Clinical trial NCT03889639
Conditions: Relapsing Multiple Sclerosis
Sponsor: Sanofi
Start date: 2019-03-29; Completion date: 2020-01-02
Enrollment: 130 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Primary Objective:

To determine the dose-response relationship for SAR442168 to reduce the number of new active brain lesions.

Secondary Objectives:

* To evaluate efficacy of SAR442168 on disease activity as assessed by imaging measures.
* To evaluate the safety and tolerability of SAR442168.

Detailed description:
The total study duration was 24 weeks which included a screening period of 4 weeks, a treatment period of 16 weeks, and a follow-up period of up to 4 weeks. Participants who completed the Week 16 visit were proposed to be enrolled in a long-term extension safety and efficacy study to assess safety, tolerability and efficacy of SAR442168.

Arms: arm 1: Participants received SAR442168 5 milligrams (mg), orally once daily for first 12 weeks then crossed over to matching placebo orally once daily for 4 weeks during the 16 weeks treatment period. To maintain the blinding, each participant was given a total of 4 tablets daily, either of SAR442168 or SAR442168 and placebo, to achieve the specified daily dose of SAR442168. arm 2: Participants received SAR442168 15 mg, orally once daily for first 12 weeks then crossed over to matching placebo orally once daily for 4 weeks during the 16 weeks treatment period. To maintain the blinding, each participant was given a total of 4 tablets daily, either of SAR442168 or SAR442168 and placebo, to achieve the specified daily dose of SAR442168. arm 3: Participants received SAR442168 30 mg, orally once daily for first 12 weeks then crossed over to matching placebo orally once daily for 4 weeks during the 16 weeks treatment period. To maintain the blinding, each participant was given a total of 4 tablets daily, either of SAR442168 or SAR442168 and placebo, to achieve the specified daily dose of SAR442168. arm 4: Participants received SAR442168 60 mg, orally once daily for first 12 weeks then crossed over to matching placebo orally once daily for 4 weeks during the 16 weeks treatment period. To maintain the blinding, each participant was given a total of 4 tablets daily, either of SAR442168 or SAR442168 and placebo, to achieve the specified daily dose of SAR442168. arm 5: Participants received placebo matching to SAR442168 tablets, orally once daily for first 4 weeks then crossed over to SAR442168 5 mg orally once daily for 12 weeks during the 16 weeks treatment period. To maintain the blinding, each participant was given a total of 4 tablets daily, either of SAR442168 or SAR442168 and placebo, to achieve the specified daily dose of SAR442168. arm 6: Participants received placebo matching to SAR442168 tablets, orally once daily for first 4 weeks then crossed over to SAR442168 15 mg orally once daily for 12 weeks during the 16 weeks treatment period. To maintain the blinding, each participant was given a total of 4 tablets daily, either of SAR442168 or SAR442168 and placebo, to achieve the specified daily dose of SAR442168. arm 7: Participants received placebo matching to SAR442168 tablets, orally once daily for first 4 weeks then crossed over to SAR442168 30 mg orally once daily for 12 weeks during the 16 weeks treatment period. To maintain the blinding, each participant was given a total of 4 tablets daily, either of SAR442168 or SAR442168 and placebo, to achieve the specified daily dose of SAR442168. arm 8: Participants received placebo matching to SAR442168 tablets, orally once daily for first 4 weeks then crossed over to SAR442168 60 mg orally once daily for 12 weeks during the 16 weeks treatment period. To maintain the blinding, each participant was given a total of 4 tablets daily, either of SAR442168 or SAR442168 and placebo, to achieve the specified daily dose of SAR442168.
Interventions: intervention 1: SAR442168 intervention 2: Placebo intervention 3: Locally approved intravenous contrast medium for contrast enhanced magnetic resonance imaging (MRI)
Intervention descriptions: intervention 1: Pharmaceutical form: Film coated tablet; Route of administration: Oral intervention 2: Pharmaceutical form: Film coated tablet; Route of administration: Oral intervention 3: Pharmaceutical form: Solution for injection; Route of administration: Intravenous

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: RDSD-002540 VERSION N° 1.0 (02-MAY-2018) based on TransCelerate CPT version 4 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 02 
Protocol title: 
A Phase 2b dose-finding study for SAR442168, a 
Bruton's tyrosine kinase inhibitor, in participants with 
relapsing multiple sclerosis 
Protocol number: 
DRI15928 
Amendment number: 
02 
Compound number 
(INN/Trademark): 
SAR442168 
Not applicable 
Short title: 
Dose-finding study for SAR442168 in relapsing multiple 
sclerosis 
Sponsor name: 
Genzyme Corporation 
Legal registered 
address: 
50 Binney Street 
Cambridge, MA 02142 USA 
Monitoring Team’s 
Representative Name 
and Contact Information 
Regulatory agency identifying number(s): 
EudraCT number: 
2018-003927-12 
IND number: 
140884 
WHO number: 
U1111-1220-0572 
NCT number: 
Not applicable 
Approval Date: 
09-Apr-2019
Total number of pages: 89 
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DOCUMENT HISTORY  
 
Document 
Country/countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial Protocol 02 
All 
09-Apr-2019, version 1 (electronic 5.0) 
Amended Clinical Trial Protocol 01 
All 
13-Feb-2019, version 1 (electronic 3.0) 
Original Protocol 
 
15-Dec-2018, version 1 (electronic 4.0) 
 
Amended clinical trial protocol 02: 09-Apr-2019 
This amended protocol (Amendment 02) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT  
This protocol is being amended primarily in response to comments from health authorities and 
ethics committees during the clinical trial application process.  
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE  
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis 
“Clinical and” removed from secondary endpoint “To 
evaluate efficacy … as assessed by clinical and imaging 
measures.” 
“Phase 2” was changed to “Phase 2b” in “The goal of this 
Phase 2 study is to define a safe, optimal dose of 
SAR442168, a small molecule, oral, once daily, 
CNS-penetrant, irreversible, covalent inhibitor of BTK“ and 
“DRI15928 is a Phase 2, randomized, double-blind, placebo-
controlled, cross-over, dose-ranging study to investigate the 
MRI efficacy and the safety of 12 weeks administration of 
SAR442168.” 
“And no exclusion” was added to “People diagnosed with 
RMS are eligible for enrollment as long as they meet all 
inclusion and no exclusion criteria.” 
Corrections 
Section 1.3 Schedule of 
Activities 
Clinical site visit (for hematology) added at Weeks 2 and 6; 
physical examination added at Week 4. 
Correction of omissions 
Section 2.1 Study 
Rationale 
“Phase 2” was changed to “Phase 2b” in “The goal of this 
Phase 2 study is to define a safe, optimal dose of 
SAR442168, a small molecule, oral, once daily, 
CNS-penetrant, irreversible, covalent inhibitor of BTK.“ 
Correction 
Section 2.3 Benefit/Risk 
Assessment 
“Thrombocytopenia” replaced with “decreased platelet count” 
in description of the event that led to an unblinding during the 
Phase 1 SAD/MAD study. 
Typographical error 
Section 3 Objectives and 
Endpoints 
“Clinical and” removed from secondary endpoint “To 
evaluate efficacy … as assessed by clinical and imaging 
measures.” 
Correction 
Section 3.1 
Appropriateness of 
Measurements 
“The count of new Gd-enhancing T1-hyperintense lesions” 
was changed to read “the total count of Gd-enhancing 
T1-hyperintense lesions.” 
Correction 
Section 4.1 Overall Design 
“Phase 2” was changed to “Phase 2b” in “DRI15928 is a 
Phase 2, randomized, double-blind, placebo-controlled, 
cross-over, dose-ranging study to investigate the MRI 
efficacy and the safety of 12 weeks administration of 
SAR442168.” 
Correction 
Section 5.1 Inclusion 
Criteria 
IO3 updated to include “OR” between the criteria 
To clarify that for I03 that the 
participant should meet either one 
of the criteria. 
Section 5.2 Exclusion 
Criteria 
E10 updated to delete “if more than 81 mg/day”. The notes 
to E10 updated from “aspirin >80 mg” to “aspirin.” 
Rectification of transcription error; 
aspirin use is prohibited in this 
study. 
 
E17 “The participant is involved with any specific situation 
during the study implementation/course that may raise” 
More concrete criteria in the same 
area (E15, E16, and E18) already 
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Section # and Name 
Description of Change 
Brief Rationale 
ethical considerations” is deleted.  
given make E17 redundant. 
Section 6.5 Concomitant 
Therapy 
Addition of short course of non-acetylsalicylic acid NSAIDs to 
permitted comedications. 
To specify that only short courses 
of NSAIDs can be used; also 
prolonged use may increase the 
risk of bleeding 
 
Deleted “if >80 mg/day in 
“•Acetylsalicylic acid (aspirin) if >80 mg/day” 
Consistency with E10 
 
 
 
 
 
Section 9.2 Sample Size 
Determination 
“12-week” removed in “The 60 participants in Cohort 2 will 
start with a 4-week placebo run-in that will be utilized as the 
12-week placebo data.” Deletion of “about” in “Assuming 
15% of participants without the primary endpoint.” Change of 
“12” to “4” in “and placebo mean number of ≥1 for new Gd-
enhancing T1-hyperintense lesions at 4 weeks.” 
Clarification of confusing text; 
corrections 
Section 10.1.1 Regulatory 
and Ethical Considerations 
Submission of protocol amendments to health authorities is 
added. 
To clarify that health authorities will 
be informed of protocol 
amendments 
Section 10.4 Appendix 4: 
Contraceptive guidance 
and collection of pregnancy 
Information 
The sentence, “As definitive reproduction toxicity studies 
have yet to be conducted with SAR442168, the investigator 
is directed to take appropriate precautions during exposure 
of WOCBP in this clinical trial” was added. 
To align the recommendations in 
appendix 4 regarding contraception 
with the inclusion criteria 
Section 10.4 Appendix 4: 
Contraceptive guidance 
and collection of pregnancy 
Information 
The sentence "Female participants of childbearing potential 
are eligible to participate if they agree to use double methods 
of contraception, including one highly effective method 
consistently and correctly as described in Table 9" was 
added. 
To align the recommendations in 
appendix 4 regarding contraception 
with I04 
Section 10.7 Appendix 7: 
List of example drugs with 
a potential to change with 
SAR442168 metabolism 
The sentence "Please note that the lists provided above are 
not exhaustive and that the product information of drugs 
intended for concomitant use should be consulted" was 
added. 
To clarify that the list in appendix 7 
is not exhaustive 
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TABLE OF CONTENTS  
AMENDED CLINICAL TRIAL PROTOCOL 02 .............................................................................................. 1 
DOCUMENT HISTORY ................................................................................................................................... 2 
OVERALL RATIONALE FOR THE AMENDMENT ........................................................................................ 2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE .................................................................. 3 
TABLE OF CONTENTS .................................................................................................................................. 5 
LIST OF TABLES ......................................................................................................................................... 10 
LIST OF FIGURES ........................................................................................................................................ 10 
1 
PROTOCOL SUMMARY ............................................................................................................... 11 
1.1 
SYNOPSIS ..................................................................................................................................... 11 
1.2 
SCHEMA ........................................................................................................................................ 16 
1.3 
SCHEDULE OF ACTIVITIES ......................................................................................................... 17 
2 
INTRODUCTION ............................................................................................................................ 21 
2.1 
STUDY RATIONALE...................................................................................................................... 21 
2.2 
BACKGROUND ............................................................................................................................. 21 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 24 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 26 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 27 
4 
STUDY DESIGN ............................................................................................................................ 28 
4.1 
OVERALL DESIGN ........................................................................................................................ 28 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 28 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 28 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 29 
5 
STUDY POPULATION .................................................................................................................. 30 
5.1 
INCLUSION CRITERIA .................................................................................................................. 30 
5.2 
EXCLUSION CRITERIA ................................................................................................................ 31 
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5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 35 
5.3.1 
Meals and dietary restrictions ........................................................................................................ 35 
5.3.2 
Caffeine, alcohol, and tobacco ....................................................................................................... 35 
5.3.3 
Activity ............................................................................................................................................ 35 
5.4 
SCREEN FAILURES...................................................................................................................... 35 
6 
STUDY INTERVENTION ............................................................................................................... 36 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 36 
6.1.1 
Investigational medicinal product ................................................................................................... 36 
6.1.2 
Noninvestigational medicinal product ............................................................................................ 36 
6.1.3 
Devices .......................................................................................................................................... 37 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 37 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 37 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 38 
6.5 
CONCOMITANT THERAPY .......................................................................................................... 39 
6.5.1 
Rescue medicine ............................................................................................................................ 40 
6.6 
DOSE MODIFICATION .................................................................................................................. 40 
6.7 
INTERVENTION AFTER THE END OF THE STUDY ................................................................... 40 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 41 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 41 
7.1.1 
Definitive discontinuation ............................................................................................................... 41 
7.1.2 
Temporary discontinuation ............................................................................................................. 42 
7.1.2.1 
Rechallenge ................................................................................................................................... 42 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 42 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 43 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 44 
8.1 
EFFICACY ASSESSMENTS ......................................................................................................... 44 
8.1.1 
Magnetic resonance imaging assessments ................................................................................... 44 
8.1.2 
Multiple sclerosis relapse ............................................................................................................... 45 
8.1.2.1 
Unscheduled assessment visits for a suspected multiple sclerosis relapse .................................. 45 
8.1.2.2 
Definition of multiple sclerosis relapse ........................................................................................... 46 
8.1.3 
Expanded Disability Status Scale evaluation ................................................................................. 46 
 
 
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8.2 
SAFETY ASSESSMENTS ............................................................................................................. 47 
8.2.1 
Physical examinations ................................................................................................................... 47 
8.2.2 
Vital signs ....................................................................................................................................... 47 
8.2.3 
Electrocardiograms ........................................................................................................................ 48 
8.2.4 
Clinical safety laboratory assessments .......................................................................................... 48 
8.2.5 
Suicide risk monitoring ................................................................................................................... 48 
8.2.5.1 
The Columbia Suicide Severity Rating Scale ................................................................................ 49 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........................................................... 49 
8.3.1 
Adverse events of special interest ................................................................................................. 49 
8.3.2 
Time period and frequency for collecting AE and SAE information ............................................... 50 
8.3.3 
Method of detecting AEs and SAEs ............................................................................................... 50 
8.3.4 
Follow up of AEs and SAEs ........................................................................................................... 51 
8.3.5 
Regulatory reporting requirements for SAEs ................................................................................. 51 
8.3.6 
Pregnancy ...................................................................................................................................... 51 
8.3.7 
Cardiovascular and death events .................................................................................................. 52 
8.3.8 
Multiple sclerosis relapse reporting ................................................................................................ 52 
8.3.9 
Reporting of safety findings from magnetic resonance imaging .................................................... 52 
8.3.10 
Guidelines for reporting product complaints .................................................................................. 52 
8.3.10.1 Medical devices .............................................................................................................................. 53 
8.4 
TREATMENT OF OVERDOSE ...................................................................................................... 53 
8.5 
PHARMACOKINETICS .................................................................................................................. 53 
8.5.1 
Sampling time ................................................................................................................................ 53 
8.5.2 
Pharmacokinetics handling procedure ........................................................................................... 53 
8.5.3 
Bioanalytical method ...................................................................................................................... 54 
8.5.4 
Pharmacokinetics parameters ....................................................................................................... 54 
 
 
 
 
 
 
 
 
 
 
 
 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 56 
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 56 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................. 56 
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9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 56 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 57 
9.4.1 
Efficacy analyses ........................................................................................................................... 57 
9.4.2 
Safety analyses .............................................................................................................................. 59 
9.4.3 
Other analyses ............................................................................................................................... 61 
 
 
9.5.1 
Independent Data Monitoring Committee (IDMC) ......................................................................... 62 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 63 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 63 
10.1.1 
Regulatory and Ethical Considerations .......................................................................................... 63 
10.1.2 
Financial Disclosure ....................................................................................................................... 63 
10.1.3 
Informed Consent Process ............................................................................................................ 64 
10.1.4 
Data Protection .............................................................................................................................. 64 
10.1.5 
Committees Structure .................................................................................................................... 65 
10.1.6 
Dissemination of Clinical Study Data ............................................................................................. 65 
10.1.7 
Data Quality Assurance ................................................................................................................. 65 
10.1.8 
Source documents ......................................................................................................................... 66 
10.1.9 
Study and Site Closure .................................................................................................................. 66 
10.1.10 Publication Policy ........................................................................................................................... 67 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 67 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ................................................ 68 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION .............................................................................................................................. 73 
 
 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS ............................................................................................................................ 78 
10.7 
APPENDIX 7: LIST OF EXAMPLE DRUGS WITH A POTENTIAL TO CHANGE WITH 
SAR44168 METABOLISM ............................................................................................................. 83 
10.8 
APPENDIX 8: LIST OF EXAMPLE DRUGS WITH A POTENTIAL TO AFFECT PLASMA 
EXPOSURE OF SAR442168 VIA REDUCTION OF GASTRIC ACID .......................................... 84 
10.9 
APPENDIX 9: COUNTRY-SPECIFIC REQUIREMENTS .............................................................. 84 
10.10 
APPENDIX 10: ABBREVIATIONS ................................................................................................. 85 
10.11 
APPENDIX 11: PROTOCOL AMENDMENT HISTORY ................................................................ 86 
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11 
REFERENCES ............................................................................................................................... 88 
 
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LIST OF TABLES  
Table 1 - Schedule of Activities ..................................................................................................................... 17 
Table 2 - Objectives and endpoints ............................................................................................................... 26 
Table 3 - Overview of study interventions administered ............................................................................... 36 
Table 4 - Blood volume per participant and total number of samples ........................................................... 53 
Table 5 - Populations for analyses ................................................................................................................ 57 
Table 6 - Efficacy analyses ........................................................................................................................... 58 
Table 7 - Safety analyses .............................................................................................................................. 60 
Table 8 - Protocol-required safety laboratory assessments .......................................................................... 67 
Table 9 - Highly effective contraceptive methods ......................................................................................... 75 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................. 16 
 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title: A Phase 2b dose-finding study for SAR442168, a Bruton's tyrosine kinase 
inhibitor, in participants with relapsing multiple sclerosis 
Short title: 
Dose-finding study for SAR442168 in relapsing multiple sclerosis 
Rationale: 
The Bruton's tyrosine kinase (BTK) pathway is critical to signaling in B lymphocytes and myeloid 
cells including central nervous system (CNS) microglia. Each of these cell types has been 
implicated in the pathophysiology of multiple sclerosis (MS). Accordingly, SAR442168, a 
CNS-penetrant BTK inhibitor has the potential for a dual mechanism of action by inhibiting 
antigen-induced B-cell activation responsible for inflammation and by modulating maladaptive 
microglial cells linked to neuroinflammation in the brain and spinal cord. There is still a 
significant unmet need for therapies that target neuroinflammation in the CNS with a goal of 
halting long-term disability and neurodegeneration in people with relapsing multiple sclerosis 
(RMS), and also in progressive forms of the disease (primary progressive multiple sclerosis 
[PPMS] and secondary progressive multiple sclerosis [SPMS]) (1). Even the most recent 
high-efficacy disease-modifying therapies act mainly on adaptive immunity in the periphery with 
only modest or temporary ability to halt neuroinflammatory and neurodegenerative processes and 
stop disease progression, as also demonstrated by recent studies in progressive MS (2, 3). The 
goal of this Phase 2b study is to define a safe, optimal dose of SAR442168, a small molecule, 
oral, once daily, CNS-penetrant, irreversible, covalent inhibitor of BTK. The proposed mechanism 
of action for SAR442168 is inhibition of formation of new, active brain lesions in MS as 
measured by magnetic resonance imaging (MRI) and thus predicted to demonstrate clinical 
efficacy in further trials in MS patients. A dose-response curve for SAR442168 in terms of 
reduction of brain MRI lesion activity will be estimated. Formation of new, active brain lesions 
has been demonstrated to be a predictive biomarker for clinical efficacy (reduction in annualized 
relapse rate [ARR]) in Phase 3 registration studies (4, 5). 
 
 
 
 The study will also characterize safety and tolerability of SAR442168 in 
participants with RMS. 
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Objectives and endpoints 
 
Objectives 
Endpoints 
Primary 
To determine the dose-response relationship for SAR442168 to 
reduce the number of new active brain lesions 
 
Number of new Gd-enhancing T1-hyperintense 
lesions at the end of 12 weeks of SAR442168 
treatment as detected by brain MRI 
Secondary 
To evaluate efficacy of SAR442168 on disease activity as 
assessed by imaging measures 
 
Number of new or enlarging T2 lesions at the end of 
12 weeks of SAR442168 treatment 
 
 Number of Gd-enhancing T1-hyperintense lesions at 
the end of 12 weeks of SAR442168 treatment 
To evaluate the safety and tolerability of SAR442168 
 
 
Adverse events (AEs), serious adverse events 
(SAEs), potentially clinically significant abnormalities 
in laboratory tests, electrocardiogram (ECG), or vital 
signs during the study period 
Overall design: 
DRI15928 is a Phase 2b, randomized, double-blind, placebo-controlled, cross-over, dose-ranging 
study to investigate the MRI efficacy and the safety of 12 weeks administration of SAR442168. 
People diagnosed with RMS are eligible for enrollment as long as they meet all inclusion and no 
exclusion criteria. 
All participants will be centrally assigned to 1 of 8 arms (4 dose groups in each of 2 cohorts at 
equal ratio to start with SAR442168 (in Cohort 1) or placebo (in Cohort 2) period before 
cross-over, using an Interactive Voice/Web Response System (IVRS/IWRS). 
 Within each cohort, participants will be randomly assigned equally to 1 of 4 SAR442168 
doses, 5, 15, 30, or 60 mg once daily, in a blinded manner. 
 Cohort 1: Participants will receive 1 of the SAR442168 doses for the first 12 weeks, then 
cross-over to placebo for 4 weeks. 
 Cohort 2: Participants will receive placebo for the first 4 weeks, then cross over to 1 of the 
SAR442168 doses for 12 weeks. 
Upon completing the double-blinded treatment period, participants will be given the option to 
enroll in a long-term safety (LTS) follow-up study to assess safety and tolerability of SAR442168. 
The LTS follow-up study will be described in a separate protocol. 
Number of participants: 
Approximately 160 people will be screened to randomize approximately 120 participants (based 
on a 25% screening failure rate) to the study intervention such that approximately 105 evaluable 
participants (based on an approximately 15% dropout rate, providing at least 26 participants for 
each dose level of SAR442168) complete 12 weeks of SAR442168 treatment. Participants from 
Cohort 2 (n = 60) will receive 4 weeks of placebo before crossing over to SAR442168, providing 
data that can be utilized in estimating a dose-response curve and comparison to placebo. This 
approach is based on the assumption of a theoretical constant rate of new Gd-enhancing 
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T1-hyperintense lesions over 12 weeks under placebo. The approach will minimize placebo 
exposure to study participants. A brief description of handling placebo data and analysis and 
additional details including sample size determination is provided in Section 9. 
Intervention groups and duration: 
The 4-week period of placebo will be introduced either after or before 12-week treatment with 
SAR442168 (Cohorts 1 and 2, respectively). 
Participants will be randomly assigned in an equal ratio to each of 8 groups (4 dose groups within 
each of 2 cohorts). 
Study intervention(s) 
Investigational medicinal product(s): 
SAR442168 
 
Formulation: 2.5 or 15 mg tablet 
 
Route(s) of administration: oral 
 
Dose regimen: up to 4 tablets once daily to achieve 5, 15, 30, and 60 mg daily doses 
Matching placebo 
 
Formulation: tablet 
 
Route(s) of administration: oral 
 
Dose regimen: up to 4 tablets administered once daily (to maintain a total of 4 tablets daily 
for SAR442168 and/or placebo in a blinded fashion)  
Post-study access to study medication: 
A separate, open-label, LTS study will be offered to participants completing the Week 16 visit of 
this study. Details of this study will be provided in a separate protocol. 
Statistical considerations: 
Primary analysis: 
The primary objective of dose-response relationship of SAR442168 with the primary endpoint, 
number of new Gd-enhancing T1-hyperintense lesions as detected by brain MRI at the end of 
12 weeks of SAR442168 treatment, will be evaluated in the modified intent-to-treat (mITT) 
population by a 2-step multiple comparison procedure with modelling techniques (MCP-Mod). 
The first step of this procedure tests for an efficacy signal (compared to the null hypothesis of a 
flat, no dose-response curve) in a procedure that controls the type 1 error. To account for the 
uncertainty of the dose-response shape, 6 candidate models have been considered to cover diverse 
and potential dose-response profiles: 2 Emax models (ED50 = 10 mg, ED50 = 30 mg), a linear 
model, a quadratic model, a logistic model, and an exponential model. The second step is the 
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estimation of the dose-response curve, provided that an efficacy signal is established in the first 
step. 
A negative binomial regression model with covariates for baseline Gd-enhancing T1-hyperintense 
lesion count, treatment, and cohort (Cohort 1 or Cohort 2) will be used to assess the mean count of 
new Gd-enhancing T1-hyperintense lesions in each of the 4 dose groups at the end of 12 weeks of 
SAR442168 treatment and at the end of 4 weeks of placebo. The 4-week post-randomization 
placebo data from Cohort 2 (ie, Week 4 data from Cohort 2) will be utilized as the placebo data at 
Week 12 in analysis, under the assumption of a constant rate of Gd-enhancing T1-hyperintense 
lesion formation if participants would be receiving placebo over 12 weeks. Participants in 
Cohort 2 contribute to the placebo data (at Week 4) as well as the data for 4 SAR442168 doses (at 
Week 16). Thus, in order to account for the potential correlation between the measurements in the 
4-week placebo period and the subsequent 12-week SAR442168 treatment period in Cohort 2, a 
generalized estimating equation (GEE) approach is used to fit the negative binomial model 
accounting for the within-participant correlation via the repeated statement in SAS PROC 
GENMOD. A minus log transformation of the mean lesion count will be entered into the 
MCP-Mod procedure. The null hypothesis of a flat dose-response curve (ie, no dose–response 
relationship) at the end of 12 weeks of SAR442168 treatment for the primary endpoint will be 
jointly evaluated for each of the 6 candidate dose response models with a contrast test that 
controls the family wise error rate at 2-sided alpha = 0.05. If step 1 yields significant results, the 
best fitting model from the 6 predefined candidate models will be chosen using the generalized 
Akaike information criterion (AIC). The dose for the Phase 3 program will then be estimated from 
the final selected model. 
The primary analysis will be based on pooled data of Cohorts 1 and 2 for each of the SAR442168 
doses (ie, data at Week 12 for Cohort 1 and at Week 16 for Cohort 2 for the number of new 
Gd-enhancing T1-hyperintense lesions). Data from Cohorts 1 and 2 may also be separately 
explored as necessary. Sensitivity analyses will be detailed in the statistical analysis plan (SAP). 
Analysis of secondary endpoints: 
For the secondary endpoint of number of Gd-enhancing T1-hyperintense lesions at the end of 
12 weeks of SAR442168 treatment, a similar negative binomial model and MCP-Mod procedure 
will be used. As it is reasonable to assume a constant rate of lesion formation over 12 weeks under 
placebo for total number of Gd-enhancing T1-hyperintense lesions, the same approach as that 
utilized for the primary endpoint will be used, by using the Week 4 data in Cohort 2 as the 
Week 12 placebo data while accounting for the within-participant correlation. Descriptive 
summary statistics over time will be provided for each of the 4 SAR442168 doses. 
For the number of new or enlarging T2 lesions, descriptive summary statistics over time (4, 8, 12, 
and 16 weeks) will be provided for each of the 4 SAR442168 doses. Further, a similar MCP-Mod 
approach will be explored if it is deemed reasonable to extrapolate the Week 4 data from Cohort 2 
to the Week 12 placebo data. 
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All safety summaries will be descriptive and will be performed on the safety population. Safety 
data for the first 4 weeks following randomization (where participants in Cohort 2 receive 
placebo) will be summarized by SAR442168 and placebo. Safety data during the 4-week placebo 
period (ie, 4 weeks) in Cohort 1 will be summarized separately and displayed by SAR442168 
dose group and overall. 
 
 
Data Monitoring Committee: Yes 
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1.2 
SCHEMA  
Figure 1 - Graphical study design  
 
C1: Cohort 1; C2: Cohort 2; R: randomization; Schedule of Activities (SoA) 
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1.3 
SCHEDULE OF ACTIVITIES  
Table 1 - Schedule of Activities  
Phase 
Screening 
Baseline /start 
of IMP 
 
Intervention Phase 
Follow-up 
phase 
Unscheduled 
visit 
Premature end 
of treatmenta 
Week (a window of ±3 days is 
allowed for all visits after 
screening) 
W-4 to 
D-1b 
D1 
W2 
W4 
W6 
W8 
W12 
W16 
Follow-up visit 
(W18 to W20)a,c  
UNSCH 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Visit at clinical site 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant medications 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Study treatment administration 
SAR442168/placebo 
(dispensation and accountability) 
 
Xl 
 
Xl 
 
Xl 
Xl 
Accountabilityl 
 
 
 
Treatment adherence diarym 
 
X 
 
X 
 
X 
X 
X 
 
 
 
Safety 
Physical examinationd 
X  
Xe 
 
X 
 
X 
X 
X 
X  
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
X 
 
X 
 
X 
X 
X 
X 
if needed 
X 
Serology tests for hepatitis B, C, 
other infectious disease if locally 
required  
X 
 
 
 
 
 
 
 
 
 
 
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Phase 
Screening 
Baseline /start 
of IMP 
 
Intervention Phase 
Follow-up 
phase 
Unscheduled 
visit 
Premature end 
of treatmenta 
Week (a window of ±3 days is 
allowed for all visits after 
screening) 
W-4 to 
D-1b 
D1 
W2 
W4 
W6 
W8 
W12 
W16 
Follow-up visit 
(W18 to W20)a,c  
UNSCH 
 
Vital signs 
X 
Xe 
 
Xe 
 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
Xe 
 
Xe 
 
X 
X 
X 
X 
if needed 
X 
Body temperature 
X 
Xe 
 
Xe 
 
X 
X 
X 
X 
X 
X 
Hematology, biochemistryf 
X 
Xe 
Xg 
Xe 
Xg 
X 
X 
X 
X 
If needed 
X 
Coagulationf 
X 
 
 
 
 
 
 
 
 
If needed 
 
Urinalysisf 
X 
Xe 
 
Xe 
 
X 
X 
X 
X 
If needed 
X 
TB/QuantiFERON-TB Gold® test 
or equivalent 
X 
 
 
 
 
 
 
 
 
 
 
β-HCG test (if applicable)h  
X 
Xe 
 
Xe 
 
X 
X 
X 
 
If needed 
 
Serum FSH 
X 
 
 
 
 
 
 
 
 
 
 
Suicidality assessment (C-SSRS) 
X 
Xe 
 
X 
 
X 
X 
X 
X 
If needed 
X 
Adverse event collection 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Efficacy 
EDSS 
X 
Xe,i 
 
 
 
 
X 
 
 
If MS relapse 
suspected 
X 
MRIj 
X  
 
 
Xe 
 
X 
X 
X 
 
 
X 
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Phase 
Screening 
Baseline /start 
of IMP 
 
Intervention Phase 
Follow-up 
phase 
Unscheduled 
visit 
Premature end 
of treatmenta 
Week (a window of ±3 days is 
allowed for all visits after 
screening) 
W-4 to 
D-1b 
D1 
W2 
W4 
W6 
W8 
W12 
W16 
Follow-up visit 
(W18 to W20)a,c  
UNSCH 
 
Pharmacokinetics 
SAR442168 pharmacokinetic 
plasma samples (sampling to be 
done as indicated ±0.5 hour) 
 
X (1 hour 
post-dose)l 
 
X (1 and 
3 hours 
post- 
dose)l 
 
X (1 
±0.5 
hour 
post- 
dose)l 
X (1 and 
3 hours 
post- 
dose)l 
X (1 hour post-
dose)l 
 
 
X (1 hour post-
dose) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
) 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: β-HCG: beta human chorionic gonadotropin; BTK: Bruton's tyrosine kinase; C-SSRS: Columbia Suicide Severity Rating Scale; 
 D: day; DME: drug-metabolizing enzymes; 
ECG: electrocardiogram; EDSS: Expanded Disability Status Scale; FSH: follicle-stimulating hormone; 
; MRI: magnetic resonance imaging; 
 
TB: tuberculosis; W: week 
a The participant should return for a follow-up visit 2 to 4 weeks after premature end-of-treatment. 
b Screening activities can be done any time starting from 4 weeks to Day 1 before intervention. 
c Only participants who do not enroll into the LTS study should come for a Week 18 to 20 follow-up visit. 
d A full physical examination must be performed at screening; a brief physical examination is sufficient thereafter. The brief physical examination needs to be extended as needed as per the judgment of the 
Investigator if any new findings occur. 
e Sample or measurement to be taken before treatment. 
f 
For a detailed list of laboratory tests, refer to Appendix 2 (Section 10.2). Pre-study tests may be accepted, if they are performed in the period Week -4 to Day -1. 
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g Hematology only 
h Serum β-HCG must be tested at screening; urine β-HCG is sufficient thereafter unless a pregnancy is detected or the urine test it is inconclusive and a serum test needs to be used for verification. 
i 
Baseline EDSS can be done in the frame of 3 days before Day 1. 
j 
MRI can be performed within a window of ±5 days. The screening MRI should be performed as close before Day 1 as feasible. 
k 
 
l 
On site visit days, participants should not take the IMP before the visit but should bring their drug wallets to the visit in order that the time of administration can be recorded in order to schedule PK sampling. 
m Treatment adherence diaries will be dispensed for a 4-week period, collected, and clarified at the following visits. Treatment compliance will be reported with the help of diary data. 
 
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2 
INTRODUCTION  
SAR442168 is a brain-penetrant, selective, covalent inhibitor of BTK. SAR442168 exhibits 
activity in the experimental allergic encephalomyelitis animal model used to evaluate 
immunomodulatory agents in treating MS. 
2.1 
STUDY RATIONALE  
The goal of this Phase 2b study is to define a safe, optimal dose of SAR442168, a small molecule, 
oral, once daily, CNS-penetrant, irreversible covalent inhibitor of BTK. The proposed mechanism 
of action for SAR442168 is inhibition of formation of new active brain lesions in MS as measured 
by MRI and thus predicted to demonstrate clinical efficacy in further trials in MS patients. This 
study will assess dose-response by measuring changes in the number of gadolinium 
(Gd)-enhancing T1-hyperintense lesions associated with inflammation. This radiographic 
outcome has been established as a highly-reliable predictive biomarker for clinical efficacy in 
pivotal studies in MS and has been demonstrated to be a predictive biomarker for clinical efficacy 
(reduction in ARR) in Phase 3 registration studies (4, 5). Dose-response for lesion suppression 
will be assessed, based on 4 dose levels and a short placebo period, with a 2-step statistical 
approach. SAR442468 efficacy relative to placebo will be assessed by evaluating inhibition of the 
formation of new active brain lesions as measured by MRI. The study will also characterize safety 
and tolerability of SAR442168 in participants with RMS. 
The DRI15928 study will employ a number of secondary outcome measures in an effort to collect 
additional data on the potential benefit of SAR442168 in neuroinflammation. 
 
 
 
2.2 
BACKGROUND  
Immunomodulatory drugs have been the mainstay of MS therapy. Recent results from clinical 
studies have demonstrated very good efficacy of agents that target B lymphocytes, especially 
B-cell-depleting agents like ocrelizumab (anti-CD20) (6). Targeting B-cells represents a departure 
from the prevailing dogma based on animal models that demonstrated therapeutic benefits from 
modulating T-cell activity and positions the B cell as the centerpiece of current MS drug 
development (7). Importance of immune cells residing in the CNS is also well known (8) and 
needs to be considered in MS pathogenesis. 
There is still a significant unmet need for therapies that target neuroinflammation in the CNS with 
a goal of halting long-term disability and neurodegeneration in people with RMS and with 
progressive forms of the disease (PPMS and SPMS) (1). Even the most recent high-efficacy 
disease-modifying therapies act mainly on adaptive immunity in the periphery with only modest 
or temporary ability to halt neuroinflammatory and neurodegenerative processes and stop disease 
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progression, as also demonstrated by recent studies in progressive MS (2, 3). Therefore, 
development of MS treatments with new modes of action is of interest. 
Beyond the existing strategy to modulate cellular elements of adaptive immunity, there is 
mounting evidence that innate immunity, mediated by myeloid cell lineages 
(bone-marrow-derived monocytes/macrophages and CNS-resident microglial cells), is responsible 
for many of the neurodegenerative aspects of MS that persist in spite of the effectiveness of 
approved disease-modifying therapies in preventing acute relapses (9, 10). Immunomodulation 
directed at innate immunity has potential to curtail “smoldering neuroinflammation” and other 
manifestations of disease progression that remain unaddressed by current, approved therapies. 
BTK is an important intracellular signaling mediator in cells of both adaptive and innate 
immunity. Accordingly, an inhibitor of BTK signaling represents a dual mechanism targeting both 
aspects of the immune system. BTK inhibits a signaling pathway in B lymphocytes and myeloid 
cells, including CNS microglia. Each of these cell types has been implicated in the 
pathophysiology of MS. Further, as BTK signaling is vital for maturation of B cells into 
antibody-secreting plasma cells, BTK inhibition can modulate both cellular and humoral 
immunity. BTK inhibition is reversible since new protein is constantly synthesized and B cells are 
not depleted. Finally, because SAR442168 is brain penetrant, it has the potential for a dual 
mechanism of action by inhibiting antigen-induced B-cell activation responsible for 
neuroinflammation and by modulating maladaptive microglial cells linked to neuroinflammation 
in the brain and spinal cord. Thus, SAR442168 has the potential to provide a superior benefit-risk 
ratio when compared to currently available MS therapies. 
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Renal and hepatic impairment: The pharmacokinetics (PK) of SAR442168 have not been 
investigated in human subjects with either renal or hepatic impairment. Based on the routes of 
elimination, SAR442168 exposures may increase in participants with hepatic impairment; 
therefore, SAR442168 should not be administered to individuals with underlying hepatic 
impairment until evaluated in clinical studies. 
Drug abuse and dependence: SAR442168 is not classified as a controlled substance. No data are 
available regarding the potential of SAR442168 for abuse and dependence. 
Phase 1 first-in-human single-ascending-dose/multiple-ascending-dose study: Seventy-four 
healthy participants (30 in the single-ascending-dose, 40 in the multiple-ascending-dose, and 4 in 
the cerebrospinal-fluid [CSF] exposure phases) have received up to 120 mg SAR442168 in the 
single-ascending-dose phase, up to 90 mg once daily for 10 days in the multiple-ascending-dose 
phase, and 120 mg (single dose) in the CSF exposure study. No serious adverse events (SAEs) 
have been reported in Phase 1. One participant in the multiple-ascending-dose 60 mg cohort was 
unblinded due to thrombocytopenia. Because of this, platelet counts will be monitored during the 
DRI15928 study. There was no platelet decrease lower than 100 x 109/L observed during the 
study. SAR442168 is rapidly absorbed (tmax is close to 1 hour) and rapidly eliminated (t1/2 was less 
than 2.5 hours). Covalent binding enables a durable pharmacodynamic (PD) effect, and steady 
state is achieved within 5 to 10 days. Cerebrospinal fluid exposure has been confirmed in humans 
with CSF concentrations of approximately 1.87 ng/mL at 2 hours, which is more than 10 times 
greater than the cell-based IC50 of 0.18 ng/mL. 
Drug-drug interactions: The potential for drug-drug interactions has been investigated in vitro 
with SAR442168 evaluated as a substrate, inhibitor, or inducer of CYP450 metabolizing enzymes. 
Based on preclinical drug metabolism studies, SAR442168 is a substrate of the CYP3A and 
CYP2C8 isoenzymes, and therefore, it is possible that plasma exposures of SAR442168 would be 
altered if coadministered with other drugs that either induce or inhibit CYP3A and/or CYP2C8 
metabolism. Based on estimations strong inhibitors/inducers could change SAR442168 
concentrations by approximately 50% from expected. This has not been studied in humans to date, 
and therefore, drugs that strongly inhibit or induce CYP3A or CYP2C8 should be avoided (see the 
list of such drugs in Appendix 7, Section 10.7). 
The results show that SAR442168 does not significantly induce nor inhibit CYP450 enzymes at 
therapeutically relevant concentrations. Therefore, SAR442168 is unlikely to alter the PK of other 
drugs that are metabolized by these enzymes. 
In vitro, SAR442168 was not an inhibitor or a substrate of drug transporters including human 
OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, BCRP, and BSEP and was a minor substrate 
for P-glycoprotein. Therefore, clinically significant transporter-related drug-drug interactions with 
SAR442168 are considered unlikely. 
No human drug-drug interaction studies have been conducted to date. 
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2.3 
BENEFIT/RISK ASSESSMENT  
SAR442168 is an oral, investigational, small molecule drug that inhibits BTK and has the 
potential to target inflammatory diseases including MS and other autoimmune diseases. It is 
anticipated that the dual proposed mechanism of action, targeting peripheral inflammation and 
neuroinflammation, will be of benefit to participants in the study and will potentially have 
efficacy superior to established MS therapies. 
Expected benefits: 
Suppression of neuroinflammation is expected to be observed as decreased MRI activity and will 
be monitored by evaluating formation and count of new Gd-enhancing T1-hyperintense lesions 
and volume and count of new or enlarging T2 lesions. Risk of MS relapse, the clinical 
manifestation of neuroinflammation, is expected to be decreased due to the anti-inflammatory 
activity of the compound, but due to the short duration of the treatment period, it is not expected 
to result in significant differences in relapse count between groups or compared to the placebo 
period. Nevertheless, MS relapse and Expanded Disability Status Scale (EDSS) data to monitor 
disability due to MS will be collected to detect any possible changes and will be used as a baseline 
for long-term observations in the LTS study, open to all participants of DRI15928. 
To summarize, SAR442168 is expected to reduce MS relapse rate, disability progression, and 
underlying CNS damage through its dual action on peripheral immune cells as well as immune 
cells and the inflammation process in the CNS. These effects will be evaluated in this study, 
which will allow dose selection and later confirmation of efficacy in Phase 3 studies. 
Risks and adverse drug reactions: 
The safety profile of 2 approved BTK inhibitors in oncology (mantle cell lymphoma and chronic 
lymphatic leukemia) patients (11) is characterized. The MS population is very different from 
oncology patients with regards to some risks, eg, hematological risks (hemorrhage, anemia, etc). 
All of these potential risks will be taken into consideration in this study. 
Human exposure of SAR442168 is limited to the exposure in the aforementioned Phase 1 study in 
healthy participants. Overall, the drug was considered generally safe and well-tolerated following 
both single dose administration of up to 120 mg, and multiple dose administration for 10 days at 
up to 90 mg daily. There were no SAEs reported in the study and no clinically significant 
abnormalities in vital signs, electrocardiogram (ECG) parameters, or laboratory changes in treated 
subjects except than dose-dependent platelet decrease. One participant who had decreased platelet 
count in the 60 mg multiple doses cohort discontinued treatment at Day 9 when the platelet count 
decreased from 145 x 109/L to 105 x 109/L. All drug-related adverse events (AEs) were classified 
as mild (Grade 1). 
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Potential risks: 
BTK inhibitors, as a potential immunosuppressant class of small molecules, have been approved 
to treat oncology patients for chronic lymphocytic leukemia and mantle cell lymphoma. 
BTK inhibitors may increase the risk of bleeding, infection, cytopenias (thrombocytopenia, 
neutropenia), and atrial arrhythmia (in particular atrial fibrillation and atrial flutter). 
In this study, platelet counts will be followed at monthly visits to timely detect any adverse 
reaction. Participants will be instructed to report any bleeding signs (such as petechiae and easy 
bruising) to the Investigator to evaluate any underlying platelet disorder and bleeding risk. Major 
hemorrhagic events, including symptomatic bleeding in a critical area or organ such as the CNS, 
will be reported as adverse event of special interest (AESI). 
Other cytopenias such as neutropenia and anemia have also occurred in the oncology setting and 
are a potential class risk. Monthly complete blood counts will be used to monitor for such events. 
Atrial fibrillation and atrial flutter have been detected with some BTK inhibitors (12); therefore, 
these are also considered as a potential class risk. Frequent ECG recording is planned in the study 
to mitigate this. QTc ≥500 ms or clinically significant arrhythmia will be collected as AESIs in 
this study. 
Detailed information about the known and expected benefits and risks and reasonably expected 
AEs of SAR442168 can be found in the Investigator’s Brochure for SAR442168. 
Overall, the benefit/risk profile is considered positive to develop this drug in the target population. 
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3 
OBJECTIVES AND ENDPOINTS  
Table 2 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
To determine the dose-response relationship for SAR442168 to 
reduce the number of new active brain lesions 
 
Number of new Gd-enhancing T1-hyperintense 
lesions at the end of 12 weeks of SAR442168 
treatment as detected by brain MRI 
Secondary 
To evaluate efficacy of SAR442168 on disease activity as 
assessed by imaging measures 
 
Number of new or enlarging T2 lesions at the end 
of 12 weeks of SAR442168 treatment 
 
 Number of Gd-enhancing T1-hyperintense 
lesions at the end of 12 weeks of SAR442168 
treatment 
To evaluate the safety and tolerability of SAR442168 
 
 
Adverse events (AEs), serious adverse events 
(SAEs), potentially clinically significant 
abnormalities in laboratory tests, 
electrocardiogram (ECG), or vital signs during the 
study period 
 
 
 
 
 
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Objectives 
Endpoints 
To evaluate PK 
 
 
Pharmacokinetics of SAR442168 
 
 
 
 
  
 
 
3.1 
APPROPRIATENESS OF MEASUREMENTS  
Magnetic resonance imaging markers of inflammatory activity in the brain will be collected as in 
most RMS clinical trials. Number of new Gd-enhancing T1-hyperintense lesions will be used as 
the primary endpoint to assess the efficacy of SAR442168. Because MS results in a leaky 
blood-brain barrier, accumulation of Gd contrast agent in brain tissue is related to inflammatory 
activity in MS patients. This radiographic outcome has been established as a highly-reliable 
predictive biomarker for clinical efficacy in pivotal studies in MS. 
Central review will be used to identify new Gd-enhancing T1-hyperintense lesions not present at 
the previous MRI. The total count of Gd-enhancing T1-hyperintense lesions will also be used as a 
secondary endpoint to detect any effect on pre-existing inflammatory foci. The number of new 
and enlarging T2 lesions, a marker of inflammatory activity and brain tissue destruction in RMS, 
will also be evaluated in central review to collect additional data with respect to the efficacy of 
SAR442168. The total volume of T2 lesions (MS burden) and the number of T1-hypointense 
lesions (black holes) will also be assessed as supportive data with respect to efficacy. 
Magnetic resonance imaging measurements will include change in brain volume, which is 
considered to be a marker of CNS degeneration but is also related to inflammatory events in RMS 
patients. Several MS drugs are known for their capacity to slow down brain atrophy, which will 
be assessed in search of a possible signal. 
Clinical relapse is the main clinical expression of RMS. Relapse-related endpoints (ARR, 
proportion of relapse-free participants) are widely used as endpoints in clinical trials. Although 
the short duration of this trial does not allow expectation of a significant difference between dose 
groups in occurrence of relapse and relapse is considered rare in PPMS, it will be assessed due to 
its clinical importance and in an attempt to collect additional efficacy data. 
The EDSS is widely used to measure neurological disability in clinical trials and routine settings 
(13). Large changes are not expected during the period of this study, but it will be used as 
supportive data for efficacy. 
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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
This is a Phase 2b, randomized, double-blind, placebo-controlled, cross-over, dose-ranging study 
to investigate the MRI efficacy and the safety of 12 weeks administration of SAR442168. People 
diagnosed with RMS are eligible for enrollment as long as they meet all inclusion and no 
exclusion criteria. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
This study is blinded for dose and for administration sequence. It is focused on dose finding but 
also takes into account the need to minimize participant exposure to placebo. Accordingly, we 
will evaluate the dose range using 4 doses: 5, 15, 30, and 60 mg once daily. In addition, to 
minimize exposure to placebo while maintaining the blinding of Investigators and participants, 
each participant will be assigned to a 4-week placebo period that will occur during either the first 
or the last 4 weeks of the study. 
The 4-week period of placebo is introduced either after or before 12-week treatment with 
SAR442168 (Cohorts 1 and 2, respectively). Participants are randomly assigned to 1 of 8 arms 
(4 dose groups at an equal ratio in each of the 2 cohorts). The duration of administration of 
placebo is limited to 4 weeks to minimize placebo exposure; a cross-over design allows all 
participants to be treated with SAR442168. This cross-over design will blind for administered 
intervention and will permit a more objective evaluation of safety events at the beginning of the 
study and of efficacy endpoints. 
The duration of treatment period of SAR442168 of 12 weeks should allow to detect its effect on 
suppressing the formation of new Gd-enhancing T1 lesions. Recent communication on an 
evobrutinib study in RMS patients confirms that meaningful reduction of such lesions may be 
observed from the Week 12 already (14). 
4.3 
JUSTIFICATION FOR DOSE  
The dose range chosen for this study is informed by several assessments. First, allometric 
modeling intended to translate BTK occupancy by SAR442168 in preclinical animals (mouse, rat, 
and dog) predicts an optimal dose range between 1 and 100 mg once daily in humans. Second, 
Phase 1 multiple-ascending-dose measurements of BTK occupancy in human peripheral blood 
mononuclear cells (PBMCs) show an asymptotic approach to saturation of the receptor by 
SAR442168 at the 7.5 mg once daily dose with a more rapid approach to saturation at higher 
doses. Finally, measurements of absolute CD19+ B-cell counts show a dose-dependent increase 
(observed maximally at Day 4) of up to 80% relative to baseline. The BTK-induced increase in 
circulating B-cells is predicted from the literature, as BTK inhibition alters expression of cell 
surface adhesion molecules leading to egress from lymph nodes (11). The dose-response 
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relationship for this effect is maximal at approximately 30 mg once daily. Taking all of these 
elements into consideration, a dose range between 5 and 60 mg once daily has been set to provide 
the best chance of capturing the optimal dose for SAR442168 in RMS. 
4.4 
END OF STUDY DEFINITION  
A participant is considered to have completed the study if he/she has completed all phases of the 
study including the last visit. 
The end of the study is defined as the date of the last visit of the last participant in the study. 
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5 
STUDY POPULATION  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
a protocol waiver or exemption, is not permitted. 
5.1 
INCLUSION CRITERIA  
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
I 01. The participant must be 18 to 55 years of age, inclusive, at the time of signing the informed 
consent. 
Type of participant and disease characteristics 
I 02. The participant must have been diagnosed with RMS according to the 2017 revision of the 
McDonald diagnostic criteria (15). 
I 03. The participant must have at least 1 documented relapse within the previous year OR 
≥2 documented relapses within the previous 2 years OR ≥1 active Gd-enhancing brain 
lesion on an MRI scan in the past 6 months and prior to screening. 
I 04. A female participant must use a double contraception method including a highly effective 
method of birth control from inclusion and up to 2 months after the last study dose, except 
if she has undergone sterilization at least 3 months earlier or is postmenopausal. 
Menopause is defined as being amenorrheic for ≥12 months with serum 
follicle-stimulating hormone (FSH) level >30 UI/L. 
I 05. Male participants, whose partners are of childbearing potential (including breastfeeding 
women), must accept to use, during sexual intercourse, a double contraceptive method 
according to the following algorithm: (condom) plus (intrauterine device or hormonal 
contraceptive) from inclusion up to 3 months after the last dose. 
I 06. Male participants whose partners are pregnant must use, during sexual intercourse, a 
condom from inclusion up to 3 months after the last dose. 
I 07. Male participants must have agreed not to donate sperm from the inclusion up to 3 months 
after the last dose. 
Weight 
Not applicable. 
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Sex 
I 08. Male or Female 
Informed Consent 
I 09. The participant must have given written informed consent prior to undertaking any 
study-related procedure. 
5.2 
EXCLUSION CRITERIA  
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
E 01. The participant has been diagnosed with PPMS according to the 2017 revision of the 
McDonald diagnostic criteria (15) or with non-relapsing SPMS (16). 
E 02. The participant has conditions or situations that would adversely affect participation in this 
study, including but not limited to: 
- 
A short life expectancy due to pre-existing health condition(s) as determined by their 
treating neurologist 
- 
Medical condition(s) or concomitant disease(s) making them nonevaluable for the 
primary efficacy endpoint or that would adversely affect participation in this study, as 
judged by the Investigator 
- 
A requirement for concomitant treatment that could bias the primary evaluation 
- 
Contraindication for MRI, ie, presence of pacemaker, metallic implants in high-risk 
areas (ie, artificial heart valves, aneurysm/vessel clips), presence of metallic material 
(eg, shrapnel) in high risk areas, known history of allergy to any contrast medium, or 
history of claustrophobia that would prevent completion of all protocol-scheduled MRI 
- 
Contraindications to use MRI Gd contrast-enhancing preparations 
E 03. The participant has a history of or currently has concomitant medical or clinical conditions 
that would adversely affect participation in this study, including but not limited to: 
- 
A history of T-lymphocyte or T-lymphocyte-receptor vaccination, transplantation 
(including solid organ, stem cell, and bone marrow transplantation) and/or 
antirejection therapy 
- 
A history of diagnosis of progressive multifocal leukoencephalopathy (PML) or 
evidence of findings suggestive of PML on the baseline MRI 
- 
As the investigational medical product (IMP) has the potential to diminish 
immunocompetence, people with a history of infection with human immunodeficiency 
virus will be excluded 
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- 
A history of active or latent tuberculosis (unless the participant has completed a full 
course of anti-tuberculosis therapy or it is documented by a specialist that the 
participant has been adequately treated and can begin treatment with an 
immunosuppressive agent); screening tuberculosis testing should be performed as per 
local health care authority recommendations prior to study start and during the study if 
clinically indicated. Blood testing (eg, QuantiFERON®-TB Gold test) is preferred; skin 
testing (eg, tuberculin skin test) will be allowed if blood testing is not available or the 
blood test result is indeterminate 
- 
Any other active infections that would adversely affect participation or IMP 
administration in this study, as judged by the Investigator 
- 
A history of malignancy within 10 years prior to the first screening visit, except 
effectively treated carcinoma in situ of the cervix or adequately treated non-metastatic 
squamous or basal cell carcinoma of the skin 
- 
A history of alcohol or drug abuse within 1 year prior to the first screening visit 
- 
A history of any psychiatric disease, behavioral condition, or depression requiring 
hospitalization within 2 years prior to the first screening visit 
- 
Presence of any screening laboratory or ECG values outside normal limits that are 
considered in the Investigator’s judgment to be clinically significant 
- 
Presence of liver injury defined as underlying hepatobiliary disease or screening 
alanine aminotransferase (ALT) >3 x upper limit of normal (ULN) 
E 04. At screening, the participant is positive for hepatitis B surface antigen and/or hepatitis B 
core antibody and/or is positive for hepatitis C antibody. 
E 05. The participant has any of the following: 
- 
A bleeding disorder or known platelet dysfunction at any time prior to the first 
screening visit 
- 
A platelet count <150 000/μL at the screening visit 
E 06. The participant has a lymphocyte count less than the lower limit of normal (LLN) at the 
screening visit. 
E 07. The participant has received any live (attenuated) vaccine (including but not limited to 
varicella zoster, oral polio, and nasal influenza) within 2 months before the first treatment 
visit. 
Prior/concomitant therapy 
E 08. The participant has received any of the following medications/treatments within the 
specified time frame before any baseline assessment (no wash-out is required for 
interferons beta or glatiramer acetate treatments): 
 
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Medication 
Exclusionary if used/used within 
required wash-out period 
Systemic corticosteroids, adrenocorticotropic hormone 
1 month prior to screening MRI scan 
Dimethyl fumarate 
1 month prior to randomization 
Intravenous (IV) immunoglobulin, fingolimod, natalizumab (participants 
who have discontinued natalizumab in the 6 months prior to 
randomization should be evaluated to rule out PML) 
2 months prior to randomization 
Teriflunomide 
2 years prior to randomization or 1 month prior to 
randomization if participant undergoes an 
accelerated elimination procedure and has 
documented teriflunomide plasma level below 
0.02 mg/L before randomization 
B-cell-depleting therapies such as ocrelizumab and rituximab 
6 months prior to randomization or until return of 
B-cell counts to normal levels, whichever is longer 
Mildly to moderately immunosuppressive/chemotherapeutic medications 
such azathioprine and methotrexate 
6 months prior to randomization 
Highly immunosuppressive/chemotherapeutic medications: mitoxantrone 
up to 120 mg/m2 body surface area, cyclophosphamide, cladribine 
2 years prior to randomization 
Alemtuzumab 
4 years prior to randomization 
Lymphoid irradiation, bone marrow transplantation, mitoxantrone (with 
evidence of cardiotoxicity following treatment, or cumulative lifetime dose 
>120 mg/m2), other strongly immunosuppressive treatments with very 
long-lasting effects 
Any time 
 
E 09. The participant is receiving strong inducers or inhibitors of CYP3A or CYP2C8 hepatic 
enzymes as listed in the Appendix 7 (Section 10.7). 
E 10. The participant is receiving anticoagulant/antiplatelet therapies, including: 
- 
Acetylsalicylic acid (aspirin) 
- 
Antiplatelet drugs (eg, clopidogrel) 
- 
Warfarin (vitamin K antagonist) 
- 
Heparin, including low molecular weight heparin (antithrombin agents) 
- 
Dabigatran (direct thrombin inhibitor) 
- 
Apixaban, edoxaban, rivaroxaban (direct factor Xa inhibitors) 
Note: All above drugs need to be stopped at least 5 half-lives before study drug administration 
except for aspirin, which needs to be stopped at least 8 days before. 
Prior/concurrent clinical study experience 
E 11. The participant has previously participated in any clinical trial of a BTK inhibitor 
E 12. The participant has taken other investigational drugs within 3 months or 5 half-lives, 
whichever is longer, before the first screening visit 
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Diagnostic assessments 
E 13. The participant has an EDSS score >5.5 at the first screening visit. 
E 14. The participant has had a relapse in the 30 days prior to randomization. 
Other exclusions 
E 15. The participant is accommodated in an institution because of a regulatory or legal order, is 
a prisoner, or is legally institutionalized. 
E 16. The participant is dependent on the Sponsor or Investigator (in conjunction with 
Section 1.61 of the International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Ordinance E6). 
E 17. The participant has sensitivity to any of the study interventions, or components thereof or 
has a drug or other allergy that, in the opinion of the Investigator, contraindicates 
participation in the study. 
E 18. The participant is pregnant or a breastfeeding woman. 
E 19. The participant has any of the following within 4 weeks of the first screening visit: 
- 
Fever (≥38°C) 
- 
Persistent chronic or active recurring infection requiring treatment with antibiotics, 
antivirals, or antifungals 
E 20. The participant has a documented history of attempted suicide over the 6 months prior to 
the screening visit, presents with suicidal ideation of category 4 or 5 on the Columbia 
Suicide Severity Rating Scale (C-SSRS) during the study, OR if in the Investigator's 
judgment, the participant is at risk for a suicide attempt. 
E 21. The participant has had major surgery within 4 weeks prior to the first screening visit, 
which could affect participant’s safety or affect immune response (as judged by the 
Investigator) or has planned any elective surgery during the course of the study. 
E 22. The participant has a history or presence of significant other concomitant illness according 
to the Investigator’s judgment such as, but not limited to cardiovascular (including 
Stage III or IV cardiac failure according to New York Heart Association [NYHA] 
classification), or renal, neurological, endocrine, gastrointestinal, hepatic, metabolic, 
pulmonary, or lymphatic disease that would adversely affect participation in this study. 
E 23. The participant is uncooperative or has any condition that could make the participant 
potentially non-compliant with the study procedures. 
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5.3 
LIFESTYLE CONSIDERATIONS  
5.3.1 Meals and dietary restrictions  
Consumption of grapefruit fruits and their juices is prohibited from 5 days prior to intervention 
administration and during further participation in the study. 
5.3.2 Caffeine, alcohol, and tobacco  
For each visit session, participants will abstain from ingesting caffeine- or xanthine-containing 
products (eg, coffee, tea, cola drinks, and chocolate) for 2 hours before the start of treatment until 
after collection of the final PK
. 
Participants will abstain from alcohol for 24 hours before the start of treatment until after 
collection of the final PK 
 
5.3.3 Activity  
Not applicable. 
5.4 
SCREEN FAILURES  
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to the study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond 
to queries from regulatory authorities. Minimal information includes demography, screen failure 
details, eligibility criteria, and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened up to 2 times. Rescreened individuals should be assigned the same participant number 
as the initial screening. If an MRI has been performed within the 4 weeks prior to treatment, it 
does not need to be repeated. 
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6 
STUDY INTERVENTION  
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. 
6.1 
STUDY INTERVENTION(S) ADMINISTERED  
This study intervention includes an IMP and a noninvestigational medicinal product (NIMP). 
6.1.1 Investigational medicinal product  
To maintain blinding, participants will receive 4 tablets once per day of SAR442168 and/or 
placebo in a blinded fashion. The IMP can be taken with or without food. The time of day and 
whether IMP is taken with or without food should be as consistent as much as possible throughout 
the study. Details for the interventions are provided in Table 3.  
Table 3 - Overview of study interventions administered  
Study intervention name 
SAR442168 
Matching placebo 
Dosage formulation 
Film coated tablet 
Film coated tablet 
Unit dose strength(s)/dosage 
level(s) 
 Up to 4 tablets daily to achieve 5, 15, 
30, and 60 mg doses 
NA 
Route of administration 
Oral 
Oral 
Dosing instructions 
Up to 4 tablets daily to achieve 5, 15, 
30, and 60 mg doses 
Up to 4 tablets daily to maintain double-blind 
Packaging and labeling 
Study intervention will be packaged in 
blister packs, which will further be 
packaged into visit box containing 
4 weeks of treatment. Each wallet and 
box will be labeled as required per 
country requirements. 
Matching placebo in blister packs, which will 
further be packaged into visit box containing 
4 weeks of treatment. Each wallet and box will 
be labeled as required per country requirements. 
Study interventions will be dispensed at regular site visits. 
6.1.2 Noninvestigational medicinal product  
A radiological, signal-enhancing, intravenous (IV) contrast medium will be used for 
T1 contrast-enhanced MRI sequences. A locally approved medium will be used. 
Due to a potential safety risk related to deposition of certain IV Gd contrast agents in the brain, 
these agents should be used in accordance with local recommendations/regulations (17). 
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Otherwise, use of these agents will be similar to their routine use and will be sourced locally. The 
study manual will provide more detail of their administration.  
6.1.3 Devices  
Not applicable. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
The Investigator or designee must confirm specified temperature conditions have been maintained 
during transit for all study intervention received and any discrepancies are reported and resolved 
before use of the study intervention. 
1. Only participants enrolled in the study may receive study intervention and only authorized 
site staff may supply or administer study intervention. All study intervention must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area 
in accordance with the labeled storage conditions with access limited to the Investigator 
and authorized site staff. 
2. The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
3. Further guidance and information for the final disposition of unused study interventions 
are provided in the Pharmacy Manual. 
Any quality issue noticed with the receipt or use of an IMP/NIMP/device (deficiency in condition, 
appearance, pertaining documentation, labeling, expiration date, etc.) must be promptly notified to 
the Sponsor. Some deficiencies may be recorded through a complaint procedure (see 
Section 8.3.10). 
Under no circumstances will the Investigator supply IMP to a third party, allow the IMP to be 
used other than as directed by this clinical trial protocol, or dispose of IMP in any other manner. 
The exception is a duties and taxes paid (DTP) shipment, for which a courier company has been 
approved by the Sponsor. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
All participants will be centrally assigned to 1 of 8 arms (4 dose groups in each of the 2 cohorts 
at equal ratio to start with SAR442168 (in Cohort 1) or placebo (in Cohort 2) period before 
cross-over, using an IVRS/IWRS. A participant cannot be randomly assigned more than once in 
the study. Before the study is initiated, the telephone number and call-in directions for the IVRS 
and/or the log in information and directions for the IWRS will be provided to each site. Study 
interventions will be dispensed at the study visits summarized in the Schedule of Activities 
(Section 1.3). Returned study interventions should not be re-dispensed to the participants. 
Investigators will remain blinded to each participant’s assigned cohort (sequence) and 
SAR442168 dose throughout the study. 
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Blind Break (IVRS/IWRS) 
The IVRS/IWRS will be programmed with blind-breaking instructions. In case of an emergency, 
the Investigator has the sole responsibility for determining if unblinding of a participant’s 
treatment assignment is warranted. Participant safety must always be the first consideration in 
making such a determination. If the Investigator decides that unblinding is warranted, the 
Investigator should make every effort to contact the Sponsor prior to unblinding a participant’s 
treatment assignment unless this could delay emergency treatment of the participant. If a 
participant’s treatment assignment is unblinded, the Sponsor must be notified within 24 hours 
after breaking the blind. The date and reason that the blind was broken must be recorded in the 
source documentation and case report form, as applicable. 
Methods of blinding 
 This study is blinded for dose and SAR442168-placebo administration sequence. Tablets 
of different SAR442168 dose levels and placebo will be identical. Due to ethical 
considerations, placebo duration is restricted to 4 weeks, which will allow more objective 
evaluation of safety events at the beginning of the study period, and will also add to 
objectivity of evaluation of clinical endpoints 
 Investigators will not have access to MRI data except for any non-MS-related findings, 
which will be communicated in order to evaluate the safety of the participant. The 
radiology service for the site will be in charge of timely reporting of any non-MS findings 
on MRI to the Investigator 
 The Independent Data Monitoring Committee (IDMC) will be used to periodically 
monitor safety of this study. Unblinded data will be provided for IDMC review by an 
unblinded independent statistician. Study team members, Investigators, and study 
participants will not have access to unblinded data 
6.4 
STUDY INTERVENTION COMPLIANCE  
At the end of the baseline visit (Day 1), the participant will receive the study intervention for the 
following 4 weeks. At each following visit, a new kit will be dispensed. 
It is the responsibility of the Investigator to check the participant’s compliance to the study 
intervention. Compliance is tracked by counting dispensed and unused tablets at each on-site visit 
after baseline until the end-of-treatment visit. The Investigator (or authorized delegate) will 
complete the appropriate pages of the electronic case report form (eCRF) and IMP source 
document logs by recording the numbers and dates of doses taken (or not) by the participant. The 
monitor in charge of the clinical trial will check the case report form data by comparing the 
recorded data with the retrieved IMP kit and data recorded on the IMP source document logs and 
in the eCRF. 
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6.5 
CONCOMITANT THERAPY  
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with: 
 
Reason for use 
 
Dates of administration including start and end dates 
 
Dosage information including dose and frequency 
The same data will be collected for all prior medications received during the 4 weeks before 
enrollment, also for all prior MS treatments and treatments considered clinically important to 
assess MS or concomitant disease. 
Standard treatment of MS relapse with high-dose glucocorticoids is permitted. Local guidance is 
to be followed for such treatments.  
In addition to the medicines excluded in Section 5.2, the following medications are prohibited 
throughout the study: 
 Other MS disease-modifying treatments 
 Acetylsalicylic acid (aspirin) 
 Anti-platelet drugs (eg, clopidogrel) 
 Anticoagulants, including:  
- 
Warfarin 
- 
Heparin, including low-molecular-weight heparins  
- 
Dabigatran  
- 
Apixaban, edoxaban, rivaroxaban  
Paracetamol/acetaminophen, at doses of ≤3 grams/day, is permitted for use at any time during the 
study. Short courses (up to 5 days) of NSAIDs (other than acetylsalicylic acid) at the 
recommended dose may be given during the course of the study if clinically necessary for the 
treatment of an existing medical condition or a new event. The Investigator must record the use of 
NSAIDs (and any other comedication) in the CRF. 
 
 Use of proton pump inhibitors  
(eg, omeprazole) should be avoided. Use of antacids (eg, calcium carbonate) should be staggered 
with respect to SAR442168 dosing, with antacid administration occurring no less than 2 hours 
before or 2 hours after SAR442168 administration. Use of H2-receptor antagonists (eg, ranitidine) 
should also be staggered with respect to SAR442168 dosing, with H2-receptor antagonist 
administration occurring no less than 10 hours before or 2 hours after SAR442168 administration. 
See Section 10.8 for a list of example drugs with a potential to affect plasma exposure of 
SAR442168 via reduction of gastric acid.  
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Based on preclinical drug metabolism studies, SAR442168 is a substrate of the CYP3A and 
CYP2C8 isoenzymes, and therefore, it is possible that plasma exposures of SAR442168 would be 
altered if co-administered with other drugs that either induce or inhibit CYP3A and/or CYP2C8 
metabolism. This has not been studied in humans to date and therefore, drugs that strongly inhibit 
or induce CYP3A or CYP2C8 should be avoided, if possible. See Appendix 7, Section 10.7 for 
the list of drugs not to be used. 
6.5.1 Rescue medicine  
Not applicable. 
6.6 
DOSE MODIFICATION  
Dose reduction is not foreseen in this study. Participants, Investigators, and the Sponsor’s team 
will be blinded with respect to assigned dose levels. Treatment might need to be interrupted or 
permanently discontinued if deemed necessary due to an AE (Section 7 and Section 8.3). 
6.7 
INTERVENTION AFTER THE END OF THE STUDY  
A separate, open-label, LTS study will be offered to participants completing the Week 16 visit of 
this study. Upon completing the double-blinded treatment period, participants already enrolled in 
the DRI study and all subsequent participants will be given the option to enroll in a LTS 
follow-up study to assess safety and tolerability of SAR442168. The LTS follow-up study will be 
described in a separate protocol. 
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
Withdrawal of consent for treatment should be distinguished from (additional) withdrawal of 
consent for follow-up visits and from withdrawal of consent for nonparticipant contact  
(eg, medical record checks) follow up. The site should document any case of withdrawal of 
consent. 
7.1 
DISCONTINUATION OF STUDY INTERVENTION  
7.1.1 Definitive discontinuation  
The IMP should be continued whenever possible. 
In case the IMP is stopped, it should be determined whether the stop can be made temporarily; 
definitive IMP discontinuation should be a last resort. Any IMP discontinuation must be fully 
documented in the eCRF. In any case, the participant should remain in the study as long as 
possible. 
Definitive intervention discontinuation is any intervention discontinuation associated with the 
definitive decision from the Investigator not to re-expose the participant to the IMP at any time 
during the study, or from the participant not to be re-exposed to the IMP, whatever the reason. 
Discontinuation of the study intervention for abnormal liver function should be considered by the 
Investigator when a participant meets one of the conditions outlined in the Section 10.6 or if the 
Investigator believes that it is in best interest of the participant.  
If a clinically significant finding is identified in the ECG (including, but not limited to changes 
from baseline in QT interval corrected using Fridericia’s formula [QTcF]) after enrollment, the 
Investigator or qualified designee will determine if the participant can continue in the study and if 
any change in participant management is needed. Review of ECG findings by a cardiologist needs 
to be taken into consideration for a decision of a definitive discontinuation of study intervention 
because of ECG changes. This review of the ECG printed at the time of collection must be 
documented. Any new clinically relevant finding should be reported as an AE. 
See the SoA (Section 1.3) for data to be collected at the time of intervention discontinuation 
(end-of-treatment visit) and follow up and for any further evaluations that need to be completed. 
Any abnormal laboratory value or ECG parameter will be immediately rechecked for 
confirmation after 24 hours before a decision of definitive discontinuation of the intervention for 
the concerned participant is made. 
In case of premature discontinuation of the intervention, the end-of-treatment visit will be 
conducted. 
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Handling of participants after definitive intervention discontinuation 
Participants will be followed up according to the study procedures specified in this protocol up to 
study completion, or up to recovery or stabilization of any AE to be followed up as specified in 
this protocol, whichever comes last. 
If possible, and after the definitive discontinuation of intervention, the participants will be 
assessed using the procedure normally planned for the last treatment day with the IMP including a 
PK sample. Details are provided in the SoA (Table 1). All cases of definitive intervention 
discontinuation must be recorded by the Investigator in the appropriate pages of the eCRF when 
considered as confirmed. 
7.1.2 Temporary discontinuation  
Temporary intervention discontinuation may be considered by the Investigator because of 
suspected AEs and/or laboratory abnormalities and/or ECG abnormalities. For all temporary 
intervention discontinuations, the duration of the discontinuation should be recorded by the 
Investigator in the appropriate pages of the eCRF. 
Temporary intervention discontinuation decided by the Investigator corresponds to >1 dose not 
administered to the participant. 
Analysis of missed doses will be described in the SAP. 
7.1.2.1 Rechallenge  
Re-initiation of intervention with the IMP will be done under close and appropriate clinical/and or 
laboratory monitoring once the Investigator will have considered, according to his/her best 
medical judgment, that the responsibility of the IMP(s) in the occurrence of the concerned event 
was unlikely and if the selection criteria for the study are still met (refer to Section 5.1). 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY  
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, or 
administrative reasons. 
 If a participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent 
 If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records 
 See the SoA (Section 1.3) for data to be collected at the time of study discontinuation and 
follow up and for any further evaluations that need to be completed 
 If participants no longer wish to take the IMP, they will be encouraged to remain in the 
study 
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Investigators should discuss key visits with participants. The value of all study data should be 
emphasized as important to the public health value of the study. 
Participants who withdraw from the study intervention should be explicitly asked about the 
contribution of possible AEs to their decision, and any AE information elicited must be 
documented. 
All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
eCRF and in the participant’s medical records. In the medical record, at least the date of the 
withdrawal and the reason should be documented. 
In addition, a participant may withdraw consent to participate in the study. Withdrawal of consent 
for intervention should be distinguished from withdrawal of consent for follow-up visits and from 
withdrawal of consent for nonparticipant contact follow up, eg, medical record checks. The site 
should document any case of withdrawal of consent. 
Participants who have withdrawn from the study cannot be re-randomized (treated) in the study. 
Their participant and kit numbers must not be reused. 
7.3 
LOST TO FOLLOW UP  
A participant will be considered lost to follow up if he/she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
 The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study 
 Before a participant is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls, and if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record 
 Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study 
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8 
STUDY ASSESSMENTS AND PROCEDURES  
Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol waivers or 
exemptions are not allowed. 
 Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue the 
study intervention 
 Adherence to the study design requirements, including those specified in the SoA 
(Section 1.3), is essential 
 All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable 
 Procedures conducted as part of the potential participant’s routine clinical management 
(eg, blood count) and obtained before signing of the informed consent form (ICF) may be 
utilized for screening or baseline purposes, provided the procedures meet the 
protocol-specified criteria and were performed within the time frame defined in the SoA 
(Section 1.3) 
 In case of premature discontinuation of study intervention, the end-of-treatment visit will 
be conducted 
 The participant will return 2 to 4 weeks after a premature end-of-treatment visit 
 The maximum amount of blood collected from each participant over the duration of the 
study, including any extra assessments that may be required, will not exceed 70 mL for 
participants of the main study
 
 Additional repeat or unscheduled samples may be taken for safety 
reasons or for technical issues with the samples 
8.1 
EFFICACY ASSESSMENTS  
8.1.1 Magnetic resonance imaging assessments  
Cranial (brain) MRI with and without Gd contrast will be performed. Basic MRIs will be 
performed for all participants at all study sites and will consist of T2- and T1-weighted sequences 
without and with Gd contrast. 
Due to a potential safety risk related to deposition of certain IV Gd contrast agents in the brain, 
these agents should be used in accordance with local recommendations/regulations (17). 
The study manual containing instructions for standard image acquisition requirements for brain 
MRI, data transfer to the central review center, archiving and shipping will be provided to all 
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participating sites. Study site personnel will undergo training regarding MRI acquisition and data 
handling procedures, training will be documented, and adherence to the manual will be monitored 
throughout the study with retraining performed as necessary. 
New T1 Gd-enhancing hyperintense and new and enlarging T2 lesions will be evaluated at each 
visit as per the SoA (Section 1.3), comparing lesion count to that from the previous MRI scan.  
Unless specified otherwise, the baseline brain MRI will be used as the reference to assess all 
MRI-derived endpoints. The baseline MRI will be the last MRI performed before the 
randomization visit. Standardized endpoint evaluation is assured by central review of brain MRI 
scans. Blinded central review will be performed for all MRI-derived endpoints. Magnetic 
resonance imaging reviewers will be blinded to treatment assignments and to other participant 
data. Details on MRI testing and central review will be described in the study manual. 
Spinal MRIs may be required if spine MS lesions are suspected by the Investigator. Spinal MRIs 
will be evaluated locally and reported in the eCRF. No central review will be performed for spinal 
MRIs. 
Magnetic resonance imaging scans need to be reviewed locally for any non-MS pathology to 
assure safety reporting as per Section 8.3.5. In case of detection of non-MS findings, the MRI 
scan report needs to be reported to the Treating Investigator. Normal MS findings on MRI should 
not be disclosed to Investigators or to the site team if not relevant to any safety concern. 
 
 
 
8.1.2 Multiple sclerosis relapse  
8.1.2.1 Unscheduled assessment visits for a suspected multiple sclerosis relapse  
Participants must be instructed to immediately report new neurological symptoms and recurring or 
worsening of previous symptoms to the Investigator. Any reported symptoms will be collected. If 
a participant reports symptoms that may be consistent with relapse, an unscheduled assessment 
visit with the Investigator will be scheduled as soon as possible (whenever possible within 7 days 
of onset of the symptoms). The Investigator will assess whether the reported episode is consistent 
with the definition of MS relapse (see Section 8.1.2.2). If it is consistent with the definition of MS 
relapse or if there is any doubt and relapse cannot be ruled out, an EDSS assessment should be 
performed. 
All MS relapses are to be reported on the MS relapse eCRF page. Multiple sclerosis relapse 
should not be reported as an AE/SAE unless, in the judgment of the Investigator, it is unusually 
severe or medically unexpected (see Section 8.3.5 for reporting rules). 
Unscheduled visit activities are detailed in SoA (Section 1.3), they need to be adapted, if other 
pathology than MS is cause for it, and additional examinations or laboratory tests are needed for 
safety follow up and optimal treatment decisions. 
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8.1.2.2 Definition of multiple sclerosis relapse  
For the purposes of this study, MS relapse is defined as acute, new neurological symptoms or 
worsening of previous neurological symptoms with an objective change on neurological 
examination. Symptoms must: 
 Be attributable to MS 
 Last for ≥24 hours, and 
 Be present at normal body temperature (ie, no infection, excessive exercise, or excessively 
high ambient temperature) 
Note: An exacerbation or recurrence of symptoms and signs that can be reasonably attributed to 
transient impairment of conduction in previously demyelinated pathways due to drugs (such as 
rarely occurs a few hours after injection of interferon beta), raised core body temperature (the 
Uhthoff phenomenon), or systemic cytokine release (such as occurs with the administration of 
alemtuzumab) will not be considered a relapse. 
It is at the Investigator’s discretion and responsibility to choose the best treatment option for any 
MS relapse, such as a high-dose glucocorticoid treatment course. 
Analysis of relapses will be detailed in the SAP. 
8.1.3 Expanded Disability Status Scale evaluation  
The Investigator will perform the EDSS evaluation (13) as indicated in the SoA (Section 1.3). 
All Investigators will be trained and certified to perform the EDSS in a consistent manner. 
EDSS scores will be captured on paper. Details will be included in the study manual. 
The Investigator will rate functional systems in the context of a standard neurological examination 
and will report these ratings as per the EDSS reporting instructions together with information on 
the participant’s mobility, gait, and use of assistive devices. Standard EDSS assessments of 
neurological symptoms in each of 7 functional domains (visual, brainstem, pyramidal [motor], 
cerebellar [coordination], sensory, cerebral and bowel/bladder) will be performed. Ambulation 
will also be scored as part of the evaluation. Fatigue may optionally be evaluated, but it will not 
contribute to the EDSS score. Details of EDSS assessment and scoring will be described in the 
study manual. 
 
  
 
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8.2 
SAFETY ASSESSMENTS  
Time points for all safety assessments are provided in the SoA (Section 1.3). 
The definitions of AEs and SAEs can be found in Appendix 3 (Section 10.3). For the purpose of 
this protocol, MS relapses (Section 8.1.2) are waived from reporting as AEs except if they meet 
the criteria of an SAE. Nonserious MS relapses will be collected on a special eCRF page and will 
be analyzed as an efficacy endpoint. Following an MS relapse assessment, (Section 8.1.2), events 
that are concluded as not meeting the criteria of an MS relapse will be reported as AEs. 
8.2.1 Physical examinations  
The complete physical examination will include, at a minimum, assessments of general 
appearance, head and neck, abdomen, lymph nodes, skin (signs of bleeding include bruises, 
petechial rash), cardiovascular, respiratory, gastrointestinal, musculoskeletal, and neurological 
systems. Height and weight will also be measured and recorded. Details will be provided in the 
study manual. 
 The brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen) 
 Investigators should pay special attention to clinical signs related to previous serious 
illnesses 
 Any new finding or worsening of a previous finding should be reported as a new AE 
 The SoA (Table 1) provides a schedule of physical examinations. A full examination 
should be performed whenever the Investigator judges a need for complete evaluation of 
the participant 
8.2.2 Vital signs  
 Temperature, pulse rate, respiratory rate, and blood pressure will be assessed. The same 
method for temperature measurement should be used throughout the study 
 Blood pressure and pulse measurements will be assessed in sitting or supine position with 
a completely automated device. Same position measurements should be used throughout 
the study for the same participant. Manual techniques will be used only if an automated 
device is not available. Caffeinated drinks to be avoided before blood pressure 
measurements 
 Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions (eg, television, cell phones) 
 Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse, 
3 blood pressure measurements (3 consecutive blood pressure readings will be recorded at 
intervals of at least 1 minute), and respiratory rate. The average of the 3 blood pressure 
readings will be recorded on the eCRF 
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8.2.3 Electrocardiograms  
 Twelve-lead ECG will be obtained as outlined in the SoA (Section 1.3) using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals. At least one longer rhythm monitoring recording needs to be part of each ECG 
testing. The ECG will be reviewed by a cardiologist for confirmation of abnormality and 
clinical evaluation. Refer to Section 7 for QTc withdrawal criteria and any additional QTc 
readings that may be necessary 
8.2.4 Clinical safety laboratory assessments  
See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and to the 
SoA (Section 1.3) for the timing and frequency.  
 The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those that are not associated with the underlying disease, 
unless judged by the Investigator to be more severe than expected for the participant's 
condition 
 All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 4 weeks after the last dose of study intervention should 
be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the Investigator or medical monitor 
- 
If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified and the Sponsor 
notified 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), must be 
conducted in accordance with the laboratory manual and the SoA (Section 1.3). 
 
If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the Investigator (eg, SAE or AE or dose modification), then the 
results must be recorded in the eCRF 
8.2.5 Suicide risk monitoring  
SAR442168 is considered to be CNS-active, and therefore routine suicide risk monitoring will be 
performed. 
The C-SSRS and thorough clinical evaluation of complaints will be used for suicide risk 
assessment. Any observations or events of clinical importance will be reported as AEs. 
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8.2.5.1 The Columbia Suicide Severity Rating Scale  
The C-SSRS is a tool used to assess the lifetime suicidality of a participant and to track suicidal 
events through the study. The structured interview prompts recollection of suicidal ideation, 
including the intensity of the ideation, behavior and attempts with actual/potential lethality. The 
scale will be administered by the Investigator or a qualified designee at the time points indicated 
in the SoA (Section 1.3). 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
8.3.1 Adverse events of special interest  
An AESI is an AE (serious or nonserious) 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. 
 
Acute hypersensitivity/anaphylaxis 
 
Pregnancy of a female participant entered in a study as well as pregnancy occurring in a 
female partner of a male participant entered in a study with IMP/NIMP; 
- 
Pregnancy occurring in a female participant entered in the clinical study or in a female 
partner of a male participant entered in the clinical study. It will be qualified as an 
SAE only if it fulfills one of the seriousness criteria (see Appendix 3 [Section 10.3]). 
- 
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  
(See Appendix 4 [Section 10.4]) 
 
Symptomatic overdose (serious or nonserious) with IMP/NIMP 
- 
An overdose (accidental or intentional) with the IMP/NIMP is an event suspected by 
the Investigator or spontaneously notified by the participant (not based on systematic 
pills count) and defined as at least twice the intended dose within the intended 
therapeutic interval, adjusted according to the tested drug. 
- 
Of note, asymptomatic overdose must be reported as a standard AE. 
 
Increase in ALT 
- 
Any increase of ALT >3 x ULN 
Other project specific AESI(s) 
 
ECG observation of QTc ≥500 ms or of clinically significant arrhythmia (eg, atrial 
fibrillation, atrial flutter) confirmed by a cardiologist 
- 
Serious infection, particularly any opportunistic infection 
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- 
Major hemorrhagic events, including symptomatic bleeding in a critical area or organ, 
such as CNS or intraocular bleeding resulting in an SAE 
- 
Thrombocytopenia platelet count <100 x 109/L (see Appendix 6, Section 10.6 for 
management flow chart) 
The definition of an AE or SAE can be found in Appendix 3 (Section 10.3). 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention (see Section 7). 
8.3.2 Time period and frequency for collecting AE and SAE information  
All SAEs will be collected from the signing of the ICF until the last study visit at the time points 
specified in the SoA (Section 1.3). 
All AEs will be collected from the signing of the ICF until the last visit at the time points 
specified in the SoA (Section 1.3). 
All SAEs and AESIs will be recorded and reported to the Sponsor or designee within 24 hours, as 
indicated in Appendix 3 (Section 10.3). The Investigator will submit any updated SAE data to the 
Sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek AEs or SAEs after conclusion of study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study and he/she considers the event to be reasonably 
related to the study intervention or study participation, the Investigator must promptly notify the 
Sponsor. 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
8.3.3 Method of detecting AEs and SAEs  
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
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8.3.4 Follow up of AEs and SAEs  
After the initial AE/AESI/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. At the prespecified study end date, all SAEs, and 
nonserious AESIs (as defined in Section 10.3), will be followed until resolution, stabilization, the 
event is otherwise explained, or the participant is lost to follow up (as defined in Section 7.3). 
Further information on follow-up procedures is given in Appendix 3 (Section 10.3). 
8.3.5 Regulatory reporting requirements for SAEs  
 Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met 
 The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators 
 Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor’s policy and 
forwarded to Investigators as necessary 
 Adverse events that are considered expected will be specified in the reference safety 
information 
 An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will review 
and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, if 
appropriate according to local requirements 
8.3.6 Pregnancy  
Details of all pregnancies in female participants and female partners of male participants will be 
collected after the start of study intervention and until the last visit of the study. 
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of learning 
of the pregnancy and should follow the procedures outlined in Appendix 4 (Section 10.4). 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, and ectopic pregnancy) are considered SAEs. 
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8.3.7 Cardiovascular and death events  
Atrial fibrillation, atrial flutter, observation of QTc ≥500 ms, or other clinically significant 
arrhythmia are AESIs in this study and subject to expedited reporting to the Sponsor. All other 
cardiovascular events will be reported per standard safety reporting and safety oversight practices 
(including data review by IDMC). Central ECG review will be performed to assure consistency in 
ECG evaluation. 
Death events will be reported per standard SAE reporting rules. Every effort will be done to 
clarify the cause of death and to report the diagnosis of the fatal event as an SAE. 
8.3.8 Multiple sclerosis relapse reporting  
Multiple sclerosis relapses, determined from the evaluations described in Section 8.1.2, as with all 
efficacy endpoints, will be exempt from being reported as AEs except when they meet the 
definition of an SAE. Hospitalization for MS relapse, if done routinely at the site (eg, for high 
dose IV methylprednisolone), will not be considered as a seriousness criterion for this study. 
Multiple sclerosis relapses will be collected on the eCRF and be analyzed as part of the efficacy 
analysis. 
Other worsening of neurological symptoms that do not meet the definition of MS relapse will be 
reported as AEs according to general safety reporting rules. 
8.3.9 Reporting of safety findings from magnetic resonance imaging  
Magnetic resonance imaging scans need to be reviewed locally for any non-MS pathology. In case 
of such findings, the MRI report needs to be provided to the Investigator for appropriate safety 
reporting. When available, a diagnosis of pathology as a cause of such MRI findings or the 
findings themselves will be reported as an AE until the diagnosis is clear. 
Multiple sclerosis findings on MRI do not need to be reported unless they are deemed unusual and 
thus a distinct safety finding. 
8.3.10 Guidelines for reporting product complaints  
Any defect in the IMP/NIMP/device must be reported as soon as possible by the Investigator to 
the monitoring team that will complete a product complaint form within required timelines. 
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE. 
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8.3.10.1 Medical devices  
Not applicable. 
8.4 
TREATMENT OF OVERDOSE  
Sponsor does not recommend specific treatment for an overdose.  
In the event of an overdose, the Investigator should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities until study 
intervention can no longer be detected systemically and activity is over (at least 9 days). 
3. Obtain a plasma sample for PK analysis within 1 day from the date of the last dose of 
study intervention if possible or later if requested by the Medical Monitor (determined on 
a case-by-case basis). 
4. Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on clinical evaluation of the participant. 
8.5 
PHARMACOKINETICS  
8.5.1 Sampling time  
Samples for SAR442168 PK analysis will be collected 1 hour post-dose (±0.5 hour) at visits 
during Weeks 1, 4, 8, 12, and 16 for all participants in both cohorts. An additional PK sample will 
be collected 3 hours post-dose (±0.5 hour) at visits during Weeks 4 and 12 for all participants in 
both cohorts. Data of the most recent meal prior to PK sampling will be noted in the eCRF. 
8.5.2 Pharmacokinetics handling procedure  
Detailed procedures of sample preparation, storage, and shipment will be described in the specific 
laboratory manual. A total of 2 mL of blood is to be collected for each PK sample. 
The total amount of blood for PK per participant and the total number of samples taken in the 
study are presented in Table 4. 
Table 4 - Blood volume per participant and total number of samples  
Number of pharmacokinetics 
samples by participant 
Blood volume per participant 
for pharmacokinetics 
Total number of samples in the 
study for pharmacokinetics 
7 
7 x 2 mL = 14 mL 
7 x 120 samples = 840 samples 
 
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8.5.3 Bioanalytical method  
SAR442168 and its metabolite PRN2677 will be assayed by a validated LC/MS method. The 
details of the bioanalytical method will be specified in the study manual. 
8.5.4 Pharmacokinetics parameters  
SAR442168 concentrations at selected time points after IMP intake will be reported using 
descriptive statistics. Additional PK parameters such as Cmax, tmax, and AUC at steady state will be 
estimated using a population PK approach. These parameters will be presented in a separate, 
stand-alone report. 
 
  
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9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES  
The primary objective of this study is to assess the dose-response relationship based on the 
primary endpoint (number of new Gd-enhancing T1-hyperintense lesions as detected by brain 
MRI) at the end of 12 weeks of SAR442168 treatment. The null hypothesis is a flat, no 
dose-response curve for the primary endpoint and the alternative is that there is a dose-response 
signal. 
9.2 
SAMPLE SIZE DETERMINATION  
The study will have 120 participants equally randomly assigned to 1 of 4 SAR442168 doses in 
2 cohorts (60 participants in each of Cohorts 1 and 2). Cohorts 1 and 2 represent different 
treatment sequences, and participants in each will cross-over to SAR442168 or placebo in a 
blinded manner. 
The 60 participants in Cohort 2 will start with a 4-week placebo run-in that will be utilized as the 
placebo data in analyses for the primary endpoint based on the assumption of the constant 
monthly mean number of new Gd-enhancing T1-hyperintense lesions over 12 weeks of placebo 
treatment. Assuming 15% of participants without the primary endpoint at the end of 12 weeks of 
SAR442168, 105 participants (26 per SAR442168 dose) has at least 83% power to detect the 
maximum reduction of 85% using a 2-step MCP-Mod with 6 pre-defined dose response curves  
(2 Emax models, a quadratic model, a linear model, a logistic model, and an exponential model). 
This calculation assumes the dispersion parameter of 2 (estimated from Week 12 placebo data 
from the vatelizumab [SAR339658] DRI13839 study), within-subject correlation ranging 
from -0.9 to 0.9 in measurements between 4-week placebo and 12-week SAR442168 in Cohort 2, 
and placebo mean number of ≥1 for new Gd-enhancing T1-hyperintense lesions at 4 weeks. 
This power was calculated using the package Dose Finding from the Comprehensive R Archive 
Network (CRAN) (18), using the 6 candidate curves considered for dose-response modelling in a 
negative binomial regression framework. 
9.3 
POPULATIONS FOR ANALYSES  
For purposes of analysis, the following populations are defined (Table 5): 
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Table 5 - Populations for analyses  
Population 
Description 
Enrolled  
All participants who sign the ICF 
Randomly assigned to study intervention 
All participants who are randomly assigned to the study intervention 
mITT 
The primary efficacy population will be the mITT population, defined as all randomly 
assigned participants exposed to study intervention. The efficacy analyses will be 
conducted according to the treatment group allocated by the randomization schedule, 
irrespective of the treatment received 
Safety 
All participants randomly assigned to the study intervention and who take at least 1 
dose of the study intervention. Participants will be analyzed according to the 
intervention they actually receive. 
Abbreviations: ICF: informed consent form; mITT: modified intent-to-treat 
9.4 
STATISTICAL ANALYSES  
The SAP will be developed and finalized before database lock and will describe the participant 
populations to be included in the analyses and procedures for accounting for missing, unused, and 
spurious data. This section is a summary of the planned statistical analyses for the primary and 
secondary endpoints. 
9.4.1 Efficacy analyses  
The primary efficacy analysis will be based on the mITT population. For the endpoints assessed 
by change from baseline, the baseline values are defined as the last measurements collected on or 
before the randomization visit (Day 1) prior to initiation of the first dose of study intervention. 
Data from Cohorts 1 and 2 will be combined for the primary analysis (ie, data at Week 12 for 
Cohort 1 and at Week 16 for Cohort 2 for the number of new Gd-enhancing T1-hyperintense 
lesions). 
For each cohort, descriptive statistics will be summarized over time (Weeks 4, 8, 12, and 16) 
when appropriate. The summary from Cohort 1 will include descriptive statistics for the 4-week 
placebo period after 12 weeks of SAR442168 treatment. Additional efficacy analyses will be 
described in the SAP. 
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Table 6 - Efficacy analyses  
Endpoint 
Statistical Analysis Methods 
Primary 
 
Number of new Gd-
enhancing 
T1-hyperintense lesions at 
the end of 12 weeks of 
SAR442168 treatment as 
detected by brain MRI 
For the mITT population, the dose-response relationship will be evaluated by a 2-step 
MCP-Mod procedure. The first step of this procedure tests for an efficacy signal 
(compared to the null hypothesis of a flat, no dose-response curve) in a procedure that 
controls the type 1 error. To account for the uncertainty of the dose-response shape, 6 
candidate models have been considered to cover diverse and potential dose-response 
profiles: 2 Emax models (ED50 = 10 mg, ED50 = 30 mg), a linear model, a quadratic model, a 
logistic model, and an exponential model. The second step is the estimation of the dose-
response curve, provided that an efficacy signal is established in the first step. 
A negative binomial regression model with covariates for baseline Gd-enhancing T1-
hyperintense lesion count, treatment, and cohort (Cohort 1 or Cohort 2) will be used to 
assess the mean count of new Gd-enhancing T1-hyperintense lesions in each of the 4 
dose groups at the end of 12 weeks of SAR442168 treatment and at the end of 4 weeks of 
placebo. The 4-week post-randomization placebo data from Cohort 2 (ie, Week 4 data 
from Cohort 2) will be utilized as the placebo data at Week 12 in analysis, under the 
assumption of a constant rate of Gd-enhancing T1-hyperintense lesion formation if 
participants would be receiving placebo over 12 weeks. Participants in Cohort 2 contribute 
to the placebo data (at Week 4) as well as the data of 5 SAR442168 doses (at Week 16). 
Thus, in order to account for the potential correlation between the measurements in the 4-
week placebo period and the subsequent 12-week SAR442168 treatment period in Cohort 
2, a GEE approach is used to fit the negative binomial model accounting for the within-
participant correlation via the repeated statement in SAS PROC GENMOD. A minus log 
transformation of the mean lesion count will be entered into the MCP-Mod procedure. The 
null hypothesis of a flat dose-response curve (ie, no dose–response relationship) at the 
end of 12 weeks of SAR442168 treatment for the primary endpoint will be jointly evaluated 
for each of the 6 candidate dose response models with a contrast test that controls the 
family wise error rate at 2-sided alpha = 0.05. If step 1 yields significant results, the best 
fitting model from the 6 predefined candidate models will be chosen using the generalized 
AIC. The dose for the Phase 3 program will then be estimated from the final selected 
model. 
Data from Cohorts 1 and 2 will be combined for the primary analysis (ie, data at Week 12 
for Cohort 1 and at Week 16 for Cohort 2 for the number of new Gd-enhancing T1-
hyperintese lesions). Data from each cohort may be separately explored. 
Descriptive statistics will also be provided for the 4 SAR442168 doses for number of new 
Gd-enhancing T1-hyperintense lesions over time (ie, Week 4/Week 8, Week 8/Week 12, 
and Week 12/Week 16 for Cohort 1/Cohort 2). 
Secondary 
 
 Number of new or 
enlarging T2 lesions at the 
end of 12 weeks of 
SAR442168 treatment 
 
Total number of Gd-
enhancing T1-
hyperintense lesions at the 
end of 12 weeks of 
SAR442168 treatment 
For the secondary endpoint of number of Gd-enhancing T1-hyperintense lesions at the 
end of 12 weeks of SAR442168 treatment, a similar negative binomial model and MCP-
Mod procedure will be used. As it is reasonable to assume a constant rate of lesion 
formation over 12 weeks under placebo for total number of Gd-enhancing T1-hyperintense 
lesions, the same approach as that utilized for the primary endpoint will be used, by using 
the Week 4 data in Cohort 2 as the Week 12 placebo data while accounting for the within-
participant correlation. Descriptive statistics over time will also be provided for the 4 
SAR442168 doses. 
 
For the secondary endpoint of number of new or enlarging T2 lesions, descriptive 
summary statistics over time (4, 8, 12, and 16 weeks) will be provided for each of the 4 
SAR442168 doses. Further, a similar MCP-Mod approach will be explored if it is deemed 
reasonable to extrapolate the Week 4 data from Cohort 2 to the Week 12 placebo data. 
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Endpoint 
Statistical Analysis Methods 
9.4.2  Safety analyses  
All safety analyses will be performed on the safety population. 
All safety summaries will be descriptive. No statistical significance tests will be performed on 
safety data. Safety endpoints are described in Table 7. 
The baseline value is defined generally as the last available value before the first administration of 
randomized study intervention. 
Safety data for the first 4 weeks following randomization (where participants in Cohort 2 receive 
placebo) will be summarized by SAR442168 and placebo. Safety data during the 4-week placebo 
period (ie, 4 weeks) in Cohort 1 will be summarized separately and displayed by the SAR442168 
dose group and overall. 
For SAR442168 treatment safety data, summaries by dose group, by time on SAR442168, and 
overall will be provided. 
For safety variables, the following observation periods are defined and used for classification of 
AEs, determination of on-treatment PCSA values, and the last on-treatment value for laboratory 
and vital sign parameters: 
 
The pretreatment period is defined as the time from the signed ICF to the first 
administration of randomized study intervention 
 For the purpose of defining ‘treatment-emergent’, the on-treatment period is defined as the 
time from the first administration of randomized study intervention until the last study 
visit. The treatment periods are further defined as: 
- 
The “Weeks 1 to 4 period” is defined as the time from first administration of 
randomized study treatment to the administration of the Week 4 study treatment. For 
Cohort 1 this is SAR442168 treatment for 4 weeks and for Cohort 2 is placebo 
treatment for 4 weeks 
- 
The “SAR442168 treatment period” is defined as Weeks 1 to 12 for Cohort 1 and 
Weeks 4 to 16 for Cohort 2 
Note: participants from the Cohort 1 Weeks 1 to 4 period are also included in the 12 weeks of the 
SAR442168 period. 
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- 
The “placebo/post-SAR442168 dose period” is defined as Week 12 to Week 16 for 
Cohort 1. This is the 4 weeks of placebo treatment following 12 weeks of SAR442168 
treatment 
All AEs reported in this study will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) version in effect at the time of database lock. The analyses of AEs will 
focus on treatment-emergent adverse events (TEAEs). 
 
Pretreatment AEs are defined as AEs that developed, or worsened, or become serious 
during the pretreatment period 
 
Treatment-emergent AEs are defined as AEs that develop, worsen, or become serious 
during the on-treatment period 
The following definitions will be applied to laboratory parameters, ECG, and vital sign results: 
 
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 are defined by the Sponsor for clinical 
laboratory tests and vital signs 
 
Potentially clinically significant abnormality criteria will determine which participants had 
at least 1 PCSA during the on-treatment period, taking into account all evaluations 
performed during the on-treatment period including unscheduled or repeated evaluations. 
The number of all such participants will be the numerator for the on-treatment PCSA 
percentage 
Table 7 - Safety analyses  
Safety measures 
Statistical Analysis Methods 
Adverse events 
 
AEs 
 
TEAEs 
 
SAEs 
 
AEs leading to 
IMP or study 
discontinuation 
 
AEs leading to 
death 
 
AESIs 
 
Adverse event incidence tables will be presented by system organ class (sorted by 
internationally agreed order), high-level group term, high level term, and preferred term sorted 
in alphabetical order and will present the number (n) and percentage (%) of participants 
experiencing an AE, by treatment period for: the Weeks 1 to 4 period for each SAR442168 
dose group or placebo, for the SAR442168 dose period, by SAR442168 dose group, and for 
the placebo/post-SAR442168 dose period. Multiple occurrences of the same event in the 
same participant will be counted only once within a treatment period in the tables. The 
denominator for computation of percentages will be the number of participants in the safety 
population (N) within each SAR442168 dose group or placebo, for the treatment period. 
 
The incidence of TEAEs will also be summarized by severity grade/intensity, and relationship 
to IMP, by treatment period for: the Weeks 1 to 4 period for each SAR442168 dose group or 
placebo, for the SAR442168 period, by SAR442168 dose group, and for the placebo/post-
SAR442168 period. 
 
Deaths and serious TEAEs will be summarized and presented as numbers and percentages 
of participants, by treatment period for: the Weeks 1 to 4 period for each SAR442168 dose 
group or placebo, for the SAR44168 period, by SAR442168 dose group, and for the 
placebo/post-SAR442168 period. 
 
The following summaries will be generated for deaths: 
- 
Numbers (%) of participants who died by the following categories and reasons for death 
summarized for the safety population by treatment received 
 
Death on study: deaths from any cause occurring after the randomization, and 
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Safety measures 
Statistical Analysis Methods 
to the end of the study: eg, to the date of last protocol planned visit if 
participants complete the whole study period as defined in the protocol 
 
Death on treatment: deaths from any cause occurring during the on-treatment 
AE period 
 
Death post-study: deaths from any cause occurring after the end of study, if 
any, eg, after the date of last protocol planned visit if participants complete the 
whole study period 
 
Deaths in nonrandomized participants 
 
Treatment-emergent AEs leading to treatment discontinuation will be summarized and 
presented as numbers and percentages of participants by treatment period for: the ‘Weeks 1-
4’ period for each SAR442168 dose group or placebo, for the ‘Active Dose’ period, by 
SAR442168 dose group, and for the ‘Placebo-Post Active Dose’ period. 
 
Numbers (%) of participants for each AESI will be summarized. by treatment period for: the 
Weeks 1 to 4 period for each SAR442168 dose group or placebo, for the SAR442168 period, 
by SAR442168 dose group, and for the placebo/post-SAR442168 period. 
Vital signs, ECG and 
laboratory data 
 
Vital signs and ECG data will be summarized by treatment period for: the Weeks 1 to 4 
period for each SAR442168 dose group or placebo, for the SAR442168 period by 
SAR442168 dose group, and for the placebo/post-SAR442168 period by baseline and 
change from baseline at scheduled visits with descriptive statistics. Numbers and 
percentages of participants with at least 1 PCSA by treatment period for: the Weeks 1 to 4 
period for each SAR442168 dose group or placebo, for the SAR442168 period by 
SAR442168 dose group, and for the placebo/post-SAR442168 period will be summarized for 
each vital sign and ECG variable. 
 
Clinical laboratory test results will be summarized by treatment period for: the Weeks 1 to 4 
period for each SAR442168 dose group or placebo, for the SAR442168 period by 
SAR442168 dose group, and for the placebo/post-SAR442168 period by baseline value and 
change from baseline value at each scheduled visit using descriptive statistics. 
 
Numbers and percentages of participants with at least 1 incident of PCSA during the 
on-treatment period will be summarized by treatment period for: the Weeks 1 to 4 period for 
each SAR442168 dose group or placebo, for the SAR442168 period by SAR442168 dose 
group, and for the placebo/post-SAR442168 period. Shift tables showing change from 
baseline will be provided as necessary. 
 
Potentially clinically significant abnormality values with flags indicating out-of-range values 
will be provided. 
9.4.3 Other analyses  
The individual PK concentrations will be descriptively summarized by visit
 
 
. 
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9.5.1 Independent Data Monitoring Committee (IDMC)  
An IDMC will be used to monitor safety of the study. Unblinded IDMC reports will be prepared 
by an independent unblinded statistician for IDMC data reviews. Timing of such reviews as well 
as the specific responsibilities and mode of operation of the IDMC will be described in the IDMC 
charter. 
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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS  
10.1.1 Regulatory and Ethical Considerations  
 This study will be conducted in accordance with the protocol and with the following: 
- 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and the applicable amendments and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines 
- 
Applicable ICH GCP Guidelines 
- 
Applicable laws and regulations 
 The protocol, protocol amendments, ICF, Investigator’s Brochure, and other relevant 
documents (eg, advertisements) must be submitted to the health authorities (competent 
regulatory authority) as required by local regulation and to an IRB/IEC by the Investigator 
and reviewed and approved by those health authorities and the IRB/IEC before the study is 
initiated 
 Any amendments to the protocol will require health authority (as required by local 
regulations) and IRB/IEC approval before implementation of changes made to the study 
design, except for changes necessary to eliminate an immediate hazard to study 
participants 
 The Investigator will be responsible for the following: 
- 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
- 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
- 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations 
10.1.2 Financial Disclosure  
Investigators and Subinvestigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow for complete disclosure or certification to the appropriate 
regulatory authorities. Investigators are responsible for providing this information before 
participating in the study and updating this information if any relevant changes occur during the 
course of the study and for 1 year after its completion. 
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10.1.3  Informed Consent Process  
 
The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study 
 
Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study center 
 
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF 
 
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study 
 
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative 
10.1.4  Data Protection  
All personal data collected related to participants, Investigators, or any person involved in the 
study that may be included in the Sponsor’s databases shall be treated in compliance with all 
applicable laws and regulations including the Global Data Protection Regulation (GDPR). 
Data collected must be adequate, relevant and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective. 
Participant race and ethnicity will be collected in this study because these data are required by 
several regulatory agencies (eg, on the African American population for the FDA or on the 
Japanese population for the Pharmaceuticals and Medical Devices Agency in Japan). 
 Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information that would make the participant identifiable will not be 
transferred  
 The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must also 
be explained to the participant 
 The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
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 When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor shall take all appropriate measures to safeguard and prevent 
access to this data by any unauthorized third party 
10.1.5 Committees Structure  
Independent Data Monitoring Committee 
An IDMC, operating independently of the Sponsor and clinical Investigators, will be responsible 
for overseeing the safety of participants throughout the study. This committee is composed of 
externally-based individuals with expertise in the disease under study, biostatistics, or clinical 
research. The primary responsibilities of the IDMC are to review and evaluate the safety data and 
to assess futility through an interim analysis during the course of the trial and to make appropriate 
recommendations to the Sponsor regarding the conduct of the clinical trial. 
Details describing the IDMC processes and procedures are outlined in the IDMC charter. To 
maintain continuous blinding and study integrity, the analysis will be conducted by an 
independent statistician who will directly transfer data to IDMC members, and measures will be 
taken to ensure the validity of the data. 
10.1.6  Dissemination of Clinical Study Data  
Sanofi shares information about clinical trials and results on publicly accessible websites, based 
on company commitments, international and local legal and regulatory requirements, and other 
clinical trial disclosure commitments established by pharmaceutical industry associations. These 
websites include clinicaltrials.gov, EU clinicaltrialsregister (eu.ctr), and sanofi.com, as well as 
some national registries. 
In addition, results from clinical trials in patients are required to be submitted to peer-reviewed 
journals following internal company review for accuracy, fair balance and intellectual property. 
For those journals that request sharing of the analyzable data sets that are reported in the 
publication, interested researchers are directed to submit their request to 
clinicalstudydatarequest.com. 
Individual participant data and supporting clinical documents are available for request at 
clinicalstudydatarequest.com. While making information available we continue to protect the 
privacy of participants in our clinical trials. Details on data sharing criteria and the process for 
requesting access can be found at clinicalstudydatarequest.com. 
10.1.7 Data Quality Assurance  
 All participant data relating to the study will be recorded on the eCRF unless transmitted 
to the Sponsor or designee electronically (eg, laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF 
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 The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF 
 The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents 
 The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data 
 Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements 
 Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 25 years after the end of the clinical study unless 
local regulations or institutional policies require a longer retention period. No records may 
be destroyed during the retention period without the written approval of the Sponsor. No 
records may be transferred to another location or party without written notification to the 
Sponsor 
10.1.8 Source documents  
 Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site 
 Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The Investigator may 
need to request previous medical records or transfer records, depending on the study. Also, 
current medical records must be available 
 The definition of what constitutes source data can be found in the study manual 
10.1.9 Study and Site Closure  
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
 Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor's procedures, or GCP guidelines 
 Inadequate recruitment of participants by the Investigator 
 Discontinuation of further study intervention development 
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10.1.10Publication Policy  
 
The results of this study will be published or presented at scientific meetings 
 
The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. A 
coordinating Investigator and other major contributors will be invited to be authors by 
mutual agreements. Authors agree to submit all manuscripts or abstracts to the Sponsor at 
least 4 weeks before submission 
 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS  
The tests detailed in Table 8 will be performed by the central or local laboratory (as mentioned in 
the table). 
Additional tests may be performed at any time during the study as determined necessary by the 
Investigator or required by local regulations. 
Table 8 - Protocol-required safety laboratory assessments  
Laboratory 
assessments 
 
Parameters 
Hematology (central) 
Platelet count  
Red blood cell (RBC) count 
Hemoglobin 
Hematocrit 
RBC indices: 
MCV 
MCH 
% reticulocytes 
White blood cell (WBC) count 
with differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Coagulation 
PT/INR 
aPTT 
 
 
Clinical chemistry 
(central)a 
Blood urea nitrogen 
(BUN) 
Potassium 
Aspartate 
aminotransferase (AST)/ 
serum glutamic-
oxaloacetic transaminase 
(SGOT) 
Total and direct 
bilirubin 
 
Creatinine 
Sodium 
Alanine 
aminotransferase 
(ALT)/ serum glutamic-
pyruvic transaminase 
(SGPT) 
Total protein 
 
Lipase 
Amylase 
Creatine phosphokinase 
 
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Laboratory 
assessments 
 
Parameters 
 
Glucose (nonfasting) 
Calcium 
Alkaline phosphatase 
Serum FSH 
 
Serum human 
chorionic 
gonadotropin (hCG) 
pregnancy test 
Routine urinalysis 
(central) 
 
Specific gravity 
 
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase by 
dipstick, urine drug screen 
 
Microscopic examination (if blood or protein) 
Other screening tests 
(central) 
 
Hepatitis B surface antigen (HBsAg), and hepatitis C virus antibody, other infectious 
disease if locally required 
Other screening tests 
(local) 
 
Urine human chorionic gonadotropin (hCG) pregnancy test (as needed for women of 
childbearing potential)b 
 
Serology (HIV antibody, or other tests)] if locally required 
 
TB/QuantiFERON-TB Gold® test or equivalent 
 The results of each locally done test must be entered into the eCRF. 
NOTES: 
a Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or monitoring event are 
given in Appendix 6, Section 10.6. All events of ALT 3 × upper limit of normal (ULN) and bilirubin 2 × ULN (>35% direct bilirubin) or 
ALT 3 × ULN and international normalized ratio (INR) >1.5, if INR measured that may indicate severe liver injury (possible Hy’s Law) 
must be reported as an SAE. 
b Local urine testing will be standard for the protocol except screening, unless only serum testing is required by local regulation or IRB/IEC, 
or needed for inconclusive urine test.  
Investigators must document their review of each laboratory safety report. 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING  
DEFINITION OF AE 
AE definition 
 An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention 
 NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention 
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Events meeting the AE definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the Investigator (ie, not related to progression of underlying 
disease) 
 Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition 
 New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication 
 Lack of efficacy or failure of expected pharmacological action per se will not be reported 
as an AE or SAE. Such instances will be captured in the efficacy assessments. However, 
the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE 
Events NOT meeting the AE definition 
 Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments associated with the underlying disease, unless judged by the Investigator to be 
more severe than expected for the participant’s condition 
 The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition 
 Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE 
 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital) 
 Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen 
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DEFINITION OF SAE 
If an event is not an AE as per the definition above, then it cannot be an SAE even if seriousness 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a) Results in death 
b) Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death, if it were more severe. 
c) Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d) Results in persistent disability/incapacity 
- 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
- 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent everyday 
life functions but do not constitute a substantial disruption. 
e) Is a congenital anomaly/birth defect 
f) 
Other situations: 
- 
Medical or scientific judgment should be exercised in deciding whether SAE 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 participant or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition. These events should usually be 
considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
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RECORDING AND FOLLOW UP OF AEs AND/OR SAEs 
AE and SAE recording 
 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event 
 
The Investigator will then record all relevant AE/SAE information in the eCRF 
 
It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor’s representative instead of completion of the AE/SAE eCRF page. 
Medical records may need to be submitted as additional data for SAE and AESI reporting. 
They must be anonymized in such a case by replacing the participant’s name and initials 
by the participant number of this study 
 
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor’s representative. In this case, all participant identifiers, with the exception of 
the participant number, will be redacted on the copies of the medical records before 
submission to the Sponsor representative 
 
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE 
Assessment of intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories: 
 
Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities 
 
Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities 
 
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe. 
Assessment of causality 
 The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE 
 A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out 
 The Investigator will use clinical judgment to determine the relationship 
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 Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated 
 The Investigator will also consult the Investigator’s Brochure and/or Product Information, 
for marketed products, in his/her assessment 
 For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality 
 There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to the Sponsor’s representative. However, it is 
very important that the Investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to the Sponsor’s 
representative 
 The Investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment 
 The causality assessment is one of the criteria used when determining regulatory reporting 
requirements 
Follow up of AEs and SAEs 
 The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor’s 
representative to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals 
 If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide the Sponsor’s representative with a copy of any 
post-mortem findings including histopathology 
 New or updated information will be recorded in the originally completed eCRF 
 The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information 
REPORTING OF SAES 
SAE reporting to the Sponsor’s representative via an electronic data collection tool 
 The primary mechanism for reporting an SAE to the Sponsor’s representative will be the 
electronic data collection tool 
 If the electronic system is unavailable for more than 24 hours, then the site will use the 
paper SAE data collection tool (see next section) 
 The site will enter the SAE data into the electronic system as soon as it becomes available. 
 After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data 
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 If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken off-
line, then the site can report this information on a paper SAE form (see next section) or to 
the Sponsor’s representative by telephone 
 Contacts for SAE reporting can be found in the study manual 
SAE reporting to the Sponsor’s representative via case report form 
 Facsimile transmission of the paper SAE is the preferred method to transmit this 
information to the Sponsor’s representative 
 In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the paper SAE data collection tool sent by overnight mail or 
courier service 
 Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the SAE case report form pages within the designated reporting time frames 
 Contacts for SAE reporting can be found in study manual 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION  
DEFINITIONS: 
Woman of childbearing potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
- 
Documented hysterectomy 
- 
Documented bilateral salpingectomy 
- 
Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
- 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high FSH level in the postmenopausal range may be used to confirm 
a postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, a 
single FSH measurement is insufficient.  
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- 
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonestrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
CONTRACEPTION GUIDANCE 
Male participants 
- 
Male participants with female partners of childbearing potential are eligible to 
participate if they agree to ONE of the following [during the protocol-defined time 
frame in Section 5.1]:  
- 
Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent 
- 
Agree to use a male condom plus partner use of a contraceptive method with a failure 
rate of <1% per year as described in Table 9 when having penile-vaginal intercourse 
with a woman of childbearing potential who is not currently pregnant 
 In addition, male participants must refrain from donating sperm for the duration of the 
study and for 3 months after the last dose of study intervention. 
 Male participants with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile 
penetration for 3 months after the last dose. 
Female participants 
As definitive reproduction toxicity studies have yet to be conducted with SAR442168, the 
Investigator is directed to take appropriate precautions during exposure of WOCBP in this clinical 
trial. Female participants of childbearing potential are eligible to participate if they agree to use a 
double contraception method including a highly effective method of contraception consistently 
and correctly as described in Table 9 from inclusion and up to 2 months after the last study dose. 
In addition, WOCBP must refrain from donating ova for the duration of the study and for 
2 months after the last dose of study intervention. 
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Table 9 - Highly effective contraceptive methods  
Highly effective contraceptive methods that are user dependenta 
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation 
 
Oral  
 
Intravaginal  
 
Transdermal 
Progestogen only hormonal contraception associated with inhibition of ovulation 
 
Oral 
 
Injectable 
Highly effective methods that are user independenta 
Implantable progestogen only hormonal contraception associated with inhibition of ovulation 
 
Intrauterine device (IUD) 
 
Intrauterine hormone-releasing system (IUS) 
 
Bilateral tubal occlusion 
Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the sole male sexual partner of the 
WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be 
used. 
Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study intervention. The reliability of sexual abstinence needs to be evaluated in relation to 
the duration of the study and the preferred and usual lifestyle of the participant. 
NOTES:  
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local regulations 
regarding the use of contraceptive methods for participants participating in clinical studies.  
PREGNANCY TESTING: 
 WOCBP should only be included after a confirmed menstrual period and a negative highly 
sensitive urine or serum pregnancy test 
 Additional pregnancy testing should be performed at monthly intervals during the 
intervention period and at 1 month after the last dose of study intervention and as required 
locally 
 Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected 
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COLLECTION OF PREGNANCY INFORMATION: 
Male participants with partners who become pregnant 
 The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive SAR442168 
 After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure. 
Female participants who become pregnant  
 The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on the 
appropriate form and submitted to the Sponsor within 24 hours of learning of a 
participant's pregnancy. The participant will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow up information on the participant and the 
neonate and the information will be forwarded to the Sponsor. Generally, follow up will 
not be required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or absence 
of anomalies) or indication for the procedure 
 Any pregnancy complication or elective termination of a pregnancy will be reported as an 
AE or SAE. A spontaneous abortion is always considered to be an SAE and will be 
reported as such. Any post-study pregnancy related SAE considered reasonably related to 
the study intervention by the Investigator will be reported to the Sponsor as described in 
Section 8.3.5 of the protocol. While the Investigator is not obligated to actively seek this 
information in former study participants, he/she may learn of an SAE through spontaneous 
reporting 
 Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study 
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10.7 
APPENDIX 7: LIST OF EXAMPLE DRUGS WITH A POTENTIAL TO CHANGE WITH 
SAR44168 METABOLISM  
The following drugs should not be taken during the study due to their potential to change 
SAR44168 kinetics due to interaction with P450-mediated metabolism, being potent inducers or 
inhibitors of CYP3A or CYP2C8 liver enzymes (per the lists of the Drug Interaction Database 
Program of the University of Washington (www.druginteractioninfo.org ).  
Please note that the lists provided are not exhaustive and that the product information of drugs 
intended for concomitant use should be consulted. 
Strong CYP3A Inhibitors: 
Viekira Pak 
Indinavir/RIT 
Tipranavir/RIT 
Ritonavir 
Cobicistat (GS-9350) 
Ketoconazole 
Indinavir 
Troleandomycin 
Telaprevir 
Danoprevir/RIT 
Elvitegravir/RIT 
Saquinavir/RIT 
Lopinavir/RIT 
Itraconazole 
Voriconazole 
Mibefradil 
LCL161 
Clarithromycin 
Posaconazole 
Telithromycin 
Conivaptan 
Nefazodone 
Nelfinavir 
Saquinavir 
Ribociclib 
Idelalisib 
Boceprevir 
Note: 
VIEKIRA PAK = 150/100 mg paritaprevir/ritonavir + 25 mg ombitasvir + 800 mg dasabuvir for 28 days 
Potent CYP3A Inducers: 
Rifampin 
Mitotane 
Avasimibe 
Rifapentine 
Apalutamide 
Phenytoin 
Carbamazepine 
Enzalutamide 
St John's Wort extract 
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Lumacaftor 
Rifabutin 
Phenobarbital 
Strong CYP2C8 Inhibitors: 
Gemfibrozil 
Clopidogrel 
Letermovir 
Teriflunomide 
Deferasirox 
10.8 
APPENDIX 8: LIST OF EXAMPLE DRUGS WITH A POTENTIAL TO AFFECT PLASMA 
EXPOSURE OF SAR442168 VIA REDUCTION OF GASTRIC ACID  
Please note that the lists provided are not exhaustive and that the product information of drugs 
intended for concomitant use should be consulted. 
Proton Pump Inhibitors: 
Esomeprazole 
Lansoprazole 
Omeprazole 
Pantoprazole 
Rabeprazole 
H2-receptor Antagonists 
Cimetidine 
Famotidine 
Nizatidine 
Ranitidine 
Other Agents 
Antacids, eg, aluminum hydroxide/carbonate 
Calcium hydroxide/carbonate 
Bismuth subsalicylate 
Buffered medications, eg, didanosine 
10.9 
APPENDIX 9: COUNTRY-SPECIFIC REQUIREMENTS  
Not applicable. 
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10.10 APPENDIX 10: ABBREVIATIONS  
 
AEs: 
adverse event 
AESI: 
adverse event of special interest 
AIC: 
Akaike information criterion 
ALT: 
alanine aminotransferase 
ARR: 
annualized relapse rate 
BTK: 
Bruton's tyrosine kinase 
CNS: 
central nervous system 
CSF: 
cerebrospinal fluid 
C-SSRS: 
Columbia Suicide Severity Rating Scale 
 
 
DTP: 
duties and taxes paid 
ECG: 
electrocardiogram 
eCRF: 
electronic case report form 
EDSS: 
Expanded Disability Status Scale 
FSH: 
follicle-stimulating hormone 
GCP: 
Good Clinical Practice 
Gd: 
gadolinium 
GEE: 
generalized estimating equation 
HRT: 
hormone replacement therapy 
ICF: 
informed consent form 
ICH: 
International Council for Harmonisation 
IDMC: 
Independent Data Monitoring Committee 
IEC: 
Independent Ethics Committee 
IMP: 
investigational medicinal product 
IRB: 
Institutional Review Board 
IV: 
intravenous(ly) 
IVRS: 
interactive voice response system 
IWRS: 
interactive web response system 
LLN: 
lower limit of normal 
LTS: 
long-term safety, long-term safety 
MCP-Mod: 
multiple comparison procedure with modelling techniques 
mITT: 
modified intent-to-treat 
MRI: 
magnetic resonance imaging 
MS: 
multiple sclerosis 
 
 
NIMP: 
noninvestigational medicinal product 
NOAEL: 
no observed adverse effect level 
 
 
PCSA: 
potentially clinically significant abnormality 
 
 
PK: 
pharmacokinetic(s) 
PML: 
progressive multifocal leukoencephalopathy 
PPMS: 
primary progressive multiple sclerosis 
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QTcF: 
QT interval corrected using Fridericia's formula 
RMS: 
relapsing multiple sclerosis 
SAE: 
serious adverse event 
SAP: 
Statistical Analysis Plan 
SPMS: 
secondary progressive multiple sclerosis 
TEAE: 
treatment-emergent adverse event 
ULN: 
upper limit of normal 
 
10.11 APPENDIX 11: PROTOCOL AMENDMENT HISTORY  
 The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents. 
Amended protocol 01: 13-Feb-2019 
This amended protocol (Amendment 01) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT  
This protocol is being amended in response to comments from US and Canadian health 
authorities.  
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis 
Update of “participants will be randomly assigned to 1 of 5 
doses …” to “participants will be randomly assigned to 1 of 4 
doses …” 
Typographical error 
Section 1.2 Schema 
Correction of Graphical Study Design (C1 and C2 switched) 
Typographical error 
Section 1.3 Schedule of 
activities 
Weeks 2 and 6 hematology tests added 
Response to request by Health 
Canada 
Section 5.1 Inclusion 
criteria  
I04: “From inclusion and up to 2 months after the last study 
dose” added to time during which female participants must 
use a double contraception method including a highly 
effective method of birth control.  
Response to request by Health 
Canada 
Section 5.1 Inclusion 
criteria 
I04: Definition of menopause edited to match Sanofi 
template definition 
Internal consistency of document 
Section 6.7 Intervention 
after the end of the study 
“LTS” changed to “DRI” when referring to current study. 
Typographical error 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 8 Study 
assessments and 
procedures 
Maximum amount of blood collected per participant over the 
duration of the study increased from 60 to 70 ml 
 
 
 
Additional 2 hematology tests 
added in Weeks 2 and 6 (see 
Section 1.3) 
Section 8.3.2 Time period 
and frequency for 
collecting AE and SAE 
information 
Definitions of time periods updated for to match current 
Sanofi template 
Internal consistency with current 
definitions 
Appendix 2 Clinical 
laboratory tests 
Creatine phosphokinase added to protocol-required safety 
laboratory assessments. 
Response to request by US FDA 
 
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11 
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13. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status 
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T A B L E  O F C O N T E N T S  
S T A TI S TI C A L A N A L Y SI S  P L A N  ................................................................................................................... 1  
T A B L E O F C O N T E N T S  .................................................................................................................................. 2  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N  O F T E R M S  .......................................................................... 5  
1  
O V E R VI E W A N D I N V E S TI G A TI O N A L P L A N  ................................................................................ 6  
1. 1  
S T U D Y D E SI G N A N D R A N D O MI Z A TI O N  ...................................................................................... 6  
1. 2  
O B J E C TI V E S  ................................................................................................................................... 6  
1. 2. 1  
Pri m ar y o bj e cti v e s  ............................................................................................................................ 6  
1. 2. 2  
S e c o n d ar y o bj e cti v e s  ....................................................................................................................... 7  
1. 3  
D E T E R MI N A TI O N O F S A M P L E SI Z E  ............................................................................................. 7  
1. 4  
S T U D Y P L A N  ................................................................................................................................... 7  
1. 5  
M O DI FI C A TI O N S T O T H E  S T A TI S TI C A L S E C TI O N  O F T H E P R O T O C O L  .................................. 8  
1. 6  
S T A TI S TI C A L M O DI FI C A TI O N S M A D E I N T H E S T A TI S TI C A L A N A L Y SI S P L A N  ....................... 8  
2  
S T A TI S TI C A L A N D A N A L Y TI C A L P R O C E D U R E S  ...................................................................... 9  
2. 1  
A N A L Y SI S E N D P OI N T S  ................................................................................................................. 9  
2. 1. 1  
D e m o gr a p hi c a n d b a s eli n e c h ar a ct eri sti c s  ...................................................................................... 9  
2. 1. 2  
Pri or or c o n c o mit a nt m e di c ati o n s  ................................................................................................... 1 0  
2. 1. 3  
Effi c a c y e n d p oi nt s  .......................................................................................................................... 1 0  
2. 1. 3. 1  
Pri m ar y effi c a c y e n d p oi nt( s)  .......................................................................................................... 1 1  
2. 1. 3. 2  
S e c o n d ar y effi c a c y e n d p oi nt s  ........................................................................................................ 1 2  
2. 1. 4  
S af et y e n d p oi nt s  ............................................................................................................................ 1 2  
2. 1. 4. 1  
A d v er s e e v e nt s v ari a bl e s  ............................................................................................................... 1 3  
2. 1. 4. 2  
A d v er s e e v e nt s of s p e ci al i nt er e st ( A E SI s)  .................................................................................... 1 3  
2. 1. 4. 3  
D e at h s  ............................................................................................................................................ 1 4  
2. 1. 4. 4  
L a b or at or y s af et y v ari a bl e s  ............................................................................................................ 1 4  
2. 1. 4. 5  
Vit al si g n s v ari a bl e s  ....................................................................................................................... 1 4  
2. 1. 4. 6  
El e ctr o c ar di o gr a m ( E C G) v ari a bl e s  ............................................................................................... 1 4  
2. 1. 4. 7  
C ol u m bi a S ui ci d e S e v erit y R ati n g S c al e ( C -S S R S)  ...................................................................... 1 4  
2. 1. 4. 8  
P h y si c al e x a mi n ati o n  ..................................................................................................................... 1 5  
2. 1. 5  
P h ar m a c o ki n eti c ( P K) v ari a bl e s  ..................................................................................................... 1 5  
V V- C LI N- 0 5 4 0 3 1 1 1. 0


St ati sti c al A n al y si s Pl a n   
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
V er si o n n u m b er: 1  
 
Pr o p ert y of  t h e S a n ofi Gr o u p  - stri ctl y c o nfi d e nti al  
P a g e 3  
2. 2  
DI S P O SI TI O N O F P A R TI CI P A N T S  ............................................................................................... 1 6  
2. 2. 1  
R a n d o mi z ati o n a n d dr u g di s p e n si n g irr e g ul ariti e s  ......................................................................... 1 7  
2. 3  
A N A L Y SI S P O P U L A TI O N S  ........................................................................................................... 1 8  
2. 3. 1  
Effi c a c y p o p ul ati o n s  ....................................................................................................................... 1 8  
2. 3. 1. 1  
M o difi e d i nt e nt -t o-tr e at p o p ul ati o n ................................................................................................. 1 8  
2. 3. 2  
S af et y p o p ul ati o n  ........................................................................................................................... 1 8  
2. 3. 3  
P h ar m a c o ki n eti c p o p ul ati o n  ........................................................................................................... 1 9  
2. 4  
S T A TI S TI C A L M E T H O D S  ............................................................................................................. 1 9  
2. 4. 1  
D e m o gr a p hi c s a n d b a s eli n e c h ar a ct eri sti c s  .................................................................................. 1 9  
2. 4. 2  
Pri or or c o n c o mit a nt m e di c ati o n s  ................................................................................................... 1 9  
2. 4. 3  
E xt e nt of i n v e sti g ati o n al m e di ci n al pr o d u ct e x p o s ur e a n d c o m pli a n c e  ......................................... 2 0  
2. 4. 3. 1  
E xt e nt of i n v e sti g ati o n al m e di ci n al pr o d u ct (I M P) e x p o s ur e  .......................................................... 2 0  
2. 4. 3. 2  
C o m pli a n c e  .................................................................................................................................... 2 0  
2. 4. 4  
A n al y s e s of effi c a c y e n d p oi nt s  ....................................................................................................... 2 1  
2. 4. 4. 1  
A n al y si s of pri m ar y effi c a c y e n d p oi nt ............................................................................................. 2 1  
2. 4. 4. 2  
A n al y s e s of s e c o n d ar y effi c a c y e n d p oi nt s  ..................................................................................... 2 3  
2. 4. 4. 3  
M ulti pli cit y i s s u e s  ........................................................................................................................... 2 3  
2. 4. 5  
A n al y s e s of s af et y d at a  .................................................................................................................. 2 4  
2. 4. 5. 1  
A n al y s e s of a d v er s e e v e nt s  ........................................................................................................... 2 5  
2. 4. 5. 2  
D e at h s  ............................................................................................................................................ 2 7  
2. 4. 5. 3  
A n al y s e s of l a b or at or y v ari a bl e s  .................................................................................................... 2 7  
2. 4. 5. 4  
A n al y s e s of vit al si g n v ari a bl e s  ...................................................................................................... 2 7  
2. 4. 5. 5  
A n al y s e s of el e ctr o c ar di o gr a m ( E C G) v ari a bl e s  ............................................................................ 2 8  
2. 4. 5. 6  
A n al y s e s of s ui ci d alit y a s s e s s m e nt  ................................................................................................ 2 8  
2. 4. 5. 7  
A n al y s e s of ot h er s af et y e n d p oi nt s  ................................................................................................ 2 8  
2. 4. 5. 8  
A n al y s e s of p h ar m a c o ki n eti c 
2. 4. 6  
A n al y s e s of q u alit y of lif e/ h e alt h e c o n o mi c s v ari a bl e s  ................................................................... 2 9  
2. 5  
D A T A H A N D LI N G C O N V E N TI O N S  .............................................................................................. 2 9  
2. 5. 1  
G e n er al c o n v e nti o n s  ...................................................................................................................... 2 9  
2. 5. 2  
D at a h a n dli n g c o n v e nti o n s f or s e c o n d ar y effi c a c y v ari a bl e s  ......................................................... 2 9  
2. 5. 3  
Mi s si n g d at a  ................................................................................................................................... 2 9  
2. 5. 4  
Wi n d o w s f or ti m e p oi nt s ................................................................................................................. 3 0  
2. 5. 5  
U n s c h e d ul e d vi sit s  ......................................................................................................................... 3 3  
2. 5. 6  
P o oli n g of c e nt er s f or st ati sti c al a n al y s e s  ...................................................................................... 3 3  
2. 5. 7  
St ati sti c al t e c h ni c al i s s u e s  ............................................................................................................. 3 3  
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St ati sti c al A n al y si s Pl a n   
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
V er si o n n u m b er: 1  
 
Pr o p ert y of  t h e S a n ofi Gr o u p  - stri ctl y c o nfi d e nti al  
P a g e 4  
4  
D A T A B A S E L O C K  ........................................................................................................................ 3 5  
5  
S O F T W A R E D O C U M E N T A TI O N  ................................................................................................. 3 6  
6  
R E F E R E N C E S  ............................................................................................................................... 3 7  
7  
LI S T O F A P P E N DI C E S  ................................................................................................................. 3 8  
A P P E N DI X A P O T E N TI A L L Y C LI NI C A L L Y SI G NI F I C A N T A B N O R M A LI TI E S ( P C S A) C RI T E RI A 
( S A N O FI V E R SI O N 2 0 1 4) ............................................................................................................................ 3 9  
A P P E N DI X B M RI P A R A M E T E R S  ............................................................................................................... 4 2  
A P P E N DI X  C A N A L Y SI S P R O G R A M M I N G C O D E N O T E S ........................................................................ 4 4  
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St ati sti c al A n al y si s Pl a n   
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
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 5  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N O F T E R M S   
 
A Es:  
a d verse e ve nts  
A E SI:  
a d verse e ve nt of s p ecial i nterest  
B T K:  
Br ut o n's t yr osi ne ki nase  
D M T:  
disease m o dif yi n g t h era p y  
E C G:  
electr ocar di o gra m  
E D S S:  
E x pa n de d Disa bilit y Stat us Scale  
E ma x : 
n o nli near m o del fre q ue ntl y use d i n d ose res p o nse a nal ys es  
G d:  
ga d oli ni u m  
H A D:  
hi g hl y acti ve dise ase  
I M P: 
i n vesti gati o nal me dici nal pr o d uct 
I V R S: 
i nteracti ve v oic e res p o ns e s yste m 
I V R S/I W R S: 
I nteracti ve V oice/ We b R es p o nse S yste m 
I W R S: 
i nteracti ve w e b res p o ns e s yste m 
I X R S: 
I V R S or I W R S 
L T S:  
l o n g ter m safet y 
M C P -M o d:  
M ulti ple C o m paris o n Pr oce d ure -M o delli n g  
Me d D R A:  
Me dical Dicti o nar y f or R e g ul at or y Acti vities  
M RI:  
ma g n etic res o n a nce i ma gi n g  
M T R:  
ma g n etizati o n tra nsfer rati o  
N A:  
N ot A p plica ble  
NI M P:  
n o ni n vesti gati o nal me dici nal pr o d uct  
P B M C:  
peri p heral bl o o d m o n o n uclear cell  
P C S As:  
p ote ntiall y cli nicall y si g ni fica nt a b n or malities  
P K:  
p har mac o ki netic  
P T:  
preferre d t er m  
R M S:  
rela psi n g m ulti ple scler osis 
S A Es:  
seri o us a d vers e e v e nts 
S D:  
sta n dar d de viati o n 
S o A:  
Sc he d ule of A cti vities  
S O C:  
pri mar y s yst e m or ga n cl ass  
S WI:  
s usce pti bilit y-wei g hte d i ma gi n g  
W H O -D D:  
W orl d Healt h Or ga nizati o n -Dr u g Dicti o nar y  
 
 
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St ati sti c al A n al y si s Pl a n   
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
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 6  
1  
O V E R VI E W A N D I N V E S TI G A TI O N A L P L A N   
1. 1  
S T U D Y D E SI G N A N D R A N D O MI Z A TI O N   
T his is a P hase 2b , ra n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d, cr oss -o ver, d ose -ra n gi n g st u d y 
i n pe o ple  wit h rela psi n g m ulti ple scler osis ( R M S). 
All  partici pa nts will be ce ntrall y assi g n e d t o 1  of 8  ar ms (4  d ose gr o u ps i n eac h of 2 c o h orts  at 
e q ual rati o  t o start wit h S A R 4 4 2 1 6 8  (i n C o h ort 1) or place b o (i n C o h ort 2) peri o d bef ore 
cr oss-o ver, usi n g a n I nteracti ve V oice/ We b Res p o nse S yste m  (I V R S/I W R S). 
 
Wit hi n eac h c o h ort, parti ci pa nts will be ra n d o ml y assi g ne d e q uall y t o 1 of 4  S A R 4 4 2 1 6 8 
d oses, 5 , 1 5, 30, or 6 0 m g o nce dail y , i n a bli n de d ma n ner 
 
C o h ort 1 : Partici pa nts will recei ve 1  of t he S A R 4 4 2 1 6 8 d oses f or t he first 1 2 wee ks , t hen 
cr oss-o ver  t o place b o f or 4 wee ks  
 
C o h ort 2 : Partici pa nts will recei ve place b o f or t he first 4 wee ks, t he n cr oss o ver  t o 1  of t he 
S A R 4 4 2 1 6 8 d oses f or 1 2 wee ks  
T he st u d y will be rater -bli n de d f or brai n ma g n etic res o na nce i ma gi n g ( M RI). All brai n sca ns will 
be re vie we d a n d i nter pret e d b y 1  or m ore M RI e x perts at a n  i n de pe n de nt, ce ntral facilit y wit h n o 
access (ie, bli n de d) t o treat me nt, t here b y a v oi di n g bias  a n d ass uri n g sta n dar dize d e n d p oi nt 
e val uati o n . 
A p pr o xi matel y 1 6 0 p e o ple will be scree ne d t o ra n d o miz e a p pr o xi matel y 1 2 0  partici pa nts ( bas e d 
o n a 2 5 % scree ni n g fail ure rat e) t o t he st u d y i nter ve nti o n s uc h t hat a p pr o xi matel y 1 0 5  e val ua ble 
partici pa nts ( bas e d o n a n a p pr o xi matel y  1 5 % dr o p o ut rate, pr o vi di n g at least 2 6  partici pa nts f or 
eac h d ose l e vel of S A R 4 4 2 1 6 8) c o m plete 1 2 wee ks of S A R 4 4 2 1 6 8 treat me nt . Partici pa nts fr o m 
C o h ort  2 ( n  =  6 0) will recei ve 4 w ee k s of place b o bef ore cr ossi n g o ver  t o S A R 4 4 2 1 6 8.  
T he 4 -wee k place b o data ca n be utilize d i n esti mati n g a d ose -res p o ns e c ur ve base d o n t he 
ass u m pti o n of a t he oretical c o nsta nt rate of ne w G d -e n ha nci n g T 1 -h y peri nt e nse lesi o ns o ver 
1 2  wee ks  u n der place b o . T he a p pr oac h will mi ni mize place b o e x p os ure t o st u d y partici p a nts.  
I n di vi d uals w h o d o n ot meet t he criteri a f or parti ci pati o n i n t he st u d y (scree n fail ure) ma y b e 
rescree ne d u p t o 2 ti mes. Rescree n e d i n di vi d uals are assi g ne d t he s a me partici pa nt n u m ber as t he 
i nitial scree ni n g.  
1. 2  
O B J E C TI V E S   
1. 2. 1  Pri m ar y o bj e cti v e s   
T he pri mar y o bje cti ve of t his st u d y is t o deter mi ne t he d ose -res p o ns e rel ati o ns hi p f or S A R 4 4 2 1 6 8 
t o re d uce t he n u m b er of ne w acti ve brai n lesi o ns.  
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St ati sti c al A n al y si s Pl a n   
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
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  
1. 2. 2  S e c o n d ar y o bj e cti v e s   
T he sec o n d ar y o bjecti ves are t o e v al uate efficac y of S A R 4 4 2 1 6 8 o n disease acti vit y, assesse d b y 
i ma gi n g meas ures a n d to e val uate t he s afet y a n d t olera bilit y of S A R 4 4 2 1 6 8 . 
1. 3  
D E T E R MI N A TI O N O F S A M P L E SI Z E   
T he st u d y will ha v e 1 2 0 partici pa nts e q uall y ra n d o ml y assi g ne d t o 1  of 4  S A R 4 4 2 1 6 8 d oses i n 
2  c o h orts ( 6 0  partici p a nts i n eac h of C o h ort s 1 a n d 2). C o h ort s 1 a n d  2 re prese nt differe nt 
treat me nt se q ue n ces, a n d partici pa nts i n eac h will cr oss-o ver  t o S A R 4 4 2 1 6 8 or place b o i n a 
bli n de d ma n ner.  
T he 6 0 partici pa nts i n C o h ort 2 will start wit h a 4 -wee k place b o r u n -i n t hat will be utilize d as t he 
pl ace b o dat a i n a nal yses f or t he pri mar y e n d p oi nt base d o n t he ass u m pti o n of t he c o nsta nt 
m o nt hl y m ea n n u m ber of ne w G d -e n ha nci n g T 1 -h y p eri nte nse  lesi o ns o ver 1 2 wee ks of place b o 
treat me nt. Ass u mi n g 1 5 % of partici pa nts wit h o ut  t he pri mar y e n d p oi nt at t he e n d of 1 2  wee ks  of 
S A R 4 4 2 1 6 8, 1 0 5  partici pa nts ( a p pr o xi matel y 2 6  per S A R 4 4 2 1 6 8  d ose) has at least 8 3 % p o wer t o 
detect t he ma xi m u m re d ucti o n of 8 5 % usi n g a 2 -st e p M ulti ple C o m paris o n Pr oce d ure -M o delli n g  
( M C P-M o d )  wit h 6  pre -defi ne d d ose res p o nse c ur ves ( 2 E ma x  m o dels, a q u a dratic m o del, a li near 
m o del,  a l o gistic m o del, a n d a n e x p o ne ntial m o del). T his calc ulati o n ass u mes t he dis persi o n 
para meter of 2 (esti mate d fr o m W ee k  1 2 place b o data fr o m t he vateliz u ma b [S A R 3 3 9 6 5 8 ] 
D RI 1 3 8 3 9 st u d y), wit hi n -s ubject c orrelati o n ra n gi n g fr o m -0. 9 t o 0. 9 i n mea s ure me nts bet w ee n 4-
wee k pla ce b o a n d 1 2 -wee k S A R 4 4 2 1 6 8 i n C o h ort  2, a n d place b o m ea n n u m ber of ≥1 f or n e w G d -
e n ha nci n g T 1 -h y p eri nte nse  lesi o ns at 4  wee ks.  
T his p o wer was calc ulat e d usi n g  t he pac ka ge D ose Fi n di n g fr o m t he C o m pr e he nsi ve R Arc hi ve 
Net w or k  ( C R AN)( 1 ), usi n g t he 6 ca n di date c ur ves c o nsi dere d f or d ose -res p o nse m o delli n g i n a 
ne gati ve bi n o mial re gressi o n fra me w or k . 
1. 4  
S T U D Y P L A N   
T his st u d y is bli n de d f or d ose a n d f or a d mi nistrati o n se q ue nce. It is f oc use d o n d ose fi n di n g b ut 
als o ta kes i nt o acc o u nt t h e nee d t o mi ni mize partici pa nt e x p os ure t o place b o.  
T he d ose ra n ge is e val u ate d usi n g 4  d oses: 5 , 1 5, 3 0, a n d 6 0 m g o n ce dail y , f or 1 2 wee ks. T o 
mi ni mize e x p os ure t o place b o w hile mai ntai ni n g t he bli n di n g of I n v esti gat ors a n d partici pa nts, 
eac h p artici pa nt will be assi g ne d t o a 4 -wee k place b o peri o d t hat will occ ur d uri n g eit her t he first 
( C o h ort 2) or t he last 4 w ee k s of t he st u d y ( C o h ort 1). A gra p hical re prese nt ati o n  of t he st u d y 
desi g n  is pr o vi de d b el o w. 
F or t he d etaile d Sc he d ule of Acti vities  ( S o A), see Secti o n 1. 3 ( Ta ble 1) of t he st u d y pr ot o c ol.  
U p o n c o m pleti n g t he d o u ble -bli n de d treat me nt peri o d, partici pa nts will be gi ve n t he o pti o n t o 
e nr oll i n a l o n g -ter m safet y ( L T S) f oll o w-u p st u d y t o assess safet y a n d t olera bilit y of S A R 4 4 2 1 6 8. 
T he L T S f oll o w -u p st u d y is descri be d i n a se p arat e pr ot oc ol, L T S 1 6 0 0 4. 
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St ati sti c al A n al y si s Pl a n   
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
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 8  
Fi g ur e  1  –  Gr a p hi c al s t u d y d e si g n   
 
C 1: C o h ort 1; C 2: C o h ort 2 ; R: ra n d o mizati o n 
 
1. 5  
M O DI FI C A TI O N S T O T H E S T A TI S TI C A L S E C T I O N O F T H E P R O T O C O L  
T he pr ot oc ol secti o n 9. 5 descri be d a p ote ntial i nteri m a nal ysis, t o be perf or me d i n t he case of 
sl o wer t ha n a ntici pat e d recr uit me nt. Recr uit me nt was n ot sl o wer t ha n a ntici pate d a n d a n i nteri m 
a nal ysis was n ot perf or m e d.   
1. 6  
S T A TI S TI C A L M O DI FI C A T I O N S M A D E I N T H E S T ATI S TI C A L A N A L Y SI S P L A N   
N ot a p plica ble . 
V V- C LI N- 0 5 4 0 3 1 1 1. 0


St ati sti c al A n al y si s Pl a n   
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
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 9  
2  
S T A TI S TI C A L A N D A N A L Y TI C A L P R O C E D U R E S   
2. 1  
A N A L Y SI S E N D P OI N T S   
2. 1. 1  D e m o gr a p hi c a n d b a s eli n e c h ar a ct eri sti c s   
T he baseli ne v al ue is ge n erall y defi n e d as t he last meas ure me nt c ollecte d o n or bef ore t he 
ra n d o mizati o n visit (Da y 1 ) pri or t o i nitiati o n of t he first d ose of st u d y i nter ve nti o n.  
All baseli ne safet y a n d efficac y p ara m eters (a part fr o m t h ose liste d bel o w) are prese nte d al o n g 
wit h t he o n -treat me nt s u m mar y statistics i n t he safet y a n d efficac y secti o ns (Secti o n s 2. 4. 4  a n d 
2. 4. 5 ). 
De m o gr a p hic c h ar acteristics  
De m o gra p hic v aria bles are ge n der ( Mal e, Fe m ale), race ( Ca ucasia n/ w hite, Blac k, Asi a n/ Orie ntal, 
A merica n I n dia n or Alas ka Nati ve, N ati ve Ha waiia n or ot her Pacific Isla n d, ot her), a ge i n years, 
a n d et h nicit y ( His pa nic, n o n -His pa nic).   
A ge cat e g ories ( < = 4 0 years, > 4 0 years) will als o be i ncl u de d.  
Me di c al or s ur gic al  hist ory  
Me dical or s ur gic al hist or y i ncl u d es all t he rel e va nt me dical or s ur gical hist or y wit hi n t he 
pre vi o us 3 m o nt hs.   
T his i nf or mati o n will be c o de d usi n g t he versi o n of Me dical Dicti o nar y f or Re g ulat or y Acti vities  
( Me d D R A) c urre ntl y i n effect at Sa n ofi at t he ti me of data bas e l oc k . 
 S u bst a nce use –  alc o h ol h a bit  
T he fre q u e nc y of alc o h ol use i n t he last 1 2 m o nt hs is re p orte d.   
M ulti ple scler osis  hist ory  a n d dise ase c h ar acteristics at b aseli ne  
M ulti ple scler osis hist or y i ncl u des t he date of first s y m pt o ms of R M S, date of R M S dia g n osis, 
date of m ost rece nt rel a pse , m ulti ple scler osis t y p e, n u m ber of rela pse(s) wit hi n t he past year  a n d 
wit hi n past 2  years , date of m ost rece nt br ai n M RI a n d n u m ber of acti ve G d-e n ha nci n g brai n 
lesi o n(s) o n t he M RI. Ti me (i n m o nt hs ) will be calc ulate d fr o m date of first 
s y m pt o ms/ dia g n osis/ m ost rece nt r ela pse t o ra n d o mizati o n visit . ( T he st u d y i ncl usi o n criteria 
i ncl u de d: ‘ T he partici pa nt m ust ha ve at least 1 d oc u me nte d rela ps e wit hi n t he pre vi o us year O R 
≥2 d oc u me nte d rel a pses wit hi n t he pre vi o us 2 years O R ≥1 acti ve G d -e n ha nci n g brai n lesi o n o n 
a n M RI s ca n i n t he past 6 m o nt hs a n d pri or t o scree ni n g .’) 
H i g hl y acti ve disease (H A D)  cate g or y ( yes, n o) is als o i ncl u de d, a n d H A D  is defi ne d as  t he 
partici pa nt ha vi n g:  
 1 rela pse i n t he pre vi o us year a n d  1 of t he f oll o wi n g:  
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St ati sti c al A n al y si s Pl a n   
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
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 1 0  
 at least 1 G d -e n h a nci n g l esi o n or  
 9 or m ore T 2 lesi o ns at b aseli ne –  f or p artici pa nts w h o were alrea d y treate d 
wit h disease  m o dif yi n g t hera p y ( D M T) (a n y treat me nt wit h D M Ts w o ul d be 
c o nsi dere d if d o c u me nte d i n 1 year peri o d * ) or  
 2 or m ore rel a pses i n t he pre vi o us year,  w het her treate d wit h D M T or n ot.  
* N ote, f or t his st u d y, pri or me dicati o ns recei ve d d uri n g t he 4 wee ks pri or t o e nr oll me nt a n d all 
pri or M S treat me nts a n d treat me nts c o nsi dere d cli nicall y i m p orta nt t o assess M S or c o nc o mita nt 
disease are c ollecte d .  
T he f oll o wi n g dise ase c h aract eristics  will be s u m marize d  at baseli ne: 
 E x pa n de d Disa bilit y Stat us Scale ( E D S S)  [assesse d  at b ot h  scree ni n g visit  a n d baseli ne ] 
 Brai n i ma gi n g c h aracteristics (e g, T 1 -H y p eri nte ns e Lesi o n V ol u mes  a n d T 2 -H y peri nte ns e 
Lesi o n V ol u mes ) [assesse d  at scree ni n g visit] 
A n y te c h nical d etails relate d t o c o m p utati o n, dates, a n d i m p utati o n f or missi n g dates are d escri b e d 
i n Secti o n  2. 5 .  
2. 1. 2  Pri or or c o n c o mit a nt m e di c ati o n s   
All me dicati o ns are c o de d usi n g t he W orl d Healt h Or ga nizati o n -Dr u g Dicti o nar y  ( W H O-D D)  
usi n g t he versi o n c urre ntl y i n effect at Sa n ofi at t h e ti me of data bas e l oc k.  
Me dicati o ns are cate g ori ze d as:  
 
Pri or me dicati o ns are t h ose t he partici pa nt  use d pri or t o first i n vesti gati o nal me dici nal 
pr o d uct ( I M P) i nta ke.  Pri or me dicati o ns ca n b e disc o nti n ue d bef ore first a d mi nistrati o n or 
ca n be o n g oi n g d uri n g tr eat me nt p hase.   
 C o nc o mita nt me dicati o ns  are a n y tr eat me nts  recei ve d b y t h e partici pa nt  c o nc o mita ntl y t o 
t he I M P, fr o m ra n d o mizati o n t o t he last st u d y visit. A gi ve n m e dicati o n ca n be classifie d 
as b ot h a pri or a n d as a c o nc o mita nt me dicati o n.     
A l ocall y a p pr o ve d n o ni n vesti gati o nal me dici n al pr o d uct ( NI M P) was use d f or T 1  c o ntr ast -
e n ha nce d M RI se q ue n ces.   
A n y te c h nical d etails relate d t o c o m p utati o n, dates, i m p utati o n f or missi n g dates for t he pri or or 
c o nc o mita nt me dicati o ns are des cri be d i n Secti o n 2. 5 . 
2. 1. 3  Effi c a c y e n d p oi nt s   
B aseli ne f or effic ac y e n d p oi nts  assesse d b y c ha n ge fr o m baseli ne  is d efi ne d as t he last n o n-
missi n g val ue  pri or t o t he first a d mi nistrati o n of ra n d o mize d st u d y i nter ve nti o n , u nless ot her wise 
s pecifie d. 
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St ati sti c al A n al y si s Pl a n   
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
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 1 1  
M RI d at a  
T he effi cac y a nal yses will be base d o n t he M RI data fr o m t he bli n de d ce ntral rea d er. Ce ntr al 
re vie w will be use d t o i d e ntif y n e w G d-e n ha n ci n g T 1 -h y p eri nte nse l esi o ns n ot prese nt at t he 
pre vi o us visit M RI , the  t otal c o u nt of G d-e n h a nci n g T 1 -h y p eri nte nse l esi o ns  a n d the n u m ber of 
ne w a n d e nl ar gi n g T 2 lesi o ns  (c o m pare d t o pr e vi o us visit M RI). T he t otal v ol u me of T 2 lesi o ns 
a n d t he n u m ber of T 1 -h y p oi nte nse lesi o ns will als o be assesse d as s u p p orti ve data wit h res p ect t o 
effic ac y.  T he c o m plete list of M RI para meters fr o m t he bli n de d ce ntral r ea di n gs is i n A p pe n di x B . 
F or all efficac y a n al ys es, t he M RI assess me nt  (all M RI para meters f or t he assess me nt) was 
e x cl u de d fr o m t he a nal ys es  if t he partici pa nt h a d a s us pecte d M S rela ps e a n d was  recei vi n g 
s yste mic c ortic oster oi ds wit hi n t he 3 0 da ys pri or t o  t he M RI assess me nt date. Treati n g t hese 
assess me nts as missi n g d ata is t o a v oi d c o nf o u n di n g t o t he efficac y a n al ys es, gi ve n t he  s h ort-ter m 
effects of s yste mic c ortic oster oi ds o n G d -e n ha n ci n g lesi o ns.  
Ma g n etizati o n tra nsfer  rati o ( M T R) a n d s usce pti bilit y-wei g hte d i ma gi n g ( S WI)  M RI para meters 
are als o s h o w n i n A p p e n di x B .  
N o ne w M RI dise ase activity  
N o ne w M RI diseas e acti vit y is defi ne d as t he pati e nt has 0 ne w  G d -e n ha n ci n g T 1 -h y p eri nte nse 
lesi o ns a n d 0 ne w a n d e nlar gi n g T 2 l esi o ns at t he M RI ass ess me nt at t he e n d of 1 2 wee ks of 
S A R 4 4 2 1 6 8 treat me nt ( Wee k 1 2 f or C o h ort 1 a n d Wee k 1 6 f or C o h ort 2).   
E D S S  
E D S S is a n or di nal cli nical rati n g s cale w hic h ra n ges fr o m 0 ( n or m al ne ur ol o gic e x a mi nati o n) t o 
1 0 ( deat h d ue t o M S) i n half -p oi nt i ncre me nts. E D S S c o nsists i n rati n g of 7 f u ncti o nal s yste ms 
( p yra mi dal, c ere b ellar, brai nste m, se ns or y, b o wel a n d bla d der, vis ual r ati n g a n d cere bral 
f u ncti o ns) a n d a m b ulati o n. 
M S rel a pse  
M S rela pse e v e nts are c li nical e ve nts t hat met t he pr ot oc ol defi ne d criteria ( pr ot oc ol Secti o n 
8. 1. 2. 2).  
2. 1. 3. 1  Pri m ar y effi c a c y e n d p oi nt( s)   
T he pri mar y effic ac y e n d p oi nt of t he st u d y is t he n u m ber of ne w G d -e n h a nci n g T 1 -h y p eri nte nse 
lesi o ns (lesi o ns n ot prese nt at t he pre vi o us visit M RI ) as detecte d b y brai n  M RI  at t he e n d of 1 2 
wee ks of S A R 4 4 2 1 6 8 treat me nt ( Wee k 1 2 f or C o h ort 1 a n d Wee k 1 6 f or C o h ort 2).  
T he 4 -wee k p ost -ra n d o mizati o n place b o data fr o m C o h ort 2 (ie, Wee k 4 dat a fr o m C o h ort 2) will 
be utilize d as t he place b o data i n t he M C P-M o d a nal ysis, u n der t he ass u m pti o n of a c o nsta nt rat e 
of G d -e n h a nci n g T 1 -h y p eri nte nse lesi o n f or m ati o n if partici pa nts w o ul d be recei vi n g place b o 
o ver 1 2 wee ks.  
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St ati sti c al A n al y si s Pl a n   
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
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 1 2  
2. 1. 3. 2  S e c o n d ar y effi c a c y e n d p oi nt s   
T he sec o n d ar y efficac y e n d p oi nt s are t he n u m ber of ne w or e nlar gi n g T 2 lesi o ns (c o m pare d  t o 
pre vi o us visit M R I) at t h e e n d of 1 2 wee ks of S A R 4 4 2 1 6 8 treat me nt a n d t he t otal n u m ber of G d -
e n ha nci n g T 1 -h y p eri nte nse lesi o ns at t he e n d of 1 2 wee ks of S A R 4 4 2 1 6 8 treat ment ( Wee k 1 2 f or 
C o h ort 1 a n d Wee k 1 6 f or C o h ort 2).  
T he 4 -wee k p ost -ra n d o mizati o n place b o data fr o m C o h ort 2 (ie, Wee k 4 dat a fr o m C o h ort 2) will 
be utilize d as t he place b o data  i n t he M C P-M o d a nal ysis .  
2. 1. 4  S af et y e n d p oi nt s   
T he safet y a nal ysis will be base d o n t he re p orte d a d verse e v e nts  ( A Es), seri o us a d verse e ve nts 
( S A Es), p ote ntiall y cli nicall y si g nifica nt a b n or malities ( P C S As) i n la b orat or y tests, vital si g ns 
( b o d y te m p erat ur e, heart rate, s yst olic bl o o d press ure, diast olic bl o o d press ure, res pir at or y rate),  
p h ysical e x a mi nati o n, electr ocar di o gra m [E C G ]  (heart rate a n d  P R, Q R S, Q T, a n d Q Tc  i nter vals) 
a n d t he C ol u m bia S uici de Se verit y Rati n g Scale ( C -S S R S) . 
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St ati sti c al A n al y si s Pl a n   
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
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 1 3  
M ulti ple scler osis rela pses  are e x e m pt fr o m b ei n g re p orte d as A Es e x ce pt w he n t he y meet t he 
defi niti o n of a n S A E.  M S rela pses are c ollecte d o n t he e C R F a n d a n al yze d as part of t he efficac y 
a nal ys es.  
O bserv ati o n peri o d s  
 F or safet y vari a bles, t he f oll o wi n g o bser vati o n peri o ds are defi n e d a n d use d f or  
classificati o n of A Es  a n d  deter mi nati o n of o n -tr eat me nt P C S A val ues: 
 T he pretr eat me nt peri o d is defi ne d as t he ti me fr o m t he si g ne d I C F t o t he first 
a d mi nistrati o n of ra n d o miz e d st u d y i nter ve nti o n  
 F or t he p ur p os e of defi ni n g ‘treat me nt -e mer ge nt’, t he o n -treat me nt p eri o d is defi ne d as t he 
ti me fr o m t he first a d mi nistrati o n of ra n d o mize d st u d y i nter ve nti o n u ntil t he last st u d y 
visit. T he treat me nt peri o ds are f urt her defi ne d as:  
- 
T he “ Wee ks 1 t o 4 peri o d ” is defi ne d as t he ti me fr o m first a d mi nistrati o n of 
ran d o mize d st u d y treat me nt t o t he a d mi nistrati o n of t he Wee k 4 st u d y tr eat me nt. F or 
C o h ort 1 t his is S A R 4 4 2 1 6 8 treat me nt f or 4 wee ks a n d f or C o h ort 2 is place b o 
treat me nt f or 4 w ee ks 
- 
T he “ S A R 4 4 2 1 6 8 treat m e nt  peri o d ” is defi n e d as Wee ks 1 t o 1 2 f or C o h ort  1 a n d 
Wee ks  4 t o 1 6 f or C o h ort 2  
N ote: partici pa nts fr o m t he C o h ort 1 Wee ks 1 t o 4 peri o d are als o i ncl u de d i n t he 1 2 wee ks of t he 
S A R 4 4 2 1 6 8 peri o d.  
- 
T he “place b o/ p ost -S A R 4 4 2 1 6 8 d ose peri o d ” is defi ne d as Wee k  1 2 t o Wee k  1 6  f or 
C o h ort  1. T his is t he 4 wee ks of place b o treat me nt f oll o wi n g 1 2 wee ks of S A R 4 4 2 1 6 8 
treat me nt 
2. 1. 4. 1  A d v er s e e v e nt s v ari a bl e s   
A dverse eve nt o bserv ati o n peri o d  
 Pretreat me nt A Es are d efi ne d as A Es t hat de vel o p e d, or w ors e ne d, or b ec o me seri o us  
d uri n g t he pretreat me nt p eri o d  
 T reat me nt-e mer ge nt A Es are defi ne d as A Es t hat de vel o p, w orse n, or bec o me seri o us  
d uri n g t he o n -treat me nt p eri o d 
All a d verse e ve nts (i ncl u di n g seri o us a d verse e ve nts) will be  c o de d t o a l o wer -le vel ter m ( L L T), 
preferre d t er m  ( P T), hi g h-le vel ter m ( H L T), hi g h-l e vel gr o u p ter m ( H L G T), a n d ass ociate d 
pri mar y s yst e m or ga n cl ass ( S O C) usi n g t he versi o n of Me dical Dicti o nar y f or Re g ul at or y 
Acti vities (Me d D R A ) c urre ntl y i n effect at Sa n ofi at t he ti me of data bas e l oc k . 
2. 1. 4. 2  A d v er s e e v e nt s of s p e ci al i nt er e st ( A E SI s )  
A n A E SI is a n A E (seri o us or n o nseri o us) of sci e ntific a n d me dical c o ncer n s pecific t o t he 
S p o ns or ’s pr o d uct or pr o gra m, f or w hi c h o n g oi n g m o nit ori n g a n d i m me diat e n otificati o n b y t h e 
I n v esti gat or t o t he S p o ns or  is re q uire d. A E SIs are descri be d i n P r ot oc ol [Secti o n 8. 3. 1 ]. 
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St ati sti c al A n al y si s Pl a n   
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
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 1 4  
A E SIs are i n dicate d b y a c hec k b o x ( yes/ n o) o n t he  a d verse e ve nt  e C R F.  
I n crease i n A L T is r ec or de d as t he a d v erse e ve nt cate g or y o n t he a d verse e ve nt e C R F.  
O ver d ose a n d pre g n a nc y are rec or de d o n se p arate e C R Fs.  
2. 1. 4. 3  D e at h s   
T he deat hs o bser vati o n p eri o d s are d efi ne d as:  
 Deat h o n -st u d y:  deat h o cc urri n g after t h e start of t he T E A E peri o d u p t o t h e last pr ot oc ol 
pla n ne d visit of t he partici pa nt  
 Deat h o n -tr eat me nt:  deat h occ urri n g d uri n g t he T E A E  peri o d  
 Deat h p ostst u d y:  deat h o cc urri n g after t h e last pr ot oc ol pla n ne d visit of t he partici pa nt  a n d 
bef ore d ata bas e l oc k   
2. 1. 4. 4  L a b or at or y s af et y v ari a bl e s   
Cli nical la b orat or y data c o nsists of bl o o d a nal ysis, i ncl u di n g he mat ol o g y, cli nical c he mistr y, a n d 
uri nal ysis.  Cli nical la b orat or y v al ues after c o n versi o n will be a nal yze d i n sta n dar d i nter n ati o nal 
u nits a n d i nter nati o nal u nits will be use d i n all listi n gs a n d t a b les. 
Bl o o d sa m ples f or cli nical la b orat ories will be ta ke n  as detaile d i n t he S o A ( P r ot oc ol 
[Secti o n  1. 3 ]) u nless ot her wise s pecifi e d.  T he la b orat or y para meters are detaile d i n t he P r ot oc ol 
(Secti o n 1 0. 2 ).   
2. 1. 4. 5  Vit al si g n s v ari a bl e s   
Vital si g ns i ncl u de: b o d y te m perat ur e ( de grees Celsi us), heart rate  ( beats/ mi n ute), res pirat or y rate 
( breat hs/ mi n ute), a n d s yst olic a n d diast olic bl o o d press ure  ( m m H g).  Bl o o d press ure a n d p ulse 
meas ure m e nts will be ass esse d  c o nsiste ntl y i n sitti n g or s u pi ne p ositi o n. 
2. 1. 4. 6  El e ctr o c ar di o gr a m ( E C G) v ari a bl e s   
T wel ve -le a d E C Gs were rec or de d a ut o maticall y b y t he de vice at t he I n vesti gat or  site, wit h ce ntral 
E C G re vie w t o e ns ure c o nsiste nc y of E C G e val uati o n  ( n or mal, a b n or mal, u na ble t o e val uate).  
E C G para meters i ncl u de heart rate, P R, Q R S, Q T, a n d c orrecte d Q Tc (acc or di n g t o 
Bazett/ Fri dericia) .  
2. 1. 4. 7   C ol u m bi a S ui ci d e S e v erit y R ati n g S c al e ( C -S S R S)   
T he C -S S R S is a t o ol use d t o assess t he lifeti me  s uici dalit y of a p artici pa nt  a n d t o trac k s uic i dal 
e ve nts t hr o u g h t he st u d y. T he str uct ure d i nter vie w pr o m pts rec ollecti o n of s uici dal i deati o n, 
i ncl u di n g t he i nte nsit y of t he i deati o n, be ha vi or a n d atte m pts wit h act ual/ p ote ntial let halit y.  
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St ati sti c al A n al y si s Pl a n   
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
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 1 5  
T he  scale is a d mi nistere d b y t he I n vesti gat or or a q ualifie d desi g nee at scree ni n g a n d at t he ti me 
p oi nts i n dicate d i n t he pr ot oc ol S o A ( pr ot oc ol Secti o n  1. 3).  
T he C -S S R S cate g ories h a ve bi nar y res p o nses ( yes, n o) : 
Cate g or y 1 –  Wis h t o be dea d  
Cate g or y 2 –  N o n -s pecifi c acti ve s uici dal t h o u g hts 
Cate g or y 3 –  Acti ve s uici dal i deati o n wit h a n y met h o ds ( n ot pla n) wit h o ut i nte nt t o act  
Cate g or y 4 - A cti ve s uici dal i deati o n wit h s o me i nte nt t o act, wit h o ut s pecific pla n  
Cate g or y 5 –  Acti ve s uici dal i deati o n wit h s pecific pla n a n d i nte nt  
Cate g or y 6 –  pr e p arat or y acts or be h a vi or  
Cate g or y 7 –  A b orte d atte m pt  
Cate g or y 8 –  I nterr u pte d atte m pt 
Cate g or y 9 –  Act ual atte m pt ( n o n -fatal) 
Cate g or y 1 0 –  S uici dal be ha vi or  
C o m p osite e n d p oi nt s are defi ne d as: 
 S uici dal i deati o n –  a ‘ yes’ a ns wer at a n y ti me d uri n g treat me nt t o a n y 1 of t he 5 s uici dal 
i deati o n q uesti o ns ( Cate g ories 1-5)  
 S uici dal be ha vi or –  a ‘ yes’ a ns wer at a n y ti me d uri n g treat me nt t o a n y 1 of t he 5 s uici dal 
be ha vi or q uesti o ns ( Cate g ories 6 -1 0)  
 S uici dal i deati o n or be ha vi or –  a ‘ yes’ a ns wer at a n y ti me d uri n g treat me nt t o a n y 1 of t he 
1 0 s uici dal a n d be ha vi or q uesti o ns ( Cate g ories 1 -1 0)  
2. 1. 4. 8  P h y si c al e x a mi n ati o n   
T he p h ysi cal e x a mi nati o n is perf or me d at all visits  a n d descri be d i n P r ot oc ol (Secti o n 8. 2. 1 ).  
2. 1. 5  P h ar m a c o ki n eti c (P K ) v ari a bl e s   
T he S A R 4 4 2 1 6 8 c o nce ntrati o ns at selecte d ti me p oi nts after I M P i nta ke w ill be s u m marize d f or 
t he C S R usi n g descri pti ve statistics a n d t he P K a n al yses will be re p ort e d se paratel y.   
V V- C LI N- 0 5 4 0 3 1 1 1. 0


St ati sti c al A n al y si s Pl a n   
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
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 1 6  
2. 2  
DI S P O SI TI O N O F P A R TI CI P A N T S   
T his secti o n descri bes p artici pa nt  dis p ositi o n f or b ot h partici pa nt  st u d y stat us a n d t he partici pa nt  
a nal ysis p o p ulati o ns.  
Scree ne d p artici pa nt s are defi ne d as a n y partici pa nt s w h o si g ne d t he i nf or me d c o nse nt f or m. 
Scree n fail ures are defi ne d as partici pa nts w h o c o nse nt e d t o partici pate i n t h e cli nical st u d y b ut 
we re n ot s u bse q u e ntl y ra n d o ml y assi g ne d t o t he st u d y i nter ve nti o n. I n di vi d uals w h o di d n ot meet 
t he criteria f or partici pati o n i n t his st u d y (scree n fail ure) c o ul d b e res cree n e d u p t o 2  times. 
Rescree n e d i n di vi d uals were  assi g n e d t he sa me partici pa nt n u m ber as t he i nitial scree ni n g.    
Ra n d o mize d partici pa nt s c o nsist of all partici pa nt s wit h a si g ne d i nf or me d c o nse nt f or m w h o ha v e 
ha d a treat me nt kit n u m ber all ocat e d a n d rec or de d i n t he I V R S/I W R S data base, re gar dless of 
w het her t he treat me nt kit was use d.  
Treate d (e x p ose d) partici pa nt s are all partici pa nt s w h o t o o k a n y of t he I M P. 
F or partici pa nt  st u d y stat us, t he t otal n u m ber of partici pa nt s i n eac h of t h e f oll o wi n g cat e g ories 
will be prese n te d i n t he cli nical st u d y re p ort usi n g a s u m mar y ta ble: 
 Scree ne d p artici pa nt s 
 Scree n fail ure partici pa nt s a n d reas o ns f or scree n fail ure 
 Ra n d o mize d partici pa nt s 
 Ra n d o mize d b ut n ot treate d partici pa nt s 
 Ra n d o mize d a n d treate d partici pa nt s 
 Partici pa nt s w h o did n ot c o m plete t he st u d y treat me nt peri o d as per pr ot oc ol  
V V- C LI N- 0 5 4 0 3 1 1 1. 0


St ati sti c al A n al y si s Pl a n   
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
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 1 7  
 Partici pa nt s w h o disc o nti n ue d st u d y tr eat me nt b y mai n reas o n f or per ma n e nt treat me nt 
disc o nti n uati o n  
F or all cate g ories of parti ci pa nt s (e x ce pt f or t he s cree ne d a n d n o nra n d o mize d cate g ories) 
perce nt a ges will be calc ulate d usi n g t he n u m ber of ra n d o mize d partici pa nt s as t he de n o mi nat or 
di vi de d b y t he n u m ber of partici pa nt s. Reas o ns f or treat me nt disc o nti n uati o n will be s u p plie d i n 
ta bles gi vi n g n u m bers a n d perce nt a ges b y t he ra n d o mize d treat me nt ar m, a n d f or t he total 
partici pa nts . A l isti n g of partici pa nts w h o disc o nti n ue d will i ncl u de treat me nt ar m a n d t he 
treat me nt t he partici p a nt was recei vi n g at t he ti me of disc o nti n uati o n.  
A s u m mar y t a ble of dis p ositi o n of scree ne d p artici pa nt s b y c o u ntr y /site will be pr o vi de d , s orte d 
b y al p h a betical or d er .  
A partici pa nt  is c o nsi dere d l ost t o f oll o w-u p at t he e n d of t he st u d y if he/s he is n ot assesse d at t he 
last pr ot oc ol pla n ne d visit a n d is u na ble t o be c o nt acte d b y t he st u d y site.  
All critical or maj or de vi ati o ns p ote ntiall y i m pacti n g efficac y a n al ys es, ra n d o mizati o n , a n d 
dr u g -dis pe nsi n g irre g ularities, a n d ot her maj or or critical  de viati o ns will be s u m marize d i n ta bles 
gi vi n g n u m bers a n d p erce nta ges of d e viati o ns b y treat me nt gr o u p.  
A d diti o nall y, t he a n al ysis p o p ulati o ns f or safet y, efficac y , a n d p h ar mac o ki netics will be 
s u m marize d i n a ta ble b y n u m ber of partici pa nt s in t he ra n d o mize d p o p ulati o n .  
 Efficac y p o p ulati o n:  m o difie d i nte nt -t o-treat ( mI T T) p o p ulati o n  
 Safet y p o p ulati o n  
 P har mac o ki netics p o p ulati o n  
2. 2. 1  R a n d o mi z ati o n a n d dr u g di s p e n si n g irr e g ul ariti e s   
Ra n d o mizati o n a n d dr u g -dis pe nsi n g irre g ularities occ ur w h e ne ver:  
1.  A ra n d o mizati o n is n ot i n acc or da nce wit h t he pr ot oc ol -defi ne d ra n d o mizati o n met h o d, 
s uc h as a) a n i neli gi ble p artici pa nt  is ra n d o mize d or  b) a partici pa nt  is ra n d o mize d t wice 
 
O R  
2.  A partici pa nt  is dis pe nse d a n IM P kit n ot all ocate d b y t he pr ot oc ol -defi n e d  ra n d o mizati o n, 
s uc h as a) a partici p a nt  at a n y ti me i n t he st u d y is dis pe nse d a differe nt treat me nt kit t ha n 
as ra n d o mize d ( w hic h m a y or ma y n ot c o ntai n t he c orrect -as-ra n d o mize d IM P), or b) a 
n o nra n d o mize d partici pa nt  is treate d wit h I M P res er ve d f or ra nd o mize d partici pa nt s. 
Ra n d o mizati o n a n d dr u g -dis pe nsi n g irre g ularities will be m o nit ore d t hr o u g h o ut t he st u d y a n d 
re vie we d o n a n o n g oi n g basis.  
All ra n d o mizati o n a n d dr u g -dis pe nsi n g irre g ulariti es will be d oc u me nte d i n t he cli nical st u d y 
re p ort.  If t h e nu m ber of irre g ularities is lar ge e n o u g h t o ma ke a ta b ular s u m mar y us ef ul, t he 
irre g ularities will be cate g orize d a n d s u m marize d a m o n g ra n d o mize d partici pa nt s ( n u m ber a n d 
perce nt a ges). N o nra n d o mize d, treate d partici pa nt s will be descri be d se p aratel y.  
V V- C LI N- 0 5 4 0 3 1 1 1. 0


St ati sti c al A n al y si s Pl a n   
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
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 1 8  
Ra n d o mizati o n a n d dr u g -dis pe nsi n g irre g ularities t o be pr os pecti vel y i de ntifie d i ncl u de b ut are 
n ot li mite d t o:  
 
R a n d o mi z ati o n a n d dr u g all o c ati o n irr e g ul ariti e s  
Kit dis p e ns ati o n wit h o ut I X R S c all at r a n d o miz ati o n 
Kit dis p e ns ati o n wit h o ut I X R S c all at r es u p ply visit(s) 
Err o n e o us kit dis p e ns ati o n  at r a n d o miz ati o n visit  
Err o n e o us kit dis p e ns ati o n  at a ny visit (s) 
Tr e at m e nt ar m n ot av ail a bl e  at sit e l ev el  
R a n d o miz ati o n of a n o n exist e nt p artici p a nt  
N o n -eli gi bl e p artici p a nt  r a n d o miz e d by err or 
P artici p a nt  r a n d o miz e d t wic e 
P artici p a nt  s witc h e d t o a n ot h er sit e 
2. 3  
A N A L Y SI S P O P U L A TI O N S   
Partici pa nt s treate d wit h o ut bei n g ra n d o mize d will n ot be c o nsi dere d ra n d o mize d a n d will n ot be 
i ncl u de d i n a n y efficac y p o p ulati o n.   
T he r a n d o mize d p o p ulati o n i ncl u des a n y partici p a nt  w h o has bee n all ocate d t o a ra n d o mize d 
treat me nt re gar dless of w het her t he treat me nt kit was use d.  
F or a n y p artici pa nt  ra n d o mize d m ore t ha n o nce, o nl y t he dat a ass ociat e d wit h t he first 
ra n d o mizati o n will be use d i n a n y a nal ysis p o p ulati o n.  T he safet y e x perie n ce ass oci ate d wit h a n y 
later ra n d o mizati o n will be assesse d s e paratel y. 
T he safet y e x perie nce of partici pa nt s treat e d a n d n ot ra n d o mize d will be re p orte d se paratel y, a n d 
t hese partici pa nt s will n ot be i n t he safet y p o p ulati o n. 
2. 3. 1  Effi c a c y p o p ul ati o n s   
2. 3. 1. 1  M o difi e d i nt e nt -t o-tr e at p o p ul ati o n   
T he m o difie d  i nte nt-t o-tr eat p o p ulati o n  is defi ne d as all ra n d o ml y assi g ne d partici pa nts a nal yze d 
i n t he treat me nt gr o u p t o w hic h t he y are ra n d o mized  (ie, I T T) a n d w h o were e x p ose d t o st u d y 
i nter ve nti o n.   
2. 3. 2  S af et y p o p ul ati o n   
T he s afet y p o p ulati o n  is defi ne d as t he ran d o mize d p o p ulati o n w h o act uall y recei v e d  at least 1  
d ose or  part of a d ose of t he IM P , a nal yz e d acc or di n g t o t he treat me nt act u all y recei ve d . 
V V- C LI N- 0 5 4 0 3 1 1 1. 0


St ati sti c al A n al y si s Pl a n   
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
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 1 9  
I n a d diti o n:  
 N o n ra n d o mize d b ut treat e d partici pa nt s will n ot be part of t he s afet y p o p ul ati o n; h o we ver, 
t heir safet y dat a will be prese nte d se p aratel y 
 Ra n d o mize d partici pa nt s f or w h o m it is u nclear w het her t he y t o o k t he I M P will be 
i ncl u de d i n t he safet y p o p ulati o n as ra n d o mize d 
2. 3. 3  P h ar m a c o ki n eti c p o p ul ati o n    
T he p har mac o ki netic p o p ulati o n i s t he sa me as t he safet y p o p ulati o n. 
2. 4  
S T A TI S TI C A L M E T H O D S   
2. 4. 1  D e m o gr a p hi c s a n d b a s eli n e c h ar a ct eri sti c s   
C o nti n u o us data will be s u m marize d usi n g t he n u m ber of a v aila ble data , m ea n, sta n dar d 
de viati o n  ( S D), me dia n, mi ni m u m, Q 1, Q 3  a n d ma xi m u m f or eac h treat me nt gr o u p.  Cate g orical 
a n d or di nal data will be s u m marize d usi n g t he n u m ber a n d perce nt a ge of p artici pa nt s i n eac h 
treat me nt gr o u p.  
Para meters will be s u m m arize d o n t he ra n d o mize d p o p ulati o n a nal yze d i n t he treat me nt gr o u p t o 
w hic h t he y were ra n d o mize d.   
Para meters  d escri be d i n Secti o n  2. 1. 1  will be s u m marize d b y tr eat me nt gr o u p a n d o verall 
S A R 4 4 2 1 6 8 treat me nt gr o u p usi n g descr i pti ve statistics. T he 4 -wee k p ost -ra n d o mizati o n place b o 
data fr o m C o h ort 2 (ie, Wee k  4 data fr o m C o h ort 2) will be utilize d as t he place b o dat a  i n 
s u m maries b y visit wee k a n d treat me nt gr o u p. F or t he S A R 4 4 2 6 8 treat me nt gr o u ps ( 5 m g, 1 5 m g, 
3 0 m g, 6 0 m g), data will be s u m marize d b y t he wee ks o n S A R 4 4 2 1 6 8 treat me nt, e g, Wee k 8 f or 
C o h ort 1 wit h Wee k 1 2 f or C o h ort 2.   
Me dical or s ur gic al hist or y d ata will be s u m marize d b y pri mar y s yste m or ga n class  ( S O C) a n d 
preferre d t er m ( P T ). E ve nts are s orte d b y S O C i nter nati o nall y a gree d or der a n d b y d ecreasi n g 
fre q ue n c y of P T bas e d o n i nci de nce i n t he o v erall treat me nt gr o u p. 
P -val ues o n de m o gra p hic a n d baseli ne c h aracteristic data will n ot be calc ul ate d.  
N o s pecific d escri pti o n of t he safet y p ara m eters will be pr o vi de d at baseli n e.  If rele va nt, t he 
baseli ne val ues will be d escri be d al o n g wit h eac h safet y a n al ysis.  
N o s pecifi c d escri pti o n of t he effi cac y p ara meters will be pr o vi de d at baseli ne.  If rele va nt, t he 
baseli ne val ues will be d escri be d al o n g wit h eac h efficac y a n al ysis.  
2. 4. 2  Pri or or c o n c o mit a nt m e di c ati o n s   
T he pri or a n d c o nc o mita nt me dicati o ns will be prese nte d f or t h e ra n d o mize d p o p ulati o n.  
V V- C LI N- 0 5 4 0 3 1 1 1. 0


St ati sti c al A n al y si s Pl a n   
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
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 2 0  
Me dicati o ns will be s u m marize d b y tr eat me nt gr o u p acc or di n g t o t he W H O -D D dicti o nar y, 
c o nsi deri n g t he first di git of t he a nat o mic cate g or y ( A T C)  class (a na t o mic cate g or y) a n d t he first 3  
di gits of t he A T C class (t hera pe utic cate g or y).  All A T C c o des c orres p o n di n g t o a me di cati o n will 
be s u m mariz e d, a n d parti ci pa nt s will be c o u nte d o nce i n eac h A T C cate g ory  (a nat o mic or 
t hera pe utic) li n ke d t o t he me dicati o n. T heref ore,  p artici pa nt s ma y be c o u nte d se veral ti mes f or t he 
sa me me dicati o n.  
T he ta ble f or pri or me dicati o ns will be s orte d b y d ecreasi n g fre q ue nc y of A T C  f oll o we d b y all 
ot her t hera p e utic class es base d o n t he o verall treat me nt gr o u p.   I n cas e of e q ual fre q u e nc y 
re gar di n g A T Cs (a nat o mic or t hera p e utic cat e g ori es), al p ha betical or der will be use d. 
T he ta bles f or c o nc o mita nt me dicati o ns will be s orte d b y d ecreasi n g fre q ue nc y of A T C f oll o we d 
b y all ot her t h era p e utic cl asses base d o n t he i n ci de nce i n t he S A R 4 4 2 1 6 8  6 0 m g treat me nt gr o u p. 
I n case of e q ual fre q u e nc y re gar di n g A T Cs (a nat o mic or t hera p e utic cate g ories), al p ha betical 
or der will be use d.  
2. 4. 3  E xt e nt of i n v e sti g ati o n al m e di ci n al pr o d u ct e x p o s ur e a n d c o m pli a n c e   
T he e xte nt of I M P e x p os ure a n d c o m plia nce  will be assesse d a n d s u m mari ze d b y act ual treat me nt 
wit hi n t he safet y p o p ulati o n ( Secti o n 2. 3. 2 ). 
2. 4. 3. 1  E xt e nt of i n v e sti g ati o n al m e di ci n al pr o d u ct (I M P) e x p o s ur e   
T he e xte nt of I M P e x p os ure will be assess e d b y t he d urati o n of I M P e x p os ure , a n d act ual d ose 
i nf or mati o n. 
D urati o n of I M P e x p os ure is defi ne d as last d ose d ate –  first d ose dat e + 1 d a y, re gar dless of 
u n pla n ne d i nter mitte nt disc o nti n uati o ns .   
D urati o n of I M P e x p os ure will be s u m marize d descri pti vel y as a q ua ntitati v e varia ble ( n u m ber, 
mea n, S D, me dia n, mi n i m u m, a n d ma xi m u m).  I n a d diti o n, d urati o n of treat me nt e x p os ure will 
als o be s u m marize d cate g oricall y b y n u m b ers  a n d perce nt a ges f or eac h of t he f oll o wi n g cate g ories 
a n d c u m ulati vel y acc or di n g t o t hese cate g ories: 1 t o 2 8 da ys  [ Wee k 4], 2 9  t o 5 6  da ys  [ Wee k 8], 
5 7  t o 8 4  da ys  [Wee k 1 2] , 8 5  t o 1 1 2  da ys  [ Wee k 1 6], a n d >1 1 2  da ys . 
A d diti o nall y, t he c u m ulati ve d urati o n of treat me nt e x p os ure will be pr o vi de d, defi ne d as t he s u m 
of t he d urati o n of tr eat me nt e x p os ure f or all partici pa nt s, a n d will be e x presse d i n partici pa nt  
m o nt hs . 
2. 4. 3. 2  C o m pli a n c e   
A gi ve n a d mi nistrati o n will be c o nsi dere d n o nc o m plia nt if t he partici pa nt  di d n ot ta ke t he pla n ne d 
d ose of treat me nt as re q uire d b y t h e pr ot oc ol.  N o i m p utati o n will be m a de f or partici pa nt s wit h 
missi n g or i nc o m plete data.  
V V- C LI N- 0 5 4 0 3 1 1 1. 0


St ati sti c al A n al y si s Pl a n   
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
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 2 1  
Perce nta ge of c o m plia n ce  f or a p artici pa nt  will be defi ne d as t he n u m b er of a d mi nistrati o ns t hat 
t he partici pa nt  was c o m plia nt di vi de d b y t he t otal n u m ber of a d mi nistrati o ns t hat t he partici pa nt  
was pl a n ne d t o ta ke fr o m t he first t o t he last a d mi nistrati o n.   
Treat me nt c o m plia nce perce nta ges will be s u m marize d descri pti vel y as q ua ntitati ve varia bles 
( n u m ber, mea n, S D, me dia n, mi ni m u m, a n d ma xi m u m).   
Cases of o ver d os e (P r ot o c ol [Secti o n 8. 3. 1 ]) will c o nstit ute seri o us a d verse e ve nts a n d will  be 
liste d as s uc h.  M ore ge n erall y, d osi n g irre g ularities will be liste d i n  Secti o n 2. 2. 1 . 
2. 4. 4  A n al y s e s of effi c a c y e n d p oi nt s   
2. 4. 4. 1  A n al y si s of pri m ar y effi c a c y e n d p oi nt   
T he p ri mar y effic ac y a n al ysis will be base d o n t he mI T T p o p ulati o n.  
T he pri mar y a n al ysis will be base d o n p o ole d dat a of C o h orts 1 a n d 2 f or eac h of t he S A R 4 4 2 1 6 8 
d oses (ie, data at W ee k 1 2 f or C o h ort 1 a n d at Wee k 1 6 f or C o h ort 2 f or t h e n u m ber of ne w G d -
e n ha nci n g T 1 -h y p eri nte nse lesi o ns  at t he e n d of 1 2 wee ks of S A R 4 4 2 1 6 8 treat me nt ). Data fr o m 
C o h orts 1 a n d 2 ma y als o be se paratel y e x pl ore d, as necessar y.  
F or eac h c o h ort, descri pti ve statistics will be s u m marize d o ver ti me ( Wee ks 4, 8, 1 2, a n d 1 6) 
w he n  a p pr o priate. T he s u m mar y fr o m C o h ort 1 will i ncl u de descri pti ve statistics f or t he 4 -wee k 
place b o peri o d after 1 2 wee ks of S A R 4 4 2 1 6 8 treat me nt  (ie, 4-wee k place b o r u n -o ut peri o d) .  
D ose -res p o nse rel ati o ns hi p 
F or t he mI T T p o p ul ati o n, t he d ose -res p o ns e rel ati o ns hi p will be e val uate d b y a 2-ste p M C P-M o d 
pr oce d ure. T he first ste p of t his pr oce d ure tests f or a n effi cac y si g nal (c o m p are d t o t he n ull 
h y p ot hesis of a flat, n o d ose -res p o ns e c ur ve) i n a pr oce d ure t hat c o ntr ols t he t y p e 1 err or. T o 
acc o u nt f or t he u n certai nt y of t he d os e -res p o nse s ha pe, 6 ca n di date m o dels ha ve bee n c o nsi dere d 
t o c o ver di vers e a n d p ote ntial d ose-res p o nse pr ofiles: 2 E ma x m o dels ( E D 5 0 = 1 0 m g, E D 5 0 = 3 0 
m g), a li near m o del, a q u a dratic m o del, a l o gistic m o del, a n d a n e x p o ne ntial m o del . T he sec o n d 
ste p is t he esti mati o n of t he d ose-res p o nse c ur ve, pr o vi de d t hat a n efficac y si g nal is esta blis he d i n 
t he first ste p. 
A ne gati ve bi n o mial re gressi o n m o del wit h c o vari ates f or bas eli ne G d -e n ha nci n g T 1 -h y peri nte ns e 
lesi o n c o u nt, treat me nt, a n d c o hort ( C o h ort 1 or C o h ort 2) will  be use d t o assess t he mea n c o u nt of 
ne w G d -e n ha nci n g T 1 -h y p eri nte nse lesi o ns i n eac h of t he 4 d ose gr o u ps at t he e n d of 1 2 wee ks of 
S A R 4 4 2 1 6 8 treat me nt a n d at t he e n d of 4 wee ks of place b o. T h e 4 -wee k p ost -ra n d o mizati o n 
plac e b o dat a fr o m C o h ort 2 (ie, Wee k 4 data fr o m C o h ort 2) will be utilize d as t he place b o d ata i n 
a nal ysis, u n d er t he ass u m pti o n of a c o nsta nt rate of G d -e n h a nci n g T 1 -h y p eri nte nse lesi o n 
f or mati o n if partici pa nts w o ul d be recei vi n g pl ace b o o ver 1 2 wee ks. Part ici pa nts i n C o h ort 2 
c o ntri b ute t o t he place b o data (at W ee k 4) as well as t he data of 4  S A R 4 4 2 1 6 8 d oses (at W ee k 
1 6). I n or der t o acc o u nt f or t he p ote ntial c orrelati o n bet wee n t he m eas ure me nts i n t he 4 -wee k 
place b o peri o d a n d t he s u bse q ue nt 1 2 -wee k S A R 4 4 2 1 6 8 treat me nt peri o d i n C o h ort 2, a G E E 
V V- C LI N- 0 5 4 0 3 1 1 1. 0


St ati sti c al A n al y si s Pl a n   
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
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 2 2  
a p pr oac h is us e d t o fit t he ne gati ve bi n o mial m o del acc o u nti n g f or t he wit hi n -partici pa nt 
c orrel ati o n via t he re p eat e d state me nt i n S A S P R O C G E N M O D , a n d t he mea n lesi o n c o u nts are 
esti mate d f or t he treat me nt gr o u ps  (s ee S A S c o de i n A p pe n di x C ).  
A mi n us l o g tra nsf or mati o n of t he mea n lesi o n c o u nt will be e ntere d i nt o t he M C P -M o d 
pr oce d ure  (see R c o de e x a m ple i n A p pe n di x C ). T he n ull h y p ot hesis of a fl at d ose -res p o ns e c ur ve 
(ie, n o d ose– res p o nse rel ati o ns hi p) at t he e n d of 1 2 wee ks of S A R 4 4 2 1 6 8 treat me nt f or t h e 
pri mar y e n d p oi nt will be j oi ntl y e val uate d f or eac h of t he 6 ca n di dat e d ose res p o nse m o dels wit h a 
c o ntrast test t hat c o ntr ol s t he fa mil y wis e err or rate at 2-si de d al p h a = 0. 0 5. If ste p 1 yiel ds 
si g nifica nt r es ults, t he best fitti n g m o del (s mallest AI C) fr o m t he 6 pre defi ne d ca n di dat e m o dels 
will be c h ose n usi n g t h e ge n eralize d AI C. T h e d ose f or t he P hase 3 pr o gra m will t he n be  
esti mate d fr o m t he fi nal s electe d m o del.  
Data fr o m C o h orts 1 a n d 2 will be c o m bi ne d f or t h e pri mar y a n al ysis (i e, data at Wee k 1 2 f or 
C o h ort 1 a n d at W ee k 1 6 f or C o h ort 2 f or t he n u m ber of ne w G d -e n ha nci n g T 1 -h y p eri ntese 
lesi o ns). Data fr o m eac h c o h ort may be se p arat el y e x pl ore d.  
T he mea n ne w G d -e n ha n ci n g T 1 h y p eri nte nse lesi o n c o u nts, o btai ne d fr o m t he ne gati ve bi n o mial 
re gressi o n m o del, f or t he 4 S A R 4 4 2 1 6 8 d ose gr o u ps a n d place b o, a n d t he relati ve re d u cti o n t o 
place b o, will be pr o vi de d  f or eac h of t he 4 S A R 4 4 2 1 6 8 d ose gr o u ps . T he m ea ns a n d 9 5 % 
c o nfi de nce i nter vals will be s h o w n gra p hicall y f or t he place b o a n d S A R 4 4 2 1 6 8 d ose gr o u ps i n a 
bar c hart.   
T he m ulti ple c o ntrasts a n d a dj uste d p -val ues f or t he ca n di dat e m o dels, t he esti mate d d ose 
res p o nse c ur ves a n d t ar get d oses, will be pr o vi de d.  
Descri pti ve statistics will als o be pr o vi de d f or t he 4  S A R 4 4 2 1 6 8  d oses f or o bser ve d n u m ber of 
ne w G d -e n ha nci n g T 1 -h y p eri nte nse  lesi o ns o ver ti me (ie, Wee k 4/ Wee k 8, Wee k 8/ Wee k 1 2, a n d 
Wee k 1 2/ W ee k 1 6 f or C o h ort 1/ C o h ort 2 ) a n d place b o ( Wee k 4 C o h ort 2) . T he mea ns  pl us 
sta n dar d de viati o n will b e dis pla ye d gra p hi call y o ver ti me.  
Missi n g d at a h a n dli n g  
All a vaila ble M RI data  f or e n d p oi nt , after a p pl yi n g t he c ortic oster oi d use e x cl usi o n, will be use d 
i n t he a nal ys es .  
 S u b gr o u p  a n d se nsitivity a n alyses  
A se nsiti vit y  a nal ys is, si milar t o t he pri mar y a nal ysis f or t he pri mar y e n d p oi nt, will be perf or me d 
wit h all Wee k 1 2 data , ie, i ncl u di n g a n y o bser vati o ns t hat ha d bee n  e x cl u d e d  fr o m t he a n al ysis if 
t he partici pa nt ha d a s us pecte d M S rela ps e a n d was recei vi n g s yste mic c ortic oster oi ds wit hi n t he 
3 0 da ys pri or t o t he M RI assess me nt date .  
T o assess t he c o nsiste nc y i n treat me nt effects i n eac h d ose gr o u p acr oss differe nt s u b gr o u p le vels, 
s u b gr o u p a nal yses usi n g descri pti ve statistics ma y be c o n d ucte d f or t he pri mar y a n d sec o n dar y 
e n d p oi nts wit h res pect t o a ge  ( < = 4 0 years, > 4 0 ye ars), se x, baseli ne E D S S sc ore ( <4. 0 , > = 4. 0 ), 
V V- C LI N- 0 5 4 0 3 1 1 1. 0


St ati sti c al A n al y si s Pl a n   
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
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 2 3  
H A D ( yes, n o) , a n d bas eli ne M RI  ( < me dia n T 1 c o u nt, > = me dia n T 1 c o u nt). T hese  will be 
pr o vi de d i n ta bles.  
S u b gr o u p a n al ys es  usi n g descri pti ve statistics , bas e d o n t y p e of i ma gi n g sca n ner, ie, 1. 5 tesl a vs 3 
tesla ma y b e perf or me d. 
If t he n u m ber of ne w G d -e n ha nci n g T 1 l esi o ns f or t he 4 -wee k place b o gr o u p is  s mall, e g, zer o, 
t he n t he M C P -M o d pr oce d ure ma y b e a p plie d t o t he 4 S A R 4 4 2 1 6 8 d ose gr o u ps, t o e val uate d ose -
res p o nse o ver t he 4 d oses of S A R 4 4 2 1 6 8. 
2. 4. 4. 2  A n al y s e s of s e c o n d ar y effi c a c y e n d p oi nt s   
T ot al n u m ber o f G d-e n h a nci n g T 1 -hy peri nte nse lesi o ns  a n d N u m ber of ne w or e nl ar gi n g T 2 
lesi o ns 
F or t he sec o n dar y e n d p oi nt s, a si milar ne gati ve bi n o mial m o del a n d M C P-M o d pr oce d ure will be 
use d . As it is reas o na ble t o ass u me a c o nsta nt r ate of lesi o n f or mati o n o ver 1 2 we e ks u n der 
place b o f or t he e n d p oi nts, t he sa me a p pr oac h as t hat utilize d f or t he pri mar y e n d p oi nt will be 
use d, ie, b y usi n g t he Wee k 4 data i n C o h ort 2 as t he Wee k 1 2 place b o data w hile acc o u nti n g f or 
t he wit hi n-partici pa nt c orrelati o n .  
Si milar ta bles a n d  fi g ures as f or t he pri mar y a nal ysis will be pr o vi de d.  
Se nsiti vit y a n al ys es usi n g all Wee k 1 2  d ata , will be perf or me d si milarl y t o t he pri mar y e n d p oi nt 
a nal ys es.  Si milar s u b gr o u p a nal ys es ma y be p erf or me d.  
2. 4. 4. 3  M ulti pli cit y i s s u e s   
F or eac h of t h e pri mar y a n d sec o n dar y a nal yses, t h e fa mil y-wise err or rate f or eac h of t he n ull 
h y p ot hes es ass ociate d wit h d ose  gr o u p  c o m paris o ns will be c o ntr olle d b y t he M C P -M o d 
pr oce d ure.  
V V- C LI N- 0 5 4 0 3 1 1 1. 0


St ati sti c al A n al y si s Pl a n   
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
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 2 4  
2. 4. 5  A n al y s e s of s af et y d at a   
T he s u m mar y of safet y res ults will be prese nte d b y treat me nt gr o u p.  Res ults will be prese nte d 
se parat el y f or t he ‘ Wee ks 1-4 peri o d’ , f or t he ‘S A R 4 4 2 1 6 8 treat me nt peri o d ’, a n d f or t he 
‘ place b o/ p ost-S A R 4 4 2 1 6 8 d ose peri o d’ .  
T he ‘ Wee ks 1 -4 p eri o d’ will i ncl u de t he data t hr o u g h Wee k 4 fr o m b ot h t he C o h ort 2 place b o 
partici pa nt s a n d t he C o h ort 1 S A R 4 4 2 1 6 8 partici pa nts  a n d will be dis pla ye d b y tr eat me nt gr o u p.   
T he ‘ S A R 4 4 2 1 6 8 treat m e nt peri o d’ i ncl u des t he C o h ort 1 part ici pa nts t hr o u g h Wee k 1 2 a n d 
C o h ort 2 partici pa nts  fr o m W ee ks 4 t hr o u g h Wee k 1 6, a n d will be dis pla ye d b y t h e S A R 4 4 2 1 6 8 
d ose gr o u p a n d o verall .  
T he res ults fr o m t he ‘ pl ace b o/ p ost -S A R 4 4 2 1 6 8 d ose peri o d’, ie, Wee k 1 2 t o Wee k 1 6 f or C o h ort 
1, will be prese nt e d se p aratel y, a n d dis pla ye d b y t he S A R 4 4 2 1 6 8 treat me nt gr o u p a n d o verall.   
Ge ner al c o m m o n r ules  
All safet y a nal yses will be perf or me d o n t he safet y p o p ulati o n  as defi ne d i n  Secti o n 2. 3. 2 , u nless 
ot her wise s pecifie d, usi n g t he f oll o wi n g c o m m o n r ules:  
 Safet y d ata i n partici pa nts  w h o d o n ot bel o n g t o t h e safet y p o p ulati o n ( e g, e x p ose d b ut n ot 
ra n d o mize d) will be liste d se parat ely  
 T he baseli ne v al ue is defi ne d as t he last meas ure m e nt c ollecte d o n or b ef ore t he 
ra n d o mizati o n visit (Da y 1 ) pri or t o i nitiati o n of t he first d ose of st u d y i nter ve nti o n.  
 T he p ote ntiall y cli nicall y si g nifica nt a b n or malit y ( P C S A) val ues are defi ne d as a b n or mal 
val ues c o nsi dere d me dicall y i m p orta nt b y t he S p o ns or acc or di n g t o pre defi ne d 
criteria/t hres h ol ds bas e d o n literat ure re vie w  a n d defi ne d b y t he S p o ns or f or cli nical 
la b orat or y tests, vital si g ns, a n d E C G ( P C S A versi o n date d J a n uar y 2 01 4  [A p pe n di x A ]) 
 P C S A criteria will deter mi ne w hic h partici pa nts  ha d at least 1  P C S A d uri n g t he tr eat me nt-
e mer ge nt a d v erse e ve nt  p eri o d, ta ki n g i nt o acc o u nt all e val uati o ns perf or me d d uri n g t he 
treat me nt-e mer ge nt a d v erse e ve nt  p eri o d, i ncl u di n g n o nsc h e d ule d or re peate d e val uati o ns.  
T he n u m ber of all s uc h p artici pa nts  will be t he n u merat or f or t he o n -tr eat m e nt P C S A 
perce nt a ge  
V V- C LI N- 0 5 4 0 3 1 1 1. 0


St ati sti c al A n al y si s Pl a n   
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
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 2 5  
 T he treat me nt -e mer ge nt P C S A de n o mi nat or b y gr o u p f or a gi ve n para met er will be base d 
o n t he n u m ber of p artici pa nts  assesse d f or t hat gi ve n para m eter i n t he tr eat me nt-e mer ge nt 
a d verse e ve nt  peri o d b y treat me nt gr o u p o n t he s afet y p o p ulati o n.  
 F or q ua ntitati ve safet y para meters base d o n ce ntral la b orat or y/rea di n g meas ure me nts, 
descri pti ve statistics will be us e d t o s u m marize res ults a n d c ha n ge fr o m bas eli ne val ues b y 
visit a n d treat me nt gr o u p ; f or t he S A R 4 4 2 6 8 treat me nt gr o u ps, data will be s u m marize d b y 
t he wee ks o n S A R 4 4 2 1 6 8 treat me nt, e g, Wee k 8 f or C o h ort 1 wit h Wee k 1 2 f or C o h ort 2.   
 T he a nal ysis of t he s afet y varia bles will be ess e ntiall y des cri pti ve a n d n o s yste matic 
testi n g is pla n ne d.   
2. 4. 5. 1  A n al y s e s of a d v er s e e v e nt s   
Ge ner alities  
T he pri mar y f oc us of a d v erse e v e nt re p orti n g will be o n treat me nt-e mer ge nt a d verse e ve nts .  
Pre treat me nt a n d p osttr eat me nt a d verse e ve nts  will be pr o vi de d  se p aratel y, i n listi n gs.  
If a n a d v erse e ve nt  dat e/ti me of o nset ( occ urre n ce, w orse ni n g, or bec o mi n g seri o us) is i nc o m plete, 
a n i m p utati o n al g orit h m will be use d t o classif y t he a d verse e v e nt  as pretr eat me nt  or  treat me nt-
e mer ge nt .  T h e al g orit h m f or i m p uti n g date/ti me of o nset will be c o nser vati ve a n d will classif y a n 
a d verse e ve nt  as tr eat me nt e mer ge nt u nless t here is defi niti ve i nf or mati o n t o deter mi ne it is 
pre treat me nt.  Details o n classificati o n of a d v erse e ve nts  wit h missi n g or partial o nset dates are 
pr o vi de d i n Secti o n  2. 5. 3 . 
A d verse e ve nt i nci de n ce ta bles will prese nt b y pri mar y S O C  a n d P T  f or eac h treat me nt gr o u p, t h e 
n u m ber ( n) a n d perce nta ge ( %) of partici pa nts  e x perie nci n g a n a d verse e v e nt .  M ulti ple 
occ ur re nces of t he sa me e ve nt i n t he sa me partici pa nt  w ill be c o u nte d o nl y o nce i n t he ta bles 
wit hi n a treat me nt p hase.  T he de n o mi nat or f or c o m p utati o n of perce nt a ges is t he safet y 
p o p ulati o n wit hi n eac h tr eat me nt gr o u p.  
S orti n g wit hi n ta bles e ns ure s t he sa me prese ntati o n f or t he set of all a d verse e ve nts  wit hi n t he 
o bser vati o n peri o d ( pretr eat me nt, treat me nt-e mer ge nt ).  F or t h at p ur p ose, t he ta ble of all 
treat me nt-e mer ge nt a d v erse e ve nts  prese nte d b y pri mar y S O C  a n d P T  s orte d b y t he 
i nter nati o nall y a gree d S O C or der a n d d ecreasi n g fre q ue n c y of P Ts  wit hi n S O Cs  will defi ne t he 
prese ntati o n or der f or all ot her ta bles u nless ot her wise s pecifie d.  S orti n g will be base d o n res ults 
f or t he e x peri me ntal ar m gi ve n wit h t he hi g hest d ose, ie, S A R 4 4 2 1 6 8 6 0 m g.  
A n alysis of all tre at m e nt-e m er ge nt a dverse eve nts  
T he f oll o wi n g tr eat me nt-e mer ge nt a d verse e ve nt  s u m maries will be ge nerat e d f or t he safet y 
p o p ulati o n.  
 O ver vie w of treat me nt-e mer ge nt a d verse e v e nts , s u m marizi n g n u m ber ( %) of partici pa nts  
wit h a n y  
- 
Treat m e nt-e mer ge nt a d v erse e v e nt  
V V- C LI N- 0 5 4 0 3 1 1 1. 0


St ati sti c al A n al y si s Pl a n   
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
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 2 6  
- 
Seri o us treat me nt-e m er ge nt a d verse e ve nt  
- 
Treat me nt -e mer ge nt a d v erse e v e nt  lea di n g t o deat h 
- 
Treat me nt -e mer ge nt a d v erse e v e nt  lea di n g t o per ma ne nt treat me nt disc o nti n uati o n 
- 
Treat me nt -e mer ge nt a d v erse e v e nt lea di n g t o st u d y disc o nti n uati o n  
 All treat me nt -e mer ge nt a d verse e v e nts b y pri mar y S O C a n d P T , s h o wi n g t he n u m ber ( %) 
of partici pa nt s wit h at least 1 treat me nt -e mer ge nt a d verse e v e nt, s orte d  b y t he 
i nter nati o nall y a gree d S O C or der a n d b y d ecreasi n g fre q ue n c y of  P Ts f or t he S A R 4 4 2 1 68 
6 0 m g gr o u p .  T his s orti n g or der will be a p plie d t o all ot her ta bles, u nless ot her wise 
s pecifie d 
 All treat me nt -e mer ge nt a d verse e v e nts re gar dless of relati o ns hi p a n d relate d b y pri mar y 
S O C, a n d P T, s h o wi n g t he n u m ber ( %) of p artici p a nt s wit h at least 1 treat me nt-e mer ge nt 
a d verse e ve nt, s orte d b y t he i nter nati o nall y a gree d S O C or der , wit h P T s s orte d b y 
decreasi n g fre q ue nc y acc or di n g t o t he all T E A Es s u m mar y  
 All treat me nt -e mer ge nt a d verse e v e nts b y ma xi mal i nte nsit y, prese nte d b y pri mar y S O C 
a n d P T, s h o wi n g t he n u m ber ( %) of partici p a nt s wit h at least 1 treat me nt-e mer ge nt 
a d verse e ve nt b y i nte nsit y (ie, mil d, m o derate, or se vere), s orte d b y t he s orti n g or der 
defi ne d a b o v e  
A n alysis of all tre at m e nt e m er ge nt seri o us a dverse eve nts 
 All treat me nt -e mer ge nt s eri ous a d verse e v e nts  b y pri mar y S O C  a n d P T, s h o wi n g t he 
n u m ber ( %) of partici p a nt s wit h at least 1  seri o us treat me nt-e mer ge nt a d verse e ve nt , 
s orte d b y t h e s orti n g or der defi ne d a b o ve  
 All treat me nt -e mer ge nt s eri o us a d verse e v e nts re gar dless of relati o ns hi p a nd relate d t o 
IM P , b y pri mar y S O C  a n d P T, s h o wi n g t he n u m b er ( %) of partici pa nt s wit h at least 1  
treat me nt-e mer ge nt seri o us a d verse e ve nt, s orte d b y t he s orti n g or der defi ne d a b o ve  
A n alysis of all tre at m e nt -e m er ge nt a dverse eve nts le a di n g t o tre at m e nt disc o nti n u ati o n  
 All treat me nt-e mer ge nt a d verse e v e nts  lea di n g t o treat me nt disc o nti n uati o n, b y pri mar y 
S O C a n d P T, s h o wi n g t he n u m ber ( %) of p artici p a nt s s orte d b y t he s orti n g or der defi ne d 
a b o ve  
A n alysis of a dverse eve nts wit h pres pecifie d m o nit ori n g ( A E SI) 
 All treat me nt e mer ge nt a d verse e v e nts wit h pres p ecifie d m o nit ori n g  ( A E SI), b y P T, 
s h o wi n g t he n u m ber ( %) of partici pa nt s, s orte d b y t he s orti n g or der defi ne d a b o ve  
A n alysis of pretre at m e nt a dverse eve nts  
 Pretreat me nt a d v erse e ve nts , i ncl u di n g seri o us pretreat me nt a d verse e v e nts,  will be 
pr o vi de d i n a listi n g  
V V- C LI N- 0 5 4 0 3 1 1 1. 0


St ati sti c al A n al y si s Pl a n   
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
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 2 7  
2. 4. 5. 2  D e at h s   
T he f oll o wi n g s u m maries of deat hs will be ge nerate d f or t he safet y p o p ulati o n. 
 Treat me nt -e mer ge nt a d v erse e v e nts  lea di n g t o deat h ( deat h as a n o utc o me o n t he a d verse 
e ve nt cas e re p ort f or m  pa ge as re p orte d b y t he I n v esti gat or) b y pri mar y S O C a n d P T 
s h o wi n g n u m ber ( %) of partici pa nt s s orte d b y t he s orti n g or der defi ne d a b o ve 
 T he n u m ber of p artici pa nt s w h o die d b y st ud y peri o d (i n T E A E peri o d: fr o m first I M P t o 
partici pa nt’s last pr ot oc ol pla n ne d visit, i n p ost -st u d y peri o d : occ urri n g after partici pa nt’s 
last pr ot oc ol pla n ne d visit a n d re p orte d i n t he cli nical data b ase) 
Deat hs f or n o nra n d o mize d or ra n d o mize d a n d n ot tr eate d partici pa nt s will be prese nt e d se paratel y.  
2. 4. 5. 3  A n al y s e s of l a b or at or y v ari a bl e s   
T he s u m mar y statistics (i ncl u di n g n u m ber, m ea n, me dia n, Q 1, Q 3 , sta n dar d de viati o n, mi ni m u m 
a n d ma xi m u m) of all la b orat or y vari a bles (ce ntral la b orat or y val u es a n d c h a n ges fr o m bas eli ne) 
will be calc ulate d f or eac h visit or st u d y assess me nt ( baseli ne, eac h p ost bas eli ne ti me p oi nt ) b y 
treat me nt gr o u p.  F or para meters C P K a n d platelets , mea n c ha n ges f r o m baseli ne wit h t he 
c orres p o n di n g sta n d ar d err or  will be pl otte d o ver ti me o n treat me nt i n eac h S A R 4 4 2 1 6 8 treat me nt 
gr o u p  (ie, Wee k 4 fr o m C o h ort 1 wit h Wee k 8 fr o m C o h ort 2).  
T he i nci de nce of P C S As (list pr o vi de d i n A p pe n di x A ) at a n y ti me d uri n g t he treat me nt-e mer ge nt 
a d verse e ve nt peri o d will be s u m marize d b y bi ol o gical f u ncti o n a n d tr eat me nt gr o u p w hate ver t he 
baseli ne le vel a n d/ or acc or di n g t o t he f oll o wi n g b aseli ne stat us cate g ories:  
 N or mal/ missi n g  
 A b n or mal acc or di n g t o P C S A criteri o n or criteria  
2. 4. 5. 4  A n al y s e s of vit al si g n v ari a bl e s   
T he s u m mar y statistics (i ncl u di n g n u m ber, m ea n, me dia n, Q 1, Q 3 , sta n dar d de viati o n, mi ni m u m 
a n d ma xi m u m) of all vital si g ns varia bles , a n d c h a n ges fr o m baseli ne , will be calc ul ate d f or eac h 
visit or st u d y assess me nt ( baseli ne, eac h p ost bas eli ne ti me p oi nt, b y treat me nt gr o u p.  F or 
para meters s yst olic bl o o d press ure, diast olic bl o o d press ure, a n d res pir at or y rate, t he mea n 
c ha n ges fr o m baseli ne  wit h t he c orres p o n di n g sta n dar d err or  will be pl otte d o ver ti me  i n eac h 
treat me nt gr o u p.  
T he i nci de nce of P C S As at a n y ti me d uri n g t h e treat me nt -e mer ge nt a d verse e ve nt peri o d will be 
s u m marize d b y treat me nt gr o u p irrespecti ve of t he baseli ne le vel a n d acc or di n g t o t he f oll o wi n g 
baseli ne stat us cate g ories:  
 N or mal/ missi n g  
 A b n or mal acc or di n g t o P C S A criteri o n or criteria  
V V- C LI N- 0 5 4 0 3 1 1 1. 0


St ati sti c al A n al y si s Pl a n   
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
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 2 8  
2. 4. 5. 5  A n al y s e s of el e ctr o c ar di o gr a m  ( E C G) v ari a bl e s   
T he s u m mar y statistics (i ncl u di n g n u m ber, m ea n, me dia n, Q 1, Q 3 , sta n dar d de viati o n, mi ni m u m 
a n d ma xi m u m) of all E C G varia bles (ce ntr al la b orat or y v al ues a n d c ha n ges fr o m baseli ne) will be 
calc ulate d f or eac h visit or st u d y ass ess me nt ( bas eli ne, eac h p ost baseli ne ti me p oi nt [ base d o n 
wee ks o n S A R 4 4 2 1 6 8 treat me nt, e g, Wee k 8 f or C o h ort 1 wit h Wee k 1 2 f or C o h ort 2] ) b y 
treat me nt gr o u p.  F or para meters heart rate, P R, Q R S, Q T a n d Q Tc , mea n c ha n ges fr o m 
baseli ne  wit h t he c orres p o n di n g sta n d ar d err ors will be pl otte d o ver ti me i n eac h tr eat me nt gr o u p.    
T he i nci de nce of P C S As at a n y ti me d uri n g t h e treat me nt -e mer ge nt a d verse e ve nt peri o d will be 
s u m marize d b y treat me nt gr o u p irres pecti ve of t he baseli ne le vel a n d/ or acc or di n g t o t he 
f oll o wi n g bas eli ne stat us cate g ories:  
 N or mal/ missi n g  
 A b n or mal acc or di n g t o P C S A criteri o n or criteria 
2. 4. 5. 6  A n al y s e s of s ui ci d alit y a s s e s s m e nt   
S u m maries of patie nts f or t he C -S S R S cate g ories of s uici dal i deati o n or s ui ci dal be ha vi or, a n d 
s hift ta bles f or baseli ne a n d d uri n g tr eat me nt res p o nses will be pr o vi de d.    
2. 4. 5. 7  A n al y s e s of ot h er s af et y e n d p oi nt s   
P h ysical e x a mi nati o n assess me nts ( n or mal, a b n or mal b ut n ot cli nicall y si g nifica nt,  a b n or mal a n d 
cli nicall y si g nifica nt) will be s u m marize d b y treat me nt gr o u p a n d visit.  
2. 4. 5. 8  A n al y s e s of p h ar m a c o ki n eti c
   
T he p har mac o ki netic 
will be base d o n t he P K p o p ulati o n.  
S A R 4 4 2 1 6 8 c o nce ntrati o ns at selecte d ti me p oi nts after I M P i nta ke will be re p orte d usi n g 
descri pti ve statistics. A d diti o nal P K para meters s uc h as C ma x , tma x , a n d A U C at stea d y stat e will be 
esti mate d us i n g a p o p ul ati o n P K a p pr oac h. T h ese para meters will be pres e nte d i n a se parate, 
sta n d-al o ne re p ort. 
T he re p ort e d perce nta ge of B T K o cc u p a nc y at t he ti me p oi nts pre d ose f or first I M P a n d 1 h o ur 
( ± 0. 5 hr) p ost d ose, Wee k 1 2 at 1 h o ur ( ± 0. 5 hr) p ost d ose, a n d  Wee k 1 6 at 1 h o ur ( ± 0. 5 hr) 
p ost d ose  will be s u m mariz e d usi n g descri pti ve statistics.  Si milar s u m maries will be pr o vi de d f or 
Nfl, C HI 3 L 1 a n d I g l e vels.  
L y m p h oc yte p h e n ot y pes para meters ( C D 3, C D 4, C D 8, C D 1 9, C D 1 6 + C D 5 6 c o u nts a n d 
perce nt a ges of l y m p h oc yte s) at t he ti me p oi nts pre d ose f or first I M P a n d 1 h o ur ( ± 0. 5 hr) 
p ost d ose, Wee k 1 2 at 1 h o ur ( ± 0. 5 hr) p ost d ose, a n d Wee k 1 6 at 1 h o ur ( ± 0. 5 hr) p ost d ose will 
be s u m mariz e d usi n g des cri pti ve statistics, a n d t he me dia ns ± I Q R dis pla ye d o ver ti me.    
V V- C LI N- 0 5 4 0 3 1 1 1. 0


St ati sti c al A n al y si s Pl a n   
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
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 2 9  
2. 4. 6  A n al y s e s of q u alit y of lif e/ h e alt h e c o n o mi c s v ari a bl e s   
N ot a p plica ble  
2. 5  
D A T A H A N D LI N G C O N V E N TI O N S   
2. 5. 1  G e n er al c o n v e nti o n s   
T he f oll o wi n g f or m ulas will be use d f or c o m p utati o n of para met ers.  
De m o gr a p hic f or m ul as  
Pri or a n d c o nc o mita nt m e dicati o ns are deri ve d usi n g t he Sa n ofi sta n dar ds.  
2. 5. 2  D at a  h a n dli n g c o n v e nti o n s f or s e c o n d ar y effi c a c y v ari a bl e s   
N ot a p plica ble  
2. 5. 3  Mi s si n g d at a   
F or cate g orical v aria bl es, partici pa nt s wit h missi n g dat a are n ot i ncl u de d i n calc ulati o ns of 
perce nt a ges u nless ot her wise s pecifie d.   W he n rel e va nt, t he n u m ber of partici pa nt s wit h missi n g 
data is prese nte d.  
H a n dli n g of c o m p ut ati o n of tre at m e nt d ur ati o n if i nvesti g ati o n al m e dici n al pr o d uct  e n d of 
tre at m e nt d ate is missi n g  
F or t he calc ulati o n of t he treat me nt d urati o n, t he date of t he last d ose of I M P is e q ual t o t he date 
of last a d mi nistrati o n re p orte d o n t he  e n d-of -treat me nt case re p ort f or m p a ge.   If t his date is 
missi n g, t he e x p os ure d urati o n s h o ul d be left as missi n g.  
T he last d ose i nta ke s h o ul d be clearl y i de ntifie d i n t he case re p ort f or m  a n d s h o ul d n ot be 
a p pr o xi mate d b y t he last ret ur ne d p ac ka ge date.  
H a n dli n g of m e dic ati o n missi n g/ p arti al d ates  
N o i m p utati o n of me dicati o n start/e n d dates or ti mes will be perf or me d.  
If t he rec or de d me dicati o n e n d date is pri or t o t he st u d y e nr oll me nt dat e f or a partici pa nt , t he 
me dicati o n is cate g orize d as a pri or me di cati o n disc o nti n ue d bef ore st u d y e nr oll me nt.      
If a me dicati o n e n d date has o nl y t he year part a n d it is pri or t o t he year of t he e nr oll me nt date, or 
if t he me dicati o n e n d dat e has o nl y m o nt h a n d year a n d b ot h are pri or t o t he m o nt h a n d year of t h e 
e nr oll me nt date, t he n t he me dicati o n is cate g orize d as a pri or me dicati o n disc o nti n ue d bef ore 
st u d y e nr oll me nt. 
Ot her wise, t he me di cati o n is cate g orize d as a c o nc o mita nt me dicati o n.  
V V- C LI N- 0 5 4 0 3 1 1 1. 0


St ati sti c al A n al y si s Pl a n   
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
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 3 0  
H a n dli n g of a dverse eve nts w he n d ate a n d ti m e of first i nvesti g ati o n al me dici n al pr o d uct 
a d mi nistr ati o n  is missi n g 
W he n t he date a n d ti me of t he first I M P a d mi nistrati o n is missi n g, all a d verse e ve nts t hat occ urre d 
o n or after t h e da y of ra n d o mizati o n s h o ul d be c o nsi dere d as tr eat me nt -e m er ge nt a d verse e ve nts.  
T he e x p os ure d urati o n s h o ul d be ke pt as missi n g. 
H a n dli n g of missi n g assess m e nt of rel ati o ns hi p of a dverse eve nts t o i nvesti g ati o n al m e dici n al 
pr o d uct  
If t he assess me nt of t he relati o ns hi p t o I M P is missi n g, t he n t he relati o ns hi p t o I M P has t o be 
ass u me d a n d t he a d v erse e ve nt c o nsi dere d as s uc h i n t he fre q ue n c y ta bles of p ossi bl y relate d 
a d verse e ve nts, b ut n o i m p utati o n s h o ul d be d o ne at t he data le vel . 
H a n dli n g of missi n g i nte nsity/severity gr a des of a dverse eve nts  
If t he i nte nsit y/se v erit y gra de is missi n g  f or a n a d verse e v e nt, t he a d v erse e ve nt will be c o u nte d as 
‘se vere’. 
H a n dli n g of p ote nti ally cli nic ally si g nific a nt a b n or m alities   
If a partici pa nt  has a missi n g baseli ne h e will be gr o u pe d i n t he cat e g or y “ n or mal / missi n g at 
baseli ne .”  
F or P C S A s wit h 2  c o n diti o ns, o ne base d o n a c ha n ge fr o m baseli ne v al ue or a n or mal ra n ge a n d 
t he ot her o n a t hr es h ol d val ue, wit h  t he first c o n diti o n bei n g missi n g, t he P C S A will be base d o nl y 
o n t he sec o n d c o n diti o n.  
F or a P C S A defi ne d o n a t hres h ol d a n d/ or a n or m al ra n g e, t his P C S A will be deri ve d usi n g t his 
t hres h ol d if t he n or mal ra n ge is missi n g ; e g, f or e osi n o p hils t he P C S A is > 0. 5 GI G A/ L or > U L N 
if U L N ≥0. 5 GI G A/ L.  W he n U L N is missi n g , t he val ue 0. 5 s h o ul d be us e d. 
Meas ure me nts fla g ge d as i n vali d b y t he la b orat or y  will n ot be s u m marize d or ta ke n i nt o acc o u nt 
i n t he c o m p utati o n of P C S A val ues.   
H a n dli n g of missi n g/ p arti al d ates  f or first M S sy m pt o ms or M S di a g n osis 
If a partici pa nt  has a c o m plete date, t he n t hat dat e will be use d f or t he calc ulati o n.  F or a partial  
date,  t he last da y of t h e m o nt h will be i m p ute d f or a missi n g da y, a n d ‘ Dece m ber’ will be i m p ute d 
f or a missi n g m o nt h. 
2. 5. 4  Wi n d o w s f or ti m e p oi nt s   
A sc he d ule d visit will be assi g ne d  t o t he s a me a n al ysis visit e q ui vale nt t o it. Data fr o m earl y 
wit h dra wal a n d u ns c he d ule d visits will be assi g ne d t o a n a p pr o priat e a nal ysis visit b y usi n g t he 
wi n d o wi n g sc h e me  i n t he ta ble bel o w, a n d f oll o wi n g t he Sa n ofi sta n d ar ds.  
V V- C LI N- 0 5 4 0 3 1 1 1. 0


St ati sti c al A n al y si s Pl a n   
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
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 3 1  
If o nl y 1 rec or d is withi n a n a nal ysis visit wi n d o w, t he data fr o m t hat rec or d will be use d i n t he 
s u m mar y statistics a n d b y visit wee k a nal yses.  If m ore t ha n 1 rec or d is wit hi n t he sa me a nal ysis 
visit wi n d o w, t he rec or d fr o m t he re g ularl y sc he d ule d visit will be use d i n t he s u m mar y statistics 
a n d b y visit a nal ys es. If m ore t ha n 1 rec or d is fr o m a re g ularl y sc h e d ule d visit, or m ore t ha n 1 
rec or d is fr o m u nsc he d ul e d visits wit hi n t he sa me a nal ysis visit wi n d o w, t h e rec or d fr o m t he visit 
nearest t o t he tar get da y will be use d i n t he s u m mar y statistics a n d b y visit a nal ys es . If 2 visits 
ha ve t he sa me dista n ce fr o m t he tar get da y , t he lat er rec or d will be use d i n t he s u m mar y statistics 
a n d b y visit a nal ys es.  If t he sc he d ule d visit d oes n ot ha ve a n y rec or d b ut t he wi n d o we d 
u nsc he d ule d visit is i n a n a nal ysis visit wi n d o w, d ata fr o m t he u nsc h e d ule d visit will be use d f or 
t he s u m mar y statistics a n d b y visit a nal yses. 
 
V V- C LI N- 0 5 4 0 3 1 1 1. 0


St ati sti c al A n al y si s Pl a n   
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
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 3 2  
 
T a bl e  1  –  A n al y si s Vi sit Wi n d o w s   
A n al ysis Visit  
(A VI SI T C ) 
A n al ysis Visit 
N u m ber 
(A VI SI T N ) 
T ar get  
D a y  
 
 
P ar a meters a n d I nter v als  
 
 
 
 
 
V S,  P E, E C G, 
Uri n al ysis, S uici d alit y 
assess me nt ( C -S S R S)  
β -H C G test  
He m at ol o g y, bi oc he mistr y  
E D S S  
M RI  
Scr e e ni n g  
‐ 9 9 
-1  
[‐ 2 8, -1]  
[‐ 2 8, -1]  
[‐ 2 8, -1]  
[‐ 2 8, -1]  
[‐ 2 8, -1]  
B as eli n e/ D a y 1  
0  
1  
[ 1, 1] 
[ 1, 1] 
[ 1, 1] 
[ 1, 1] 
 
Wee k 1  
1  
7  
 
 
 
 
 
Wee k 2  
2  
1 4  
 
 
[ 2, 2 1] 
 
 
Wee k 3  
3  
2 1  
 
 
 
 
 
Wee k 4  
4  
2 8  
[ 2, 4 2] 
[ 2, 4 2] 
[ 2 2, 3 5] 
 
[ 1, 4 2] 
Wee k 5  
5  
3 5  
 
 
 
 
 
Wee k 6  
6  
4 2  
 
 
[ 3 6, 4 9] 
 
 
Wee k 7  
7  
4 9  
 
 
 
 
 
Wee k 8  
8  
5 6  
[ 4 3, 7 0] 
[ 4 3, 7 0] 
[ 5 0, 7 0] 
 
[ 4 3, 7 0] 
Wee k 9  
9  
6 3  
 
 
 
 
 
Wee k 1 0  
1 0  
7 0  
 
 
 
 
 
Wee k 1 1  
1 1  
7 7  
 
 
 
 
 
Wee k 1 2  
1 2  
8 4  
[ 7 1, 9 8] 
[ 7 1, 9 8] 
[ 7 1, 9 8] 
[ 2, 9 9 9 9 9] 
[ 7 1, 9 8] 
Wee k 1 3  
1 3  
9 1  
 
 
 
 
 
Wee k 1 4  
1 4  
9 8  
 
 
 
 
 
Wee k 1 5  
1 5  
1 0 5  
 
 
 
 
 
Wee k 1 6  
1 6  
1 1 2  
[ 9 9, 1 1 9] 
[ 9 9, 9 9 9 9 9 9] 
[ 9 9, 1 1 9] 
 
[ 9 9, 9 9 9 9 9 9] 
Wee k 1 7  
1 7  
1 1 9  
 
 
 
 
 
Wee k 1 8 -2 0  
1 8  
1 2 6  
[ 1 2 0, 9 9 9 9 9 9] 
 
[ 1 2 0, 9 9 9 9 9 9] 
 
 
 
V V- C LI N- 0 5 4 0 3 1 1 1. 0


St ati sti c al A n al y si s Pl a n   
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
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 3 3  
2. 5. 5  U n s c h e d ul e d vi sit s   
U nsc he d ule d visit meas ure me nts of la b orat or y dat a, vital si g ns, a n d E C G will n ot be i ncl u de d i n 
t he b y-visit s u m maries , b ut will be  use d f or c o m p utati o n of baseli ne, a n d P C S As . 
2. 5. 6  P o oli n g of c e nt er s f or st ati sti c al a n al y s e s   
N o p o oli n g of ce nters, e g, re gi o nal p o oli n g, is pla n ne d.  
2. 5. 7  St ati sti c al t e c h ni c al i s s u e s   
N ot a p plica ble . 
V V- C LI N- 0 5 4 0 3 1 1 1. 0


St ati sti c al A n al y si s Pl a n   
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
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 3 4  
V V- C LI N- 0 5 4 0 3 1 1 1. 0


St ati sti c al A n al y si s Pl a n   
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
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 3 5  
4  
D A T A B A S E L O C K   
T he data bas e is pla n ne d t o be l oc ke d i n J a n uar y 2 0 2 0. 
V V- C LI N- 0 5 4 0 3 1 1 1. 0


St ati sti c al A n al y si s Pl a n   
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
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 3 6  
5  
S O F T W A R E D O C U M E N T A TI O N   
All s u m maries a n d stat istical a nal yses will be ge nerate d usi n g S A S versi o n 9. 0 or hi g h er. 
 
 
 
 
V V- C LI N- 0 5 4 0 3 1 1 1. 0


St ati sti c al A n al y si s Pl a n   
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
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 3 7  
6  
R E F E R E N C E S   
 
1 . B or n ka m p B, Pi n heir o J, Bretz F. Pac ka ge ' D ose Fi n di n g', J a n uar y 4, 2 0 1 8.  
 
V V- C LI N- 0 5 4 0 3 1 1 1. 0


St ati sti c al A n al y si s Pl a n   
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
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 3 8  
7  
LI S T O F A P P E N DI C E S   
A p pe n di x A : 
P ote ntiall y cli nicall y si g nifica nt a b n or malities ( P C S A) criteria  
A p pe n di x B : 
M RI para meters  
A p pe n di x C : 
A nal ysis pr o gra m mi n g c o de  n otes  
V V- C LI N- 0 5 4 0 3 1 1 1. 0


St ati sti c al A n al y si s Pl a n   
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
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 3 9  
A P P E N DI X A P O T E N TI A L L Y C LI NI C A L L Y SI G NI FI C A N T A B N O R M A LI TI E S  ( P C S A) 
C RI T E RI A ( S A N O FI V E R SI O N 2 0 1 4)   
 
P ar a m et er  
P C S A  
Cli ni c al C h e mi stry  
A L T  (Ala ni n e A mi n otra nsferas e)  
> 3 U L N  
 
A S T  (As partate A mi n otra nsfer ase)  > 3 U L N  
 
Alk ali n e P h os p h at as e  
> 1. 5 U L N  
T BI LI ( T ot al Bilir u bi n ) 
> 1. 5 U L N  
 
Dir ect B ilir u bi n a n d T ot al Bilir u bi n  
Dir ect bilir u bi n > 3 5 % T ot al Bilir u bi n a n d T ot al 
Bilir u bi n > 1. 5 U L N  
A L T a n d T ot al Bilir u bi n  
AL T > 3 U L N a n d T BI LI > 2 U L N  
C K ( Cr e ati n e ki n as e)  
> 3 U L N  
 
C P K  
> 3 U L N  
> 1 0 U L N  
Cr e ati ni n e  
≥1 5 0 μ m ol/ L ( Ad ults)  
≥3 0 % c h a n g e fr o m b as eli n e  
 
B U N ( Bl o o d Ur e a Nitr o g e n ) 
≥1 7 m m ol/ L  
S o di u m  
≤1 2 9 m m ol/ L  
≥1 6 0 m m ol/ L  
P ot assi u m  
< 3 m m ol/ L  
≥5. 5 m m ol/ L  
Li p as e  
Li p as e mi a  
≥3 U L N  
A myl as e  
A myl as e mi a  
≥3 U L N  
Gl uc os e  
Hy p o glyc a e mi a  
Hy p er glyc a e mi a  
 
≤3. 9 m m ol/ L a n d < L L N  
≥1 1. 1 m m ol/ L ( u nf ast e d); ≥7 m mol/ L (f ast e d)  
C R P  
> 2 U L N or > 1 0 m g/ L (if U L N n ot pr ovi d e d)  
V V- C LI N- 0 5 4 0 3 1 1 1. 0


St ati sti c al A n al y si s Pl a n   
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
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 4 0  
P ar a m et er  
P C S A  
H e m at ol o g y  
L e uk ocyt e c o u nt ( W B C ) 
< 3. 0 * 1 0 ^ 9 / L ( N o n-Bl ack); < 2. 0  * 1 0 ^ 9 / L ( Bl ack) 
≥1 6. 0  * 1 0 ^ 9 / L 
Ly m p h ocyt es  
> 4. 0  * 1 0 ^ 9 / L 
N e utr o p hils  
< 1. 5  * 1 0 ^ 9 / L ( N o n-Bl ack); < 1. 0  * 1 0 ^ 9 / L ( Bl ack) 
M o n ocyt es  
> 0. 7 * 1 0 ^ 9 / L 
B as o p hils  
> 0. 1  * 1 0 ^ 9 / L 
E osi n o p hils  
> 0. 5  * 1 0 ^ 9 / L or > U L N (if U L N ≥0. 5  * 1 0 ^ 9 / L) 
H e m o gl o bi n  
≤1 1 5 g/ L ( M al e); ≤9 5 g/ L ( F e m ale)  
≥1 8 5 g/ L ( M al e); ≥1 6 5 g/ L ( F e m al e) 
D ecr e as e fr o m B as eli n e ≥2 0 g/ L  
H e m at ocrit  
≤0. 3 7 v/v ( M al e)  ; ≤0. 3 2 v/v ( F e mal e) 
≥0. 5 5 v/v ( M al e)  ; ≥0. 5 v/v ( F e m al e)  
Eryt hr ocyt e c o u nt ( R B C ) 
≥6  * 1 0 ^ 1 2 / L 
Pl at el et  c o u nt 
< 1 0 0  * 1 0 ^ 9 / L 
≥7 0 0  * 1 0 ^ 9 / L 
Uri n al y si s  
p H  
≤4. 6  
≥8  
Vit al si g n s  
S B P  
≤9 5 m m H g a n d d ecr e as e fr o m b as eli n e 
≥2 0 m m H g  
≥1 6 0 m m H g a n d i ncr e as e fr o m b as eli n e ≥2 0 
m m H g  
D B P  
≤4 5 m m H g a n d d ecr e as e fr o m b as eli n e ≥1 0 
m m H g  
≥1 1 0 m m H g a n d i ncr e as e fr o m b as eli n e ≥1 0 
m m H g  
W ei g ht  
≥5 % i ncr e as e fr o m b as eli n e  
≥5 % d ecr e as e fr o m b as eli n e  
 
V V- C LI N- 0 5 4 0 3 1 1 1. 0


St ati sti c al A n al y si s Pl a n   
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
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 4 1  
E C G  
H R  
< 5 0 b p m  
< 5 0 b p m a n d d ecr e as e fr o m b as eli n e ≥2 0 b p m  
< 4 0 b p m  
< 4 0 b p m a n d d ecr e as e fr o m b as eli n e ≥2 0 b p m  
< 3 0 b p m  
< 3 0 b p m a n d d ecr e as e fr o m b as eli n e ≥2 0 b p m  
 
> 9 0 b p m  
> 9 0 b p m a n d i ncr e as e fr o m b as eli n e ≥2 0 b p m  
> 1 0 0 b p m  
> 1 0 0 b p m a n d i ncr e as e fr o m b as eli n e ≥2 0 b p m  
> 1 2 0 b p m  
> 1 2 0 b p m a n d i ncr e as e fr o m b as eli n e ≥2 0 b p m  
P R  
> 2 0 0 ms  
> 2 0 0 ms a n d i ncr e as e fr o m b as eli n e ≥2 5 %  
> 2 2 0 ms  
> 2 2 0 ms a n d i ncr e as e fr o m b as eli n e ≥2 5 %  
> 2 4 0 ms  
> 2 4 0 ms a n d i ncr e as e fr o m b as eli n e ≥2 5 %  
Q R S  
> 1 1 0 ms  
> 1 1 0 ms ec a n d i ncr e as e fr o m b as eli n e ≥2 5 %  
> 1 2 0 ms  
> 1 2 0 ms a n d i ncr e as e fr o m b as eli n e ≥2 5 %  
Q T  
> 5 0 0 ms  
Q Tc B az ett  
Q Tc Fri d erici a  
> 4 5 0 ms ec  
> 4 8 0 ms ec  
> 5 0 0 ms ec  
I ncr e as e fr o m b as eli n e [ 3 0 -6 0] ms ec  
I ncr e as e fr o m bs eli n e > 6 0 ms ec 
V V- C LI N- 0 5 4 0 3 1 1 1. 0


St a ti sti c al A n al y si s Pl a n  
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
V er si o n n u m b er: 1  
 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al  
P a g e 4 2  
A P P E N DI X B M RI P A R A M E T E R S   
T a bl e  2  –  M RI p ar a m et er s   
 
M RI  
m e a s ur e m e
nt  
T e st 
n a m e  
T e st  c o d e  
S cr e e ni n
g  
W e e k 
4  
W e e k 
8  
W e e k 
1 2  
W e e k 
1 6  
W e e k 
E T  
 
 
 
 
 
 
 
 
 
s ec o n d ary 
e n d p oi nt –  
n u m b er of G d -
e n h a nci n g T 1 -
hy p eri nt e ns e 
l esi o ns at t h e 
e n d of 1 2 
w e eks of 
S A R 4 4 2 1 6 8 
tr e at m e nt 
G a d oli ni u m  
e n h a nci n g 
l esi o n c o u nt 
G D C O U N T  
X  
X  
X  
X  
X  
X  
pri m ary 
e n d p oi nt –  
n u m b er of n e w 
G d -e n h a nci n g 
T 1 -
hy p eri nt e ns e 
l esi o ns at t h e 
e n d of 1 2 
w e eks of 
S A R 4 4 2 1 6 8 
tr e at m e nt 
N e w G a d 
e n h a nci n g 
l esi o n c o u nt 
N E W G D C N T  
 
X  
( pr evi o u
s) 
X  
( pr evi o u
s) 
X  
( pr evi o u
s) 
X  
( pr evi o us) 
X  
( pr evi o us) 
 
 
s ec o n d ary 
e n d p oi nt –  
n u m b er of n e w 
or e nl ar gi n g T 2 
l esi o ns at t h e 
e n d of 1 2 
w e eks of 
S A R 4 4 2 1 6 8 
tr e at m e nt 
N e w /e nl ar gi
n g T 2 l esi o n 
c o u nt 
N E W T 2 C N T  
 
X  
( pr evi o u
s) 
X  
( pr evi o u
s) 
X  
( pr evi o u
s) 
X  
( pr evi o us) 
X  
( pr evi o us) 
V V- C LI N- 0 5 4 0 3 1 1 1. 0


St a ti sti c al A n al y si s Pl a n  
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
V er si o n n u m b er: 1  
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al  
P a g e 4 3  
V V- C LI N- 0 5 4 0 3 1 1 1. 0


St a ti sti c al A n al y si s Pl a n  
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
V er si o n n u m b er: 1  
 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al  
P a g e 4 4  
A P P E N DI X C A N A L Y SI S P R O G R A M MI N G C O D E N O T E S   
B T K S A P: pri mar y a n al ysis usi n g M C P -m o d  
T he pri mar y e n d p oi nt, t h e d ose -res po nse relati o n of t he fi ve d oses, will be assesse d usi n g t he 
m ulti ple c o m paris o n pr oce d ure wit h m o delli n g tec h ni q ues ( M C P -m o d). T his a p pr oac h c o nsists of 
t w o ke y st e ps. Ste p 1 is t he i nfere ntial part of t he m o del t hat tests f or a n efficac y si g nal ( a n o n-fl at 
d ose -res p o ns e c ur ve) i n a pr oce d ure c o ntr olli n g f or t y pe 1 err or. T he pr oce d ure re q uir es a set of 
d ose -res p o ns e c ur ves t o be pre-d efi ne d; t he c h ose n pr ofiles are select e d t o c o ver b ot h pla usi ble 
a n d di verse d os e -res p o nse pr ofiles, r eflecti n g t he ra n ge of ca n di date m o dels belie ve d t o be 
ca pa ble of descri bi n g t he d ose -res p o ns e relati o n. Ste p 2 is t he esti mati o n part of t he m o del t hat 
will be d o ne o nl y if Ste p 1 s h o ws a n effi cac y si g n al. I n t his ste p, t he best -fitti n g d ose-res p o nse 
c ur ve is esti mate d. I n t his st u d y, a ne gati ve bi n o mial re gressi o n m o del will be use d t o assess t he 
mea n T 1 lesi o n c o u nt i n eac h d ose gr o u p a n d t he r u n -i n place b o. T h e n a mi n us l o g tra nsf or mati o n 
of t he mea n lesi o n c o u nt will be e ntere d i nt o t he M C P -m o d pr ocess. I n t he first ste p, 6  d ose 
res p o nse c ur ves will be c o nsi dere d, w hic h c o ver t he pla usi ble s ha pes of i nt erest (see pl ot 1). 
W he n data  are a vaila ble, t he n ull h y p ot hesis of a flat  d ose -res p o ns e rel ati o n (i.e., n o d ose 
res p o nse) at 3 m o nt hs f or t he pri mar y e n d p oi nt ( t h e mea n T 1 lesi o ns c o u nt i n differe nt d ose 
gr o u ps vs  t he r u n-i n c o ntr ol) will be j oi ntl y teste d f or eac h of t he ca n di date d ose-res p o ns e m o dels 
wit h a c o ntrast test t hat c o ntr olle d f or t he fa mil y wise  at t w o-si de d al p ha = 0. 0 5. If s uc h test res ults 
i n si g nifica n ce, t he b est-fitte d m o del will be selecte d.  Fr o m t he selecte d m o del, t he d oses of 
i nterest ca n b e esti mate d.  
 
 
V V- C LI N- 0 5 4 0 3 1 1 1. 0


St a ti sti c al A n al y si s Pl a n  
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
V er si o n n u m b er: 1  
 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al  
P a g e 4 5  
 
 
Si x pre -defi ne d d os e res p o nse c ur ves : 
• 
T w o E ma x m o dels ( E D 5 0 = 1 0 m g, E D 5 0 = 3 0 m g)  
• 
Li ne ar m o del  
• 
Q ua dratic m o del ( ma x effect at 4 0 -4 5 m g)  
• 
L o gistic m o del (fl at t o 1 0 m g a n d ma x at 5 0 m g) 
• 
E x p o ne ntial m o del (sl o w effect t o 3 0 m g)  
 
T o acc o u nt f or t he p ote ntial c orrel ati o n f or c o h ort 2 bet wee n t he m eas ure me nts i n t he r u n -i n 
peri o d a n d t he treat me nt peri o d, a ge n eralize d esti mati n g e q u ati o n a p pr oac h ( G E E) is use d t o fit 
t he m o del acc o u nti n g f or t he wit h-s u bject c orrelati o n.   We will pre pare dat a acc or di n g t o t he 
f oll o wi n g str uct ur e : 
 
V V- C LI N- 0 5 4 0 3 1 1 1. 0


St a ti sti c al A n al y si s Pl a n  
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
V er si o n n u m b er: 1  
 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al  
P a g e 4 6  
 
 
Here “ Y” d e n otes t he ne w T 1 le si o n c o u nts, “c o h ort = 1” mea ns t h e c o h ort wit h o ut place b o r u n-i n 
a n d c o h ort = 2 ” mea ns t he c o h ort wit h place b o r u n -i n, “trt” is t he d ose vari a ble wit h 0 de n oti n g t he 
r u n-i n place b o, 1 t o 5 d e n ote t he act ual d ose gr o u ps. Bli ne is s o me baseli n e varia bles (i.e. lesi o n 
c o u nt at baseli ne) t h at we ma y n ee d t o a dj ust f or.     
 
T he f oll o wi n g is t he s a m ple S A S c o de f or fitti n g t he G E E m o del is  
 
o d s  o u t p u t  G E E E m p P E s t = t e s t  G E E R C o r r = c o r r ;  
p r o c  g e n m o d  d a t a = t h a l l 0 ;  
c l a s s  i d  t r t ( p a r a m = r e f  r e f = f i r s t ) ;  
m o d e l  y = t r t  b l i n e    C O H O R T    / d i s t = n e g b i n ;  
r e p e a t e d  s u b j e c t = i d  / t y p e = i n d  c o r r b ;  
r u n ;  
 
S u p p ose 𝜇𝐴= (𝑎0 ,𝑎1 ,… ,𝑎5 ) be t he c oefficie nts of t he i nterce pt a n d “trt” wit h varia nce 𝑉. T he 
d ose -s pecifi c l o g-ris k will be 𝜇𝐵= (𝑏0 ,𝑏1 ,… ,𝑏5 ), w here 𝑏0 = 𝑎0 ,𝑏𝑗= 𝑎0 + 𝑎𝑗,𝑗= 1 ,… ,5 . 
Usi n g t he matri x e x pressi o n, 𝜇𝐵= 𝐺𝜇𝐴. T he varia n ce of  𝜇𝐵 will be  𝑊
= 𝐺𝑉𝐺T .  
 
T he para meter 𝜇𝐵= (𝑏0 ,𝑏1 ,… ,𝑏5 ) a n d 𝑊 will be e ntere d i nt o t he M C P -m o d a nal ysis i n R usi n g 
t he pac ka ge “ D os e Fi n di n g”, t h e sa m ple c o d es are  
V V- C LI N- 0 5 4 0 3 1 1 1. 0


St a ti sti c al A n al y si s Pl a n  
2 5 -O ct -2 0 1 9  
S A R 4 4 2 1 6 8 -D RI 1 5 9 2 8  -   
V er si o n n u m b er: 1  
 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al  
P a g e 4 7  
 
# # # I nstall a n d l o a d t he p ac ka ge i n R  
i nstall. pac ka ges(" D os e Fi n di n g") 
li brar y( D ose Fi n di n g) 
 
# # # E nter (i n p ut) 𝜇𝐴 a n d 𝑎 
m u B = m u B S A S  
W = W S A S  
 
# # # E nter t he 5 d oses  
d oses < - c( 0, 2. 5, 7. 5, 1 5, 3 0, 6 0)  
 
# # # E nter t he para meters f or t he si x d ose res p o nse c ur ves  
f m o dels <-M o ds(e m a x =c( 1 0, 3 0), q ua dratic = -0. 7/ 6 0,li near = N U L L,  
               l o gistic = c( 2 5, 5),e x p o ne ntial =c( 1 5), d oses = d oses, plac Eff = -l o g(1. 0 ), ma x Eff = -
l o g(0. 1 )) 
pl ot(f m o dels, yla b =" -l o g( mea n lesi o n c o u nt)", xla b =" D os e") # T his will re -pr o d uce Fi g ure 1.   
 
# # # Calc ulate t he o pti mal c o ntrast matri x  
c o nt Mat <- o p t C o ntr(f m o dels, S = W ) 
 
# # # D oi n g M C P M o d m o deli n g a n d us e AI C criteria t o fi n d t he best m o del, fr o m w hic h t he d ose 
le vel wit h # # # t he ris k re d ucti o n at least 9 0 % fr o m c o ntr ol is calc ulate d.  
M C P M o d( d oses, m u B, S = W, m o dels =f m o dels, t y pe =” ge neral”, crit V = T R U E,  sel M o del =” AI C”, 
al p ha = 0. 0 5, alter nati ve =”t w o.si de d”,  d ose T y pe =" T D", Delta = -l o g( 0. 1)). 
 
V V- C LI N- 0 5 4 0 3 1 1 1. 0


Si g nat ure Pa ge f or V V- C LI N- 0 5 4 0 3 1 1 v 1. 0
dri 1 5 9 2 8- 1 6- 1- 9-sa p
A p pr o ve & e Si g n
A p pr o ve & e Si g n
V V- C LI N- 0 5 4 0 3 1 1 1. 0