 95% CIs. The SAR156597 to placebo 
difference of these estimates will be provided with its corresponding 95% and 90% CIs and 
p-value. 
Within each randomization stratum (as per IRT, SSc-ILD: Yes/No), baseline adjusted LSmeans 
estimates at Week 24 will also be provided for both treatment groups with their corresponding 
SEs and 95% CIs, as well as their difference with the corresponding 95% and 90% CIs. 
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In order to assess the robustness of the analyses to randomization stratum mistakes (ie, the stratum 
recorded in IRT differs from the actual one), if more than 15% of patients have been randomized 
to the wrong stratum, the MMRM model will be re-run including the actual stratum as per the 
eCRF instead of the stratum recorded in IRT. 
In addition, the observed FVC at Week 24 will also be analyzed through a linear mixed effects 
model. The model will assume random intercept and random slope to take into account 
between-subject heterogeneity and assume a linear evolution of the observed FVC over time 
(time will be included as a continuous variable in the model). The analysis will be also adjusted 
for fixed categorical effects of treatment group (placebo, SAR156597), randomization strata (as 
per IRT, SSc-ILD: Yes/No). The following interaction terms will be added to the model: 
treatment-by-time and randomization strata-by-time. All the visits are taken into account in this 
analysis.  
2.4.4.3 Multiplicity issues 
No adjustment will be made. For secondary and exploratory efficacy endpoints, p-values will be 
provided for descriptive purpose only. 
2.4.4.4 Analyses of exploratory efficacy endpoints 
All exploratory endpoints are described in Section 2.1.4 and will be analyzed using the ITT 
population unless otherwise specified.  
Change in continuous exploratory efficacy endpoints from baseline to Week 24 will be analyzed 
using the same MMRM model as for the primary and continuous secondary efficacy endpoints. 
Specifically, the model will contain fixed categorical effects of treatment group, randomization 
strata (as per IRT), time point, randomization strata-by-time point interaction and 
treatment-by-time point interaction, as well as the continuous fixed covariates of corresponding 
baseline value and baseline-by-time point interaction. All post-baseline data available from 
Week 4 to Week 24 analysis windows will be included in the analysis, regardless of adherence to 
treatment.  Missing data will be accounted for by the MMRM. This model will provide baseline 
adjusted LSmeans estimated at Week 24 in both treatment groups with their corresponding  
95% CIs. The SAR156597 to placebo differences of these estimates will be provided with its 
corresponding 95% and 90% CIs and p-value. 
Change in continuous exploratory efficacy endpoints from baseline to Week 35 will be analyzed 
using the same model. All post-baseline data available from Week 4 to Week 35 analysis 
windows will be included in the analysis, regardless of adherence to treatment. 
2.4.4.4.1 mRSS 
Responder rates (proportion of patients with an improvement from baseline in mRSS of at least 
20%, 40% and 60%) at Week 24 and Week 35 will be analyzed using a logistic regression with 
the categorical effects of treatment group and randomization strata (as per IRT) and the 
continuous effect of mRSS at baseline. This model will provide the SAR156597 to placebo odds 
ratio estimate and its 95% and 90% confidence intervals. The p-value will be obtained from the 
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Wald Chi-square test. Patients with missing value at Week 24, respectively Week 35, will be 
considered as non-responders. Cumulative distribution function (CDF) graphs will be also 
presented (percentage of patients according to the relative improvement from baseline in mRSS) 
at W24 and W35.  
Furthermore, the change from baseline to Week 35 will be analyzed using the MMRM model 
described in Section 2.4.4.4. 
Three supplementary definitions for responder rate at Week 24 will be used and analyzed using a 
logistic regression with the categorical effects of treatment group and randomization strata (as per 
IRT) and the continuous effect of mRSS at baseline: 
 Responder rate defined as the proportion of patients with an improvement from baseline in 
mRSS of at least 25% at Week 24. 
 Responder rate defined as the proportion of patients with an improvement from baseline in 
mRSS of at least 25% at Week 24 and no intake of rescue medication.  
 Overall responder rate defined as the proportion of patients with an improvement from 
baseline in mRSS of at least 25% and without CRISS event and no intake of rescue 
medication and alive at W24 are defined as responder.  
2.4.4.4.2 VAS from SHAQ 
Change in VAS from SHAQ from baseline to Week 24 and from baseline to Week 35 will be 
analyzed using the MMRM model described in Section 2.4.4.4. 
CDF graphs will be also presented for each VAS (percentage of patients according to the relative 
improvement from baseline in VAS) at Week 24 and Week 35.  
2.4.4.4.3 UCLA SCTC GIT 2.0 score 
Change in UCLA SCTC GIT 2.0 score from baseline to Week 24 and from baseline to Week 35 
will be analyzed using the MMRM model described in Section 2.4.4.4. 
2.4.4.4.4 TJC28 
Change in TJC28 from baseline to Week 24 and from baseline to Week 35 will be analyzed using 
the MMRM model described in Section 2.4.4.4. 
2.4.4.4.5 Digital ulcer count 
Change in digital ulcer count (sum of active or new plus indeterminate/healing digital ulcers 
secondary to SSc) from baseline to Week 24 and from baseline to Week 35 will be analyzed using 
the MMRM model described in Section 2.4.4.4. 
The digital ulcer count, as well as the subcategories: number of active/new ulcers and number of 
indeterminate/healing ulcers, will also be descriptively summarized by treatment group and by 
time point.   
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2.4.4.4.6 EQ-5D-5L  
Change in EQ-5D-5L (VAS and index) from baseline to Week 24 and from baseline to Week 35 
will be analyzed using the MMRM model described in Section 2.4.4.4. The EQ-5D-5L (index and 
VAS) will be summarized descriptively at each time point.  
CDF graphs will be also presented for EQ-5D-5L index and EQ-5D-5L VAS (percentage of 
patients according to the relative improvement from baseline in EQ-5D-5L value [index or VAS]) 
at Week 24 and Week 35.  
2.4.4.4.7 HAQ-DI 
Change in HAQ-DI total score from baseline to Week 35 will be analyzed using the MMRM 
model described in Section 2.4.4.4.  
CDF graphs will be also presented (percentage of patients according to the relative improvement 
from baseline in HAQ-DI) at Week 24 and Week 35.  
2.4.4.4.8 FVC 
Due to the non-normality of the distribution of % predicted FVC, the change from baseline at 
Week 24, respectively Week 35, will be analyzed using a rank-based analysis of covariance  
(rank analysis of covariance [ANCOVA]) model adjusted for baseline and stratified on 
randomization stratum (as per IRT). This model will use the ranks of absolute change from 
baseline to Week 24 (respectively Week 35) in % predicted FVC as the outcome and the ranks of 
baseline % predicted FVC as a covariate stratified on the stratification factor (with/without ILD). 
In case of ties, the mean of the corresponding ranks will be assigned.  
The ranking will be done within each stratum of the stratification factor (with/without ILD) in 
ITT population (both treatment groups combined).  
 Missing data due to death will be ranked based on a time-to-death, with shortest time until 
death as the worst (lowest) rank (from 1 to nstratum, death).  
 Absolute change from baseline at Week 24 (respectively Week 35) in % predicted FVC 
values will be calculated from Week 24 (respectively Week 35) % predicted FVC values 
and then ranked (from nstratum, death + 1 to nstratum). 
 Standardization of ranks using SAS PROC RANK. 
Furthermore, the adjustment on baseline % predicted FVC covariate will be done. The residuals 
from the linear regression of response ranks on baseline ranks will be calculated within each 
stratum of the stratification factor (with/without ILD).  
Finally, treatment effect will be tested using the residuals as scores. The active treatment group 
will be compared to placebo using a Mantel-Haenszel mean score chi-square test at a one-sided 
Type-I error level of 5%. This test will be stratified on the stratification factor.  
In case of more than 20% of missing data on the % predicted FVC value at Week 24, missing data 
will be imputed following methods described in Section 2.5.2. Otherwise, the data will not be 
imputed. 
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Furthermore, the change in observed FVC from baseline to Week 35 will be analyzed using the 
MMRM model described in Section 2.4.4.4. 
The number of patients with an absolute decreased % predicted FVC from baseline at W24 
superior or equal to 5% and respectively 10% will be presented by treatment group. 
2.4.4.4.9 DLco  
Same rank ANCOVA as for % predicted FVC will be done for the change in % predicted DLco 
from baseline at Week 24 and Week 35, using % predicted DLco as the outcome and the ranks of 
baseline % predicted DLco as a covariate stratified on the stratification factor.  
Furthermore the change in observed DLco (corrected for hemoglobin) from baseline to Week 35 
will be analyzed using the MMRM model described in Section 2.4.4.4. 
The number of patients with an absolute decreased % predicted DLCO from baseline at W24 
superior or equal to 5% and respectively 10% will be presented. 
2.4.4.4.10 CRISS  
The distribution of the predicted probability of improving obtained using the CRISS at Week 24 
and Week 35 will be compared between SAR156597 and the placebo group using a Van Elteren’s 
test stratified on randomization strata.  
In case of more than 20% of missing data on the CRISS value at Week 24, missing data will be 
imputed following methods described in Section 2.5.2. Otherwise, the data will not be imputed. 
In addition, rate of patients for whom the predicted probability of improving obtained using the 
CRISS at Week 24 and Week 35 is ≥60% will be provided.  
2.4.5 Analyses of safety data 
The summary of safety results will be presented by treatment group.  
General common rules 
All safety analyses will be performed on the safety population as defined in Section 2.3.2, unless 
otherwise specified, using the following common rules: 
 Safety data in patients who do not belong to the safety population (eg, exposed but not 
randomized) will be listed separately. 
 The baseline value is defined as the last available value before the first administration of 
the IMP. 
 The potentially clinically significant abnormality (PCSA) values are defined as abnormal 
values considered medically important by the Sponsor according to predefined 
criteria/thresholds based on literature review and defined by the Sponsor for clinical 
laboratory tests, vital signs, and ECG (PCSA version dated May 2014 [Appendix A]). 
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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 treatment-emergent PCSA percentage. 
 The treatment-emergent PCSA denominator by group for a given parameter will be based 
on the number of patients assessed for that given parameter in the TEAE period by 
treatment group on the safety population. 
 For quantitative safety parameters based on central laboratory/reading measurements, 
descriptive statistics will be used to summarize results and change from baseline values by 
visit (baseline and post-baseline time points) and treatment group. Summaries will include 
the last and the worst on-treatment value. Only data sampled before or on the day of the 
last IMP administration will be included in the analysis. The worst on-treatment value is 
defined as the nadir and/or the peak post-baseline before or on the day of the last IMP 
administration according to the direction (minimum or maximum) of the abnormality as 
defined in the PCSA list. 
 All measurements (scheduled or unscheduled) will be assigned to time points according to 
analysis windows as defined in Section 2.5.4.  
 The analysis of the safety variables will be essentially descriptive and no systematic 
testing is planned. Relative risks versus placebo and their 95% confidence intervals may 
be provided, if relevant. 
2.4.5.1 Analyses of adverse events 
Generalities 
The primary focus of adverse event reporting will be on TEAEs. Pre-treatment and post-treatment 
adverse events will be described separately.  
If an adverse event date/time of onset (occurrence, worsening, or becoming serious) is incomplete, 
an imputation algorithm will be used to classify the adverse event as pre-treatment, 
treatment-emergent, or post-treatment. The algorithm for imputing date/time of onset will be 
conservative and will classify an adverse event as treatment emergent unless there is definitive 
information to determine it is pre-treatment or post-treatment. Details on classification of adverse 
events with missing or partial onset dates are provided in Section 2.5.3. 
Adverse event incidence tables will present by SOC, HLGT, HLT, and PT, sorted in alphabetical 
order for each treatment group, the number (n) and percentage (%) of patients experiencing an 
adverse event. 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. 
Sorting within tables ensures the same presentation for the set of all adverse events within the 
observation period (pre-treatment, treatment-emergent, and post-treatment). For that purpose, the 
table of all TEAEs presented by SOC and PT sorted by the internationally agreed SOC order and 
decreasing frequency of PTs within SOCs will define the presentation order for all other tables 
unless otherwise specified. Sorting will be based on results for the experimental treatment arm. 
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 Analysis of all treatment-emergent adverse events 
The following TEAE summaries will be generated for the safety population. 
 Overview of TEAEs, summarizing number (%) of patients with any 
- 
TEAE, 
- 
Serious TEAE, 
- 
TEAE leading to death, 
- 
TEAE leading to permanent treatment discontinuation. 
 All TEAEs by primary SOC, HLGT, HLT, and PT, showing number (%) of patients with 
at least 1 TEAE sorted by the SOC internationally agreed order. The other levels (HLGT, 
HLT, PT) will be presented in alphabetical order. 
 All TEAEs by primary SOC and PT, showing the number (%) of patients with at least  
1 TEAE, sorted by the internationally agreed SOC order and by decreasing incidence of 
PTs within each SOC. This sorting order will be applied to all other tables, unless 
otherwise specified. 
 All TEAEs regardless of relationship and related to IMP by primary SOC, HLGT, HLT 
and PT, showing the number (%) of patients with at least 1 TEAE, sorted by the 
internationally agreed SOC order. The other levels (HLGT, HLT, PT) will be presented in 
alphabetical order. 
 All TEAEs by maximal severity, presented by primary SOC and PT, showing the  
number (%) of patients with at least 1 TEAE by maximal severity (ie, mild, moderate, or 
severe), sorted by the sorting order defined above. 
Analysis of all treatment emergent SAEs 
 All treatment-emergent SAEs by primary SOC, HLGT, HLT, and PT, showing the  
number (%) of patients with at least 1 serious TEAE, sorted by the internationally agreed 
SOC order. The other levels (HLGT, HLT, PT) will be presented in alphabetical order. 
 All treatment-emergent SAEs by primary SOC and PT, showing the number (%) of 
patients with at least 1 serious TEAE, sorted by the sorting order defined above.  
 All treatment-emergent SAEs regardless of relationship and related to IMP, by primary 
SOC, HLGT, HLT, and PT, showing the number (%) of patients with at least  
1 treatment-emergent SAE, sorted by the internationally agreed SOC order. The other 
levels (HLGT, HLT, PT) will be presented in alphabetical order. 
 Listings will be provided for all SAEs by treatment arm during the TEAE period. 
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Analysis of all TEAEs leading to treatment discontinuation 
 All TEAEs leading to treatment discontinuation, by primary SOC, HLGT, HLT, and PT, 
showing the number (%) of patients sorted by the internationally agreed SOC order. The 
other levels (HLGT, HLT, PT) will be presented in alphabetical order. 
 All TEAEs leading to treatment discontinuation, by primary SOC and PT, showing the 
number (%) of patients with at least 1 TEAE, sorted by the internationally agreed SOC 
order and by decreasing incidence of PTs within each SOC. 
 Listing will be provided for all TEAE leading to permanent treatment discontinuation by 
treatment arm. 
Analysis of treatment-emergent AESIs 
All treatment-emergent AESIs, by AESI category and PT, showing the number (%) of patients by 
treatment group, sorted by decreasing incidence of PT within each AESI category. The AESIs 
categories and details of the MedDRA coding are provided in Section 2.1.5.1. 
 Listing of all Treatment emergent AESIs experienced per patient and by treatment arm: 
Patient ID, AESI category, PT, time to onset of event, date of first and last IMP 
administration, duration, intensity, corrective treatment, seriousness, relationship to SAR. 
Analysis of pre-treatment and post-treatment adverse events  
If any pre-treatment or post-treatment AE lead to death or any pre-treatment AE lead to treatment 
discontinuation, a listing will be provided.  
2.4.5.2 Deaths 
The following summaries of deaths will be generated for the safety population by treatment 
group. 
 Number (%) of patients who died by study period (on-study, on-treatment, post-study).  
 Deaths in non-randomized patients or randomized but not treated patients. 
 TEAEs leading to death (death as an outcome on the adverse event case report form page 
as reported by the Investigator) by primary SOC, HLGT, HLT, and PT showing number 
(%) of patients sorted by internationally agreed SOC order, with HLGT, HLT, and PT 
presented in alphabetical order within each SOC.  
 Listings of deaths will be provided. 
2.4.5.3 Analyses of laboratory variables  
The summary statistics (including number, mean, median, standard deviation, minimum and 
maximum) of all laboratory variables (central laboratory values and changes from baseline) will 
be calculated for each visit (baseline and post-baseline time points) and presented by treatment 
group. This section will be organized by biological function as specified in Section 2.1.5.3. 
For parameters creatinine, glucose, neutrophils, monocytes, basophils, eosinophils and 
bicarbonate, the last on-treatment and worst on-treatment value will also be provided.  
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The incidence of PCSAs (list provided in Appendix A) at any time during the TEAE period will 
be summarized by biological function and treatment group whatever the baseline level and/or 
according to the following baseline status categories:  
 Normal/missing. 
 Abnormal according to PCSA criterion or criteria. 
For parameters for which no PCSA criteria are defined, similar table(s) using the normal range 
will be provided. 
Listing will be provided with flags indicating the out of range values as well as PCSA values.  
Drug-induced liver injury 
The liver function tests, namely AST, ALT, alkaline phosphatase, and total bilirubin, are used to 
assess possible drug-induced liver toxicity. The proportion of patients with PCSA values at any 
post-baseline visit by baseline status will be displayed by treatment group for each parameter.  
A graph of distribution of peak values of ALT versus peak values of total bilirubin will also be 
presented. Note that the ALT and total bilirubin values are presented on a logarithmic scale. The 
graph will be divided into 4 quadrants with a vertical line corresponding to 3 x ULN for ALT and 
a horizontal line corresponding to 2 x ULN for total bilirubin. 
The normalization (to ≤1 x ULN or return to baseline if baseline >ULN) of elevated liver function 
tests will be summarized for each parameter by categories of elevation (3 x, 5 x,  
10 x, 20 x ULN for ALT and AST, 1.5 x ULN for alkaline phosphatase, and 1.5 x and 2 x ULN 
for total bilirubin), with the following categories of normalization: no worsening as compared to 
the baseline PCSA status, returned to baseline PCSA status before last IMP dose, returned to 
baseline PCSA status after last IMP dose, never returned to baseline PCSA status, no assessment 
after the worst on-treatment value. Note that a patient will be counted only under the maximum 
elevation category. 
The incidence of liver-related adverse events will be summarized by treatment group. The 
selection of PTs will be based on the hepatic disorder SMQ.  
2.4.5.4 Analyses of vital sign variables 
The summary statistics (including number, mean, median, standard deviation, minimum and 
maximum) of all vital signs variables (values and changes from baseline) will be calculated for 
each visit (baseline and post-baseline time points) by treatment group. For parameters heart rate, 
systolic and diastolic blood pressures, the last on-treatment and worst on-treatment value will also 
be provided.  
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The incidence of PCSAs at any time during the TEAE period will be summarized by treatment 
arm irrespective of the baseline level and according to the following baseline status categories 
(only for SBP and DBP):  
 Normal/missing. 
 Abnormal according to PCSA criterion or criteria. 
Listing will be provided with flags indicating the out of range values as well as PCSA values.  
2.4.5.5 Analyses of electrocardiogram variables 
The summary statistics (including number, mean, median, standard deviation, minimum and 
maximum) of all ECG variables (values and changes from baseline) will be calculated for each 
visit (baseline and post-baseline time points) by treatment group.  
The incidence of PCSAs at any time during the TEAE period will be summarized by treatment 
group irrespective of the baseline level and according to the following baseline status categories:  
 Normal/missing. 
 Abnormal according to PCSA criterion or criteria. 
Listing will be provided with flags indicating the out of range values as well as PCSA values.  
2.4.6 Analyses of pharmacokinetic variables 
Ctrough concentrations of SAR156597 in plasma will be described on the PK population for each 
time point by treatment group using descriptive statistics (number of patients,  
arithmetic mean (SD), geometric mean, coefficient of variation, minimum and maximum).  
In a separate table, Ctrough,av,ss and CFollow-up will be described on the PK population by treatment 
group using descriptive statistics (number of patients, arithmetic mean (SD), geometric mean, 
coefficient of variation, minimum and maximum). 
The graphical representation of time profiles for Ctrough concentration (mean ±SD or Median, as 
appropriate) will be also provided by treatment group. Average steady state achievement will be 
performed by visual inspection of mean plots. 
According to study results, additional plots will be prepared, as deemed necessary (eg, to explore 
the relationship with some safety or efficacy endpoints of interest).  
The results of population PK modeling will be reported separately from the study report. 
2.4.7 Analyses of immunogenicity data 
The following summaries will be performed on the ADA population, taking into account all 
samples regardless of timing in relation to injections: 
 ADA results (negative, positive or inconclusive) by time point and by treatment arm.  
 Neutralizing status (inconclusive or positive) for positive ADA by time point and by 
treatment arm. 
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 ADA titers using descriptive statistics (median, Q1, Q3, minimum and maximum) for 
positive ADA by time point and by treatment arm. 
 Number (%) of patients with pre-existing ADA and number (%) of patients with 
treatment-emergent ADA positive response by treatment arm. 
 Number (%) of patients with persistent/transient/indeterminate treatment-emergent ADA 
positive response by treatment arm.  
 Time to onset of treatment-emergent ADA positive response (in days) using descriptive 
statistics by treatment arm and also according to peak titer. 
 Duration of ADA (in days, only for subjects with at least 2 positive ADA samples) using 
descriptive statistics by treatment arm. 
Correlations between ADA parameters (eg, titers, treatment-emergent ADA positive status, 
neutralizing status) and PK, safety and/or main efficacy endpoint(s) will be explored (eg, scatter 
plot) according to the study results. 
2.4.8 Analyses of Biomarker data 
The biomarkers will be summarized by treatment arm and time-point: number of values below 
Lower Limit of Quantification (LLOQ), mean, SD. The biomarkers may be log-transformed based 
on their distribution. A biomarker could be discarded from the analysis if too many values are 
missing or below LLOQ. In addition, the values below LLOQ will be imputed by LLOQ/2. 
To assess the effect of SAR156597 on each biomarker, the change from baseline to Week 24 will 
be analyzed using a mixed model for repeated measures with treatment, visit and 
treatment-by-visit interaction as fixed effects, baseline biomarker value as fixed covariates, and 
assuming an unstructured covariance structure. 
The biomarkers at baseline will be tested one-by-one for a potential prognostic and predictive 
effect for mRSS endpoint. The change from baseline of mRSS to Week 24 will be assessed using 
biomarker main effect (prognostic effect), treatment effect, randomization stratum (as per IRT) 
and interaction between biomarker and treatment (predictive effect). As a second step, the 
biomarkers will be dichotomized using median value. 
2.4.9 Analyses of quality of life/health economics variables 
See Section 2.4.4.4.6 and Section 2.4.4.4.7.  
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2.5 
DATA HANDLING CONVENTIONS 
2.5.1 General conventions 
The following formulas will be used for computation of parameters. 
Study day 
Study day = assessment date - first IMP injection date + 1 (if assessment date ≥first IMP injection 
date), otherwise study day = assessment date - first IMP injection date, the day of first IMP 
injection being Day 1. For randomized but not treated patients, Day 1 is the day of randomization.  
Demographic formulas 
Age (years) = (date of informed consent - date of birth)/365.25 
Renal function formulas  
Creatinine clearance value will be derived using the equation of Cockroft and Gault: 
For male:  
CLCR (mL/min) = 
)
/
(
*
814
.0
)
(
*
))
(
140
(
L
mol
inine
serumcreat
kg
weight
years
age


 
For Female: result above multiplied by 0.85.  
Date of last dose of investigational medicinal product 
The date of the last dose of IMP is equal to the last date of administration reported on the IMP 
administration case report form page, or missing if the last administration date is unknown.  
Lipids variables, laboratory safety variables, hs-CRP 
For data below the lower limit of quantification (LLOQ)/limit of linearity, half of the lower limit 
value (ie, LLOQ/2) will be used for quantitative analyses. For data above the upper limit of 
quantification (ULOQ) / limit of linearity, the upper limit value (ie, ULOQ) will be used for 
quantitative analyses. 
For ANCA parameter: values “<1:20” are considered as negative; other results are considered as 
positive.  
2.5.2 Data handling conventions for efficacy variables 
Handling of CRISS missing data 
Two different methods will be used to impute CRISS missing data, depending on the nature of the 
missing item. 
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If the missing item at a given time-point relates to organ involvement (Step 1 of CRISS 
derivation): 
 If there was already an organ involvement at a previous post-baseline time-point (CRISS 
already evaluated as 0 at a previous time point), CRISS will be imputed the value of 0. 
 Otherwise, if at the current time-point, one organ has worsened (CRISS evaluated  
as 0 due to new or worsening of another organ for which the evaluation is non missing), 
CRISS will be imputed the value of 0. 
 Otherwise, if no other organ has worsened, as such an event should have been classified as 
a serious adverse event, it is assumed that no organ had worsened otherwise the event 
would have been recorded, so CRISS will be derived using Step 2. Each missing 
component (FVC, DLco, mRSS, PT-glob, MD-glob and HAQ-DI) at Week 24 will be 
imputed using the method explained below.  
Handling of FVC, DLco and CRISS missing data 
In order to impute the FVC, DLco and CRISS missing data at Week 24, the following steps will 
be performed: 
 Patients in active arm and taking treatment at Week 24 (treatment discontinuation is 
defined for this analysis as last injection + 7 days): Missing values at Week 24 will be 
imputed using a model estimated from the subset of patients in the active arm who 
completed the 24-week treatment period and with a Week 24 value. The imputation model 
will be based on a MMRM with fixed categorical effect of stratification (as per IRT, 
with/without ILD) and repeated categorical effect for time point (baseline, Week 4 (except 
for % predicted DLco and % predicted FVC), Week 8 (except for % predicted DLco and 
% predicted FVC), Week 12 and Week 24). Parameters will be estimated with the 
Newton-Raphson algorithm, an unstructured covariance matrix will model the 
within-patient errors, and the denominator degrees of freedom will be estimated using 
Kenward-Roger’s approximation. Missing values at Week 24 will be imputed using the 
Empirical Best Linear Unbiased Prediction (EBLUP). 
 Other patients (patients in active arm and not taking treatment at Week 24; or patients in 
placebo arm): Missing values at Week 24 will be imputed similarly but using a model 
estimated from the subset of patients in the placebo arm who completed the 24-week 
treatment period and with a Week 24 value.  
 When running the imputation model: 
- 
If the mRSS value is inferior to 0, then it will be set to 0. If the mRSS value is superior 
to 51, it will be set to 51, 
- 
If the % predicted FVC value is inferior to 0, it will be set to 0, 
- 
If the % predicted DLco value is inferior to 0, it will be set to 0,  
- 
If the PT-glob value is inferior to 0 or superior to 10 it will be set to 0 and respectively 
to 10, 
- 
If the MD-glob value is inferior to 0 or superior to 10, it will be set to 0 and 
respectively to 10, 
- 
If the HAQ-DI value is inferior to 0 or superior to 3, it will be set to 0 and respectively 
to 3. 
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2.5.3 Missing data 
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified. When relevant, the number of patients with missing data 
is presented. 
Handling of computation of treatment duration if investigational medicinal product end of 
treatment date is missing  
For the calculation of the treatment duration, the date of the last dose of IMP is equal to the date 
of last administration reported on the end-of-treatment case report form page. If this date is 
missing, the exposure duration should be left as missing.  
The last dose intake should be clearly identified in the case report form and should not be 
approximated by the last returned package date. 
Handling of medication missing/partial dates 
No imputation of medication start/end dates or times will be performed. If a medication date or 
time is missing or partially missing and it cannot be determined whether it was taken prior or 
concomitantly, it will be considered as prior, concomitant, and post-treatment medication. 
Handling of adverse events with missing or partial date/time of onset 
Missing or partial adverse event onset dates and times will be imputed so that if the partial 
adverse event onset date/time information does not indicate that the adverse event started prior to 
treatment or after the treatment-emergent adverse event period, the adverse event will be 
classified as treatment-emergent. No imputation of adverse event end dates/times will be 
performed. These data imputations are for categorization purpose only and will not be used in 
listings. No imputation is planned for date/time of adverse event resolution. 
Handling of adverse events when date and time of first investigational medicinal product 
administration is missing 
When the date and time of the first IMP administration is missing, all adverse events that occurred 
on or after the day of randomization should be considered as treatment-emergent adverse events. 
The exposure duration should be kept as missing. 
The last dose intake should be clearly identified in the case report form and should not be 
approximated by the last returned package date. 
Handling of missing assessment of relationship of adverse events to investigational medicinal 
product  
If the assessment of the relationship to IMP is missing, then the relationship to IMP has to be 
assumed and the adverse event considered as such in the frequency tables of possibly related 
adverse events, but no imputation should be done at the data level. 
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Handling of missing severity of adverse events 
If the severity is missing for 1 of the treatment-emergent occurrences of an adverse event, the 
maximal severity on the remaining occurrences will be considered. If the severity is missing for 
all the occurrences, a “missing” category will be added in the summary table. 
Handling of potentially clinically significant abnormalities  
If a patient has a missing baseline he will be grouped in the category “normal/missing at 
baseline.” 
For PCSAs with 2 conditions, one based on a change from baseline value or a normal range and 
the other on a threshold value, with the first condition being missing, the PCSA will be based only 
on the second condition. 
For a PCSA defined on a threshold and/or a normal range, this PCSA will be derived using this 
threshold if the normal range is missing; eg, for eosinophils the PCSA is >0.5 GIGA/L or >ULN 
if ULN ≥0.5 GIGA/L. When ULN is missing, the value 0.5 should be used. 
Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSA values. 
2.5.4 Windows for time points 
Data analyzed by time point (including efficacy, safety, PK, BM and ADA) will be summarized 
using the analysis windows below. The analysis windows will be exhaustive so that data recorded 
at any time point (including unscheduled visits) have the potential to be summarized. These 
analysis windows will be applicable for all analyses, and they are defined to provide more 
homogeneous data for time point-specific analyses.  
 For efficacy, if multiple valid values of a variable exist within an analysis window, the 
nearest from the targeted study day will be selected. In case of ties, the worst value will be 
displayed.  
 For PK, BM and ADA, if multiple valid values of a variable exist within an analysis 
window, the value before the injection will be selected.  
 For safety, if multiple valid values of a variable exist within an analysis window, the 
nearest from the targeted study day will be selected. In case of ties, the last value will be 
displayed (except for ANCA).  
 For ANCA and ANA, if multiple valid values of a variable exist within an analysis 
window, the nearest from the targeted study day will be selected. In case of ties, the 
positive value with the highest titer will be displayed.  
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Table 3 - Analysis windows definition for efficacy and safety 
Time point 
Targeted study day 
Analysis window in study days 
for efficacy (except CRISS) 
and safety 
Analysis window in study 
days for CRISS 
Baseline 
1 
Last value before first IMP* 
Week 2 
15 
2 to 21** 
Week 4 
29 
2 to 42*** 
Week 8 
57 
43 to 70*** 
Week 12 
85 
71 to 126 
71 to 126 
Week 24 (EOT) 
169 
127 to 207 
127 to 207 
Week 35 (EOS) 
246 
>207
>207
Note: Study days are calculated from the day of first IMP injection, the day of first IMP injection being Day 1. For randomized but not treated 
patients, Day 1 is the day of randomization.  
*except for ANCA.
**only for vital signs.
***except for FVC, DLco, EQ-5D-5L.
The BM, PK and ADA will be analyzed according to the date of corresponded injection. A time 
windows superior or inferior to 2 days will be accepted. If the date of the previous injection is 
unknown, the SAR156597 concentration will not be considered for the analysis. 
2.5.5 Unscheduled visits 
For all analyses, unscheduled visit measurements may be used to provide a measurement for a 
time point. 
2.5.6 Pooling of centers for statistical analyses 
Not applicable. 
2.5.7 Statistical technical issues 
Not applicable. 
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3 
INTERIM ANALYSIS 
As there is no major enrollment issue, no futility analysis is planned. 
Early analysis: 
The primary analysis of efficacy and safety will be performed on the data collected during the 
24-week treatment period. The results of this analysis will not be used to change the conduct of
the follow-up in any aspect.
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 24 collected and validated, and will consist in the final
analysis of the efficacy endpoints up to Week 24. The safety analysis will be performed on
all safety data collected and validated at the time of first analysis. The results of the first
analysis will not be used to change the conduct of the ongoing study in any aspect. The
24-week data will not be reanalyzed at the end of the study. Individuals who have access
to patients’ source documents will remain blinded with regards to the treatment arm of
individual patients throughout the study. Treatment arm will not be disclosed on
Data Surveillance reports.

Second step: Final analysis.

The second analysis will be conducted at the end of the study and will consist in the final
analysis of Week 35 efficacy endpoints and final safety analysis.
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4 
DATABASE LOCK 
The database is planned to be locked 28 days after last patient last visit. 
There are two database locks planned for this study as follows: 

First database lock (for early analysis of the main efficacy and safety analyses evaluation
at Week 24): 4 weeks after last patient last efficacy visit (Visit 7 Week 24).

Final database lock (for final analysis of efficacy endpoints and final safety analysis at
Week 35): 4 weeks after last patient last visit (Visit 8 Week 35).
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5 
SOFTWARE DOCUMENTATION 
All summaries and statistical analyses will be generated using SAS Version 9.0 or higher. 
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6 
REFERENCES 
1. Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, et al.
Second symposium on the definition and management of anaphylaxis: Summary report
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis
Network symposium. J Allergy Clin Immunol. 2006;117:391-7.
2. Khanna D, Furst DE, Hays RD, Park GS, Wong WK, Seibold JR, et al. Minimally important
difference in diffuse systemic sclerosis: results from the D-penicillamine study. Ann Rheum
Dis. 2006;65:1325-9.
3. Amjadi S, Maranian P, Furst DE, Clements PJ, Wong WK, Postlethuaite AE, et al. Course of
Modified Rodnan Skin Score in systemic sclerosis clinical trials: analysis of three large
multicenter, randomized clinical trials. Arthritis Rheum. 2009;60(8):2490-8.
4. Dolan P. Modeling valuations for EuroQol health states. Med Care. 1997;35(11):1095-10
5. Van Hout B, Janssen MF, Feng YS, Kohlmann T, Busschbach J, Golicki D, et al. Interim
Scoring for the EQ-5D-5L: Mapping the EQ-5D-5L to EQ-5D-3L Value Sets. Value Health
2012;15(5):708-15.
6. Ratitch B and O’Kelly M. Implementation of Pattern-Mixture Models Using Standard
SAS/STAT Procedures. PharmaSUG2011 - Paper SP04.
7. Kenward G. Controlled multiple imputation methods for sensitivity analyses in longitudinal
clinical trials with dropout and protocol deviation. Clin Invest. (Lond) 2015;5(3):311-20.
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7 
LIST OF APPENDICES 
Appendix A
Potentially clinically significant abnormalities (PCSA) criteria 
Appendix B
Summary of statistical analyses 
Appendix C
mRSS 
Appendix D
SHAQ 
Appendix E
UCLA SCTC GIT 2.0 Questionnaire 
Appendix F
EQ-5D-5L Questionnaire (UK version) 
Appendix G 
Patient and physician global assessments of overall health using the 0-10 Likert 
scale 
Appendix H
TJC28 
Appendix I
Digital ulcer count 
Appendix J
Codelists for background therapy definitions, AESIs and related hepatic disorder 
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Appendix A 
Potentially clinically significant abnormalities criteria  
 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for Phase 2/3 studies (oncology excepted) 
Parameter 
PCSA 
Comments 
Clinical Chemistry 
ALT 
By distribution analysis: 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be expressed in ULN, not in 
IU/L.  
Concept paper on DILI - FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning 
zero can be deleted. 
AST 
By distribution analysis: 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be expressed in ULN, not in 
IU/L.  
Concept paper on DILI - FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning 
zero can be deleted. 
Alkaline 
Phosphatase 
>1.5 ULN 
Enzymes activities must be expressed in ULN, not in 
IU/L. 
Concept paper on DILI - FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Total Bilirubin 
>1.5 ULN 
>2 ULN 
Must be expressed in ULN, not in µmol/L or mg/L. 
Categories are cumulative. 
Concept paper on DILI - FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Conjugated Bilirubin >35% Total Bilirubin and TBILI>1.5 ULN 
Conjugated bilirubin dosed on a case-by-case basis. 
ALT and Total 
Bilirubin 
ALT >3 ULN and TBILI >2 ULN 
Concept paper on DILI - FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
To be counted within a same treatment phase, 
whatever the interval between measurement. 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for Phase 2/3 studies (oncology excepted) 
Parameter 
PCSA 
Comments 
CPK 
>3 ULN 
>10 ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning 
zero can be deleted. 
CLcr (mL/min) 
(Estimated creatinine 
clearance based on 
the Cokcroft-Gault 
equation)  
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - <60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥90 (normal GFR) 
FDA draft Guidance 2010. 
Pharmacokinetics in patients with impaired renal 
function-study design, data analysis, and impact on 
dosing and labeling. 
eGFR 
(mL/min/1.73m2) 
(Estimate of GFR 
based on an MDRD 
equation)  
 
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - <60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥90 (normal GFR) 
FDA draft Guidance 2010. 
Pharmacokinetics in patients with impaired renal 
function-study design, data analysis, and impact on 
dosing and labeling. 
Creatinine 
≥150 μmol/L (Adults) 
≥30% change from baseline 
≥100% change from baseline 
Benichou C., 1994. 
 
Uric Acid 
Hyperuricemia  
Hypouricemia  
 
>408 μmol/L 
<120 μmol/L  
Harrison- Principles of internal Medicine 17th Ed., 2008. 
Blood Urea Nitrogen ≥17 mmol/L 
 
Chloride 
<80 mmol/L 
>115 mmol/L 
 
Sodium 
≤129 mmol/L 
≥160 mmol/L 
 
Potassium 
<3 mmol/L 
≥5.5 mmol/L 
FDA Feb 2005. 
Total Cholesterol 
≥7.74 mmol/L  
Threshold for therapeutic intervention. 
Triglycerides 
≥4.6 mmol/L 
Threshold for therapeutic intervention. 
Lipasemia 
≥3 ULN 
 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for Phase 2/3 studies (oncology excepted) 
Parameter 
PCSA 
Comments 
Amylasemia 
≥3 ULN 
 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
≤3.9 mmol/L and <LLN 
≥11.1 mmol/L (unfasted); ≥7 mmol/L (fasted) 
 
ADA May 2005. 
ADA Jan 2008. 
HbA1c 
>8% 
 
Albumin 
≤25 g/L 
 
CRP 
>2 ULN or >10 mg/L (if ULN not provided) 
 FDA Sept 2005. 
Hematology 
WBC 
<3.0 Giga/L (Non-Black); <2.0 Giga/L (Black) 
≥16.0 Giga/L 
Increase in WBC: not relevant. 
To be interpreted only if no differential count available. 
Lymphocytes 
>4.0 Giga/L 
 
Neutrophils 
<1.5 Giga/L (Non-Black);<1.0 Giga/L (Black) 
International Consensus meeting on drug-induced 
blood cytopenias, 1991. 
FDA criteria. 
Monocytes 
>0.7 Giga/L 
 
Basophils 
>0.1 Giga/L 
 
Eosinophils 
>0.5 Giga/L or >ULN (if ULN≥0.5 Giga/L) 
Harrison- Principles of internal Medicine 17th Ed., 2008. 
Hemoglobin 
≤115 g/L (Male); ≤95 g/L (Female) 
≥185 g/L (Male); ≥165 g/L (Female) 
 
Decrease from Baseline ≥20 g/L 
Criteria based upon decrease from baseline are more 
relevant than based on absolute value. Other 
categories for decrease from baseline can be used 
(≥30 g/L, ≥40 g/L, ≥50 g/L). 
Hematocrit 
≤0.37 v/v (Male) ; ≤0.32 v/v (Female) 
≥0.55 v/v (Male) ; ≥0.5 v/v (Female) 
 
RBC 
≥6 Tera/L 
Unless specifically required for particular drug 
development, the analysis is redundant with that of Hb. 
Otherwise, consider FDA criteria. 
Platelets 
<100 Giga/L 
≥700 Giga/L 
International Consensus meeting on drug-induced 
blood cytopenias, 1991. 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for Phase 2/3 studies (oncology excepted) 
Parameter 
PCSA 
Comments 
Urinalysis 
pH 
≤4.6 
≥8 
 
Vital signs 
HR 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline≥20 bpm 
To be applied for all positions (including missing) 
except STANDING. 
SBP 
≤95 mmHg and decrease from baseline ≥20mmHg 
≥160 mmHg and increase from baseline ≥20 mmHg 
To be applied for all positions (including missing) 
except STANDING. 
DBP 
≤45 mmHg and decrease from baseline ≥10 mmHg 
≥110 mmHg and increase from baseline ≥10 mmHg 
To be applied for all positions (including missing) 
except STANDING. 
Orthostatic 
Hypotension 
Orthostatic SDB 
Orthostatic DBP 
 
 
≤-20 mmHg 
≤-10 mmHg 
 
Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
FDA Feb 2007. 
ECG 
Ref.: ICH E14 guidance (2005) and E14 Q&A (2012), 
and Cardiac Safety Research Consortium White Paper 
on PR and QRS (Nada et al. Am Heart J. 
2013;165(4):489-500) 
HR 
<50 bpm 
<50 bpm and decrease from baseline ≥20 bpm 
<40 bpm 
<40 bpm and decrease from baseline ≥20 bpm 
<30 bpm 
<30 bpm and decrease from baseline ≥20 bpm 
 
>90 bpm 
>90 bpm and increase from baseline ≥20bpm 
>100 bpm  
>100 bpm and increase from baseline ≥20bpm 
>120 bpm  
>120 bpm and increase from baseline ≥20 bpm 
Categories are cumulative. 
 
 
 
 
 
 
Categories are cumulative. 
 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for Phase 2/3 studies (oncology excepted) 
Parameter 
PCSA 
Comments 
PR 
>200 ms 
>200 ms and increase from baseline ≥25% 
>220 ms 
>220 ms and increase from baseline ≥25% 
>240 ms 
>240 ms and increase from baseline ≥25% 
Categories are cumulative. 
 
QRS 
>110 ms 
>110 msec and increase from baseline ≥25% 
>120 ms 
>120 ms and increase from baseline ≥25% 
Categories are cumulative. 
QT 
>500 ms 
 
QTc 
 
Absolute values (ms) 
 
 
>450 ms 
>480 ms 
>500 ms 
 
Increase from baseline 
Increase from baseline ]30-60] ms 
Increase from baseline >60 ms 
To be applied to any kind of QT correction formula.  
Absolute values categories are cumulative. 
 
QTc >480 ms and QTc >60 ms are the 2 PCSA 
categories to be identified in individual subjects/patients 
listings. 
 
 
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Appendix B 
Summary of statistical analyses 
EFFICACY ANALYSIS 
Criteria 
Analysis 
population 
Primary 
analysis 
Supportive 
analysis 
Subgroup 
analysis 
Other 
analyses 
Primary endpoint 
mRSS 
ITT 
Change from baseline to W24: MMRM with 
following covariates: treatment group, 
randomization strata, time point, randomization 
strata by time point interaction, treatment by 
time point interaction, mRSS at baseline, 
mRSS at baseline by time point interaction 
Analysis on safety population 
including only post-baseline data 
measured during the on-treatment 
period 
Analysis replacing the planned 
stratum with the actual stratum  
(if more than 15% of patients 
randomized to the wrong stratum) 
Analysis on patients with same rater  
Control-based pattern multiple 
imputation 
Randomization 
stratum (as per 
IRT) 
Gender 
(male/female) 
Background 
therapy (yes/no) 
Change from baseline to Week 35 
(exploratory endpoint): same MMRM 
model as primary analysis 
Secondary endpoints 
HAQ-DI 
ITT 
Change from baseline to Week 24: MMRM with 
following covariates: treatment group, 
randomization strata, time point, randomization 
strata by time point interaction, treatment by 
time point interaction, HAQ-DI at baseline, 
HAQ-DI at baseline by time point interaction 
Analysis replacing the planned 
stratum with the actual stratum  
(if more than 15% of patients 
randomized to the wrong stratum) 
 
Randomization 
stratum (as per 
IRT) 
 
Change from baseline to Week 35 
(exploratory endpoint): same MMRM 
model as primary analysis  
Cumulative distribution function at  
Week 24 and Week 35 
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Criteria 
Analysis 
population 
Primary 
analysis 
Supportive 
analysis 
Subgroup 
analysis 
Other 
analyses 
Observed FVC 
ITT 
Change from baseline to Week 24: MMRM with 
following covariates: treatment group, 
randomization strata, time point, randomization 
strata by time point interaction, treatment by 
time point interaction, FVC at baseline, FVC at 
baseline by time point interaction 
Analysis replacing the planned 
stratum with the actual stratum  
(if more than 15% of patients 
randomized to the wrong stratum) 
Linear mixed effects model with 
random intercept and random slope 
with following covariates: treatment 
group, randomized srata, time, 
randomization strata by time 
interaction, treatment by time 
interaction, FVC at baseline, FVC at 
baseline by time interaction 
Randomization 
stratum (as per 
IRT) 
 
Change from baseline to Week 35 
(exploratory endpoint): same MMRM 
model as primary analysis  
Observed DLco 
ITT 
Change from baseline to Week 24: MMRM with 
following covariates: treatment group, 
randomization strata, time point, randomization 
strata by time point interaction, treatment by 
time point interaction, Dlco at baseline, Dlco at 
baseline by time point interaction 
Analysis replacing the planned 
stratum with the actual stratum  
(if more than 15% of patients 
randomized to the wrong stratum) 
 
Randomization 
stratum (as per 
IRT) 
 
Change from baseline to Week 35 
(exploratory endpoint): same MMRM 
model as primary analysis  
Exploratory endpoints 
mRSS: responder 
rates 
ITT 
Logistic regression for improvement of at least 
20%, 40% and 60% at Week 24 with following 
covariates: treatment group, randomization 
strata, mRSS at baseline  
No 
 
No 
Same logistic regression for 
improvement of at least 20%, 40% and 
60% at Week 35 as primary analysis 
Cumulative distribution function at W24 
and W35 
Same logistic regression as primary 
analysis for 3 supplementary definitions 
for responder rate at Week 24  
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Criteria 
Analysis 
population 
Primary 
analysis 
Supportive 
analysis 
Subgroup 
analysis 
Other 
analyses 
Each of the 
6 VAS from 
SHAQ (pain, 
breathing, 
vascular, 
gastrointestinal, 
digital ulcers, 
global 
assessment) 
ITT 
Change from baseline to W24: MMRM with 
following covariates: treatment group, 
randomization strata, time point, randomization 
strata by time point interaction, treatment by 
time point interaction, VAS at baseline, VAS at 
baseline by time point interaction 
No 
Change from baseline to W35: same 
MMRM model as primary analysis 
Cumulative distribution function at 
Week 24 and W35 
UCLA SCTC GIT 
2.0 score 
ITT 
Change from baseline to W24: MMRM with 
following covariates: treatment group, 
randomization strata, time point, randomization 
strata by time point interaction, treatment by 
time point interaction, UCLA SCTC GIT 2.0 
score at baseline, UCLA SCTC GIT 2.0 score 
at baseline by time point interaction 
No 
No 
Change from baseline to W35: same 
MMRM model as primary analysis  
TJC28 
ITT 
Change from baseline to W24: MMRM with 
following covariates: treatment group, 
randomization strata, time point, randomization 
strata by time point interaction, treatment by 
time point interaction, TJC28 at baseline, 
TJC28 at baseline by time point interaction 
No 
No 
Change from baseline to W35: same 
MMRM model as primary analysis 
Digital ulcer count 
ITT 
Change from baseline to W24: MMRM with 
following covariates: treatment group, 
randomization strata, time point, randomization 
strata by time point interaction, treatment by 
time point interaction,digital ulcer count at 
baseline, digital ulcer count at baseline by time 
point interaction 
No 
No 
Change from baseline to W35: same 
MMRM model as primary analysis 
Descriptive summary by treatment group 
and by time point of the digital ulcer 
count, and its subcategories: number of 
active/new ulcers and number of 
indeterminate/healing ulcers  
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Statistical Analysis Plan  
 
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Page 62 
Criteria 
Analysis 
population 
Primary 
analysis 
Supportive 
analysis 
Subgroup 
analysis 
Other 
analyses 
EQ-5D-5L index 
and VAS 
ITT 
Change from baseline to W24: MMRM with 
following covariates: treatment group, 
randomization strata, time point, randomization 
strata by time point interaction, treatment by 
time point interaction, EQ-5D-5L value at 
baseline, EQ-5D-5L value at baseline by time 
point interaction 
No  
No 
Change from baseline to W35: same 
MMRM model as primary analysis 
 
Cumulative distribution function at  
Week 24 and Week 35 
% predicted FVC 
ITT 
Change from baseline at W24: Rank ANCOVA 
adjusted for baseline and stratified on 
randomization stratum 
No 
No 
Change from baseline at W35: same 
Rank ANCOVA as primary analysis 
Number (%) of patients with absolute 
decrease in % predicted FVC ≥5% or 
absolute increase in % predicted 
FVC ≥10% from baseline to W24 
% predicted DLco 
ITT 
Change from baseline to W24: Rank ANCOVA 
adjusted for baseline and stratified on 
randomization stratum 
No 
No 
Change from baseline at W35: same 
Rank ANCOVA as primary analysis 
Number (%) of patients with absolute 
decrease in % predicted DLco ≥5% or 
absolute increase in % predicted 
DLco ≥10% from baseline to W24 
CRISS 
ITT 
Van Elteren’s test stratified on randomization 
strata at Week 24 
No 
No 
Van Elteren’s test stratified on 
randomization strata at Week 35 
Rate of patients with predicted probability 
of improving obtained using the CRISS at 
W24 and W35 is ≥60%  
mRSS: modified Rodnan Skin Score, FVC: forced vital capacity, MMRM: mixed-effect model with repeated measures, ITT: Intent-to-treat population, ANCOVA: Analysis of Covariance. 
 
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Statistical Analysis Plan  
 
21-Feb-2019 
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Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 63 
SAFETY ANALYSES 
Endpoint 
Analysis 
population 
Primary analysis 
Supportive 
analysis 
Subgroup 
analysis 
Other 
analyses 
Adverse events 
Safety 
Description of Adverse Events 
No 
No 
No 
Vital signs 
Safety 
Description of vital signs 
No 
No 
No 
Laboratory variables 
Safety 
Description of laboratory variables 
 
 
 
ECG  
Safety  
Description of ECG 
 
 
 
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Statistical Analysis Plan  
21-Feb-2019 
SAR156597-ACT14604 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 64 
Appendix C 
mRSS 
 
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Statistical Analysis Plan  
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Property of the Sanofi Group - strictly confidential 
Page 65 
Appendix D 
SHAQ 
VV-CLIN-0196174 2.0


Statistical Analysis Plan  
21-Feb-2019 
SAR156597-ACT14604 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 66 
VV-CLIN-0196174 2.0


Statistical Analysis Plan  
21-Feb-2019 
SAR156597-ACT14604  
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 67 
VV-CLIN-0196174 2.0


Statistical Analysis Plan  
21-Feb-2019 
SAR156597-ACT14604  
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 68 
Appendix E 
UCLA SCTC GIT 2.0 Questionnaire 
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Statistical Analysis Plan  
21-Feb-2019 
SAR156597-ACT14604  
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 69 
 
VV-CLIN-0196174 2.0


Statistical Analysis Plan  
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Property of the Sanofi Group - strictly confidential 
Page 70 
VV-CLIN-0196174 2.0


Statistical Analysis Plan  
21-Feb-2019 
SAR156597-ACT14604  
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 71 
 
VV-CLIN-0196174 2.0


St ati sti c al A n al y si s Pl a n   
2 1 -F e b -2 0 1 9  
S A R 1 5 6 5 9 7 -A C T 1 4 6 0 4   
V er si o n n u m b er: 1  
Pr o p ert y of t h e Sa n ofi  Gr o u p  - stri ctl y c o nfi d e nti al  
P a g e 7 2  
A p p e n di x F  
E Q -5 D -5 L Q u e sti o n n air e ( U K v er si o n)  
 
V V- C LI N- 0 1 9 6 1 7 4 2. 0


Statistical Analysis Plan  
21-Feb-2019 
SAR156597-ACT14604  
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 73 
 
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Statistical Analysis Plan  
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Property of the Sanofi Group - strictly confidential 
Page 74 
Appendix G 
Patient and physician global assessments of overall health using 
the 0-10 Likert scale 
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Statistical Analysis Plan 
21-Feb-2019
SAR156597-ACT14604 
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 75 
Appendix H 
TJC28 
VV-CLIN-0196174 2.0


Statistical Analysis Plan  
 
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Property of the Sanofi Group - strictly confidential 
Page 76 
Appendix I 
Digital ulcer count  
 
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Statistical Analysis Plan  
 
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Property of the Sanofi Group - strictly confidential 
Page 77 
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Statistical Analysis Plan  
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Property of the Sanofi Group - strictly confidential 
Page 78 
Appendix J 
Codelists for background therapy definitions, AESIs and related 
hepatic disorder 
 
Requested 
list 
Type 
(cmq, 
smq, 
others) 
Name or Code 
(cmqname, 
smqcd, others) 
Description  
(cmqdesc or SMQ_ShortName, others) 
Scope 
(smq) / 
prim_sec 
(soc) 
Reqlist 
Type 
Codename 
Desc 
Scope 
Background 
therapy 
definition 2 
CDG 
CDG00103 
METHOTREXATE_mono_and_multiingredients 
 
Background 
therapy 
definition 2 
CDG 
CDG20046 
MYCOPHENOLATE_MOFETIL_mono_and_multi_ingredients 
 
Background 
therapy 
definition 2 
CDG 
CDG00039 
AZATHIOPRINE_mono_and_multi_ingredients 
 
Background 
therapy 
definition 2 
CDG 
CDG20011 
CICLOSPORIN_mono_and_multi_ingredients 
 
Background 
therapy 
definition 2 
CDG 
CDG00040 
CYCLOPHOSPHAMIDE_mono_and_multi_ingredients 
 
Background 
therapy 
definition 1 
CDG 
CDG00014 
ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS 
 
Background 
therapy 
definition 1 
CDG 
CDG10109 
SYSTEMIC HORMONAL PREPARATIONS, EXCL. SEX 
HORMONES AND INSULINS 
 
Acute renal 
failure  
SMQ 
Acute renal failure 
(SMQ) 
Acute renal failure Narrow 
Narrow 
Tuberculosis 
CMQ 
GLB_TUBERCULOSIS 
Tuberculosis 
 
Anaphylactic 
reactions or 
acute allergic 
reactions that 
require 
immediate 
treatment 
CMQ 
Anaphylactic reaction 
Narrow 
 
Anaphylactic reaction Narrow 
 
Hepatic 
disorder 
SMQ 
Hepatic disorders 
(SMQ) 
Hepatic disorders Narrow 
Narrow 
 
 
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