Clinical trial NCT04410978
Conditions: Relapsing Multiple Sclerosis
Sponsor: Sanofi
Start date: 2020-06-30; Completion date: 2024-07-15
Enrollment: 974 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objective:

To assess efficacy of daily SAR442168 compared to a daily dose of 14 mg teriflunomide (Aubagio) measured by annualized adjudicated relapse rate (ARR) in participants with relapsing forms of MS

Secondary Objective:

To assess efficacy of SAR442168 compared to teriflunomide (Aubagio) on disability progression, MRI lesions, cognitive performance and quality of life To evaluate the safety and tolerability of daily SAR442168 To evaluate population pharmacokinetics (PK) of SAR442168 and relevant metabolites and its relationship to efficacy and safety To evaluate pharmacodynamics (PD) of SAR442168

Detailed description:
This was an event-driven (6-month confirmed disability worsening \[CDW\]) trial with a variable treatment duration (end-of-study \[EOS\] duration: up to approximately 48 months).

Arms: arm 1: 60 mg oral SAR442168 + placebo to match the teriflunomide tablet once daily arm 2: 14 mg oral teriflunomide + placebo to match the SAR442168 tablet once daily
Interventions: intervention 1: Tolebrutinib intervention 2: Teriflunomide intervention 3: Placebo to match Tolebrutinib intervention 4: Placebo to match Teriflunomide
Intervention descriptions: intervention 1: Pharmaceutical form: Tablet

Route of administration: Oral intervention 2: Pharmaceutical form: Tablet

Route of administration: Oral intervention 3: Pharmaceutical form: Tablet

Route of administration: Oral intervention 4: Pharmaceutical form: Tablet

Route of administration: Oral

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° 3.0 (19-FEB-2019) based on TransCelerate CPT version 5 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 10             
Protocol title: 
A Phase 3, randomized, double-blind efficacy and 
safety study comparing SAR442168 to teriflunomide 
(Aubagio®) in participants with relapsing forms of 
multiple sclerosis (GEMINI 1) 
Protocol number: 
EFC16033 
Amendment number: 
10 
Compound number 
(INN/Trademark): 
SAR442168 
(Tolebrutinib/not applicable) 
Study phase: 
Phase 3 
Short title: 
RMS study of BTK inhibitor tolebrutinib (SAR442168) 
(GEMINI 1) 
Sponsor name: 
Genzyme Corporation* 
*Sanofi corporation organized and existing under the 
laws of France is the ultimate parent of a worldwide 
group of affiliates including Sanofi US Services Inc., 
Sanofi Genzyme, and Genzyme Corporation 
Legal registered 
address: 
450 Water Street, Cambridge, MA, 02141, USA 
Monitoring Team’s 
Representative Name 
and Contact Information 
 
Regulatory agency identifier number(s): 
IND: 
140884 
EudraCT: 
2020-000637-41 
NCT: 
NCT04410978 
WHO: 
U1111-1238-1418 
Other: 
Not applicable 
 
 
Approval Date: 
20-Dec-2023 
Total number of pages: 136 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY 
 
Document 
Country/countries impacted 
by amendment 
Date, version 
Amended Clinical Trial Protocol 10 
All 
20 December 2023, version 1 (electronic 13.0) 
Amended Clinical Trial Protocol 09 
All 
17 November 2023, version 1 (electronic 12.0) 
Amended Clinical Trial Protocol 08 
All 
12 December 2022, version 1 (electronic 11.0) 
Amended Clinical Trial Protocol 07 
All 
13 September 2022, version 1 (electronic 10.0) 
Amended Clinical Trial Protocol 06 
All 
24 May 2022, version 1 (electronic 9.0) 
Amended Clinical Trial Protocol 05 
All 
18 November 2021, version 1 (electronic 8.0) 
Amended Clinical Trial Protocol 04 
All 
14 April 2021, version 1 (electronic 6.0) 
Amended Clinical Trial Protocol 03 
All 
28 September 2020, version 1 (electronic 5.0) 
Amended Clinical Trial Protocol 02 
Austria, Czech Republic, 
Denmark, Finland, Italy, 
Lithuania, Poland, Spain, 
Sweden 
24 August 2020, version 1 (electronic 4.0) 
Amended Clinical Trial Protocol 01 
All 
07 May 2020, version 1 (electronic 1.0) 
Original Protocol 
 
28 February 2020, version 1 (electronic 1.0) 
Amended protocol 10 (20 December 2023) 
This amended protocol (amendment 10) is considered to be non-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 
The rationale for this protocol amendment is to include liver function test monitoring guidance 
previously in the study manual and update the co-medication guidance as per Health Authority 
request.  
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Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of activities (SoA) 
Week 3 added in the visit header and in footnote ‘l’. 
Update. 
10.6 Appendix 6: Liver and other 
safety: actions and follow-up 
assessments 
Liver function test monitoring guidance provided. 
Update. 
10.8 Appendix 8A: Examples of drugs 
with a potential to change SAR442168 
metabolism 
Removed the reference to 
www.druginteractioninfo.org. 
Only keeping the 
recommendation for the sites 
to refer to the drug label for 
metabolic interactions. 
 
Removed ‘modafinil’ from the list of moderate 
CYP3A inducers. 
Correction of error as, 
according to the label, 
modafinil is a weak CYP3A 
inducer, and therefore not 
prohibited. 
 
Removed ‘deferasirox’ from the list of potent 
CYP2C8 inhibitors. Table 7: removed ‘rifabutin’ from 
the list of potent CYP3A inducers. Table 8: moved 
‘rifabutin’ from the list of potent CYP3A inducers to 
the list of moderate CYP3A inducers. 
Correction of error as per 
updated guidance for CYP 
inhibitors/inducers based on 
information from DDI study. 
 
Updated to provide guidance to the US. 
Update to provide guidance. 
10.11.5 Country-specific provisions for 
the US  
New section added to reflect the prohibited use of 
CYP3A and CYP2C8 inhibitors and the restriction of 
grapefruit/grapefruit juice (a CYP3A4 inhibitor). 
Update. 
10.14 Appendix 12: Protocol 
amendment history 
Updated. 
Update. 
Throughout the document 
Reformatted existing content when necessary. 
Minor, editorial, stylistic changes as necessary. 
Updated table of contents, section numbers, 
abbreviations as necessary. 
Update in accordance with 
Sponsor’s standards. 
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TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 10 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 4 
LIST OF TABLES ........................................................................................................................................... 9 
LIST OF FIGURES .......................................................................................................................................... 9 
1 
PROTOCOL SUMMARY ............................................................................................................... 10 
1.1 
SYNOPSIS ..................................................................................................................................... 10 
1.2 
SCHEMA ........................................................................................................................................ 17 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 18 
2 
INTRODUCTION ............................................................................................................................ 27 
2.1 
STUDY RATIONALE...................................................................................................................... 27 
2.2 
BACKGROUND ............................................................................................................................. 28 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 29 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 34 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 36 
4 
STUDY DESIGN ............................................................................................................................ 37 
4.1 
OVERALL DESIGN ........................................................................................................................ 37 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 37 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 38 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 39 
5 
STUDY POPULATION .................................................................................................................. 40 
5.1 
INCLUSION CRITERIA .................................................................................................................. 40 
5.2 
EXCLUSION CRITERIA ................................................................................................................ 42 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 47 
5.3.1 
Meals and dietary restrictions ........................................................................................................ 47 
5.3.2 
Caffeine, alcohol, and tobacco ....................................................................................................... 47 
5.3.3 
Activity ............................................................................................................................................ 47 
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5.4 
SCREEN FAILURES...................................................................................................................... 47 
5.5 
CRITERIA FOR TEMPORARILY DELAYING ADMINISTRATION OF STUDY 
INTERVENTION ............................................................................................................................ 48 
6 
STUDY INTERVENTION ............................................................................................................... 49 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 49 
6.1.1 
Noninvestigational medicinal product ............................................................................................ 49 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 50 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 50 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 52 
6.5 
CONCOMITANT THERAPY .......................................................................................................... 53 
6.5.1 
Rescue medicine ............................................................................................................................ 55 
6.6 
DOSE MODIFICATION .................................................................................................................. 55 
6.7 
INTERVENTION AFTER THE END OF THE STUDY ................................................................... 55 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 56 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 56 
7.1.1 
Definitive discontinuation ............................................................................................................... 56 
7.1.2 
Temporary discontinuation ............................................................................................................. 57 
7.1.2.1 
Rechallenge ................................................................................................................................... 58 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 58 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 59 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 60 
8.1 
EFFICACY ASSESSMENTS ......................................................................................................... 60 
8.1.1 
Expanded disability status scale .................................................................................................... 61 
8.1.1.1 
Confirmed disability worsening ...................................................................................................... 61 
8.1.1.2 
Confirmed disability improvement .................................................................................................. 62 
8.1.2 
Multiple sclerosis relapse assessment ........................................................................................... 62 
8.1.2.1 
Definition of multiple sclerosis relapse ........................................................................................... 62 
8.1.2.2 
Unscheduled assessment visits ..................................................................................................... 62 
8.1.3 
Magnetic resonance imaging ......................................................................................................... 63 
8.1.4 
Timed 25-foot walk test .................................................................................................................. 64 
8.1.5 
9-hole peg test ............................................................................................................................... 64 
8.1.6 
Cognitive tests ................................................................................................................................ 64 
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8.1.7 
Composite analyses ....................................................................................................................... 65 
8.1.7.1 
Modified multiple sclerosis functional composite-3 ........................................................................ 65 
8.1.7.2 
Assessment of no evidence of disease activity ............................................................................. 65 
8.1.8 
Clinical outcome assessment and health-related quality-of-life parameters ................................. 65 
8.2 
SAFETY ASSESSMENTS ............................................................................................................. 66 
8.2.1 
Physical examinations ................................................................................................................... 66 
8.2.2 
Vital signs ....................................................................................................................................... 66 
8.2.3 
Electrocardiograms ........................................................................................................................ 67 
8.2.4 
Clinical safety laboratory assessments .......................................................................................... 67 
8.2.5 
Suicidal ideation and behavior risk monitoring .............................................................................. 67 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........................................................... 68 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 69 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 69 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 69 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 70 
8.3.5 
Pregnancy ...................................................................................................................................... 70 
8.3.6 
Cardiovascular and death events .................................................................................................. 71 
8.3.7 
Multiple sclerosis relapse reporting ................................................................................................ 71 
8.3.8 
Magnetic resonance imaging ......................................................................................................... 71 
8.3.9 
Guidelines for reporting product complaints .................................................................................. 71 
8.4 
TREATMENT OF OVERDOSE ...................................................................................................... 72 
8.5 
PHARMACOKINETICS .................................................................................................................. 72 
8.6 
PHARMACODYNAMICS ............................................................................................................... 72 
8.7 
GENETICS ..................................................................................................................................... 73 
8.8 
BIOMARKERS ............................................................................................................................... 73 
8.9 
MEDICAL RESOURCE UTILIZATION AND HEALTH ECONOMICS ........................................... 73 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 74 
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 74 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................. 74 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 75 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 75 
9.4.1 
General consideration .................................................................................................................... 76 
9.4.2 
Primary endpoint(s) ........................................................................................................................ 76 
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9.4.3 
Secondary endpoint(s) ................................................................................................................... 77 
9.4.4 
Tertiary/exploratory endpoint(s) ..................................................................................................... 78 
9.4.5 
Other safety analyses .................................................................................................................... 78 
9.4.6 
Other analyses ............................................................................................................................... 79 
9.5 
INTERIM ANALYSES .................................................................................................................... 79 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 80 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 80 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 80 
10.1.2 
Financial disclosure........................................................................................................................ 80 
10.1.3 
Informed consent process .............................................................................................................. 81 
10.1.4 
Data protection ............................................................................................................................... 81 
10.1.5 
Committees structure ..................................................................................................................... 82 
10.1.5.1 Independent Data Monitoring Committee ...................................................................................... 82 
10.1.5.2 Scientific Advisory Committee ....................................................................................................... 82 
10.1.5.3 Relapse Adjudication Committee: .................................................................................................. 83 
10.1.5.4 Independent Hepatology Assessment Committee ......................................................................... 83 
10.1.6 
Dissemination of clinical study data ............................................................................................... 83 
10.1.7 
Data quality assurance .................................................................................................................. 84 
10.1.8 
Source documents ......................................................................................................................... 84 
10.1.9 
Study and site closure .................................................................................................................... 85 
10.1.10 Publication policy ........................................................................................................................... 85 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 86 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ................................................ 87 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION .............................................................................................................................. 92 
10.5 
APPENDIX 5: GENETICS ............................................................................................................. 95 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: ACTIONS AND FOLLOW-UP 
ASSESSMENTS ............................................................................................................................ 96 
10.7 
APPENDIX 7: MEDICAL DEVICE INCIDENTS: DEFINITION AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING .............................................. 105 
10.8 
APPENDIX 8A: EXAMPLES OF DRUGS WITH A POTENTIAL TO CHANGE SAR442168 
METABOLISM .............................................................................................................................. 105 
10.9 
APPENDIX 8B: EXAMPLES OF DRUGS WITH A POTENTIAL TO CHANGE 
TERIFLUNOMIDE DISPOSITION ............................................................................................... 106 
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10.10 
APPENDIX 8C: EXAMPLES OF DRUGS WHICH CAN BE POTENTIALLY AFFECTED BY 
TERIFLUNOMIDE ........................................................................................................................ 106 
10.11 
APPENDIX 9: COUNTRY-SPECIFIC REQUIREMENTS ............................................................ 107 
10.11.1 Contraception requirements in UK, Germany, and Denmark ...................................................... 107 
10.11.2 Pregnancy tests in Austria, Czech Republic, Denmark, Finland, Germany, Italy, Lithuania, 
Poland, Romania, Spain, and Sweden ........................................................................................ 108 
10.11.3 Additional requirements for Japan ............................................................................................... 108 
10.11.4 Country-specific differences for China ......................................................................................... 110 
10.11.5 Country-specific provisions for the US ......................................................................................... 110 
10.12 
APPENDIX 10: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................. 111 
10.12.1 Informed consent ......................................................................................................................... 111 
10.12.2 Study procedures ......................................................................................................................... 111 
10.12.3 Temporary discontinuation ........................................................................................................... 112 
10.12.4 Statistical analysis ........................................................................................................................ 112 
10.13 
APPENDIX 11: ABBREVIATIONS ............................................................................................... 112 
10.14 
APPENDIX 12: PROTOCOL AMENDMENT HISTORY .............................................................. 114 
10.14.1 Amended protocol 01 (07 May 2020)........................................................................................... 114 
10.14.2 Amended protocol 02 (24 August 2020) ...................................................................................... 117 
10.14.3 Amended protocol 03 (28 September 2020) ................................................................................ 119 
10.14.4 Amended protocol 04 (14 April 2021) .......................................................................................... 121 
10.14.5 Amended protocol 05 (18 November 2021) ................................................................................. 127 
10.14.6 Amended protocol 06 (24 May 2022)........................................................................................... 129 
10.14.7 Amended protocol 07 (13 September 2022) ................................................................................ 130 
10.14.8 Amended protocol 08 (12 December 2022) ................................................................................. 131 
10.14.9 Amended protocol 09 (17 November 2023) ................................................................................. 132 
11 
REFERENCES ............................................................................................................................. 133 
 
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LIST OF TABLES  
Table 1 - Objectives and endpoints ............................................................................................................... 34 
Table 2 - Overview of study interventions administered ............................................................................... 49 
Table 3 - Populations for analyses ................................................................................................................ 75 
Table 4 - Safety analyses .............................................................................................................................. 79 
Table 5 - Protocol-required laboratory assessments .................................................................................... 86 
Table 6 - Clinical and MRI features suggestive of PML .............................................................................. 104 
Table 7 - Potent and moderate CYP3A inducers and potent CYP2C8 inhibitors ....................................... 105 
Table 8 - Mild, moderate, and potent inhibitors of CYP3A and CYP2C8, and moderate and potent inducers 
of CYP3A ..................................................................................................................................................... 106 
Table 9 - Examples of herbal and dietary supplements involved in hepatotoxicity ..................................... 109 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................. 17 
 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title:  A Phase 3, randomized, double-blind efficacy and safety study comparing 
SAR442168 to teriflunomide (Aubagio®) in participants with relapsing forms of 
multiple sclerosis (GEMINI 1) 
Short title: 
RMS study of BTK inhibitor tolebrutinib (SAR442168) (GEMINI 1) 
Rationale: 
Despite a number of disease-modifying therapies (DMTs) approved for relapsing multiple 
sclerosis (RMS), there is still a need for additional efficacious treatments, especially treatments 
that target disease mechanisms in the central nervous system (CNS) behind a closed or partially 
closed blood-brain barrier. Current treatments cannot ensure long-term suppression of multiple 
sclerosis (MS) inflammatory activity including relapse and new magnetic resonance imaging 
(MRI) lesion control. Some medications delay RMS progression, but the disease may still not be 
completely controlled, and it affects life activities and wellbeing. Even the most recent 
high-efficacy DMTs mainly act on adaptive immunity in the periphery with only modest ability to 
slow neuroinflammatory and neurodegenerative processes, as demonstrated by recent studies in 
progressive MS (1, 2). Therefore, development of MS treatments with new modes of action is of 
interest. 
In addition to the current focus on suppressing B- or T-cell mediated immunity in MS treatments, 
there is mounting evidence that innate immunity, including myeloid lineage bone-marrow-derived 
monocytes, macrophages, and CNS-resident microglial cells, is responsible for many of the 
neurodegenerative aspects of MS (3, 4). Modulation of innate immunity could therefore provide 
additional benefit in treatment of MS. SAR442168 shows in vitro capacity to inhibit Bruton’s 
tyrosine kinase (BTK), which is responsible for downstream signaling in macrophages and 
microglial cells and is expected to act on these targets in the brain due to its ability to penetrate 
the blood-brain barrier.  
Based on this knowledge of the mode of action of SAR442168, its ability to penetrate the 
blood-brain barrier, and available evidence from nonclinical and healthy volunteer studies, 
SAR442168 is expected to prove itself as a high-efficacy disease-modifying treatment for MS. 
The ability of SAR442168 to reduce formation of new, active brain lesions in MS was assessed in 
a Phase 2b dose-finding trial in participants with RMS (DRI15928). This radiographic outcome 
has been established as a highly reliable predictive biomarker for clinical efficacy in pivotal 
studies in MS including Phase 3 RMS studies (5). The dose selected on the basis of the 
SAR442168 effect on gadolinium- (Gd-) enhancing T1-hyperintense lesions on MRI in the 
Phase 2b trial will be used for this and other Phase 3 trials with SAR442168 in MS. 
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The goal of this Phase 3 study is to assess SAR442168 in the RMS population. Efficacy will be 
assessed by adjudicated relapse rate, disability progression, and MRI findings of disease activity 
(Gd-enhancing lesions and new/enlarging T2-hyperintense lesions). Together with evaluation of 
other secondary and exploratory endpoints, this study will provide a comprehensive evaluation of 
the efficacy and safety of SAR442168 in the RMS population. 
Objectives and endpoints 
Objectives 
Endpoints 
Primary 
• 
To assess efficacy of daily SAR442168 
compared to a daily dose of 14 mg 
teriflunomide (Aubagio) measured by 
annualized adjudicated relapse rate (ARR) in 
participants with relapsing forms of MS 
• 
ARR during the study period assessed by confirmed 
protocol-defined adjudicated relapses 
Secondary 
• 
To assess efficacy of SAR442168 compared to 
teriflunomide (Aubagio) on disability 
progression, magnetic resonance imaging 
(MRI) lesions, cognitive performance and 
quality of life 
• 
Time to onset of confirmed disability worsening (CDW), 
confirmed over at least 6 months, defined as follows: 
- 
increase of ≥1.5 points from the baseline Expanded 
Disability Status Scale (EDSS) score when the 
baseline score is 0, OR 
- 
increase of ≥1.0 point from the baseline EDSS score 
when the baseline score is 0.5 to ≤5.5, OR 
- 
increase of ≥0.5 point from the baseline EDSS score 
when the baseline score is >5.5 
• 
Time to onset of CDW, assessed by the EDSS score and 
confirmed over at least 3 months  
• 
Total number of new and/or enlarging T2-hyperintense 
lesions as detected by MRI, defined as the sum of the 
individual number of new and/or enlarging T2 lesions at 
all scheduled visits starting after baseline up to and 
including the End-of-Study (EOS) visit and number of new 
and/or enlarging T2-hyperintense lesions by visit over 
time  
• 
Total number of new gadolinium- (Gd-) enhancing 
T1-hyperintense lesions as detected by MRI, defined as 
the sum of the individual number of new Gd-enhancing 
T1-hyperintense lesions at all scheduled visits starting 
after baseline up to and including the EOS visit 
• 
Time to confirmed disability improvement (CDI), defined 
as a ≥1.0 point decrease on the EDSS from the baseline 
EDSS score confirmed over at least 6 months  
• 
Percent change in brain volume loss as detected by brain 
MRI scans at the EOS compared to Month 6  
• 
Change in cognitive function at the EOS compared to 
baseline as assessed by the Symbol Digit Modalities Test 
(SDMT) 
• 
Change in cognitive function at the EOS compared to 
baseline as assessed by the CVLT-II, where available 
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Objectives 
Endpoints 
• 
Change in Multiple Sclerosis Quality of Life 54 
(MSQoL-54) questionnaire score at the EOS compared to 
baseline 
• 
To evaluate the safety and tolerability of daily 
SAR442168 
• 
Adverse events (AEs), serious AEs, AEs leading to 
permanent study intervention discontinuation, AEs of 
special interest, and potentially clinically significant 
abnormalities in laboratory tests, safety scales, ECG, 
and vital signs during the study period  
• 
To evaluate population pharmacokinetics (PK) 
of SAR442168 and relevant metabolite(s) and 
its relationship to efficacy and safety 
• 
Plasma concentration of SAR442168 and relevant 
metabolite(s) (population PK assessment) at Months 6, 
9, and 12 
• 
To evaluate pharmacodynamics (PD) of 
SAR442168  
• 
Change in plasma neurofilament light chain (NfL) levels 
at the EOS compared to baseline, where available 
• 
Change in lymphocyte phenotype subsets in whole 
blood at the EOS compared to baseline in a subset of 
population 
• 
Changes in serum immunoglobulin level at the EOS 
compared to baseline  
• 
Change in serum Chi3L1 levels at the EOS compared to 
baseline  
Overall design: 
This is a Phase 3, randomized, double-blind, double-dummy, 2-arm, active-controlled, parallel 
group, multicenter, event-driven (6-month confirmed disability worsening [CDW]) trial with 
a variable treatment duration ranging from approximately 18 to 36 months. 
Disclosure Statement: This is a parallel treatment study with 2 arms that is blinded/masked for 
participants, any Investigator, site staff, and the Sponsor. 
Number of participants: 
Approximately 1200 people will be screened to achieve approximately 900 (±10%) participants 
randomly assigned to the study intervention with a total sample size of at least 1800 patients 
across the 2 RMS studies of identical design (EFC16033 and EFC16034).  
Intervention groups and duration: 
Participants will be randomly assigned at a 1:1 ratio to receive the 60 mg selected dose 
(established from dose-finding Study DRI15928) of oral SAR442168 daily as well as a placebo to 
match the teriflunomide tablet or 14 mg oral teriflunomide as well as a placebo to match the 
SAR442168 tablet daily. Randomization will be stratified by the Expanded Disability Status Scale 
(EDSS) score at screening (<4 versus ≥4) and geographic region (US versus non-US). 
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Study intervention(s) 
Investigational medicinal product 
• Formulation: SAR442168 film-coated tablet 
• Route(s) of administration: oral 
• Dose regimen: 60 mg once daily 
Investigational medicinal product 
• Formulation: teriflunomide tablet 
• Route of administration: oral 
• Dose regimen: 14 mg once daily 
Investigational medicinal product 
• Formulation: placebo to match SAR442168 film-coated tablet  
• Route of administration: oral 
• Dose regimen: once daily 
Investigational medicinal product 
• Formulation: placebo to match teriflunomide tablet 
• Route of administration: oral 
• Dose regimen: once daily 
Noninvestigational medicinal products 
• Formulation: MRI contrast-enhancing preparations 
• Route(s) of administration: intravenous (IV) 
• Dose regimen: as per respective label 
Noninvestigational medicinal products 
• Formulation: cholestyramine 
• Route(s) of administration: oral 
• Dose regimen: 8 g 3 times daily for 11 days for accelerated elimination procedure 
(4 g 3 times daily for 11 days in case of intolerance). The teriflunomide local label should 
be followed. 
Temporary investigational medicinal product (IMP) interruption due to surgery 
If surgery is needed during the study, consider the benefit/risk of withholding the IMP for at least 
3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.  
Devices 
Not applicable. 
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Post-trial access to study medication 
After the end of this study, participants who successfully complete the trial and are taking the IMP 
until the end of the trial will be offered the opportunity to participate in a long-term safety (LTS) 
study for an additional 2 years, or until the drug is approved in their respective country, whichever 
comes first. Details of the LTS study will be described in a separate protocol. Post-trial access for 
more than 2 years may be considered if mandated by local regulations. 
Statistical considerations: 
• Primary analysis: 
The purpose of the primary analysis of annualized adjudicated relapse rate (ARR) is to assess the 
efficacy of SAR442168 in an intent to treat (ITT) setting. In this primary approach, off-treatment 
events of participants who prematurely discontinue study intervention will be included for 
analysis per the ITT principle. Participants who permanently discontinue study intervention will 
be asked and encouraged to return to the clinic for all remaining study visits. In this case, all 
events during the planned treatment period will be included and the observation duration will be 
from randomization to EOS. If a participant withdraws from the study prior to the common study 
end date, all observed events up to the last contact date will be included in the analysis, and the 
observation duration will be from randomization to the last contact date. No imputation will be 
performed for the unobserved events that may happen after study discontinuation. This estimand 
compares the rate of ARR for the participants randomized to SAR442168 versus teriflunomide, 
regardless of what treatment participants actually received. It assesses the benefits of the treatment 
policy or strategy relative to teriflunomide. 
Annualized adjudicated relapse rate will be analyzed using a negative binomial regression model. 
The model will include the total number of adjudicated relapses occurring during the observation 
period as the response variable, with treatment group, EDSS score at screening (<4, ≥4), and 
geographic region (US, non-US) as covariates. Log transformed observation duration will be the 
offset variable. The estimated ARR for each treatment group and corresponding 2-sided 95% 
confidence interval will be derived from the negative binomial model. The relative reduction in 
ARR with SAR442168 compared to teriflunomide, its 2-sided 95% confidence interval and 
p-value will be provided. 
• Analysis of secondary endpoints: 
The primary analysis of time to onset of 6-month CDW will be based on the pooled data across 
Studies EFC16033 and EFC16034 in the ITT population. The time to onset of 6-month CDW will 
be analyzed by a Cox proportional hazards model with terms for treatment, EDSS score at 
screening (<4, ≥4), geographic region (US, non-US) and study. A log-rank test stratified by EDSS 
score at screening (<4, ≥4), geographic region (US, non-US), and study to compare SAR442168 
to teriflunomide will also be examined. Kaplan-Meier plots of the cumulative incidence rate will 
be provided by treatment group to depict the course of onset of 6-month CDW over time. The 
proportion of participants with events at given time points (eg, Month 24) will be calculated using 
the Kaplan-Meier estimates.  
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In this primary ITT analysis: 
• For participants who complete the study without an initial disability worsening or 
prematurely discontinue the study before 6-month confirmation of an onset of disability 
worsening, the participant’s event time will be censored at the date of last EDSS 
assessment.  
• For participants who have an initial onset of disability worsening but reach the common 
study end date prior to 6-month confirmation, the event status of the participant will be 
determined by an imputation approach. Since in this setting, the partial missing data can 
reasonably be assumed to be missing at random, this approach leverages the partial 
information and follows the ITT principle. A logistic model with terms for EDSS score at 
screening (<4, ≥4) and geographic region (US, non-US) will be used as the imputation 
model within each treatment of each study population. A multiple imputation approach 
will be used to summarize the results. Details will be provided in the Statistical Analysis 
Plan (SAP).  
All EDSS assessments (with or without relapse) will be used to determine onset of disability 
worsening. However, for the purpose of confirmation, only EDSS score(s) measured more than 
30 days after the onset of a confirmed relapse and in the absence of an ongoing relapse will be 
used. In case of such MS relapse, the next quarterly EDSS assessment will be used for CDW 
confirmation. The minimum increase in score required for worsening must also be maintained for 
any non-confirmatory (ie, intervening) EDSS assessment(s) between the initial (onset) and 
confirmation EDSS scores.  
Multiplicity consideration 
To control the overall type 1 error rate, a hierarchical testing procedure will be applied to the 
primary and secondary efficacy endpoints (Section 3). If the primary endpoint has met 
significance, a selective set of secondary efficacy endpoints will be tested in a hierarchical order 
at α = 0.05 (2-sided) that will be prespecified in the SAP. For the time to onset of the CDW 
endpoint, the main analysis will be based on pooled data from this study and Study EFC16034. 
Analysis of safety data: 
All safety summaries will be descriptive; no statistical significance tests will be performed on 
safety data. This includes treatment-emergent adverse events (TEAEs) and other safety 
information (eg, clinical laboratory evaluations, safety scales, electrocardiograms (ECGs), and 
vital signs). TEAEs are defined as AEs that developed, or worsened, or became serious during the 
treatment period. These analyses will be based on the safety population, defined as all participants 
randomly assigned and exposed to study intervention, regardless of the amount of exposure, 
analyzed according to the treatment actually received. 
Interim analysis: 
No formal efficacy interim analysis is planned. 
Data Monitoring Committee: Yes 
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Scientific Advisory Committee: Yes 
Relapse Adjudication Committee: Yes 
Independent Hepatology Assessment Committee: Yes 
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1.2 
SCHEMA  
Figure 1 - Graphical study design  
  
Abbreviations: EOS, end of study; MRI, magnetic resonance imaging; R, randomization 
‘Month-1 (D-28 – D-1)’ refers to screening period as "Day-28 to Day-1"; ‘Month 0 (D1)’ refers to randomization on Day 1. 
Screening 
Period
Treatment Period : approximately 18 to 36 months
All patients continue in the study until Common Study End (EOS)
0
12
24
15
18
Months
Teriflunomide
14 mg Oral
N=450
SAR442168
60 mg Oral
N=450
3
6
9  
21
-1
1 Tablet Daily (SAR442168) + 1 Tablet Placebo to match teriflunomide 
MRI Scan:
Disability
assessments:
End of Study and start of Long-term Safety Study
1 Tablet Daily (Teriflunomide) + 1 Tablet Placebo to match SAR442168
27
33
30
EOS
36
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1.3 
SCHEDULE OF ACTIVITIES (SOA)  
 
Procedure 
Screeninga 
Randomization /Start of IMP 
 
Year 1 (M12)b 
From M15 to EOSb 
Only for participants who 
prematurely discontinue IMP 
For all participants 
Only for participants who 
completed treatment to EOS 
but do not enter LTSc 
Visit (a window 
of ±7 days is 
allowed for all 
visits after D1) 
 
D-28 to D-1 
D1 
M0.5 (W2) 
M0.75 (W3) 
M1 (W4)d  
M1.25 (W5) 
M1.5 (W6) 
M1.75 (W7) 
M2 (W8)d 
M2.25 (W9) 
 M2.5 (W10)  
M2.75 (W11) 
M3 
M4, M5d 
M6 
M7 
M8 
M9 
M10 
M11 
M12 
Quarterly visits 
(M15, M18, M21, 
M24, M27, M30, 
M33, M36…) 
Semi-annual 
visits (M18, 
M24, M30, 
M36…) 
pEOTe 
EOSf 
“Common 
study end 
date”visit 
Follow-up visit  
(4 weeks)  
Visit number 
V1 
V2 
 
V3 
 
V4 
 
V5 
V6, 
V7 
V8 
 
V9 
 
V10 
V11, V12, V13, 
V14, V15, V16, 
V17, V18… 
V12, V14, 
V16, V18… 
pEOTe 
EOS 
FUV 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/ 
concomitant 
medicationsg 
=============================================================================================================================================→ 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRT contact 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
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Procedure 
Screeninga 
Randomization /Start of IMP 
 
Year 1 (M12)b 
From M15 to EOSb 
Only for participants who 
prematurely discontinue IMP 
For all participants 
Only for participants who 
completed treatment to EOS 
but do not enter LTSc 
Visit (a window 
of ±7 days is 
allowed for all 
visits after D1) 
 
D-28 to D-1 
D1 
M0.5 (W2) 
M0.75 (W3) 
M1 (W4)d  
M1.25 (W5) 
M1.5 (W6) 
M1.75 (W7) 
M2 (W8)d 
M2.25 (W9) 
 M2.5 (W10)  
M2.75 (W11) 
M3 
M4, M5d 
M6 
M7 
M8 
M9 
M10 
M11 
M12 
Quarterly visits 
(M15, M18, M21, 
M24, M27, M30, 
M33, M36…) 
Semi-annual 
visits (M18, 
M24, M30, 
M36…) 
pEOTe 
EOSf 
“Common 
study end 
date”visit 
Follow-up visit  
(4 weeks)  
Visit number 
V1 
V2 
 
V3 
 
V4 
 
V5 
V6, 
V7 
V8 
 
V9 
 
V10 
V11, V12, V13, 
V14, V15, V16, 
V17, V18… 
V12, V14, 
V16, V18… 
pEOTe 
EOS 
FUV 
IMP 
dispensatione, t 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
 
 
IMP compliance 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
Xe 
X 
 
Paper diary 
dispensation/ 
collection 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examinationh 
and vital signs 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
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Procedure 
Screeninga 
Randomization /Start of IMP 
 
Year 1 (M12)b 
From M15 to EOSb 
Only for participants who 
prematurely discontinue IMP 
For all participants 
Only for participants who 
completed treatment to EOS 
but do not enter LTSc 
Visit (a window 
of ±7 days is 
allowed for all 
visits after D1) 
 
D-28 to D-1 
D1 
M0.5 (W2) 
M0.75 (W3) 
M1 (W4)d  
M1.25 (W5) 
M1.5 (W6) 
M1.75 (W7) 
M2 (W8)d 
M2.25 (W9) 
 M2.5 (W10)  
M2.75 (W11) 
M3 
M4, M5d 
M6 
M7 
M8 
M9 
M10 
M11 
M12 
Quarterly visits 
(M15, M18, M21, 
M24, M27, M30, 
M33, M36…) 
Semi-annual 
visits (M18, 
M24, M30, 
M36…) 
pEOTe 
EOSf 
“Common 
study end 
date”visit 
Follow-up visit  
(4 weeks)  
Visit number 
V1 
V2 
 
V3 
 
V4 
 
V5 
V6, 
V7 
V8 
 
V9 
 
V10 
V11, V12, V13, 
V14, V15, V16, 
V17, V18… 
V12, V14, 
V16, V18… 
pEOTe 
EOS 
FUV 
Serology 
tests for 
hepatitis 
B, C. 
(HIV and other 
infectious 
diseases, if 
required locally) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TB/ 
QuantiFERON® 
TB Gold test or 
equivalenti 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body 
temperature 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
Yearly 
X 
X 
 
Hematology, 
biochemistryj 
X 
Xy 
 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
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Procedure 
Screeninga 
Randomization /Start of IMP 
 
Year 1 (M12)b 
From M15 to EOSb 
Only for participants who 
prematurely discontinue IMP 
For all participants 
Only for participants who 
completed treatment to EOS 
but do not enter LTSc 
Visit (a window 
of ±7 days is 
allowed for all 
visits after D1) 
 
D-28 to D-1 
D1 
M0.5 (W2) 
M0.75 (W3) 
M1 (W4)d  
M1.25 (W5) 
M1.5 (W6) 
M1.75 (W7) 
M2 (W8)d 
M2.25 (W9) 
 M2.5 (W10)  
M2.75 (W11) 
M3 
M4, M5d 
M6 
M7 
M8 
M9 
M10 
M11 
M12 
Quarterly visits 
(M15, M18, M21, 
M24, M27, M30, 
M33, M36…) 
Semi-annual 
visits (M18, 
M24, M30, 
M36…) 
pEOTe 
EOSf 
“Common 
study end 
date”visit 
Follow-up visit  
(4 weeks)  
Visit number 
V1 
V2 
 
V3 
 
V4 
 
V5 
V6, 
V7 
V8 
 
V9 
 
V10 
V11, V12, V13, 
V14, V15, V16, 
V17, V18… 
V12, V14, 
V16, V18… 
pEOTe 
EOS 
FUV 
Liver function 
testsl 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
 
 
 
Iron panel 
(serum): iron, 
ferritin, 
transferrin 
saturation, 
TIBC; to be 
repeated during 
the study if 
needed 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation: 
PT/INR, aPTT 
(to be repeated 
during the 
study, if 
needed)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
 
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Procedure 
Screeninga 
Randomization /Start of IMP 
 
Year 1 (M12)b 
From M15 to EOSb 
Only for participants who 
prematurely discontinue IMP 
For all participants 
Only for participants who 
completed treatment to EOS 
but do not enter LTSc 
Visit (a window 
of ±7 days is 
allowed for all 
visits after D1) 
 
D-28 to D-1 
D1 
M0.5 (W2) 
M0.75 (W3) 
M1 (W4)d  
M1.25 (W5) 
M1.5 (W6) 
M1.75 (W7) 
M2 (W8)d 
M2.25 (W9) 
 M2.5 (W10)  
M2.75 (W11) 
M3 
M4, M5d 
M6 
M7 
M8 
M9 
M10 
M11 
M12 
Quarterly visits 
(M15, M18, M21, 
M24, M27, M30, 
M33, M36…) 
Semi-annual 
visits (M18, 
M24, M30, 
M36…) 
pEOTe 
EOSf 
“Common 
study end 
date”visit 
Follow-up visit  
(4 weeks)  
Visit number 
V1 
V2 
 
V3 
 
V4 
 
V5 
V6, 
V7 
V8 
 
V9 
 
V10 
V11, V12, V13, 
V14, V15, V16, 
V17, V18… 
V12, V14, 
V16, V18… 
pEOTe 
EOS 
FUV 
Pregnancy test 
(if 
applicable)k,m 
X 
X 
 
X
m 
 
 
 
X 
Xm 
X 
 
X 
 
X 
X 
Xm 
X 
X 
X 
Serum FSHn 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Suicidality 
assessment by 
C-SSRS 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Adverse event 
collection 
=============================================================================================================================================→ 
Efficacy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EDSS 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
Timed 25-foot 
walk test 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
9-hole peg test 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
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Procedure 
Screeninga 
Randomization /Start of IMP 
 
Year 1 (M12)b 
From M15 to EOSb 
Only for participants who 
prematurely discontinue IMP 
For all participants 
Only for participants who 
completed treatment to EOS 
but do not enter LTSc 
Visit (a window 
of ±7 days is 
allowed for all 
visits after D1) 
 
D-28 to D-1 
D1 
M0.5 (W2) 
M0.75 (W3) 
M1 (W4)d  
M1.25 (W5) 
M1.5 (W6) 
M1.75 (W7) 
M2 (W8)d 
M2.25 (W9) 
 M2.5 (W10)  
M2.75 (W11) 
M3 
M4, M5d 
M6 
M7 
M8 
M9 
M10 
M11 
M12 
Quarterly visits 
(M15, M18, M21, 
M24, M27, M30, 
M33, M36…) 
Semi-annual 
visits (M18, 
M24, M30, 
M36…) 
pEOTe 
EOSf 
“Common 
study end 
date”visit 
Follow-up visit  
(4 weeks)  
Visit number 
V1 
V2 
 
V3 
 
V4 
 
V5 
V6, 
V7 
V8 
 
V9 
 
V10 
V11, V12, V13, 
V14, V15, V16, 
V17, V18… 
V12, V14, 
V16, V18… 
pEOTe 
EOS 
FUV 
SDMT and 
CVLT-II, where 
availableo 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
Basic or 
expanded MRI 
scanp 
Xq 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
M18, M24, 
M36 
X 
X 
 
Clinical outcome assessmentr 
 
MSQoL-54 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
 
EQ-5D-5L 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
 
Pharmacokineticss 
SAR442168 and 
relevant 
metabolite(s) 
pharmacokinetic 
plasma samplest 
 
 
 
 
 
 
 
 
 
Xu 
 
Xv 
 
Xu 
 
 
Xe 
 
 
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Procedure 
Screeninga 
Randomization /Start of IMP 
 
Year 1 (M12)b 
From M15 to EOSb 
Only for participants who 
prematurely discontinue IMP 
For all participants 
Only for participants who 
completed treatment to EOS 
but do not enter LTSc 
Visit (a window 
of ±7 days is 
allowed for all 
visits after D1) 
 
D-28 to D-1 
D1 
M0.5 (W2) 
M0.75 (W3) 
M1 (W4)d  
M1.25 (W5) 
M1.5 (W6) 
M1.75 (W7) 
M2 (W8)d 
M2.25 (W9) 
 M2.5 (W10)  
M2.75 (W11) 
M3 
M4, M5d 
M6 
M7 
M8 
M9 
M10 
M11 
M12 
Quarterly visits 
(M15, M18, M21, 
M24, M27, M30, 
M33, M36…) 
Semi-annual 
visits (M18, 
M24, M30, 
M36…) 
pEOTe 
EOSf 
“Common 
study end 
date”visit 
Follow-up visit  
(4 weeks)  
Visit number 
V1 
V2 
 
V3 
 
V4 
 
V5 
V6, 
V7 
V8 
 
V9 
 
V10 
V11, V12, V13, 
V14, V15, V16, 
V17, V18… 
V12, V14, 
V16, V18… 
pEOTe 
EOS 
FUV 
Pharmacogeneticss 
DNA samplew 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacodynamics/biomarkers s 
 
Blood sample 
for archivingx 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma 
samples (NfL), 
serum samples 
(Chi3L1) 
 
X 
 
 
 
 
 
X 
 
Xv 
 
 
 
Xv 
 
Yearly 
X 
X 
 
Lymphocyte 
phenotypes by 
flow cytometryz 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Serum samples 
(Ig levels) 
 
X 
 
 
 
 
 
 
 
Xv 
 
 
 
Xv 
 
Yearly 
X 
X 
 
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aPTT: activated partial thromboplastin time; β-HCG: β-human chorionic gonadotropin; AST: aspartate aminotransferase; ALT: alanine aminotransferase; Chi3L1: chitinase-3 like protein-1; CRF: case report form; 
C-SSRS: Columbia Suicide Severity Rating Scale; D: day; DNA: deoxyribonucleic acid; ECG: electrocardiogram; EDSS: Expanded Disability Status Scale; EOS: end of study; EOT: end of treatment; EQ-5D-5L: 
EuroQol 5-dimension 5-level questionnaire; FSH: follicle-stimulating hormone; FU: follow-up; Ig: immunoglobulin; HIV: human immunodeficiency virus; ICF: informed consent form; IMP: investigational medicinal 
product; INR: international normalized ratio; IRT: interactive response technology; LDH: lactate dehydrogenase; LTS: long-term safety study; M: month (28 days); MRI: magnetic resonance imaging; MS: multiple 
sclerosis; MSQoL-54: Multiple Sclerosis Quality of Life-54; NfL: neurofilament light chain; pEOT: premature end of treatment; PK: pharmacokinetic(s); PT: prothrombin time; SDMT: Symbol Digit Modalities Test; SWI: 
susceptibility-weighted imaging; TB: tuberculosis; TIBC: total iron-binding capacity 
Note: All assessments shall be done as designated in this SoA unless not permitted according to local regulations. All visit assessments should be performed during the visit window unless otherwise specified in this 
protocol. 
a Screening period can range from D-28 to D-1; Randomization visit can be performed only once IMPs are available at site. The interval between screening and randomization visits can range from 11 days 
(minimum) to 28 days (maximum). However, if required, the randomization visit can be performed earlier than 11 days upon IMP receipt at the site, assuming the participant is eligible for randomization. In case the 
screening MRI must be rescheduled (eg, technical issues) or repeated, an additional 1 week (7 days) is allowed. See Appendix 9 (Section 10.11.3), for additional screening requirements for Japan. 
b From D1 to EOS, unscheduled visits may be performed at any time by the Investigator (eg, for evaluation of an adverse event). Assessments may be done as needed to evaluate the participant in accordance with 
the Investigator’s best judgment and in line with the study protocol. At a minimum, a physical examination should be performed, and body temperature and vital signs should be measured. 
c At the EOS, the participants who have completed the study and remain on IMP will be offered participation in a long-term safety study. Follow-up visit assessment only performed for those participants who are not 
willing to take part in the long-term safety study. For other situations where a follow-up visit is needed, please see Section 7.1 and the Study Manual. 
d These visits may be done as home health visits (where applicable) or onsite visits (preferable that tests are performed at the central laboratory). In any situations where this is not possible (to be documented in 
source documents), the tests for these visits may be performed at a local laboratory.  
e If a participant prematurely permanently discontinues treatment with IMP, the participant will undergo a premature EOT visit as soon as possible. A PK sample should also be collected if the pEOT visit can be 
scheduled within a maximum 24 hours after the last IMP dose. Participants will then be asked to continue with the study visits as scheduled until global EOS visit is reached. During these visits, all study 
procedures/assessments will be performed except IMP administration and blood sampling for PK and biomarkers (NfL, Chi3L1, and Ig levels). MRI scans for these participants will only be performed annually 
(using the next annual visit as the starting point). 
f 
Common EOS visit will be done when the prespecified number of events for 6-month CDW is expected to be reached. The timing and window of this visit will be communicated to sites. 
g Any disease-modifying therapy for MS taken at any time prior to signing the informed consent need to be reported in the CRF; other prior medications will be reported for the period of 6 months prior to signing the 
ICF. 
h Complete physical examination due at screening, baseline, yearly and EOS. Brief physical examination is sufficient for the rest of the visits (complete and brief physical examination will include neurological 
examination and collection of the following vital signs: arterial blood pressure, heart rate, and temperature). 
i 
To be performed at screening for all participants. To be repeated based on clinical judgment, borderline results, or clinical suspicion of TB infection. Screening tests for TB are described in Appendix 2 
(Section 10.2). 
j 
Hematology (platelet count, red blood cell count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, reticulocytes, white blood cell count with differential: neutrophils, lymphocytes, 
monocytes, eosinophils, basophils). See Appendix 9 (Section 10.11.3) for additional visit schedule requirements for Japan. 
Biochemistry (blood urea nitrogen [BUN], creatinine, glucose, potassium, sodium, chloride, bicarbonate, calcium; liver function tests [AST, ALT, albumin, alkaline phosphatase, total and direct bilirubin, total protein, 
creatine phosphokinase], lipase at Screening Visit, then quarterly). Monthly visits (M1, M2, M4, M5) will include hematology and full liver panel only. Additional safety assessments can be performed if required by 
local regulations (eg, KL-6, CRP, and LDH in Japan). Such testing shall be performed at local laboratories. See Appendix 9 (Section 10.11.3) for additional screening and visit schedule requirements for Japan. 
Note: a one-time retest at screening may be performed if an abnormal laboratory test value is considered temporary. Additional visits may be added if required by local regulations. 
k Serum ß-HCG pregnancy test at central laboratory at screening and urine pregnancy tests within 24 hours before the first dose of IMP and at scheduled times during study. Additional serum or urine pregnancy 
tests may be performed, as determined necessary by the Investigator or required by local regulation, to establish the absence of pregnancy at any time during the participant’s participation in the study. 
Communication by phone of the result of a pregnancy test performed at home to the site is allowed. See also Appendix 4 (Section 10.4). 
l 
At intermediate timepoints (W2, W3, W5, W6, W7, W9, W10, W11, M7, M8, M10, and M11) only liver function tests will be collected (AST, ALT, albumin, alkaline phosphatase, total and direct bilirubin, total protein) 
and creatine phosphokinase); these can be performed at central laboratory (preferred, as on-site visits or home nursing as applicable for the site) or at local laboratory. 
m Pregnancy tests will be performed monthly in all concerned EU countries (See Appendix 9 [Section 10.11.2]).  
n Only in female participants, if needed to establish menopausal status. 
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o SDMT and CVLT-II will be performed in all participants. If for some reason, CVLT-II is not available at a given site due to reasons such as lack of translation, local certification, etc., then only the SDMT will be 
assessed for that participant. 
p A subset of sites that have 3T MRI capacity will perform additional sequences (eg, SWI). Further details will be defined in a separate central MRI manual. For systemic corticosteroids and adrenocorticotropic 
hormone, 1 month washout is required prior to the MRI scans. A visit window of ±21 days is acceptable for MRIs performed after D1. 
q The screening MRI scan should be performed as close as possible before the start of IMP. As much as possible, the MRI scan should be performed during the screening period after it has been established that 
the participant meets all inclusion and no exclusion criteria. 
r 
When available, clinical outcome assessments are to be completed by the participant prior to discussing their health status and prior to study treatment administration or other study-related procedures.  
s Where available per local regulations. 
t 
On days of PK sampling the IMP needs to be taken at the study site after a regular meal. In case a participant took IMP prior to arriving at the site on the day of visits with PK sampling, he/she will be asked to have 
a PK assessment within 3 days of the missed PK sampling. A PK assessment shall be done as soon as possible after an overdose or if otherwise specified per protocol (eg, investigation of abnormal laboratory 
test values).  
u Two samples: one sample between 30 and 90 minutes and one sample between 2.5 and 5 hours after IMP administration. 
v One sample between 30 and 90 minutes after IMP administration, if applicable per local regulation. Pharmacodynamics/biomarkers samples collected at other visits are not timed samples. 
w The DNA testing may be done, if locally applicable, at any time after signature of consent (in case it could not be done for some reason at Day 1). 
x This sample will be collected and stored for use if any unexpected safety issue occurs to ensure that a pre-dose baseline value is available for previously not assessed parameters (eg, serology) and for 
biomarkers research, if agreed. 
y Samples for hematology and biochemistry tests on Day 1 (randomization) must be collected prior to administration of the first IMP dose. 
z Blood collection for lymphocyte phenotypes by flow cytometry will be performed in a subset of participants randomized (approximately 400). 
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2 
INTRODUCTION  
SAR442168 is a brain penetrant inhibitor of Bruton’s tyrosine kinase (BTK). SAR442168 is being 
developed for the treatment of MS. This study is designed to collect evidence of its efficacy and 
safety in a relapsing multiple sclerosis (RMS) population.  
2.1 
STUDY RATIONALE  
Despite a number of disease-modifying therapies (DMTs) approved for RMS, there is still a need 
for additional efficacious treatments, especially treatments that target disease mechanisms in the 
central nervous system (CNS) behind a closed or partially closed blood-brain barrier. Current 
treatments cannot ensure long-term suppression of multiple sclerosis (MS) inflammatory activity 
including relapse and new magnetic resonance imaging (MRI) lesion control. Some medications 
delay RMS progression, but the disease may still not be completely controlled, and it affects life 
activities and wellbeing. Even the most recent high-efficacy DMTs mainly act on adaptive 
immunity in the periphery with only modest ability to slow neuroinflammatory and 
neurodegenerative processes, as demonstrated by recent studies in progressive MS (1, 2). 
Therefore, development of MS treatments with new modes of action is of interest. 
In addition to the current focus on suppressing B- or T-cell mediated immunity in MS treatments, 
there is mounting evidence that innate immunity, including myeloid lineage bone-marrow-derived 
monocytes, macrophages, and CNS-resident microglial cells, is responsible for many of the 
neurodegenerative aspects of MS (3, 4). Modulation of innate immunity could therefore provide 
additional benefit in treatment of MS. SAR442168 shows in vitro capacity to inhibit BTK, which 
is responsible for downstream signaling in macrophages and microglial cells and is expected to 
act on these targets in the brain due to its ability to penetrate the blood-brain barrier.  
Based on this knowledge of the mode of action of SAR442168, its ability to penetrate the 
blood-brain barrier, and available evidence from nonclinical and healthy volunteer studies, 
SAR442168 is expected to prove itself as a high-efficacy disease-modifying treatment for MS. 
The ability of SAR442168 to reduce formation of new, active brain lesions in MS was assessed in 
a Phase 2b dose-finding trial in participants with RMS (DRI15928). This radiographic outcome 
has been established as a highly reliable predictive biomarker for clinical efficacy in pivotal 
studies in MS including Phase 3 RMS studies (5). The dose selected on the basis of the 
SAR442168 effect on gadolinium- (Gd-) enhancing T1-hyperintense lesions on MRI in the 
Phase 2b trial will be used for this and other Phase 3 trials with SAR442168 in MS. 
The goal of this Phase 3 study is to assess SAR442168 in the RMS population. Efficacy will be 
assessed by adjudicated relapse rate, disability progression, and MRI findings of disease activity 
(Gd-enhancing lesions and new/enlarging T2-hyperintense lesions). Together with evaluation of 
other secondary and exploratory endpoints, this study will provide a comprehensive evaluation of 
the efficacy and safety of SAR442168 in the RMS population. 
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Adjudicated relapse rate is the primary endpoint in this trial, being a standard endpoint used in 
pivotal RMS clinical studies and in clinical practice. Six-month confirmed disability worsening 
(CDW) is selected as the key secondary endpoint. Confirmed disability worsening is widely used 
as an endpoint in clinical trials (6). Six-month CDW is considered both clinically more 
meaningful and statistically more robust than 3-month CDW. 
Population pharmacokinetic (PK) analysis will be done in order to confirm the PK profile in a 
larger RMS population, to assess sources of PK variability (ethnicity, special population), and to 
establish exposure correlation to clinical efficacy, biomarkers, and safety endpoints. Analysis of 
population PK data will be performed as soon as all participants have completed the Month 12 
visit (a separate, unblinded team will be used to preserve blinding integrity). 
This study will employ other secondary efficacy outcome measures to collect additional data in 
an effort to assess the benefit of SAR442168 for participants with RMS. 
Exploratory assessments are expected to provide additional evidence for SAR442168 activity on 
neuroinflammation and neurodegeneration and the impact of SAR442168 on participants’ daily 
living functionality and quality of life. 
2.2 
BACKGROUND  
Immunomodulatory drugs have been the mainstay of MS therapy. Recent clinical trials have 
demonstrated efficacy of agents that target B lymphocytes, especially B-cell-depleting agents like 
ocrelizumab (-CD20) (7). Targeting B cells represents a departure from the prevailing dogma 
based on animal models that demonstrated therapeutic benefits from modulating T-cell activity. 
Thus, B cells have become the cellular focus of current MS drug development (7). However, the 
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 all diagnostic categories of MS 
(ie, RMS as well as progressive forms of the disease, primary progressive MS [PPMS] and 
secondary progressive MS [SPMS]) (9). Even the most recent high-efficacy DMTs act mainly on 
adaptive immunity in the periphery with only modest or temporary ability to slow 
neuroinflammatory and neurodegenerative processes and stop disease progression (1, 10). 
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 cells of a myeloid lineage 
(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 DMTs in preventing acute relapses (3, 4). Modulation of innate 
immunity has the potential to curtail “smoldering neuroinflammation” and other manifestations of 
disease progression that remain unaddressed by current, approved therapies. 
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BTK is an important intracellular signaling mediator in adaptive and innate immune cells. 
Accordingly, an inhibitor of BTK signaling represents a dual mechanism targeting both aspects of 
the immune system. BTK inhibitors block 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 to address 
“outside-in and inside-out” pathological mechanisms by inhibiting antigen-induced B-cell 
activation in the periphery 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.  
2.3 
BENEFIT/RISK ASSESSMENT  
SAR442168 is a covalent, irreversible inhibitor of BTK that has a dual mode of action. In 
peripheral adaptive immunity, it inhibits signaling between the B-cell receptor and downstream 
signaling events associated with cellular proliferation, maturation, and production of secreted 
immunoglobulins. BTK is also a key signaling pathway in macrophage/microglial phagocytic 
cells of innate immunity. By modulating both adaptive and innate immunity, SAR442168 has the 
potential to reduce lymphocyte-mediated acute inflammation peripherally and neuroinflammation 
mediated by innate immunity in the CNS. 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of SAR442168 may be found in the Investigator’s Brochure. 
Benefit assessment: 
SAR442168 is expected to reduce MS relapse rate, disability progression, and underlying CNS 
damage through its dual action on adaptive immunity in the periphery and innate immunity and 
the inflammation process in the CNS.  
The results from the Phase 2b trial (DRI15928) demonstrated a dose–response relationship for 
SAR442168 as evidenced by a reduction in the number of new Gd-enhancing T1-hyperintense 
brain lesions detected by brain MRI after 12 weeks of treatment. There was an 85% relative 
reduction in lesions at 12 weeks in the 60 mg dose group as compared with placebo. This was 
obtained from the negative binomial regression model adjusted for baseline Gd-enhancing 
T1-hyperintense lesion activity. 
The potential benefits of SAR442168 are as follows: 
Potential benefits 
• Decrease of annualized relapse rate (ARR).  
• Reduction in the risk of loss of mobility. 
• Reduction in the accumulation of confirmed disability worsening (as expressed by 
an increase in the Expanded Disability Status Scale [EDSS] score). 
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• Reduction of disease activity as assessed by MRI (Gd-enhancing lesions and 
new/enlarging T2 lesions). 
• Trend toward normalization of brain volume loss. 
• Reduction in neuroinflammation, as assessed by modulation of chronic active lesions 
(slowly evolving lesions [SEL], T2 phase rims) observed by MRI. 
Risk assessment  
SAR442168 has been studied in healthy participants and participants with RMS. In the completed 
Phase 1 clinical trials in healthy participants, oral administration of SAR442168 was generally 
safe and well tolerated.  
The results from the Phase 2b trial (DRI15928) suggest that SAR442168 is generally safe and 
well tolerated in patients with RMS. No new risks were identified in this trial. The key results are 
summarized as follows:  
• There was no death or treatment-emergent adverse event (TEAE) leading to permanent 
treatment discontinuation during the study. One treatment-emergent serious adverse event 
(SAE) (MS relapse) was reported in a participant treated with 60 mg SAR442168; the 
remainder of the reported TEAEs were of mild or moderate intensity.  
• There was no direct correlation between the doses of SAR442168 administered and 
number or intensity of TEAEs. The most common events reported in participants in the 
SAR442168 treatment arms were headache, upper respiratory tract infection, and 
nasopharyngitis.  
• Two participants had treatment-emergent transient alanine aminotransferase (ALT) 
increase >3 x upper limit of normal (ULN), 1 during the 30 mg SAR442168 treatment 
period [at Week 8, 105 U/L (normal range 6 to 34 U/L)] that returned to normal range 
within 4 days and 1 during the 60 mg SAR442168 treatment period [at Week 4, 107 U/L 
(normal range 6 to 34 U/L)]. The participant in the 60 mg group had slightly elevated ALT 
at screening (48 U/L) and at baseline (50 U/L); ALT levels returned to the normal range in 
8 weeks. Both participants continued study treatment during this period. All other liver 
enzyme levels for both participants were within normal ranges during the treatment period; 
one event was assessed as related and one as unrelated to the study drug by the 
Investigators. Both participants completed the DRI15928 study and successfully rolled 
over to the LTS follow-up study.  
• One event of mild petechia in a female participant (at Week 8 in the SAR442168 30 mg 
group) and 2 events of mild microscopic hematuria in 2 male participants (1 event at 
Week 16 in the SAR442168 30 mg group and 1 event on Day 1 in the SAR442168 60 mg 
group, with occult blood noted in urine) were reported during the treatment period in the 
SAR442168 Phase 2b trial. The hematology results were clinically insignificant for all 
3 participants from the onset of the events. The participant with mild petechia had benign 
pigmentary lesions noted during screening, and the event was assessed as related to the 
study drug by the Investigator. The 2 events of mild microscopic hematuria were assessed 
as unrelated to the study drug. All 3 events resolved spontaneously.  
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• No severe infections occurred. The most frequently reported (≥3 events total) in the 
SAR442168 treatment period were upper respiratory tract infection, nasopharyngitis, 
gastroenteritis, and respiratory tract infection.  
• No clinically significant cytopenia, including thrombocytopenia and neutropenia, were 
reported or detected based on hematologic laboratory results, and no clinically significant 
cardiac arrhythmia was observed via ECG monitoring during the study.  
Based on SAR442168 nonclinical safety data, Phase 1 results from healthy participants, Phase 2b 
results in participants with RMS, and the published data of other marketed or investigational BTK 
inhibitors for various indications, the potential risks of SAR442168 are as follows:  
• Bleeding (hemorrhage) 
• Infections 
• Cytopenia including thrombocytopenia 
• Atrial arrhythmias (atrial fibrillation and atrial flutter) 
In the ongoing Phase 3 and LTS studies, tolebrutinib has been generally well tolerated to date. An 
identified risk for tolebrutinib has been identified as follows: 
• Treatment-emergent SAEs of drug-induced liver injury (DILI) were reported in the 
ongoing Phase 3 trials; all cases occurred between Months 1 to 3, with potential 
confounders identified for some of the cases.  
Risks associated with use of teriflunomide as a comparator: 
Teriflunomide is approved for RMS treatment in many countries and there are extensive safety 
data collected in clinical trials and postmarketing use. The key safety information from the 
Aubagio (teriflunomide) United States prescribing information (USPI), 09/2019 is summarized as 
follows:  
• In clinical trials, the most frequent adverse reactions for teriflunomide 
(incidence ≥10% and ≥2% greater than placebo) in placebo-controlled studies were 
headache, diarrhea, nausea, alopecia, and increase in ALT. 
• Warnings and Precautions:  
- 
Hepatotoxicity  
- 
Embryofetal toxicity  
- 
Procedure for accelerated elimination of teriflunomide  
- 
Bone marrow effects/immunosuppression potential/infections  
- 
Hypersensitivity and serious skin reactions  
- 
Peripheral neuropathy  
- 
Increased blood pressure  
- 
Respiratory effects (in particular, interstitial pneumonia and lung fibrosis, 
See Appendix 9, Section 10.11.3, for additional testing requirements for Japan) 
- 
Concomitant use with immunosuppressive or immunomodulating therapies 
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Detailed safety monitoring measures and risk mitigations measures for SAR442168 are provided 
in the study protocol.  
For details on safety monitoring measures and risk mitigations measure for the comparator drug 
Aubagio (teriflunomide), please refer to the approved local labels in respective countries and the 
study protocol.  
Assessment of COVID-19 in trial participants: 
Antiviral responses are likely to be driven mainly by T cells, in particular CD8+ cytotoxic 
T lymphocytes, and natural killer cells, and less so, at least initially, by B cells (11, 12). In vitro 
and cell-based assays indicate that SAR442168 does not deplete B lymphocytes and does not 
exhibit significant cellular off-target activity in human T lymphocytes. In the completed Phase 2b 
study in participants with RMS (DRI15928), the mean counts of CD19+ B cells, CD4 and CD8 
T cells, CD16+56 natural killer cells, and the levels of IgG and IgM remained stable at the end of 
12 weeks of treatment with SAR442168. In addition, the latest clinical research showed that the 
administration of acalabrutinib, a highly specific covalent inhibitor of BTK, was associated with 
reduced inflammation and improved clinical outcome in 19 patients hospitalized with severe 
COVID-19, without discernable toxicity, over a 10- to 14-day treatment course (13). Infections 
are an important potential risk for SAR442168, and severe infections are being monitored as 
an adverse event of special interest (AESI) in all ongoing and future clinical trials. In the 
completed Phase 2b trial in 130 patients with RMS, 23.8% of participants reported only mild or 
moderate infections at the end of 12 weeks of treatment with SAR442168. No participant 
discontinued treatment due to infection or any other TEAE. At present, it is unknown if people 
with MS are at increased risk for SARS-CoV-2 infection, acquiring COVID-19 or developing 
severe COVID-19 (11). 
The risk of COVID-19 in participants who receive SAR442168 is unknown based on currently 
available data. Out of precaution, the current trial excludes people with known risk factors for 
severe COVID-19 including advanced age and comorbidities that may put patients at higher risk 
for serious illness such as chronic cardiovascular disease, liver disease, kidney disease, respiratory 
system compromise, and malignancies. Concomitant use of immunosuppressive or 
chemotherapeutic medications is excluded. In addition, appropriate safety monitoring measures 
are in place including physical examination, monitoring of vital signs and clinical labs, ECG, and 
collection of AEs and AESIs. Every effort will be made to complete trial visits and trial 
assessments and to provide study drug for participants. If needed, temporary treatment 
discontinuation can be considered by the Investigator or by the participant for any reason, 
including due to any safety concerns because of COVID-19 or another illness or if there is a need 
for a prohibited concomitant medication. Treatment can be resumed later when it is considered 
safe and appropriate.   
Lastly, the Sponsor will update the ICF to inform participants of the general risks for COVID-19 
during the pandemic and the importance of appropriate behavioral modifications to reduce or 
ideally prevent exposure to the SARS-CoV-2 virus.  
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In conclusion, considering the mechanism of action of SAR442168, the lack of data on the 
COVID-19 course in MS patients receiving DMTs, the safety monitoring and mitigation measures 
already in place, and the favorable benefit/risk profile observed in the completed Phase 2b study 
in RMS patients, the Sponsor maintains that the trial can be initiated and conducted as planned.  
Overall benefit: risk conclusion 
No safety or tolerability concerns have been identified in the completed Phase 1 studies in healthy 
participants or the Phase 2b trial (DRI15928) in participants with RMS. In addition, the positive 
Phase 2b primary endpoint results support the potential for clinical efficacy.  
Drug-induced liver injury has been identified in the ongoing Phase 3 trials. The reported events 
occurred in Months 1 to 3 after the start of the IMP. Exclusion criteria and monitoring frequency 
have been updated in all actively recruiting protocols to mitigate risk of hepatic injury.  
The potential risks associated with SAR442168 are well defined and appropriate safety 
monitoring measures and risk mitigation strategies are in place. The overall benefit/risk balance is 
acceptable for further clinical development of SAR442168. 
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3 
OBJECTIVES AND ENDPOINTS  
Table 1 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
• 
To assess efficacy of daily SAR442168 
compared to a daily dose of 14 mg 
teriflunomide (Aubagio) measured by 
annualized adjudicated relapse rate 
(ARR) in participants with relapsing 
forms of MS 
• 
ARR during the study period assessed by confirmed 
protocol-defined adjudicated relapses 
Secondary 
• 
To assess efficacy of SAR442168 
compared to teriflunomide (Aubagio) 
on disability progression, magnetic 
resonance imaging (MRI) lesions, 
cognitive performance and quality of 
life 
• 
Time to onset of confirmed disability worsening (CDW), 
confirmed over at least 6 months, defined as follows: 
- 
increase of ≥1.5 points from the baseline Expanded 
Disability Status Scale (EDSS) score when the baseline 
score is 0, OR 
- 
increase of ≥1.0 point from the baseline EDSS score when 
the baseline score is 0.5 to ≤5.5, OR 
- 
increase of ≥0.5 point from the baseline EDSS score when 
the baseline score is >5.5 
• 
Time to onset of CDW, assessed by the EDSS score and 
confirmed over at least 3 months 
• 
Total number of new and/or enlarging T2-hyperintense lesions 
as detected by MRI, defined as the sum of the individual number 
of new and/or enlarging T2 lesions at all scheduled visits starting 
after baseline up to and including the EOS visit and number of 
new and/or enlarging T2-hyperintense lesions by visit over time  
• 
Total number of new gadolinium- (Gd-) enhancing 
T1-hyperintense lesions as detected by MRI, defined as the sum 
of the individual number of new Gd-enhancing T1-hyperintense 
lesions at all scheduled visits starting after baseline up to and 
including the EOS visit 
• 
Time to confirmed disability improvement (CDI), defined as 
a ≥1.0 point decrease on the EDSS from the baseline EDSS 
score confirmed over at least 6 months  
• 
Percent change in brain volume loss as detected by brain MRI 
scans at the EOS compared to Month 6  
• 
Change in cognitive function at the EOS compared to baseline 
as assessed by the SDMT 
• 
Change in cognitive function at the EOS compared to baseline 
as assessed by the CVLT-II, where available  
• 
Change in Multiple Sclerosis Quality of Life 54 (MSQoL-54) 
questionnaire score at the EOS compared to baseline 
• 
To evaluate the safety and tolerability 
of daily SAR442168 
• 
Adverse events (AEs), serious AEs, AEs leading to permanent 
study intervention discontinuation, AEs of special interest, and 
potentially clinically significant abnormalities in laboratory tests, 
safety scales, ECG, and vital signs during the study period  
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Objectives 
Endpoints 
• 
To evaluate population 
pharmacokinetics (PK) of SAR442168 
and relevant metabolite(s) and its 
relationship to efficacy and safety 
• 
Plasma concentration of SAR442168 and relevant metabolite(s) 
(population PK assessment) at Months 6, 9, and 12 
• 
To evaluate pharmacodynamics (PD) 
of SAR442168  
• 
Change in plasma neurofilament light chain (NfL) levels at the 
EOS compared to baseline, where available 
• 
Change in lymphocyte phenotype subsets in whole blood at the 
EOS compared to baseline in a subset of participants 
• 
Changes in serum immunoglobulin level at the EOS compared 
to baseline  
• 
Change in serum Chi3L1 levels at the EOS compared to 
baseline  
Tertiary/exploratory 
• 
To evaluate the efficacy of SAR442168 
on disease activity as measured by 
additional clinical, brain MRI, and 
composite measurements 
• 
EDSS score change from baseline at scheduled visits starting 
after baseline and including the EOS visit 
• 
Proportion of adjudicated relapse-free participants from 
randomization until the EOS visit 
• 
Time to onset of 20% worsening in the 9-hole peg test (9-HPT) 
confirmed over at least 3 and 6 months 
• 
Time to onset of 20% worsening in the timed 25-foot walk 
(T25-FW) test confirmed over at least 3 and 6 months 
• 
Time to onset of 4-point decrease in Symbol Digit Modalities 
Test (SDMT) confirmed over at least 3 and 6 months 
• 
Change from baseline of total volume of T2-hyperintense lesions 
as detected by brain MRI at Months 18, 24, and the EOS 
• 
Magnetization transfer ratio recovery at the EOS in new 
magnetization transfer ratio lesions detected at Months 6 and 12 
• 
Change in number of phase rim lesions in susceptibility-
weighted imaging (SWI) MRI from baseline by visit over time 
(subset of centers with capacity of 3T MRI) 
• 
Proportion of participants with no evidence of disease activity 
(NEDA-3) at Months 18, 24, and the EOS 
• 
Change from baseline to Months 12, 18, and 24 and to the EOS 
in modified Multiple Sclerosis Functional Composite 3 (MSFC-3), 
assessed as the composite of the T25-FW test, 9-HPT, and 
SDMT 
• 
Change from baseline by visit over time in volume of 
T1-hypointense lesions, and cumulative number of new 
T1-hypointense lesions 
• 
Number and volume of slowly evolving lesions (SELs) 
• 
Normalized T1 intensity evolution in SELs 
• 
To evaluate the treatment effect of 
SAR442168 via changes in 
participants’ health-related quality of 
life (HRQoL), and working capacity 
• 
Change in EuroQol 5-dimension 5-level questionnaire (EQ-5D-
5L) from baseline by visit over time 
 
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3.1 
APPROPRIATENESS OF MEASUREMENTS  
Clinical relapse is the main clinical manifestation of RMS. Relapse-related endpoints (ARR and 
proportion of relapse-free participants) are accepted and widely used as primary endpoints in 
clinical trials for RMS. 
The EDSS is widely used to measure neurological disability in clinical trials and routine settings 
(14). Due to known fluctuation in EDSS scores, CDW confirmed after 3 or 6 months is used as 
an endpoint in clinical trials of MS (2, 14). Confirmed disability worsening lasting for at least 
6 months is considered to be more clinically relevant and superior in ruling out EDSS score 
fluctuations, and therefore was chosen as a supportive efficacy endpoint in this trial.  
The total number of Gd-enhancing T1-hyperintense lesions as detected by MRI will be used as 
a secondary endpoint to assess the efficacy of SAR442168 on inflammation. This radiographic 
outcome has been established as a highly reliable predictive biomarker for clinical efficacy in 
pivotal studies in MS (5). 
Central review will be used to identify new Gd-enhancing T1-hyperintense lesions not present at 
the previous MRI scans. 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-hyperintense lesions, another MRI marker of disease activity in MS, will 
also be evaluated to collect additional efficacy data. Total T2-hyperintense lesion volume and 
number of T1 hypointense lesions will also be assessed. 
In addition, MRI measurements will include analysis of brain volume loss rate. Brain atrophy, as 
measured by brain volume loss rate, is known to occur early in RMS and to worsen with disease 
progression. Several MS drugs, including teriflunomide used as a comparator in this study (15), 
are known for their capacity to slow down brain volume loss; therefore, brain volume loss will be 
assessed in search of a possible signal. Magnetic resonance imaging at Month 6 will serve as the 
baseline for analyses of magnetization transfer ratio (MTR) and brain atrophy, the latter to 
exclude the potential confounding effect of transient changes in brain volume associated with 
resolution of inflammation after introduction of treatment (so-called pseudoatrophy) (16). 
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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
This trial is a Phase 3, randomized, double-blind, double-dummy, 2-arm, active-controlled, 
parallel-group, multicenter, event-driven (6-month CDW) trial with a variable treatment duration 
ranging from approximately 18 to 36 months. The study will consist of the following study 
periods: 
Screening Period: Day-28 to Day-1. 
Randomization/start of IMP: Eligible participants will be randomly assigned at a 1:1 ratio to 
receive the 60 mg selected dose (established from dose-finding Study DRI15928) of oral 
SAR442168 daily as well as placebo to match the teriflunomide tablet daily or 14 mg oral 
teriflunomide as well as placebo to match the SAR442168 tablet daily. 
Intervention Period: double-blind, double-dummy, treatment period for assessment of efficacy and 
safety up to the end of study (EOS) as described in Section 4.4. 
A month is defined as a period of 28 days by convention. 
Safety follow-up period/EOS: 4 weeks after the last dose of study treatment (for participants 
completing IMP double-blind treatment and not entering the LTS study) to collect safety data. 
A participant is considered to have completed the study if he/she has completed all periods of the 
study including the EOS visit, whether remaining on IMP or not. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
Duration of the study 
The treatment period duration will vary for individual participants, depending on the time of 
recruitment and trial end as described in Section 4.4. All recruited participants will be followed in 
the trial until the common EFC16033 and EFC16034 trial end, which will be estimated and 
announced by the Sponsor to ensure that approximately 162 events of 6-month CDW are observed 
from the pooled data of both trials and the power related to the primary objective of each 
individual trial is preserved (≥90%). With an estimated recruitment period of approximately 
18 months and an assumed event rate discussed in Section 9.2, the duration of the trial is expected 
to be approximately 36 months, with an estimated mean treatment duration of 24 to 27 months. 
Mean exposure duration corresponds to data generated in many MS pivotal trials and is 
considered sufficient to provide solid evidence of efficacy and safety of SAR442168 in the RMS 
population.  
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Choice of Control Group 
Teriflunomide is considered an appropriate comparator in RMS trials for the following reasons: 
• Since its initial approval, teriflunomide has been rapidly adopted for treatment of RMS 
and is considered a standard of care, comparable to other approved therapies in terms of 
safety and efficacy. This is further supported by the fact that other development candidates 
in MS (eg, ponesimod, ofatumumab, and ublituximab) are being compared to 
teriflunomide in pivotal trials. 
• Double blinding will be more feasible with teriflunomide compared with other oral 
products, as the AE profile for teriflunomide is relatively benign, minimizing the risk of 
unblinding physicians and participants. 
• Both treatments (SAR442168 and teriflunomide) will be taken once daily. 
• As a once daily oral therapy, teriflunomide is more conveniently administered than 
injectable or infused therapies, potentially enhancing adherence. 
Other disease-modifying treatments that are approved for treatment of RMS were considered but 
not chosen due to higher risk of unblinding due to safety profile (eg, flushing due to 
dimethylfumarate) or to sample size requirements (eg, ocrelizumab). 
Gadolinium contrast-enhancing preparations for MRI (noninvestigational medicinal product 
[NIMP]) will be used for routine T1 contrast-enhanced sequences. These sequences are part of 
standard MRI controls in MS and are used in clinical practice as well as in routine management of 
RMS. Local recommendations and labeling of the Gd preparations used will need to be followed. 
Cholestyramine will be used in the study as a NIMP for an accelerated elimination procedure for 
teriflunomide. It is approved for teriflunomide accelerated elimination and will be used for early 
IMP termination in some situations (See Appendix 4 [Section 10.4]). 
4.3 
JUSTIFICATION FOR DOSE  
The choice of the dose of 60 mg SAR442168 taken with a meal is based on the results of the 
Phase 2b dose-finding trial for SAR442168 in participants with RMS (DRI15928).  
In this study, doses of 5, 15, 30, and 60 mg SAR442168 were tested in a 12-week double-blind 
treatment period with the number of new Gd-enhancing T1-hyperintense lesions at the end of the 
12 weeks of SAR442168 treatment as the primary endpoint. The results demonstrated 
a dose-response relationship for SAR442168 as evidenced by a reduction in the number of new 
Gd-enhancing T1-hyperintense brain lesions detected by brain MRI after 12 weeks of treatment. 
There was an 85% relative reduction in lesions at 12 weeks in the 60 mg dose group as compared 
with placebo. This was obtained from the negative binomial regression model adjusted for 
baseline Gd-enhancing T1-hyperintense lesion activity. The dose-response relationship for the 
secondary endpoint of new or enlarging T2 lesions also supported the choice of the 60 mg dose.  
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Analysis of the PK data and effect of fed status on SAR442168 exposure showed a positive food 
effect with an increase in AUC0-24 of approximately 2-fold. Moreover, the correlation between the 
treatment response and the exposure to SAR442168 showed that higher exposure was associated 
with low numbers of new Gd-enhancing T1-hyperintense lesions after 12 weeks of treatment. 
Approximately 35% of all study visits from Phase 2b were well documented as being under fed 
conditions. Among these documented visits, 78 participants were under fed conditions. At the 
60 mg dose, most participants (19 of 32) were under a fed condition. No safety or tolerability 
issues were apparent under fed conditions. Taken together, these data support the recommendation 
to take SAR442168 with a meal.  
There was no correlation between the dose of SAR442168 administered and the number of 
TEAEs. The most common events (preferred terms) observed in participants in the SAR442168 
treatment arms were headache, upper respiratory tract infection, and nasopharyngitis. There were 
low numbers of AESIs and PCSAs observed in multiple dose groups. Overall, no new risks were 
identified in this trial.  
4.4 
END OF STUDY DEFINITION  
A participant is considered to have completed the study if he/she has completed all periods of the 
study including the EOS visit, whether remaining on IMP or not. 
The end of the study is defined as the date announced in advance by the Sponsor to ensure that 
approximately 162 events of 6-month CDW are observed from pooled data of this study and the 
parallel EFC16034. With an estimated recruitment period of approximately 18 months and 
an assumed event rate as discussed in Section 9.2, duration of the study is expected to be 
approximately 36 months, with an estimated mean treatment duration of 24 to 27 months. 
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5 
STUDY POPULATION  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, 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 (17). 
I 03. The participant has an EDSS score ≤5.5 at the first visit (Screening Visit) 
I 04. The participant must have at least 1 of the following prior to screening: 
• ≥1 documented relapse within the previous year OR 
• ≥2 documented relapses within the previous 2 years, OR 
• ≥1 documented Gd-enhancing lesion on an MRI scan within the previous year.  
Note: The initial clinical demyelinating episode of MS should be counted as a relapse for 
the first 2 criteria. 
Weight 
I 05. Not applicable. 
Sex 
I 06. Male or Female 
Contraceptive use by men or women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 
Male participants wishing to conceive a child and female participants becoming pregnant or 
wishing to become pregnant must permanently discontinue the study intervention (Section 7.1.1) 
and follow the local teriflunomide label recommendation.  
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A) Male participants 
Male participants are eligible to participate if they agree to the following during the 
intervention period and until the accelerated elimination procedure (when appropriate, 
see Section 6.1.1) is performed.  
• Refrain from donating sperm 
Plus either:  
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent 
on a long-term and persistent basis) and agree to remain abstinent  
OR 
• Must agree to use contraception/barrier method as detailed below 
- 
Agree to use a male condom and should also be advised of the benefit for a female 
partner to use a highly effective method of contraception as a condom may break or 
leak when having sexual intercourse with a woman of childbearing potential 
(WOCBP) who is not currently pregnant 
B) Female participants 
• A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least one of the following conditions apply: 
- 
Is not a WOCBP  
OR 
- 
Is a WOCBP and agrees to use a contraceptive method that is highly effective (with 
a failure rate of <1% per year), preferably with low user dependency, as described in 
Appendix 4 (Section 10.4) during the intervention period and until the accelerated 
elimination procedure is completed after the last dose of study intervention (when 
appropriate, see Section 6.1.1). 
- 
A WOCBP must have a negative highly sensitive pregnancy test at screening and 
within 24 hours before the first dose of study intervention. 
- 
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.  
• Additional requirements for pregnancy testing during the study and after study 
intervention are located in the schedule of activities (SoA) (Section 1.3). 
• The Investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy, if allowed by local regulations.  
• See Appendix 9 (Section 10.11) for country-specific contraception requirements.  
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Informed consent 
I 07. The participant must have given written informed consent prior to undertaking any 
study-related procedure. This includes consent to comply with the requirements and 
restrictions listed in the informed consent form (ICF) and in this protocol. In countries 
where the legal age of maturity is greater than 18 years, a specific ICF for such legally 
minor participants must also be signed by the participant’s legally authorized 
representative (Appendix 1 [Section 10.1.3]). 
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 (17) or with non-relapsing SPMS (18). 
E 02. The participant has a history of infection or may be at risk for infection: 
• A history of T-lymphocyte or T-lymphocyte-receptor vaccination, transplantation 
(including solid organ, stem cell, and bone marrow transplantation) and/or 
antirejection therapy. 
• 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. 
• The participant has a lymphocyte count less than the lower limit of normal (LLN) at 
the Screening Visit. 
• A history of diagnosis of progressive multifocal leukoencephalopathy (PML) or 
evidence of findings suggestive of PML on the screening MRI. 
• A history of infection with human immunodeficiency virus (HIV) (eg, any known 
positive HIV test or information from participant interview). 
• A history of active or latent tuberculosis (TB); TB testing should be performed at 
screening and again during the study, if clinically indicated, and may be repeated 
based on clinical judgment, borderline results, or clinical suspicion of TB infection. 
Screening tests for TB are described in Appendix 2 (Section 10.2). 
NOTE: The Investigator may consult with an infectious disease expert if required, 
eg, test results are unclear or there is a suspicion of false positive test results. If the 
infectious disease expert considers the test results as false positive and not clinically 
relevant and confirms that the participant can be enrolled in the trial, the Investigator 
must document this in source data and may then randomize the participant. 
• Persistent chronic or active recurring infection requiring treatment with antibiotics, 
antivirals, or antifungals. 
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• Fever within 4 weeks of the Screening Visit (≥38°C; however, if due to brief and mild 
ear, nose, throat viral infection participant may be included based on the Investigator’s 
judgment). 
• Participants at risk of developing or having reactivation of hepatitis, ie, results at 
screening for serological markers for hepatitis B and C viruses indicating acute or 
chronic infection. See the Study Manual for further details. 
• Any other active infections that would adversely affect participation or IMP 
administration in this study, as judged by the Investigator. 
E 03. The presence of psychiatric disturbance or substance abuse as evidenced by: 
• A history of any psychiatric disease, behavioral condition, or depression requiring 
hospitalization within 2 years prior to the Screening Visit. 
• A documented history of attempted suicide or suicidal ideation of category 4 or 
5 according to the Columbia Suicide Severity Rating Scale (C-SSRS) 
baseline/screening version over the 6 months prior to the Screening Visit, OR if in the 
Investigator's judgment, the participant is at risk for a suicide attempt. 
• Active alcohol use disorder or a history of alcohol or drug abuse within 1 year prior to 
the Screening Visit. 
• Current alcohol intake >2 drinks per day for men and >1 drink per day for women 
(1 drink = approximately 14 grams of alcohol = 350 mL beer = 140 mL wine = 40 mL 
of spirits) 
E 04. The following findings obtained during the Screening Visit considered in the Investigator’s 
judgment to be clinically significant in the context of this clinical trial: 
• Any screening laboratory values outside normal limits  
• Abnormal ECG 
E 05. Conditions that may predispose the participant to excessive bleeding: 
• A bleeding disorder or known platelet dysfunction at any time prior to the Screening 
Visit 
• A platelet count <150 000/μL at the Screening Visit 
• The participant has had major surgery within 4 weeks prior to the Screening Visit, 
which could affect the participant’s safety or affect immune response (as judged by the 
Investigator) or has planned any elective major surgery during the study. 
• A history of significant bleeding event within 6 months prior to screening, according to 
the Investigator’s judgment such as, but not limited to cerebral or gastrointestinal 
bleeding. 
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E 06. Conditions that would adversely affect participation in the study or make the primary 
efficacy endpoint non-evaluable:  
• 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 
• A short life expectancy due to pre-existing health condition(s) as determined by their 
treating neurologist 
• 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 (ie, undergoing dialysis), neurological, endocrine, 
gastrointestinal, metabolic, pulmonary (eg, interstitial pneumonia or pulmonary 
fibrosis), or lymphatic disease that would adversely affect participation in this study 
• Acute liver disease, cirrhosis, chronic liver disease (unless considered stable for 
>6 months) 
• Confirmed screening ALT >1.5 x ULN OR AST >1.5 x ULN OR alkaline phosphatase 
>2 x ULN (unless caused by non-liver-related disorder or explained by a stable chronic 
liver disorder) OR total bilirubin >1.5 x ULN (unless due to Gilbert syndrome or 
non-liver-related disorder) 
• At screening, elevated transferrin saturation (>50% in males and >40% in females) 
and/or with elevated ferritin levels >500 μg/L  
• Any malignancy within 5 years prior to the Screening Visit (except for effectively 
treated carcinoma in situ of the cervix or adequately treated non-metastatic squamous 
or basal cell carcinoma of the skin) will also be exclusionary.  
• Any other medical condition(s) or concomitant disease(s) making them non-evaluable 
for the primary efficacy endpoint or that would adversely affect participation in this 
study, as judged by the Investigator. 
Prior/concomitant therapy 
E 07. The participant has received any of the following medications/treatments within the 
specified time frame before any baseline assessment (no washout is required for dimethyl 
fumarate, interferon beta, or glatiramer acetate treatments): 
 
Medication 
Washout period duration 
Systemic corticosteroids, adrenocorticotropic hormone 
1 month prior to screening MRI scan 
Siponimod 
1 week before randomization with MRI and clinical 
assessment for PML prior to randomization 
Plasma exchange 
1 month prior to randomization 
Intravenous immunoglobulin 
2 months prior to randomization 
Fingolimod, ozanimod 
6 weeks before randomization with MRI and clinical 
assessment for PML 
Mildly to moderately immunosuppressive/chemotherapeutic 
medications such as azathioprine and methotrexate, mycophenolate 
3 months prior to randomization 
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Medication 
Washout period duration 
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 
A participant who has received any of these 
treatments at any time is not eligible. 
Teriflunomide 
• 
<3 months treatment 
 
3 months prior to randomization* 
• 
≥3 months treatment  
A participant who has received this treatment at 
any time is not eligible. 
Natalizumab 
2 months before randomization with MRI and 
clinical assessments for PML 
B-cell-depleting therapies such as ocrelizumab and rituximab 
6 months prior to randomization 
Ofatumumab 
4 months prior to randomization 
Highly immunosuppressive/chemotherapeutic medications: 
mitoxantrone up to 120 mg/m2 body surface area, 
cyclophosphamide, cladribine, cyclosporine 
2 years prior to randomization 
Alemtuzumab 
4 years prior to randomization 
Other MS-disease modifying treatments 
5 half-lives or until end of pharmacodynamics 
activity, whichever is longer 
Abbreviations: MRI: magnetic resonance imaging, MS: multiple sclerosis, PML: progressive multifocal leukoencephalopathy 
* No time restriction if accelerated elimination procedure is done 
E 08. The participant is receiving potent and moderate inducers of cytochrome P450 (CYP) 3A 
or potent inhibitors of CYP2C8 hepatic enzymes as listed in Appendix 8A (Section 10.8). 
E 09. The participant is receiving anticoagulant/antiplatelet therapies, including: 
• Acetylsalicylic acid (aspirin) >81 mg/day 
• 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 the above-mentioned drugs must be stopped at least 5 half-lives before study 
drug administration except for aspirin, which must be stopped at least 8 days before. 
These washout periods are only applicable in the case that the Investigator deems it 
clinically appropriate to discontinue the listed medications or there is a recent history 
of use of these medications (as in the case when short term treatment with 
anticoagulants is clinically recommended for certain thrombotic events), and therefore 
these washout periods will need to be followed prior to enrollment. 
If, however, the participant has a chronic underlying medical condition (stroke, 
coronary or carotid artery disease, heart valvular disease etc) requiring continued use 
of these medications, the participant cannot be enrolled in the study. 
E 10. A history of a hypersensitivity reaction to teriflunomide, leflunomide, or to any of the 
inactive ingredients in Aubagio (this includes anaphylaxis, angioedema, and serious skin 
reactions) 
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Prior/concurrent clinical study experience 
E 11. The participant was previously exposed to any BTK inhibitor, including SAR442168. 
E 12. The participant has taken other investigational drugs within 3 months or 5 half-lives, 
whichever is longer, before the Screening Visit. 
Diagnostic assessments 
E 13. The participant has had a relapse in the 30 days prior to randomization. 
E 14. The participant has 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 
scans. 
Note: People with a contraindication to Gd can be enrolled into the study but cannot 
receive Gd contrast dyes during their MRI scans. 
Other exclusions 
E 15. Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or participants who are legally institutionalized. 
E 16. Any country-related specific regulation that would prevent the participant from entering 
the study. (See Appendix 9 [Section 10.11]) 
E 17. Participant not suitable for participation, whatever the reason, as judged by the 
Investigator, including medical or clinical conditions, or participants potentially at risk of 
noncompliance to study procedures or not able to follow the schedule of protocol 
assessments due to other reasons.  
E 18. Participants are 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 19. Participants are employees of the clinical study site or other individuals directly involved 
in the conduct of the study, or immediate family members of such individuals. 
E 20. Any other situation during study implementation/course that may raise ethics 
considerations.  
E 21. See Appendix 9, Section 10.11.3, for additional exclusion requirements for Japan. 
Note: a one-time retest at screening may be performed if an abnormal laboratory test value is 
considered temporary. 
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5.3 
LIFESTYLE CONSIDERATIONS  
5.3.1 Meals and dietary restrictions  
SAR442168 shall be taken with a regular meal. When possible, the meal with which SAR442168 
is taken (eg, breakfast, lunch, or dinner) should be consistent throughout the study. The typical 
meal with which the IMP is taken will be recorded at each visit. In case the mealtime for IMP 
administration needs to be changed, a gap of a minimum of 12 hours between 2 doses should be 
maintained.  
5.3.2 Caffeine, alcohol, and tobacco  
For each visit with PK/PD assessment (refer to Section 1.3), 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 and/or PD sample later 
that day. 
For each visit with PK/PD assessment (refer to Section 1.3), participants will abstain from alcohol 
for 24 hours before the start of treatment until after collection of the final PK and/or PD sample 
later that day.  
During the entire study, participants should be warned not to consume substantial quantities of 
alcohol, defined as >14 grams (1 standard drink) per day in female participants or >28 grams 
(2 standard drinks) per day in male participants on a regular basis. 
5.3.3 Activity  
No special restrictions. 
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 a different participant 
number. More information on rescreening procedures is provided in the Study Manual. 
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5.5 
CRITERIA FOR TEMPORARILY DELAYING ADMINISTRATION OF STUDY 
INTERVENTION  
During a regional or national emergency declared by a governmental agency, if the site is unable 
to adequately follow protocol mandated procedures, contingency measures proposed in 
Appendix 10 (Section 10.12): Contingency measures for a regional or national emergency that is 
declared by a governmental agency should be considered for administration of study intervention. 
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6 
STUDY INTERVENTION  
Study intervention is defined as any investigational intervention(s), marketed product(s), or 
placebo intended to be administered to a study participant according to the study protocol. 
6.1 
STUDY INTERVENTION(S) ADMINISTERED  
Table 2 - Overview of study interventions administered  
ARM name 
SAR442168 
Teriflunomide 
Intervention name 
SAR442168 60 mg 
Placebo matched to teriflunomide  
Teriflunomide 14 mg 
Placebo matched to SAR442168 
Type 
Drug 
Drug 
Dose formulation 
SAR442168: Film-coated tablet 
Placebo matched to teriflunomide: 
Tablet 
Teriflunomide: Tablet 
Placebo matched to SAR442168: 
Film-coated tablet  
Unit dose strength(s) 
60 mg 
14 mg 
Dosage level(s) 
Once daily 
Once daily 
Route of administration 
Oral 
Oral 
IMP and NIMP 
IMP 
IMP 
Packaging and labeling 
Study intervention will be provided in 
wallet blister packaging. The content 
of the labeling is in accordance with 
the local regulatory specifications and 
requirements. 
Study intervention will be provided 
in wallet blister packaging. The 
content of the labeling is in 
accordance with the local regulatory 
specifications and requirements. 
Current/Former name(s) or 
alias(es) 
Not applicable 
Aubagio 
The details of this table are specific to IMP; information of non-IMP is described separately in Section 6.1.1. 
IMP: investigational medicinal product, NIMP: noninvestigational medicinal product 
Between the protocol-scheduled, onsite visits, interim visits may be required for IMP dispensing. 
As an alternative to these visits or to replace onsite IMP dispensation, if needed, IMP may be 
supplied from the site to the participant via a Sponsor-approved courier company (direct-to-
patient shipment) where allowed by local regulations and approved by the Sponsor. 
For a regional or national emergency declared by a governmental agency that results in travel 
restrictions, confinement, or restricted site access, contingency measures are included in 
Appendix 10 (Section 10.12): Contingency Measures for a regional or national emergency that is 
declared by a governmental agency. 
6.1.1 Noninvestigational medicinal product  
MRI contrast-enhancing preparations 
• Route(s) of administration: IV 
• Dose regimen: as per respective label 
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Cholestyramine 
• Route(s) of administration: oral 
• Dose regimen: 8 g 3 times daily for 11 days for accelerated elimination procedure 
(4 g 3 times daily for 11 days in case of intolerance). The teriflunomide local label should 
be followed.  
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
1. The Investigator or designee must confirm appropriate 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. In case of DTP shipment, 
temperature monitoring is under vendor responsibility. 
2. Only participants enrolled in the study may receive study intervention and only authorized 
site staff may supply or administer study intervention. All study interventions 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. 
3. 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). 
Any quality issue noticed with the receipt or use of an IMP/NIMP (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 8.3.9). 
A potential defect in the quality of IMP/NIMP may be subject to initiation of a recall procedure 
by the Sponsor. In this case, the Investigator will be responsible for promptly addressing any 
request made by the Sponsor, in order to recall the IMP/NIMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP/NIMP to a third party (except for direct-
to-patient shipment, for which a courier company has been approved by the Sponsor), allow the 
IMP/NIMP to be used other than as directed by this clinical trial protocol, or dispose of 
IMP/NIMP in any other manner. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
All participants will be centrally assigned to randomized study intervention using an interactive 
response technology (IRT). The randomized intervention kit number will be stratified for EDSS 
score at screening (<4, ≥4) and geographic region (US, non-US). A participant cannot be 
randomized more than once in the study. A participant assigned to a specific arm at randomization 
may be allocated, by the IRT, to several (varying) intervention numbers (and corresponding 
intervention kit numbers) for multiple visits despite having the same intervention arm assignment 
from randomization. That is, in these cases, the intervention/kit number varies but the arm 
assignment at randomization does not change. Before the study is initiated, the log-in information 
and instructions for the interactive web response system (IWRS) will be provided to each site. 
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Study intervention will be dispensed at the study visits summarized in the SoA (Section 1.3). 
Returned study intervention should not be re-dispensed to the participants. 
The Treating Investigator, Examining Investigator/rater, clinical site staff, and Sponsor’s clinical 
trial team members will not have access to the randomization (treatment) codes. The IRT 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 
(eg, in case of available antidote). Participant safety must always be the first consideration in 
making such a determination. 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 electronic case report form (eCRF), as 
applicable. If unblinded, information pertaining to the treatment allocation should not be shared 
with other members of the study team or Sponsor. 
Methods of blinding 
This study is blinded for treatment group allocation (SAR442168 or teriflunomide). Tablets of 
placebo to match SAR442168 and placebo to match teriflunomide will be used in 
a double-dummy fashion to assure blinding. Participants will receive 2 tablets daily which will be 
identical between treatment groups (SAR442168 60 mg and placebo matching teriflunomide or 
teriflunomide 14 mg and placebo matching SAR442168). 
In order to maintain the study blind and ensure participant safety, each site will have 2 types of 
Investigators: a Treating Investigator and an Examining Investigator (blinded rater). The study 
site personnel designated to conduct efficacy assessments (Examining Investigators/raters or other 
qualified site staff) must be different from physicians responsible for participants’ medical 
management (Treating Investigators) in order to protect against possible unblinding of the 
treatment assignment during regular clinical care of participants. In view of the extended duration 
of this study, each site will identify primary and back-up Treating and Examining 
Investigators/raters. A Treating Investigator cannot change roles to an Examining 
Investigator/rater during the study. 
The Treating Investigator is the physician responsible for participant care and should be 
a neurologist experienced in the care of MS patients. The Treating Investigator will not have 
access to efficacy data including EDSS scores other than the score at screening. The Treating 
Investigator will have access to the participant’s other collected data and will follow the 
participant, collect safety events data, and make treatment decisions based on the participant’s 
clinical response and laboratory test findings. Once the participant has been randomly assigned to 
treatment, the Treating Investigator will use local laboratory if needed for additional safety 
assessments. 
The Examining Investigator/rater should be trained and certified in administering the EDSS and 
other efficacy tests. Details for certification and re-certification requirements for administering the 
EDSS will be provided in the Study Manual. The Examining Investigator/rater will be responsible 
for assessment with the EDSS including the screening EDSS score assessment and other clinical 
efficacy tests and will have access only to data needed for these assessments. The Examining 
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Investigator/rater can delegate assessment of T25-FW, 9-HPT, SDMT and CVLT-II to qualified 
study staff. The Examining Investigator/rater will not have access to scores and results of prior 
EDSS assessments. Whenever possible, the same individual should perform the assessments and 
examinations for the full study duration. All efforts should be made to keep the Examining 
Investigator/rater blinded to a participant’s treatment assignment, treatment dates, and 
consequently to AE data, non-neurological symptoms, laboratory data, concomitant and prior 
medications, and any other information not related to the EDSS and other efficacy assessments. 
Participants will be instructed not to discuss any symptoms related to the IMP with the Examining 
Investigator/rater; the Examining Investigator/rater will remind the participant of this at the start 
of the examination and will not ask any questions that are not related to the neurological 
examination. Participants will be asked not to communicate any comedication used or symptoms 
unless requested by the Examining Investigator/rater for efficacy evaluation. 
An independent Data Monitoring Committee (DMC) will be used to periodically monitor safety 
of this study. Unblinded data will be provided for DMC 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  
• Methods used by the Investigator or his/her delegate to ensure that the IMP was 
administered may include mouth inspection (eg, for onsite visits). 
• Measures taken to ensure study intervention accountability include: 
- 
Intervention units are returned by the participant at each visit. In case of 
direct-to-patient process, the intervention units can be returned by the carrier 
(if defined in the contract). 
- 
The Treating Investigator or his/her delegate counts the number of tablets remaining in 
the returned packs and fills in the Intervention Log Form. 
- 
The Treating Investigator or his/her delegate records the dosing information on the 
appropriate page(s) of the eCRF. 
- 
The monitor in charge of the study then checks the eCRF data by comparing them with 
the IMP which he/she has retrieved and Intervention Log Form. 
A paper diary, to capture the details of the use of study medication, timing of meals, change in 
mealtime for IMP administration, missed doses, and overdoses, will be provided to each study 
participant after they have received training on how to use the diary. Participants should bring the 
diary to each site visit for review by the Investigator and/or study staff and monitoring of 
compliance and exposure data. At each visit when study medication will be dispensed, a new 
paper diary should be provided to the study participant. In case of direct-to-patient shipment, the 
new paper diary will be dispensed along with IMP, and the participant will return the previous 
completed paper diary to the study site via the carrier. 
Participant compliance with study intervention will be assessed at each study site visit. 
Compliance will be assessed by counting returned tablets. Deviation(s) from the prescribed 
dosage regimen should be recorded 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 
Participants must abstain from taking prescription or nonprescription drugs (including vitamins 
and dietary or herbal supplements) within 7 days (or 14 days if the drug is a potential enzyme 
inducer) or 5 half-lives (whichever is longer) before the start of study intervention until 
completion of the follow-up visit, unless, in the opinion of the Investigator, the medication will 
not interfere with the study.  
Live (attenuated) vaccines should not be administered during the intervention period. 
Therapies for MS noted in the exclusion criterion E07 are not permitted after randomization while 
the participant is on study treatment. Short term use (3 to 5 days) of glucocorticoids (eg, for MS 
relapse treatment or an acute illness) and local corticosteroids (eg, topical, nasal, ocular, otic, 
intra-articular) are allowed. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
For some prohibited concomitant medications (eg, aspirin >81 mg/day for headache), if use is not 
chronic, temporary discontinuation of IMP can be considered prior to a decision to permanently 
stop the IMP. 
Medications for treatment of MS symptoms (eg, walking impairment, fatigue, spasticity, 
incontinence, pain) should be maintained at a stable dose prior to screening and for the duration of 
the treatment period, if clinically feasible. 
Anticoagulant/antiplatelet therapies are not permitted to be taken concomitantly with the IMP, 
including: 
• Acetylsalicylic acid (aspirin) >81 mg/day 
• 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) 
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Paracetamol/acetaminophen, at doses of ≤3 grams/day, is permitted for use at any time during 
the study. A short course (up to 5 days) of nonsteroidal anti-inflammatory drugs (NSAIDs) (other 
than acetylsalicylic acid), preferably selective cyclooxygenase-2 inhibitors at the lowest effective 
dose, may be given during 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 eCRF. 
CYP Inhibitor/inducer: 
Potent and moderate inducers of CYP3A or potent inhibitors of CYP2C8 hepatic enzymes are not 
permitted throughout the study (See Appendix 8A [Section 10.8]).  
• SAR442168: SAR442168 is a substrate of the CYP3A4 and CYP2C8 isoenzymes. In 
healthy participants, potent CYP3A4 inhibitor (itraconazole 200 mg once daily for 4 days) 
increased SAR442168 area under the curve (AUC) exposure 1.8-fold (INT16385 study) 
and potent CYP2C8 inhibitor (gemfibrozil 600 mg twice daily for 6 days) increased 
SAR442168 (AUC) exposure 8.4-fold (INT16726 study). Based on a satisfactory safety 
and tolerability profile and on the observed exposure in healthy participants who received 
SAR442168 at a dose of up to 240 mg once daily for 14 days under fed conditions 
(TDR16862 study), drugs that strongly inhibit CYP3A4 are allowed and drugs that 
strongly inhibit CYP2C8 are not permitted. In healthy participants, potent CYP3A4 and 
moderate CYP2C8 induction by rifampicin (600 mg once daily for 8 days) decreased 
SAR442168 exposure 6-fold (INT16726 study). Therefore, potent and also moderate 
(based on prediction) CYP3A inducers are not permitted due to their potential to decrease 
SAR442168 exposure and efficacy. See Appendix 8A (Section 10.8) for the list of drugs 
not to be used.  
• Teriflunomide: Other potent CYP and transporter inducers should be avoided due to their 
potential to decrease teriflunomide exposure. Rifampicin and other known potent CYP and 
transporter inducers such as carbamazepine, phenobarbital, phenytoin, avasimibe, 
lumacaftor, rifapentine, rifabutin, and St John’s wort, should be avoided. Leflunomide is 
prohibited, because teriflunomide is a metabolite of leflunomide. 
Cholestyramine (and other bile acid sequestrants) and activated charcoal use should be avoided 
because these may lead to significant decrease in plasma concentration of teriflunomide. 
Cholestyramine can be used only when an accelerated elimination procedure is needed. In 
exceptional situations (eg, when cholestyramine is not tolerated, or cholestyramine is not 
available) use of activated charcoal (as per the current Aubagio SmPC) can be considered. 
Breast cancer resistance protein (BCRP) inhibitors (eg, eltrombopag and gefitinib) should be 
avoided. Based on in vitro studies, teriflunomide is a substrate of the efflux transporter BCRP, so 
these drugs may increase exposure of teriflunomide (Appendix 8B [Section 10.9]). 
A number of drugs need to be used with caution as their exposure may be altered by teriflunomide 
(Appendix 8C [Section 10.10]). Adequate arrangements need to be made to monitor their effects 
and to ensure timely decision for change of medication. 
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• Medicinal products metabolized by CYP2C8 (eg, repaglinide, pioglitazone, and 
rosiglitazone) should be used with caution during treatment with the IMP due to potential 
of increase of concentrations of these drugs following CYP2C8 inhibition by 
teriflunomide. 
• Increase in ethinylestradiol and levonorgestrel exposure following repeated doses of 
teriflunomide has been observed (19). While this interaction of teriflunomide is not 
expected to adversely impact the efficacy of oral contraceptives, it should be considered 
when selecting or adjusting oral contraceptive treatment used during this trial.  
• Medicinal products metabolized by CYP1A2 (eg, duloxetine, alosetron, theophylline, and 
tizanidine) should be used with caution during treatment with IMP due to the capacity of 
teriflunomide to induce CYP1A2 and to reduce efficacy of these products. 
• Administration of substrates of organic anion transporter 3 (OAT3) (eg, cefaclor, 
benzylpenicillin, ciprofloxacin, indomethacin, ketoprofen, furosemide, and cimetidine) 
should be performed with caution during the study due to the potential of teriflunomide to 
increase exposure to these medications through inhibition of OAT3.  
• For substrates of BCRP (eg, sulfasalazine) and the organic anion transporter polypeptide 
(OATP) family (eg, rosuvastatin, simvastatin, atorvastatin, pravastatin, nateglinide, 
repaglinide, and rifampicin), concomitant administration with teriflunomide should be 
used with caution during the study due to the potential of teriflunomide to increase 
exposure to these products. Participants should be closely monitored for signs and 
symptoms of excessive exposure to the medicinal products, and reduction of the dose 
should be considered. If used together with the IMP, the dose of rosuvastatin should not 
exceed 10 mg once daily. 
6.5.1 Rescue medicine  
There is no rescue medication planned for this study.  
Multiple sclerosis relapse treatments are allowed as per local routine practice (eg, high 
dose IV methylprednisolone for 3 to 5 days). These and all other concomitant medications must 
be reported in the eCRF.  
6.6 
DOSE MODIFICATION  
Dose reduction is not foreseen in this study. Treatment may 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  
After the end of this study, participants who successfully complete the trial and are taking the IMP 
until the end of the trial will be offered the option to participate in the LTS study for an additional 
2 years, or until the drug is approved in their respective country, whichever comes first. Details of 
the LTS study will be described in a separate protocol. Post-trial access for more than 2 years may 
be considered if mandated by local regulations. 
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
7.1 
DISCONTINUATION OF STUDY INTERVENTION  
7.1.1 Definitive discontinuation  
The study intervention should be continued whenever possible. 
Permanent intervention discontinuation is any treatment discontinuation associated with the 
definitive decision from the Investigator or the participant not to re-expose the participant to the 
study intervention at any time. 
In rare instances, it may be necessary for a participant to permanently discontinue the study 
intervention. If study intervention is permanently discontinued, the participant shall be asked to 
remain in the study to be evaluated until the EOS visit. This will be important to continue to 
evaluate for safety. See the SoA (Section 1.3) for data to be collected at the time of discontinuation 
of the study intervention. In the case that the study intervention is permanently discontinued, the 
participant should be treated for MS according to local clinical practice and the best judgment of 
the Investigator. 
The following may be justifiable reasons for the Investigator or Sponsor to discontinue 
a participant from study treatment: 
• Adverse events that endanger the safety of the participant, or if discontinuation of study 
intervention is desired or considered necessary by the Investigator and/or participant. 
• If IMP discontinuation criteria are met as per guidance for the follow up of laboratory 
abnormalities in Appendix 6 (Section 10.6). 
• The participant is no longer deriving a therapeutic/clinical benefit in the opinion of the 
Investigator. 
• At participant’s request, ie, withdrawal of the consent for treatment. 
• If a female participant becomes pregnant or wishes to become pregnant during the study. 
• If a male participant wishes to conceive a child during the study. 
• Any serious opportunistic infections (eg, PML [See Appendix 6, Section 10.6], HIV). 
• Continued need for/chronic use of a prohibited concomitant medication (see Section 6.5, 
Appendix 8A [Section 10.8], Appendix 8B [Section 10.9], and Appendix 8C 
[Section 10.10]). 
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 algorithm (Appendix 6, 
[Section 10.6]) or if the Investigator believes that it is in the best interest of the participant.  
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Any clinically significant abnormal laboratory value or ECG parameter will be immediately 
rechecked for confirmation after 24 hours before making a decision of definitive discontinuation 
of the IMP for the concerned participant.  
If a clinically significant finding is identified in the ECG (including, but not limited to changes 
from baseline in QT interval corrected (QTc) using Fridericia’s formula [QTcF] after enrollment), 
the Investigator or a 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 
may be considered for a decision of a definitive discontinuation of study intervention because of 
ECG changes. This review of the ECG findings recorded at the time of collection must be 
documented. Any new clinically relevant ECG finding should be reported as an AE. 
See the SoA (Section 1.3) for data to be collected at the time of intervention discontinuation and 
follow up and for any further evaluations that need to be completed. 
Handling of participants after definitive intervention discontinuation 
Participants will be followed up according to the study procedures specified in this protocol up to 
the scheduled date of study completion or up to recovery or stabilization of any AE to be followed 
up as specified in this protocol, whichever comes last. The participant should be treated for MS 
according to local clinical practice and the best judgement of the Treating Investigator. 
If possible, and after the definitive discontinuation of study drug, the participants will be assessed 
using the procedures planned for the pEOT visit, including collection of a PK sample if the pEOT 
visit can be scheduled within a maximum of 24 hours after the last IMP dose. 
Participants will be asked to continue in the study, attending all scheduled visits as per SoA 
(Section 1.3, footnote e), if possible, until the end of the study. If the participant does not agree to 
the full visit schedule after a decision for permanent EOT, a reduced visit schedule may be agreed 
with the participant. Every effort should be made to collect endpoint information and vital status 
at least once a year and at the EOS. 
For participants with definitive discontinuation of study drug who do not agree to remain in the 
study after the premature EOT visit, if the premature EOT visit is less than 3 weeks after the last 
dose of the study drug, an additional visit should be performed with assessments normally 
planned for the follow-up visit.  
All cases of definitive study drug discontinuation must be recorded by the Treating Investigator in 
the appropriate pages of the eCRF when considered as confirmed. 
7.1.2 Temporary discontinuation  
Temporary intervention discontinuation, because of suspected AEs or disruption of the clinical 
trial due to a regional or national emergency declared by a governmental agency (Appendix 10 
[Section 10.12.3]: Contingency measures for a regional or national emergency that is declared by 
a governmental agency), may be considered by the Treating Investigator. For all temporary 
intervention discontinuations, duration should be recorded by the Investigator in the appropriate 
pages of the eCRF. 
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If surgery is needed during the study, consider the benefit/risk of withholding the IMP for at least 
3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding 
The following shall lead to temporary treatment discontinuation: 
• Cytopenia: follow the safety algorithm for neutropenia and thrombocytopenia as per 
Appendix 6 (Section 10.6) 
• Serum creatinine, creatine phosphokinase (CPK), and liver enzyme increase: follow 
corresponding safety algorithms as per Appendix 6 (Section 10.6) 
• Cardiac arrhythmia (atrial fibrillation): Any Grade 3 event (symptomatic, urgent 
intervention indicated; device [eg, pacemaker]; ablation; new onset) 
• Suicidal risk as per C-SSRS: if a participant scores “yes” on items 4 or 5 of the Suicidal 
Ideation Section, or “yes” on any item of the Suicidal Behavior Section 
7.1.2.1 Rechallenge  
Reinitiation of 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, that 
there are no safety concerns, and if the criteria for permanent treatment discontinuation have not 
been met (refer to Section 5.1 and Section 5.2). 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 10 (Section 10.12): Contingency measures for a regional or national 
emergency that is declared by a governmental agency.  
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. This is expected to be uncommon. 
• At the time of discontinuing from the study, if possible, a premature EOT Visit should be 
conducted, as shown in the SoA (Section 1.3). See the SoA 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 the 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. 
If participants no longer wish to take the IMP, they will be encouraged to remain in the study until 
the common study end (EOS). 
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The Investigators should discuss with participants key visits to attend. The value of all their study 
data collected during their continued involvement will 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 his/her consent to stop participating 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 non-participant 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 randomly assigned again in the study. 
Their inclusion and intervention 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 
no contact can be made with 3 telephone calls, a certified letter to the participant’s last 
known mailing address or local equivalent methods). Participants who are unable to be 
reached should be contacted again at the time of the EOS visit to confirm that indeed 
no contact could be made. 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. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 
(Section 10.1.9). 
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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. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• 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 participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA. Such assessments shall be recorded on the 
designated field in the case report form (CRF). 
• Blood sampling details including volume for all laboratory assessments will be provided in 
the laboratory manual and the informed consent form. Repeat or unscheduled samples may 
be taken for safety reasons or for technical issues with the samples. 
• In exceptional cases, under regional or national emergencies (eg, natural disaster, epidemic 
disease, terrorist attack), onsite visits may be replaced with telephone/remote visits. For 
example, participant interviews for medical history/prior medications could be performed 
by phone, local safety labs and some efficacy assessments could be performed off-site/at 
the participant's home (eg, home nursing) if agreed by the participant and permissible per 
local regulations. In such circumstances, the visit window may be expanded, if needed 
(eg, ±14 days for quarterly visits). 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 10 (Section 10.12): Contingency measures for a regional or national 
emergency that is declared by a governmental agency. 
8.1 
EFFICACY ASSESSMENTS  
Planned time points for all efficacy assessments are provided in the SoA (Section 1.3). 
Key efficacy assessments will be scored by an Examining Investigator/rater or a blinded imaging 
rater who is not otherwise involved in the management of participants in this study. 
Key assessments of disability (eg, EDSS) will be performed by a blinded Examining 
Investigator/rater who will have no access to laboratory and AE reports. The MRI scans for 
efficacy analyses will be analyzed by a blinded, independent, central, MRI-reading unit. 
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8.1.1 Expanded disability status scale  
The Examining Investigator/rater will perform the EDSS evaluation (14). All Examining 
Investigators/raters will be trained and certified to perform the EDSS in a consistent manner.  
The EDSS score will be captured using an electronic EDSS tool. Quality control measures will be 
put in place to ensure scoring error detection and thus minimize the impact of any scoring and 
calculation errors. 
The Examining Investigator/rater 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 7 functional domains (visual, brainstem, pyramidal [motor], cerebellar 
[coordination], sensory, cerebral, and bowel/bladder) scoring will be performed by assessing 
neurological symptoms in each of these domains. Ambulation scoring will be done to conclude 
evaluation. The fatigue evaluation may be optionally recorded, but it will not contribute to 
assignment of the EDSS score. The total EDSS score will be assigned according to EDSS scoring 
rules. The Examining Investigator/rater will not have access to previous EDSS scores and will be 
blinded to all data that could unblind the participant’s treatment assignment (see Section 6.3).  
A screening EDSS assessment must be completed to confirm eligibility, and the EDSS assessment 
must be repeated at the randomization visit.  
The EDSS scores, with the exception of screening EDSS scores, will not be communicated to any 
study staff including the Treating Investigator. Participants will not be informed of their EDSS 
scores.  
Additional details on the EDSS score reporting will be provided in the Study Manual. 
8.1.1.1 Confirmed disability worsening  
Confirmed disability worsening at 3 or 6 months is a confirmed, sustained increase from baseline 
in EDSS score (of ≥1.5 points when the baseline score is 0, of ≥1.0 point when the baseline score 
is 0.5 to ≤5.5, of ≥0.5 points when the baseline EDSS score is >5.5) over at least the specified 
number of months and is not attributable to another etiology (eg, fever, concurrent illness, or 
concomitant medication). 
• The initial onset increase from baseline EDSS score can be from a scheduled or 
unscheduled assessment. 
• All intermediate EDSS scores (EDSS scores obtained after onset of disability and before 
the confirmatory assessment), if any, must maintain at least the minimum increase. 
• Confirmatory EDSS assessments must be obtained over at least the specified number of 
months (3 or 6 months) after onset, at a routine quarterly visit, at least 30 days after any 
confirmed clinical relapse, and not be associated with an ongoing relapse. 
Confirmed disability worsening at 6 months will serve as the basis of conclusion for the key 
secondary endpoint. 
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8.1.1.2 Confirmed disability improvement  
Confirmed disability improvement is defined as a decrease of ≥1 point from baseline in the EDSS 
score lasting at least 6 months. 
8.1.2 Multiple sclerosis relapse assessment  
8.1.2.1 Definition of multiple sclerosis relapse  
For the purposes of this study, MS relapse is defined as a monophasic, acute or subacute onset of, 
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, with or without recovery, 
• Be present at normal body temperature (ie, no infection, excessive exercise, or excessively 
high ambient temperature), and 
• Be preceded by ≥30 days of clinical stability (including no previous MS relapse).  
Note: An exacerbation or recurrence of symptoms and signs in a participant with MS 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 injections of interferon beta), or raised core 
body temperature (the Uhthoff phenomenon) will not be considered a relapse. 
Confirmation of MS relapse will be done by the Relapse Adjudication Committee and will be 
based on the EDSS score (14) (provided by the Examining Investigator/rater), based on the 
following definition:  
• A confirmed MS relapse is one accompanied by a clinically relevant change in the EDSS 
score performed by the Examining Investigator/rater, ie, an increase of at least 0.5 points 
in the EDSS score, an increase of 1 point on 2 functional scores, or an increase of 2 points 
on 1 functional score, excluding changes involving bowel/bladder and cerebral functional 
score compared to the previously available rating (the last EDSS rating that did not occur 
during a relapse). 
Refer to Section 8.3.7 for details regarding MS relapse reporting. 
8.1.2.2 Unscheduled assessment visits  
Participants must be instructed to immediately report new neurological symptoms and recurring or 
worsening of previous symptoms to the Treating Investigator. Any reported symptoms will be 
recorded. If a participant reports symptoms that may be consistent with relapse, an unscheduled 
assessment visit to the Treating Investigator and the Examining Investigator (blinded rater) must 
be scheduled as soon as possible (whenever possible within 7 days of onset of the symptoms). The 
assessment, management, and reporting of MS relapse is made by the Treating Investigator. 
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Diagnosing MS relapses during the study: The Treating Investigator will assess whether the 
reported episode is consistent with the definition of MS relapse, per protocol. If it is consistent 
with the definition of MS relapse or if there is any doubt and the possibility of relapse cannot be 
ruled out, the standard neurological examination (for the EDSS score) will be performed by the 
Examining Investigator/rater. If the participant is not referred for neurological examination, this 
will be documented with an explanation of the reason. Whenever possible, the Examining 
Investigator/rater should perform the EDSS rating the same day as the examination is performed 
by the Treating Investigator. Subsequent EDSS assessments can still be utilized for confirmation 
of MS relapses but should be avoided to reduce the risk of changes in participant status in 
between the assessments by the Treating and Examining Investigators/raters. 
All MS relapses are to be reported on the MS relapse eCRF page. Multiple sclerosis relapse 
should not be reported as an AE unless, in the judgment of the Investigator, it is unusually severe, 
medically unexpected, or matches definition of SAE. 
Safety laboratory tests are optional for this unscheduled assessment visit if no intercurrent disease 
is suspected. If any intercurrent disease is diagnosed, it will be reported as an AE as per the safety 
reporting rules. 
The participant will be actively asked about possible relapse symptoms at each study visit. If 
relapse is suspected, the above decision-making and reporting rules apply. 
8.1.3 Magnetic resonance imaging  
Cranial (brain) MRI before and after administering Gd contrast agent will be performed.  
• The basic MRI will be performed at all sites and will consist of the following sequences: 
T2- and T1-weighted sequences before and after administering a Gd contrast agent 
(if there is no contraindication). 
• An expanded MRI protocol will be conducted using additional MRI sequences such as 
MTR (all centers) and susceptibility-weighted imaging (SWI) (subset of centers with 
capacity of 3T MRI). 
• Basic MRI sequences will be used to evaluate MRI-related endpoints of change in 
T2-hyperintense lesion volume, new and enlarging T2-hyperintense lesion count, number 
and volume of T1-hypointense lesions, brain volume loss rate, volume, number, and 
intensity (T1) of SELs, and Gd-enhancing T1-hyperintense lesion count (see Section 3). 
The expanded MRI protocol will be used to evaluate gadolinium enhancement recovery 
(MTR) and phase rim lesions (SWI). Additional details about MRI assessments will be 
provided in the central MRI manual. 
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 (20). 
A central MRI manual, containing instructions for brain MRI standard image acquisition 
requirements, MRI acquisition validation, data transfer to the central review center, archiving and 
shipping, and image approval process, will be provided to all participating sites. Study site 
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personnel will undergo training regarding MRI acquisition and data handling procedures. Training 
will be documented, and adherence to the central MRI manual will be monitored throughout the 
study with retraining performed as necessary. 
Unless specified otherwise, the screening brain MRI scan will be used as the reference to assess 
all MRI-derived endpoints. Standardized endpoint evaluation is assured by central review of brain 
MRI scans. A blinded MRI central review will be performed for all MRI-derived endpoints. All 
MRI reviewers will be blinded to treatment assignments and to other participant data. Details on 
MRI scanning and central review will be described in the central MRI manual. In addition, in 
accordance with standard clinical practice, during the blinded intervention period, the Treating 
Investigator can access MRI reports once a year starting at Month 12 through the local radiologist.  
The local radiologist needs to review MRI scans for unexpected safety-related findings, such as 
suspected PML. The local radiologist needs to contact the Treating Investigator in case of 
unexpected safety-related findings detected on the MRI scan, as per Section 8.3.8.  
As use of systemic corticosteroids for treatment of MS relapse or any other medical reasons could 
interfere with the MRI findings, study MRI should be postponed for a minimum of 1 month 
following the completion of a course of systemic corticosteroids whenever possible. Alternatively, 
if a study MRI is planned within 7 days of the initiation of a corticosteroid treatment, the study 
MRI should be rescheduled to be performed earlier and prior to the initiation of corticosteroid 
treatment when possible. 
8.1.4 Timed 25-foot walk test  
The T25-FW test will be used to assess a participant’s walking ability. The participant is directed 
to one end of a clearly marked 25-foot course and is instructed to walk 25 feet as quickly as safely 
possible with several repetitions (21, 22). The mean walk time will be used for assessment of the 
participant’s walking ability. An increase of >20% from the baseline score in the T25-FW test is 
considered as meaningful worsening (23). The Examining Investigator/rater or qualified study 
staff will perform this test. 
8.1.5 9-hole peg test  
Time to complete the 9-HPT will be used to assess a participant’s manual dexterity and fine motor 
skills. A participant will be asked to place the pegs into the holes and remove them with the 
dominant and nondominant hand for several repetitions (22). The mean time to test completion 
will serve for assessment of the participant’s hand dexterity. An increase of >20% from the 
baseline score in the 9-HPT is considered meaningful worsening (23). The Examining 
Investigator/rater or qualified study staff will perform this test. 
8.1.6 Cognitive tests  
The oral version of the SDMT, a test for cognitive function by measuring information processing 
speed (24) involves a simple substitution task using a reference key. The number of correct 
pairings made in 90 seconds is recorded. A decrease of 4 points from baseline on the SDMT is 
considered meaningful worsening (25).  
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The CVLT-II (26) measures verbal learning and memory by using a 16-item word list. The list is 
read by the examiner, and participants listen to the list and report as many of the items as possible. 
Five successive trials are scored.  
8.1.7 Composite analyses  
Data from the clinical assessments described under Section 8.1.1 to Section 8.1.6 will be utilized 
in various composite analyses and endpoints to assess effects of SAR442168 on range of clinical 
measures. The following sections provide additional details on these composite scales and related 
criteria for analyses. 
8.1.7.1 Modified multiple sclerosis functional composite-3  
The Multiple Sclerosis Functional Composite-3 (MSFC-3) tool is the composite of the T25-FW 
test, 9-HPT, and SDMT (22, 27). The MSFC-3 score will be calculated from these component 
tests. 
8.1.7.2 Assessment of no evidence of disease activity  
No evidence of disease activity-3 (NEDA-3) is defined as absence of all of the following (28): 
• 6-month CDW 
• Active MRI lesions (both new or enlarged T2-hyperintense lesions and Gd-enhancing 
T1-hyperintense lesions) 
• MS relapses 
8.1.8 Clinical outcome assessment and health-related quality-of-life parameters  
Participants will use a handheld electronic device to record clinical outcome assessment and 
health-related quality-of-life parameters during onsite visits. Prior to the first attempt to complete 
the clinical outcome assessment, the study coordinator will train the participant in the use of the 
device and how to answer the questions. Participants must record clinical outcome assessment at 
the clinic prior to any study procedures or discussion of health-related issues to ensure the 
objectivity of their responses. This device replaces the paper questionnaires that are normally 
used. Although the software is not approved as a medical device, appropriate validation of the 
device to ensure accurate and consistent functioning has been performed. 
• Multiple Sclerosis Quality of Life-54: The MSQol-54 (29, 30) is a standardized 
instrument comprising generic and MS-specific items. It includes the SF-36, which has 
been used in many MS clinical trials, especially of DMTs (eg, teriflunomide). This 
54-item instrument generates 12 subscales and 2 single-item measures. The 12 subscales 
are: physical health (10 items), emotional wellbeing (5 items), cognitive function 
(4 items), role limit physical (4 items), energy (5 items), health distress (4 items), overall 
quality of life (2 items), health perceptions (5 items), role limitations emotional (3 items), 
sexual function (4 items), pain (3 items), and social function (3 items), covering all aspects 
of MS. The single-item measures are satisfaction with sexual function and change in 
health. A linguistically validated MSQoL-54 is available in multiple languages. 
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• EuroQoL 5-Dimension Questionnaire, 5-Level Version (EQ-5D-5L): The EQ-5D-5L is 
a generic quality of life instrument used for measuring utility (31). It consists of 2 parts: 
a descriptive part (5 questions) and a visual assessment scale. It is routinely used in the 
majority of MS (32), (eg, daclizumab NCT01797965) and non-MS clinical studies. The 
EQ-5D-5L is available in multiple languages. 
8.2 
SAFETY ASSESSMENTS  
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1 Physical examinations  
The complete physical examination will include, at a minimum, assessments of the general 
appearance, head and neck, abdomen, lymph nodes, skin, cardiovascular system, respiratory 
system, musculoskeletal system, and neurological examination by the Treating Investigator. 
A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, neurological examination, and abdomen (liver and spleen). Further details 
will be provided in the Study Manual. 
The extent of the physical examination can be broadened at the discretion of the Treating 
Investigator in order to evaluate AEs or abnormal clinical laboratory test values.  
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
• Any clinically significant new finding or worsening of a previous finding should be 
reported as an AE, per Investigator’s judgment. 
8.2.2 Vital signs  
• Body temperature, heart rate, and blood pressure will be assessed. 
• Blood pressure and heart rate measurements will be assessed with a completely automated 
device with the participant in a supine or sitting position. Manual techniques will be used 
only if an automated device is not available. 
• Blood pressure and heart rate measurements should be preceded by at least 5 minutes of 
rest for the participant in a quiet setting without distractions (eg, television or cell phones). 
• Blood pressure and heart rate measurements will be taken before blood collection for 
laboratory tests and will consist of 1 heart rate and 3 blood pressure measurements 
(3 consecutive blood pressure readings will be recorded at intervals of at least 1 minute). 
Further details will be provided in the Study Manual. 
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8.2.3 Electrocardiograms  
• 12-lead ECGs will be performed using an ECG machine that automatically calculates the 
heart rate and measures PR, QRS, QT, and QTcF intervals. Refer to Section 7.1.1 for 
QTcF withdrawal criteria. In case the ECG machine does not automatically calculate 
QTcF, manual calculation using nomogram or automatic website calculator 
(eg, https://reference.medscape.com/calculator/48/ecg-corrected-qt) is acceptable. 
• ECGs and (longer) rhythm strips will be obtained locally. Further details will be included 
in the Study Manual. 
8.2.4 Clinical safety laboratory assessments  
See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed. 
The Treating Investigator may solicit emergency local laboratory data in case of emergent safety 
events to allow for appropriate treatment decisions. All clinically relevant solicited emergency 
local laboratory data will be recorded in the eCRF. 
• The Treating 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 which 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 30 days 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. 
- 
If abnormal laboratory test values do not return to normal or 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. In the event 
the laboratory assessments in Appendix 6 (Section 10.6) indicate discontinuation of 
IMP, temporary discontinuation should be considered unless otherwise specified. 
- 
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 Suicidal ideation and behavior risk monitoring  
SAR442168 crosses the blood-brain barrier. Assessment of suicidal ideation and 
behavior/treatment-emergent suicidal ideation and behavior will be monitored during Study 
EFC16033 using the C-SSRS. For safety reasons, C-SSRS will be administered throughout the 
study by the Treating Investigator or delegated to an individual that is certified to administer the 
scale. Study drug administration must be interrupted if a participant scores “yes” on items 4 or 
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5 of the Suicidal Ideation Section of the C-SSRS, or “yes” on any item of the Suicidal Behavior 
Section. A mental health professional will be consulted and will decide whether the study drugs 
can be restarted and if any additional risk mitigation strategies are required (eg, increased 
monitoring, antidepressant administration).  
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
Adverse events of special interest 
An AE of special interest (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. 
• 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; 
- 
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, the 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 
- 
An overdose (accidental or intentional) with the IMP 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 (eg, ≥2 tablets of the IMP within a 12-hour interval). 
Of note, asymptomatic overdose must be reported as a standard AE.  
• Increase in ALT 
- 
Any increase of ALT >3 × ULN confirmed by retest within 72 hours or in the absence 
of a retest within 72 hours. 
• Project-specific AESI(s) are: 
- 
ECG observation of atrial fibrillation or atrial flutter. 
- 
Severe infection (NCI CTCAE Grade 3 or above), that may or may not meet 
seriousness criteria (eg, a Grade 3 opportunistic infection). 
- 
Moderate or severe hemorrhagic events (NCI CTCAE Grade 2 or above), including, 
but not limited to, symptomatic bleeding, bleeding in a critical area or organ such as 
the CNS, or intraocular bleeding. 
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- 
Thrombocytopenia, platelet count <75 × 109/L (see Appendix 6 [Section 10.6] for 
management flow chart). 
The definitions of an AE and 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). 
8.3.1 Time period and frequency for collecting AE and SAE information  
All SAEs will be collected from the signing of the ICF throughout the study at the time points 
specified in the SoA (Section 1.3). 
All AEs will be collected from the signing of the ICF 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 immediately and 
under no circumstance should this exceed 24 hours, as indicated in Appendix 3 (Section 10.3). 
The Investigator will submit any updated AESI or 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. 
8.3.2 Method of detecting AEs and SAEs  
The method of recording, evaluating, and assessing causality of AEs and SAEs and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3 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 8.3), 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). 
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8.3.4 Regulatory reporting requirements for SAEs  
• Prompt notification by the Investigator to the Sponsor of a 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 
(IRBs)/Independent Ethics Committees (IECs), and Investigators. 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. Reporting of SUSARs will be in accordance with 
Directive 2001/20/EC or as per national regulatory requirements in participating countries. 
• 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 IB and will notify the IRB/IEC, if appropriate, according to 
local requirements. 
8.3.5 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 EOS visit (Note: A separate informed 
consent must be obtained for data collection from partners of male participants). The participant 
will be followed to determine the outcome of the pregnancy and should be followed even after the 
end of the study (See Appendix 4 [Section 10.4]). 
• 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). 
• A negative pregnancy test is required prior to starting a treatment course. In the event that 
a pregnancy is confirmed during a course of treatment, the IMP should be discontinued 
(Section 7.1).  
• If a female participant becomes pregnant (or wishes to become pregnant) during the study 
and confirms plans to continue the pregnancy, the Investigator can arrange with the 
Sponsor unblinding so that a SAR442168-treated female participant need not be exposed 
to the accelerated elimination procedure. 
• A pregnancy will qualify as an SAE only if it fulfills at least 1 of the seriousness criteria 
(see Appendix 3 [Section 10.3]). 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
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• AEs that occur to study participants who become pregnant are to be reported according to 
the relevant portion of Appendix 3 (Section 10.3). 
Note: pregnancy tests will be performed monthly in all concerned EU countries (see Appendix 9, 
Section 10.11.2). 
8.3.6 Cardiovascular and death events  
Atrial fibrillation and atrial flutter 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 the DMC). 
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. 
8.3.7 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 a SAE or are unusually severe or medically unexpected. Hospitalization for MS 
relapse, if done routinely at the site (eg, for high dose IV methylprednisolone administration), will 
not be considered as a seriousness criterion for this study. 
Data for MS 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. 
8.3.8 Magnetic resonance imaging  
Magnetic resonance imaging scans need to be reviewed locally for any pathology. In case of 
clinically significant findings, relevant information needs to be provided to the Treating 
Investigator for appropriate safety reporting and also to ensure the appropriate management of the 
participant’s identified safety finding. When available, a diagnosis of pathology at cause of such 
MRI findings or the findings themselves will be reported as an AE until the diagnosis is clear.  
Multiple sclerosis findings from MRI scans do not need to be reported unless they are deemed 
unusual and thus a distinct safety finding. 
8.3.9 Guidelines for reporting product complaints  
Any defect in the IMP/NIMP 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 Treating 
Investigator will assess whether or not the quality issue has to be reported together with an AE or 
SAE. 
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8.4 
TREATMENT OF OVERDOSE  
The Sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the Treating Investigator should do the following: 
• Contact the Sponsor immediately. 
• Closely monitor the participant for any AE/SAE and abnormal laboratory test values 
• Obtain a plasma sample for PK analysis within 24 hours of the last documented IMP dose. 
• Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF. 
Decisions regarding dose interruptions will be made by the Investigator in consultation with the 
Sponsor based on the clinical evaluation of the participant. 
8.5 
PHARMACOKINETICS  
• Blood samples of approximately 2 to 3 mL will be collected for measurement of plasma 
concentrations of SAR442168 and relevant metabolite(s) as specified in the SoA 
(Section 1.3). The 5 scheduled samples will be collected at selected time points during the 
study. If warranted and agreed upon between the Investigator and the Sponsor, additional 
PK samples may be collected (eg, for retest, pEOT, or if clinically indicated). Instructions 
for the collection and handling of biological samples will be provided by the Sponsor. The 
actual date and time (24-hour clock time) of each sample will be recorded. 
• Each plasma sample will be divided into 2 aliquots (1 each for PK analyses and a backup). 
Samples collected for analyses of SAR442168 and relevant metabolite(s) plasma 
concentration may also be used to evaluate safety or efficacy aspects related to concerns 
arising during or after the study. 
• SAR442168 and relevant metabolite(s) PK samples will be used for population PK 
analysis. A standalone report will be issued containing all individual PK parameters. 
Drug concentration information that would unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded. 
Any changes in the timing or addition of time points for any planned study assessments must be 
documented and approved by the relevant study team member and then archived in the Sponsor 
and site study files but will not constitute a protocol amendment. The IRBs/IECs will be informed 
of any safety issues that require alteration of the safety monitoring scheme or amendment of the 
ICF. 
8.6 
PHARMACODYNAMICS  
Blood samples for lymphocyte phenotyping will be collected during the study as detailed in the 
SoA (Section 1.3) for a subset of participants randomized (approximately 400). Flow cytometry 
will be used for evaluation of change from baseline in lymphocyte count and phenotype subsets. 
Additional pharmacodynamics evaluations will include assessment of neurofilament light chain 
(NfL) levels in plasma, Chi3L1, and Ig levels in serum. 
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For country-specific differences in China, see Appendix 9 (Section 10.11.4). 
8.7 
GENETICS  
A 6 mL blood sample will be collected for deoxyribonucleic acid (DNA) isolation from 
participants who have consented to participate in the genetic analysis component of the study. 
Participants who do not wish to participate in the genetic research may still participate in the 
study. The DNA samples will be collected during the study as detailed in the SoA (Section 1.3). 
Samples will be stored, and analysis may be performed on genetic variants thought to play a role 
in MS including, but not limited to, specific candidate genes/genome analyses to evaluate their 
association with observed clinical responses to SAR442168. 
In the event of DNA extraction failure, a replacement genetic blood sample may be requested 
from the participant. Signed informed consent will be required to obtain a replacement sample 
unless it was included in the original consent.  
Details on processes for collection and shipment and destruction of these samples can be found in 
the specific laboratory manual. 
For country-specific differences in China, see Appendix 9 (Section 10.11.4). 
8.8 
BIOMARKERS  
Blood samples for biomarkers research will be collected from all participants in this study as 
specified in the SoA (Section 1.3). 
• Collection of serum and plasma samples for biomarker research is also part of this study.  
• Samples will be tested to evaluate their association with the observed clinical responses to 
SAR442168. 
• In addition, samples will be stored, and analysis may be performed on biomarker variants 
thought to play a role in MS including, but not limited to, serum or plasma analytes to 
evaluate their association with observed clinical responses to SAR442168 (in accordance 
with local regulations). 
Samples may be stored for a maximum of 2 years (or according to local regulations) following the 
last participant’s last visit for the study at a facility selected by the Sponsor to enable further 
analysis of biomarker responses to SAR442168. 
For country-specific differences in China, see Appendix 9 (Section 10.11.4). 
8.9 
MEDICAL RESOURCE UTILIZATION AND HEALTH ECONOMICS  
Clinical outcome assessment will be evaluated in this study through health-related quality-of-life 
parameters (see Section 8.1.8). The parameters will be evaluated as specified in the SoA 
(Section 1.3). 
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9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES  
The null hypothesis for the primary efficacy endpoint of ARR is that there is no treatment 
difference between SAR442168 and teriflunomide and the alternative is that there is a between-
treatment difference. To strongly control the type 1 error rate for the study, a hierarchical testing 
procedure will be applied at a 2-sided 5% significance level, ie, each hypothesis will be formally 
tested only if the preceding one is significant at the 5% level. If SAR442168 is significant for the 
primary endpoint, a selective set of secondary endpoints will be tested following the hierarchical 
testing procedure. The complete list of the secondary endpoints that will be adjusted for 
multiplicity with their testing order will be detailed in the statistical analysis plan prior to database 
lock. The study will be declared positive if the null hypothesis for ARR for SAR442168 versus 
teriflunomide is rejected.  
9.2 
SAMPLE SIZE DETERMINATION  
Approximately 1200 people will be screened to achieve approximately 900 (±10%) participants to 
be randomly assigned to the study intervention: approximately half to each intervention group, 
SAR442168 and teriflunomide. A total sample size of at least 1800 participants will be included 
across the 2 studies of identical design (EFC16033 and EFC16034). The study sample size of 
approximately 900 provides greater than 90% power to detect a 45% relative reduction of ARR 
(primary endpoint) with SAR442168 compared to teriflunomide, based on a negative binomial 
distribution for the number of relapses with the following assumptions: 
• ARR of 0.29 for teriflunomide  
• 1:1 randomization 
• variance inflation factor (defined as variance divided by mean) of 1.5 for each arm 
• 20% study discontinuation by Month 24 
These calculations are based on 2-sided α = 0.05. For the primary ITT analysis, study duration 
will be variable (approximately 18 to 36 months) given the event-driven trial design based on the 
key secondary efficacy endpoint. All randomized participants are expected to have at least 
an 18-month study duration, with more than 60% (approximately 550 participants) having at least 
24 months. In this subset of participants, the study will also have 90% power to detect 
a 45% reduction for the analysis of 24-month ARR (ie, ARR during a fixed 24-month period from 
randomization).  
This study, along with RMS study EFC16034, is planned as an event-driven trial in order to have 
90% power, by pooling the two studies, for assessing the key secondary efficacy endpoint of time 
to onset of 6-month CDW. Each study will continue until 162 events are projected to have 
occurred in the pooled data, to ensure approximately 90% power to detect a 40% risk reduction in 
6-month CDW with SAR442168 compared to teriflunomide, based on an assumed 24-month 
event rate of 12% in the teriflunomide arm. Without pooling (ie, approximately 81 events), the 
study will have more than 60% power to detect a 40% risk reduction in 6-month CDW. These 
calculations are based on 2-sided testing and α = 0.05. 
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Event rates in the SAR442168 arm are assumed to be similar to those observed in the ocrelizumab 
arms of RMS trials (7). The forecast of CDW risk reduction by 40% is based on current 
knowledge of SAR442168, including a new mode of action and brain penetration, which permit 
an expectation of high efficacy, similar to that of ocrelizumab (7). The forecast of the event rates 
in the teriflunomide group is based on observations in previous teriflunomide trials, taking into 
account tendencies of event rate decrease in recent trials of other MS DMTs such as those that 
have been observed in beta-interferon groups in ocrelizumab pivotal trials (7, 33).  
Note: "Enrolled" means a participant's, or their legally acceptable representative’s, agreement to 
participate in a clinical study following completion of the informed consent process. Potential 
participants who are screened for the purpose of determining eligibility for the study, but do not 
participate in the study, are not considered enrolled, unless otherwise specified by the protocol 
9.3 
POPULATIONS FOR ANALYSES  
For purposes of analysis, the following populations are defined (Table 3): 
Table 3 - Populations for analyses  
Population 
Description 
Enrolled 
All participants who sign the ICF. 
Randomly Assigned to Study 
Intervention 
All participants with a treatment kit number allocated and recorded in the IRT 
database, regardless of whether the treatment kit was used or not. 
Participants treated without being randomized will not be considered randomized 
and will not be included in any efficacy population. 
ITT 
The primary efficacy population will be the ITT population, defined as all randomly 
assigned participants. All 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 and exposed to study intervention, regardless of 
the amount of exposure, analyzed according to the treatment actually received.  
Randomized participants for whom it is unclear whether they took the study 
medication will be included in the safety population as randomized. 
The pharmacodynamic (PD) analyses will be performed on the safety population. 
PK 
All participants in the safety population with at least one non- missing PK sample 
after first dose of the study intervention. Participants will be analyzed according to 
the treatment actually received. 
ICF: informed consent form; ITT: intent to treat; PK: pharmacokinetic(s) 
9.4 
STATISTICAL ANALYSES  
The SAP will be developed and finalized before database lock and it will include a more technical 
and detailed description of the statistical analyses described in this section. This section is 
a summary of the planned statistical analyses of the most important endpoints including primary 
and key secondary endpoints. 
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9.4.1 General consideration  
The baseline value of efficacy parameters is generally defined as the last available value up to 
randomization but prior to the first dose of study medication unless otherwise specified. For 
EDSS, the baseline value will be taken as the average of the screening and randomization visit 
values. The baseline value of safety parameters is defined as the last available value prior to the 
first dose of IMP. Unless otherwise indicated, 2-sided p-values and 95% confidence intervals will 
be provided for assessment of treatment differences. 
9.4.2 Primary endpoint(s)  
The purpose of the primary analysis of ARR is to assess the efficacy of SAR442168 in an ITT 
setting. In this primary approach, off-treatment events of participants who prematurely 
discontinue study intervention will be included for analysis per the ITT principle. Participants 
who permanently discontinue study intervention will be asked and encouraged to return to the 
clinic for all remaining study visits. In this case, all events during the planned treatment period 
will be included and the observation duration will be from randomization to the EOS. If 
a participant withdraws from the study prior to the common study end date, all observed events up 
to the last contact date will be included in the analysis, and the observation duration will be from 
randomization to the last contact date. No imputation will be performed for the unobserved events 
that may happen after study discontinuation. This estimand compares the rate of ARR for the 
participants randomized to SAR442168 versus teriflunomide, regardless of what treatment 
participants actually received. It assesses the benefits of the treatment policy or strategy relative to 
teriflunomide. 
Annualized adjudicated relapse rate will be analyzed using a negative binomial regression model. 
The model will include the total number of adjudicated relapses occurring during the observation 
period as the response variable, with treatment group, EDSS score at screening (<4, ≥4), and 
geographic region (US, non-US) as covariates. Log transformed observation duration will be the 
offset variable. The estimated ARR for each treatment group and corresponding 2-sided 
95% confidence interval will be derived from the negative binomial model. The relative reduction 
in ARR with SAR442168 compared to teriflunomide, its 2-sided 95% confidence interval and 
p-value will be provided.  
Multiple sensitivity analyses to assess the robustness of the conclusion of the main model will be 
performed, including, but not limited to, an analysis of annualized relapse rate based on relapses 
reported by the Investigator, an analysis of ARR based on a fixed 24-month treatment duration 
(for the subset of participants completing at least 24 months) and an analysis to assess the efficacy 
of SAR442168 if participants adhere to the study intervention as directed. For the last analysis, 
off-treatment events of participants who prematurely discontinue study intervention will be 
excluded from the analysis. A negative binomial model with the same set of covariates as 
specified in the primary analysis will be used. This model will include relapses (or adjudicated 
relapses) occurring during the treatment epoch (first administration of IMP to last administration 
inclusive) as the response variable and the log transformed duration of the treatment epoch will be 
the offset variable. This approach defines the estimand to be the efficacy of SAR442168 with 
treatment adherence. Details of all sensitivity analyses will be included in the SAP. 
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Additionally, subgroup analyses will be explored to assess consistency of treatment effect. The 
subgroup factors include disease burden (baseline EDSS <4, ≥4), EDSS stratification factor, 
EDSS score at screening (<4, ≥4), geographic region (US, non-US), MRI activity at baseline, age 
at screening (>40, ≤40 years), sex (male, female) and highly active disease at baseline, including 
rapidly evolving severe RMS (34, 35, 36, 37). Participants with highly active disease are defined 
as having 1 relapse in the previous year AND one of the following: at least 1 Gd enhancing 
T1-hyperintense lesion; or 9 or more T2-hyperintense lesions at baseline for participants who 
were already treated with DMT (any treatment with DMTs would be considered, if documented, 
during the prior year) or who had 2 or more relapses in the previous year, whether treated with 
DMTs or not. The detailed list of subgroups and additional details of the subgroup analyses will 
be provided in the SAP. 
9.4.3 Secondary endpoint(s)  
Key Secondary Endpoint 
Time to 6-month CDW, pooled across EFC16033+EFC16034  
The primary analysis of time to onset of 6-month CDW will be based on the pooled data across 
Studies EFC16033 and EFC16034 in the ITT population. The time to onset of 6-month CDW will 
be analyzed by a Cox proportional hazards model with terms for treatment, EDSS score at 
screening (<4, ≥4), geographic region (US, non-US) and study. A log-rank test stratified by EDSS 
score at screening (<4, ≥4), geographic region (US, non-US), and study to compare SAR442168 
to teriflunomide will also be examined. Kaplan-Meier plots of the cumulative incidence rate will 
be provided by treatment group to depict the course of onset of 6-month CDW over time. The 
proportion of participants with events at given time points (eg, Month 24) will be calculated using 
the KM estimates.  
In this primary ITT analysis: 
• For participants who complete the study without an initial disability worsening or 
prematurely discontinue the study before 6-month confirmation of an onset of disability 
worsening, the participant’s event time will be censored at the date of last EDSS 
assessment.  
• For participants who have an initial onset of disability worsening but reach the common 
study end date prior to 6-month confirmation, the event status of the participant will be 
determined by an imputation approach. Since in this setting the partial missing data can 
reasonably be assumed to be missing at random, this approach leverages the partial 
information and follows the ITT principle. A logistic model with terms for EDSS score at 
screening (<4, ≥4) and geographic region (US, non-US) will be used as the imputation 
model within each treatment of each study population. A multiple imputation approach 
will be used to summarize the results. Details will be provided in the SAP.  
Confirmation of onset of disability worsening and 6-month CDW are defined in Section 8.1.1.1. 
Time to onset of 6-month CDW will also be analyzed based on data from the current study only 
using similar statistical methods as for the primary analysis, but without study included in the 
model.  
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In order to assess robustness of the primary analysis, sensitivity analyses handling missing or 
incomplete data differently will be conducted. This will include an analysis that treats missing or 
incomplete data as censored data. 
Additionally, the same subgroup analyses as for the primary endpoint will be explored to assess 
consistency of treatment effect. 
Other secondary efficacy endpoints 
For other time-to-event endpoints (time to onset of 3-month CDW, time to CDI), similar analysis 
as for the primary analysis of the key secondary efficacy endpoint will be performed in the ITT 
population. 
Continuous endpoints (percent change in brain volume loss, change in cognitive function, change 
in physical function, and change in MSQoL-54 at the EOS) will be analyzed using a mixed-effect 
model with repeated measures (MMRM) approach in the ITT population. The model will include 
change/percent change values for the respective endpoint at each visit as response variables, and 
treatment, EDSS score at screening (<4, ≥4), geographic region (US, non-US), visit, treatment 
by-visit interaction, baseline value for the endpoint being assessed and baseline value-by-visit 
interaction as covariates. Difference in least squares means, the corresponding 95% CI, and 
p-value will be provided for the comparison of SAR442168 versus teriflunomide. Participants 
who discontinue study intervention before the common study end date will be asked and 
encouraged to return for all remaining study visits and the additional off-treatment values 
measured up through EOS will be included in the primary analysis. For participants who 
withdraw from the study before EOS, values will be missing after study discontinuation. 
No imputation will be performed for missing values in the primary analysis. For endpoints for 
which a normality assumption may not hold (eg, change in brain volume), MMRM analysis of log 
transformed data will be conducted for estimating treatment effects; p-values, when appropriate, 
will be provided using the ranked ANCOVA when a normality assumption is violated. 
For categorical efficacy endpoints with count data (eg, new and/or enlarging T2 hyperintense and 
new Gd-enhancing T1-hyperintense lesion counts), similar analysis as for the primary analysis of 
the primary efficacy endpoint will be performed in the ITT population. 
9.4.4 Tertiary/exploratory endpoint(s)  
Methods for analysis of tertiary/exploratory endpoints will be included in the SAP. 
9.4.5 Other safety analyses  
All safety analyses will be performed on the safety population. 
All safety summaries will be descriptive, ie, no statistical significance tests will be performed on 
safety data. The summary of safety results will be presented by treatment group.  
Safety analyses will be based on the reported AEs and other safety information, such as clinical 
laboratory data, vital signs, and ECG. 
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The observation period will be divided into 3 epochs: 
• The screening epoch is defined as the time from the signed informed consent date up to the 
first administration of the study intervention. 
• The treatment epoch is defined as the time from the first administration of the study 
intervention to the earlier of last administration of the study intervention plus 10 days or 
first IMP in the LTS study. 
• If applicable, the post-treatment epoch is defined as the time from the day after the end of 
treatment epoch to the participant’s final study contact date. 
The safety analysis of AEs will focus on TEAEs, defined as AEs that developed, worsened or 
became serious during the treatment period. 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.  
Table 4 - Safety analyses  
Endpoint 
Statistical Analysis Methods 
Adverse Events including 
• 
AE 
• 
TEAE 
• 
SAE 
• 
AE leading to treatment 
discontinuation 
• 
AE leading to death 
• 
AESI 
• 
The number and percentage of participants with at least one TEAE, serious 
TEAE, TEAE leading to treatment discontinuation, TEAE leading to death, and 
treatment-emergent AESI will be tabulated by treatment group. Multiple 
occurrences of the same event in the same participant will be counted only 
once in the tables. The denominator for computation of percentages will be 
the safety population within each treatment group.  
• 
Serious AEs and AEs leading to study discontinuation or death that occur 
outside the treatment-emergent period will be summarized separately. 
Vital signs and laboratory data and 
ECG parameters 
• 
Descriptive statistics of values and change from baseline values for each 
parameter will be summarized by treatment group at each time point.  
• 
The number and percentage of participants with at least one incidence of 
potentially clinically significant abnormality at any time during the treatment-
emergent period will be summarized by treatment group. 
AE: adverse event; AESI: adverse event of special interest; IMP, investigational medicinal product; SAE: serious adverse event; TEAE: 
treatment-emergent adverse event 
9.4.6 Other analyses  
Pharmacokinetic, pharmacodynamic (PD), and biomarker exploratory analyses will be described 
in the SAP finalized before database lock. The population PK analysis and PD analyses will be 
presented in a separate document from the main clinical study report (CSR). 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 10 (Section 10.12): Contingency measures for a regional or national 
emergency that is declared by a governmental agency.  
9.5 
INTERIM ANALYSES  
No formal efficacy interim analysis is planned. 
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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, IB, and other relevant documents 
(eg, advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed 
and approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require 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 Code of Federal Regulations (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 the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
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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. 
• A participant who is rescreened is required to sign another ICF. 
• The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research. The Investigator or authorized designee will 
explain to each participant the objectives of the exploratory research. Participants will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period. A separate signature will be required to 
document a participant's agreement to allow any remaining specimens to be used for 
exploratory research. Participants who decline to participate in this optional research will 
not provide this separate signature. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 10 (Section 10.12): Contingency measures for a regional or national 
emergency that is declared by a governmental agency.  
10.1.4 Data protection  
All personal data collected related to participants, Investigators, or any person involved in the 
study, which may be included in the Sponsor’s databases, shall be treated in compliance with all 
applicable laws and regulations including the GDPR (Global Data Protection Regulation). 
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 authorities (eg, on Afro American population for FDA, or on Chinese 
population for the National Medicinal Product Administration, China). 
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Since a participant’s response to treatment may vary by factors such as race or ethnicity due to 
intrinsic or extrinsic factors, subgroup analyses by race and ethnicity are therefore planned for the 
primary endpoints and may be performed for other efficacy or safety endpoints to demonstrate the 
applicability of the overall trial results to a specific subgroup (38, 39). 
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 which 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. 
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  
10.1.5.1 Independent Data Monitoring Committee  
A DMC, 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 DMC are to review and evaluate the safety data and 
to make appropriate recommendations to the Sponsor regarding the conduct of the clinical trial. 
Details describing the DMC processes and procedures are outlined in the DMC charter. To 
maintain continuous blinding and study integrity, the analysis will be conducted by 
an independent statistician who will directly transfer data to DMC members, and measures will be 
taken to ensure the validity of the data. 
10.1.5.2 Scientific Advisory Committee  
A Scientific Advisory Committee will provide advice to the Sponsor regarding scientific issues 
and operational conduct of the study. This committee will be composed of a Chairperson, selected 
by the Sponsor, field experts, and Sponsor-based scientists with clinical and methodological 
expertise. The Scientific Advisory Committee will also review any amendments and provide input 
regarding interpretation of study results. The members will remain blinded until completion of the 
study. Among its responsibilities, the Scientific Advisory Committee will receive blinded study 
status reports from the Sponsor and will review the recommendations from the DMC throughout 
the study. 
The responsibilities of the Scientific Advisory Committee are provided in the Scientific Advisory 
Committee charter. 
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10.1.5.3 Relapse Adjudication Committee:  
To ensure objectivity in the assessment of relapses, a Relapse Adjudication Committee will be 
convened to evaluate all relapses reported during the study. This committee will consist of 
independent neurologists with expertise in MS clinical research who will be trained on study 
procedures. Relapses, as adjudicated by the committee, need to meet protocol criteria 
(Section 8.1.2.1). 
Relapse Adjudication Committee assessments will be performed using blinded data. Details of the 
responsibilities of the Relapse Adjudication Committee, and workflow will be described in 
a separate charter. 
10.1.5.4 Independent Hepatology Assessment Committee  
An expert committee of independent hepatologists will review all cases of potential DILI and will 
provide guidance on case evaluation and risk mitigation. The Hepatology Assessment Committee 
recommendations will be made available to the DMC. Details of the responsibilities of the 
Independent Hepatology Assessment Committee and its workflow will be described in a separate 
charter. 
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, European Union Clinical Trial Register (eu.ctr), 
euclinicaltrials.eu, and sanofi.com, as well as some national registries. 
In addition, results from clinical trials in participants 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 vivli.org. 
Individual participant data and supporting clinical documents are available for request at vivli.org. 
While making information available we continue to protect the privacy of participants in our 
clinical trials. Details on data sharing criteria and process for requesting access can be found at 
this web address: vivli.org. 
Professionals involved in the study or in the drug development program 
Sanofi undertakes the legal obligation to disclose the full name of the Investigator and his/her 
affiliated institute/hospital’s name and location on the China Trial Disclosure website as required 
by the National Medical Products Administration (NMPA) in its guidance “Implementation of 
Drug Clinical Trial Information Registration and Disclosure” (“Notification No. 28”), requesting 
name disclosure of Chinese and foreign investigational sites and Investigators in any eligible 
clinical trial.  
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Sanofi may publicly disclose, and communicate to relevant authorities/institutions, the funding, 
including payments and transfers of value, direct or indirect, made to healthcare organizations and 
professionals and/or any direct or indirect advantages and/or any related information or document 
if required by applicable law, by regulation or by a code of conduct such as the “EFPIA Code on 
Disclosure of Transfers of Value from Pharmaceutical Companies to Healthcare Professionals and 
Healthcare Organisations”. 
10.1.7 Data quality assurance  
All participant data relating to the study will be recorded on printed or eCRFs 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. 
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. 
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality such as 
Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), methods, 
responsibilities and requirements, including handling of noncompliance issues and monitoring 
techniques (central, remote, or onsite monitoring) are provided in separate study documents. 
The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
The Sponsor assumes accountability for actions delegated to other individuals (eg, Contract 
Research Organizations). 
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 signature of the final CSR 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. 
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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. 
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 study termination by the Sponsor, as well as reasons for the early closure of a study 
site by the Sponsor or Investigator may include but are not limited to: 
• For study termination: 
- 
Information about the product leads to doubt as to the benefit/risk ratio 
- 
Discontinuation of further study intervention development 
• For site termination: 
- 
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 or no recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator 
- 
Total number of participants included earlier than expected 
10.1.10 
Publication policy  
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. 
This allows the Sponsor to protect proprietary information and to provide comments. 
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. In this case, a coordinating 
Investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
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10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS  
The tests detailed in Table 5 will be performed by the central laboratory when feasible. Local 
laboratory results are only required if the central laboratory results are not available in time for 
study intervention administration and/or response evaluation. Additionally, if the local laboratory 
results are used to make either a study intervention decision or response evaluation, the results 
must be entered into the eCRF. 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in Section 5. 
Additional tests may be performed at any time during the study as determined necessary by the 
Investigator or required by local regulations. 
Table 5 - Protocol-required laboratory assessments  
Laboratory 
assessments 
Parameters 
Hematology 
Platelet count 
RBC indices: 
WBC count with differential: 
 
RBC count 
MCV 
Neutrophils 
 
Hemoglobin 
MCH 
Lymphocytes 
 
Hematocrit 
% Reticulocytes 
Monocytes 
 
 
 
Eosinophils 
 
 
 
Basophils 
Clinical chemistrya BUN 
Sodium 
AST 
 
Creatinineb 
Calcium 
ALT 
 
Glucose (fasting not required) 
Total and direct bilirubin 
Alkaline phosphatase 
 
Potassium 
Total protein 
Creatine phosphokinase 
 
 
Chloride 
Albumin 
 
 
Bicarbonate 
Lipase 
Routine urinalysis 
• 
Specific gravity 
• 
pH, glucose, protein, blood, ketones (bilirubin, urobilinogen, nitrite, leukocyte esterase) by dipstick 
• 
Microscopic examination (if blood or protein is abnormal and for signs of infection) 
Other screening 
tests 
• 
FSH and estradiol (if needed, only in female participants to confirm postmenopausal state) 
• 
Highly sensitive serum or urine β-hCG pregnancy test (as needed for women of childbearing 
potential)c 
• 
Coagulation: PT/INR, aPTT 
• 
Serology tests for hepatitis B virus (HBsAg, anti-HBc IgM and total, anti-HBs) and C virus 
(anti-HCV); in case these results are inconclusive (eg anti-HBs negative and anti-HBc positive 
or anti-HCV IgG positive), HBV-DNA and/or HCV-RNA testing, respectively, should be 
performed for confirmation. HIV and other infectious diseases if required locally. 
• 
Tuberculosis test: Blood testing (eg, QuantiFERON TB Gold test) is preferred; skin testing 
(eg, tuberculin skin test) with ancillary testing will be allowed if blood testing is not available and 
a T-SPOT can also be performed, if available. 
• 
 Iron panel (serum): iron, ferritin, transferrin saturation, TIBC. 
Abbreviations: ALT, alanine aminotransferase; anti-HBc, antibody to hepatitis B core antigen; anti-HBs, hepatitis B surface antibody; aPTT, 
activated partial thromboplastin time; AST, aspartate aminotransferase; BUN, blood urea nitrogen; β-hCG, human chorionic gonadotrophin; 
CrCl, creatinine clearance; eGFR, estimated glomerular filtration rate; FSH; follicle-stimulating hormone; EC, independent ethics committee; 
INR, international normalized ratio; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human 
immunodeficiency virus; Ig, immunoglobulin; IRB, institutional review board; MCV, mean corpuscular volume; MCH, mean corpuscular 
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hemoglobin; PT, prothrombin time; RBC, red blood cell; TB, tuberculosis; TIBC: total iron-binding capacity; ULN, upper limit of normal; WBC, 
white blood cell. 
a Details of liver chemistry stopping criteria and required actions and follow-up assessments after observations of ALT >3 × ULN are given 
in Appendix 6 (Section 10.6). Clinical laboratory findings of ALT >3 × ULN and bilirubin ≥2 × ULN (>35% direct bilirubin) or ALT >3 × ULN 
and INR >1.5, if INR measured, may suggest severe liver injury and must be reported as SAEs. 
b Other renal function parameters, creatinine clearance (CrCl) will be calculated.  
c Local urine testing will be standard for the protocol (except Screening Visit when serum pregnancy test is required) unless serum testing 
is required by local regulation or IRB/IEC. 
Investigators must document their review of each laboratory safety report. 
Laboratory/analyte results that could unblind the study will not be reported to investigative sites 
or blinded personnel until the study has been unblinded. This includes PK assessments and any 
post-baseline biomarker or PD assessments. 
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. 
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), eg: 
- 
Leading to IMP discontinuation or modification of dosing, and/or  
- 
Fulfilling a seriousness criterion, and/or  
- 
Defined as an AESI 
• 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. 
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• 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 fulfil the definition of an AE or SAE. 
Events NOT meeting the AE definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are 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. 
DEFINITION OF SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 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, which 
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. 
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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) which 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. 
RECORDING AND FOLLOW UP OF AE AND/OR SAE 
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 representative in lieu of completion of the SAE eCRF page. 
• There may be instances when copies of medical records for certain cases are requested by 
the Sponsor 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. 
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Assessment of severity 
The Investigator will assess the severity for each AE and SAE using the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0, published on 
27 November 2017. Listings of MedDRA terms should be consulted first in NCI CTCAE to look 
for severity grade description for a particular AE. For AEs not listed in the NCI CTCAE, the 
Investigator will be required to assess the severity of the AE using general guideline: 
1. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
2. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL*. 
3. Grade 3 Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL**. 
4. Grade 4 Life-threatening consequences; urgent intervention indicated. 
5. Grade 5 Death related to AE. 
Note: Activities of Daily Living (ADL)  
* Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc.  
** Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
Any Grade 4 and 5 event must be reported as a SAE. Grade 1-3 event is defined as serious when it 
meets at least 1 of the predefined outcomes as described in the definition of an SAE. 
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. 
• 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 IB 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. 
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• 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 a 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, then the site will use the paper SAE data collection 
tool (see next section) in order to report the event within 24 hours. 
• 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. 
• 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. 
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Back-up SAE reporting to the Sponsor’s representative via paper CRF 
• In case of failure of electronic reporting of SAE via the electronic data capture system, 
facsimile transmission of the SAE paper CRF 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 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 CRF pages within the designated reporting time frames. 
• Contacts for SAE reporting can be found in the 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 postmenopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
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 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, Mullerian agenesis, androgen insensitivity), Investigator discretion should be 
applied to determining study entry. 
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. 
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- 
A high follicle-stimulating hormone (FSH) level (eg, >30 IU/L or as per laboratory 
reference range) in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormone 
replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, 
confirmation with more than one FSH measurement is required. 
- 
Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-estrogen 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 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per year when used 
consistently and correctly. 
• 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationc 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS)c 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual partner of the 
woman of childbearing potential and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. Spermatogenesis cycle is approximately 90 days.) 
Highly Effective Methodsb That Are User Dependent Failure rate of <1% per year when used consistently and 
correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulationc 
• 
oral 
• 
intravaginal 
• 
transdermal 
• 
injectable 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
• 
oral 
• 
injectable 
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.) 
a Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for those 
participating in clinical studies. 
b Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when used consistently and 
correctly. 
c If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited to 
those which inhibit ovulation as the primary mode of action. 
Note: Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus interruptus), condoms only (male or 
female), spermicides only, and lactational amenorrhea method (LAM) are not acceptable sole methods of contraception. Male condom 
and female condom should not be used together (due to risk of failure with friction) 
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PARTICULAR SITUATIONS: 
In case of premature EOT or after EOS: 
• A WOCBP must follow the local teriflunomide label.  
• A male participant must undergo the accelerated elimination procedure if planned per local 
teriflunomide labeling.  
• Participants must be advised that if they wish to conceive a child at any point after the 
study is completed, they should refer to teriflunomide label recommendations. 
In the situation where the participant rolls over to the proposed LTS study: 
• Refer to the LTS study protocol recommendation. 
If a female participant becomes pregnant during the study (if a female participant confirms 
plans to continue the pregnancy): 
• The Investigator can arrange with the Sponsor unblinding so that a SAR442168-treated 
female participant need not be exposed to the accelerated elimination procedure. 
In the situation where the participant leaves the study (ie, does not participate in the LTS 
study and cannot remain in the study to be evaluated until the EOS visit): 
• The treating neurologist following the participant after the study will refer to local 
teriflunomide labeling.  
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. 
• 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 1 day 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 can be collected either 
during site visits or by phone (in case a pregnancy test has been performed at home by the 
participant) and it will be recorded on the appropriate form and submitted to the Sponsor 
within 1 day of learning of a participant's pregnancy. The participant will be followed to 
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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 8.3.4 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. 
• The participant will be invited to remain in the study in any case. The pregnancy outcome 
and data of the newborn will be reported to the Sponsor as per usual pharmacovigilance 
reporting practice. 
10.5 
APPENDIX 5: GENETICS  
Use/Analysis of DNA 
• Genetic variation may impact a participant’s response to study intervention, susceptibility 
to, and severity and progression of disease. Variable response to study intervention may be 
due to genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular subtype of 
the disease being treated. Therefore, where local regulations and IRB/IEC allow, a blood 
sample will be collected for DNA analysis from consenting participants. 
• DNA samples will be used for research related to SAR442168 or RMS and related 
diseases. They may also be used to develop tests/assays including diagnostic tests related 
to SAR442168 and RMS patients. Genetic research may consist of the analysis of one or 
more candidate genes or the analysis of genetic markers throughout the genome. 
• DNA samples will be analyzed for human leukocyte antigen genotyping. Specific analysis 
of these samples will be determined at a later date once the blinded clinical data becomes 
available. These analyses may be conducted if it is hypothesized that this may help further 
understand the clinical data. 
• The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to SAR442168 or study interventions of this class to understand 
study disease or related conditions. 
• The results of genetic analyses may be reported in the CSR or in a separate study 
summary. 
• The Sponsor will store the DNA samples in a secure storage space with adequate measures 
to protect confidentiality. 
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• The samples will be retained while research on SAR442168 for MS continues but for no 
longer than 15 years, or other period as per local requirements. 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: ACTIONS AND FOLLOW-UP 
ASSESSMENTS  
These actions are required for ALT increase and thrombocytopenia events ONLY. For all other 
safety events described, these are suggested per the Investigator’s medical judgement. 
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Neutropenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting AEs in Appendix 3 (Section 10.3) is met. 
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aPTT, activated partial thromboplastin time; EDTA, Ethylenediaminetetraacetic acid; INR, international normalized ratio; PK, pharmacokinetic(s); 
PT, prothrombin time. 
Thrombocytopenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting AEs in Appendix 3 (Section 10.3) is met. 
Platelets <75 000/mm3 (rule out EDTA-induced 
pseudo-thrombocytopenia with sample using citrate
Repeat immediately locally the count (rule out EDTA 
anticoagulant in the sample using citrate)
Platelets <75 000/mm3
confirmed with bleeding
Platelets <75 000/mm3
confirmed with no bleeding
1. DISCONTINUE
Investigational Medicinal 
Product
2. HOSPITALIZATION
should be considered if 
platelet count is <50 000/mm3
1. DISCONTINUE
Investigational Medicinal 
Product
2. INVESTIGATE for 
bleeding
3. INFORM the local monitor
4. QUESTION about alcohol habits, any drug intake including (quinine), heparin 
administration, aspirin, immunotherapy, etc.
5. PERFORM or collect the following investigations:
•
Complete blood count, schizocytes, creatinine
•
Locally: 
•
Bleeding time and coagulation tests (INR, PT, aPTT, D-Dimers) 
•
Infectious serologies to be performed according to clinical symptoms / medical history
6. COLLECT/STORE one sample following handling procedures described in PK sections 
(for studies with PK sampling)
7. DECISION for bone marrow aspiration to be taken in specialized unit
8. MONITOR the platelet count every day for at least one week and then regularly until it 
returns to normal
In both situations
THROMBOCYTOPENIA
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LIVER FUNCTION TEST MONITORING ADDITIONAL GUIDANCE: 
To allow timely review for these data, please enter the date of collection for the central lab and the 
date of collection and the results for the local lab in the eCRF within 24 hours of their availability. 
1. If 1 LFT monitoring timepoint is missed, the study site should:  
- 
Reach out to the study participant as soon as possible to schedule an alternative 
timepoint as soon as possible and prior to the next scheduled timepoint.  
- 
Retrain the study participant on the LFT monitoring rationale and requirements and 
inform the study participant that IMP will need to be interrupted if LFTs cannot be 
monitored as required.  
2. If 2 consecutive LFTs timepoints are missed, the site should:  
- 
Call the participant immediately to reschedule the next LFTs timepoint as soon as 
possible and discuss with them about the underlying reasons of missing the timepoints.  
- 
Instruct participant to hold IMP immediately if they decline to reschedule the 
timepoint or miss the rescheduled timepoint.  
- 
Inform the participant that IMP can resume only after LFTs monitoring compliance is 
achieved. 
- 
Inform the monitoring team of any underlying reason identified for participant 
non-compliance and work with the monitoring team to resolve underlying issues to 
ensure compliance. 
 
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*If unable to retest in 72 hours, use original laboratory results to decide on further reporting/monitoring/discontinuation.  
Note: “Baseline” refers to ALT sampled at baseline visit; or if baseline value unavailable, to the latest ALT sampled before the baseline visit. The algorithm does not apply to the instances of increase in ALT during 
screening. See Section 8.3 for guidance on safety reporting. Normalization is defined as ≤ULN or baseline value if baseline value is >ULN. 
ALT >3 X ULN
Increase in ALT Algorithm
Confirm ALT >3 X ULN
Retest within 72 hours of initial sample*
Yes
No
•
COMPLETE the specific CRF forms for ALT increase and inform 
the monitoring team within 24 hours
•
Consider alternative etiologies
•
Complete mandatory testing if ALT >5 X ULN
•
ALT >8 X ULN, OR
•
ALT >5 X ULN for >2 weeks, OR
•
ALT >3 X ULN 
AND 
Total Bilirubin >2 X ULN OR INR >1.5, OR
•
ALT >3 X ULN with appearance of 
fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, 
rash, and/or eosinophilia (>5%)
Continue IMP 
administration
No
•
If clinically appropriate, IMP administration  
can be continued, as long as conditions for 
discontinuation per protocol are not met. 
•
ALT, AST, and bilirubin must be monitored 
2-3 times weekly. 
Reassess
Interrupt IMP administration and 
monitor every 2-3 days until ALT 
down trending, then monitor 
weekly until ALT <1.5 X ULN
Yes
If abnormalities stabilize or IMP is 
discontinued and the participant is 
asymptomatic, the monitoring 
frequency can decrease to weekly or 
bi-weekly until ALT <1.5 X ULN
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ALT, alanine aminotransferase; AST, aspartate aminotransferase; CMV, cytomegalovirus; CPK, creatine phosphokinase; CRF, case report form; 
EBV, Epstein-Barr virus; GGT, gamma glutamyl transferase; HAV, hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HEV, hepatitis 
E virus; IgG, immunoglobulin G; IgM, immunoglobulin M; IMP, investigational medicinal product; INR, international normalized ratio; LFT, liver 
function test; LKM, liver-kidney microsomal antibody; PT, prothrombin time; ULN, upper limit of normal.  
 
In ANY CONFIRMED CASE of ALT >5 x ULN, or ALT >3 x ULN with bilirubin > 2 x ULN, the following steps are 
REQUIRED (recommended for ALT >3 x ULN but ALT <5 x ULN, as clinically indicated):  
• 
INFORM the Site Monitor, who will forward the information to the Study Manager. 
• 
INVESTIGATE specifically for malaise with or without loss of consciousness, dizziness, and/or hypotension and/or 
episode of arrhythmia since the last visit, particularly in the previous 72 hours; rule out muscular injury. 
• 
PERFORM the following tests/actions: 
- LFTs: AST, ALT, alkaline phosphatase, GGT, total and conjugated bilirubin, and prothrombin time/INR (mandatory 
assessments for ALT >3 x ULN); 
- CPK, serum creatinine, complete blood count; 
- Anti-HAV IgM, anti-HBc IgM, (HBV-DNA if clinically indicated), hepatitis B surface antigen (HBsAg), anti-HCV and 
HCV RNA, anti-CMV IgM, and anti-HEV IgM antibodies; 
- Iron, ferritin, transferrin saturation;  
- Auto-antibodies: serum IgG levels, antinuclear, anti-DNA, anti-smooth muscle, anti-LKM, anti-mitochondrial; 
- Evaluate recent infection with EBV, herpes viruses. Depending on the clinical context, consider testing for 
toxoplasma; 
- Collect and freeze serum sample (5 mL x 2); 
- Collect and store one PK sample following the instructions in the central laboratory manual; 
- Perform hepatobiliary imaging (ultrasonography or other imaging investigations is required); 
- Consider DNA test for Gilbert’s disease if clinically indicated; 
- Recommend consulting a hepatologist (mandatory if ALT >8 x ULN or is associated with elevated bilirubin); 
• Discuss with the hepatologist the clinical indication for potential liver biopsy (strongly recommended if the 
participant meets Hy’s law criteria or has ALT >20 x ULN) and/or initiation of treatment with steroids; 
- Consider patient hospitalization if INR >2 (or PT <50%) and/or central nervous system disturbances suggesting 
hepatic encephalopathy. 
• 
MONITOR LFTs after discontinuation of IMP: 
- Monitor closely (every 2-3 days) until ALT is down-trending, then weekly until <1.5 x ULN, and then at every 
scheduled visit; 
- This frequent LFT monitoring may be done through central or local lab, or via home visit (depending on the 
Investigator’s assessment and/or local regulatory requirements). 
• 
RECHALLENGE: Re-initiation of the study drug can only be considered after discussion with the Sponsor’s Medical 
Monitor once the ALT/AST decreases to <1.5 x ULN, and there is no clinical contraindication. Rechallenge is not 
permitted for the following participants unless a clear non-DILI etiology is identified: 
▪ 
ALT >8 x ULN 
▪ 
ALT >5 x ULN for greater than two weeks 
▪ 
ALT >3 x ULN and total bilirubin >1 x ULN 
- In case it is agreed to re-start the study drug, it is recommended that ALT/AST be assessed per protocol schedule of 
assessments for the first 6 months of the treatment period.   
- The occurrence of new elevation to >3 x ULN for the ALT/AST values will lead to permanent discontinuation of the 
study drug.  
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ARF, acute renal failure; ULN, upper limit of normal; DIC, disseminated intravascular coagulation; CPK, creatine phosphokinase; ECG, 
electrocardiogram; PK, pharmacokinetic(s).  
Increase in serum creatinine is to be recorded as an AE only if at least 1 of the criteria listed in the 
general guidelines for reporting AEs in Appendix 3 (Section 10.3) is met. 
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CK-MB, creatine kinase-MB; CK-MM, creatine kinase-MM; ECG, electrocardiogram; PK, pharmacokinetic(s); ULN, upper limit of normal. 
Increase in CPK is to be recorded as an AE only if at least 1 of the criteria in the general 
guidelines for reporting AEs in Appendix 3 (Section 10.3) is met. 
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SUSPECTED PML  
If either the clinical presentation or MRI features of a participant are suggestive of PML, the 
following diagnostic and action algorithm is recommended. 
 
 
Abbreviations: CSF, cerebrospinal fluid; Gd, gadolinium; IMP, investigational medicinal product; JCV, John Cunningham virus; MRI, magnetic 
resonance imaging; PCR, polymerase chain reaction; PML, progressive multifocal leukoencephalopathy 
Clinical manifestations or MRI lesions features suspicious for PML are proposed in Table 6 
(based on 40 and 41). 
Table 6 - Clinical and MRI features suggestive of PML  
Clinical history  
Subacute onset of weakness, sensory deficits, cognitive or behavioral abnormalities, gait dysfunction, 
speech/language difficulties or any other signs of cortical dysfunction, retrochiasmal visual defects or seizure  
Brain MRI  
≥1 T2/FLAIR hyperintense and T1 hypointense lesions involving the subcortical and juxtacortical white matter, 
sparing the cortex, with no mass effect, with a continuous progression; new lesions with no enhancement (even 
when large) or with faint rim enhancement  
• The detection of John Cunningham virus (JCV) DNA in the cerebrospinal fluid of a 
patient with clinical and MRI features suggestive of PML establishes the diagnosis of 
PML.  
• If JCV DNA is not detected in cerebrospinal fluid and if clinical suspicion of PML 
remains high, another lumbar puncture should be performed. 
PML suspicion based on clinical history
PERFORM a lumbar puncture and CSF JCV PCR assessment 
PML suspicion based on MRI findings
PERFORM IMMEDIATELY an MRI assessment w/wo 
Gd enhancement 
1.
INFORM the local monitor / study medical manager 
2.
TEMPORARY DISCONTINUATION of IMP administration
RESUME IMP 
administration  
CONSIDER
Brain biopsy
PCR is 
positive
PCR is negative and low 
clinical suspicion
PCR is negative and still  high 
clinical suspicion
Histology finding and/or 
positive tissue PCR
No histology findings 
and negative tissue 
PCR
MRI findings 
exclude PML
PCR is positive
1.
INFORM the local monitor /  study medical 
manager 
2.
PERMANENTLYdiscontinue IMP
3.
TREAT as PML as per local standard of care 
REPEAT lumbar 
puncture and CSF PCR
PCR is negative
MRI findings reinforce  PML suspicion 
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• If diagnosis remains uncertain and suspicion of PML remains high, a brain biopsy may be 
considered to establish a definitive diagnosis 
Clinical or MRI features suggestive of PML should be recorded as an AE/AESI/SAE following 
the definitions and procedures in Appendix 3 (Section 10.3).  
10.7 
APPENDIX 7: MEDICAL DEVICE INCIDENTS: DEFINITION AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING  
Not applicable. 
10.8 
APPENDIX 8A: EXAMPLES OF DRUGS WITH A POTENTIAL TO CHANGE 
SAR442168 METABOLISM  
The following drugs should not be taken during the study concomitantly with the IMP due to their 
potential to change SAR442168 kinetics due to interaction with P450-mediated metabolism, being 
potent and moderate inducers of CYP3A, or potent inhibitors of CYP2C8 liver enzymes (Table 7).  
Additionally, participants in the US must not take medications that are mild, moderate, or potent 
inhibitors of CYP3A or CYP2C8 (Table 8). 
Please note that the lists provided in Table 7 and Table 8 are not exhaustive and that the product 
information of drugs intended for concomitant use should be consulted. 
Table 7 - Potent and moderate CYP3A inducers and potent CYP2C8 inhibitors  
Potent CYP3A Inducers: 
Rifampin 
Carbamazepine 
St John's wort extract  
Phenobarbital  
Avasimibe 
Lumacaftor 
Rifapentine 
 
Phenytoin 
 
 
Potent CYP2C8 Inhibitors: 
Gemfibrozil 
Clopidogrel  
 
Moderate CYP3A Inducers 
Semagacestat 
Asunaprevir/beclabuvir/daclatasvir 
Cenobamate 
Nafcillin 
Lesinurad 
Telotristat ethyl 
Bosentan 
Elagolix 
Thioridazine 
Rifabutin 
 
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Table 8 - Mild, moderate, and potent inhibitors of CYP3A and CYP2C8, and moderate and potent 
inducers of CYP3A  
CYP2C8 inhibitors 
Potent 
Moderate 
Mild 
Clopidogrel 
Gemfibrozil  
Trimethoprim 
Sulfamethoxazole 
trimethoprim 
Fluvoxamine 
CYP3A inducers 
Potent 
Moderate 
Avasimibe 
Rifampin 
Carbamazepine 
Lumacaftor 
Phenobarbital 
Phenytoin 
Rifapentine  
St. John's Wort 
Elagolix 
Cenobamate 
Nafcillin 
Asunaprevir/beclabuvir/daclatasvir 
Lesinurad 
Bosentan 
Thioridazine  
Rifabutin 
CYP3A inhibitors 
Potent 
Moderate 
Mild 
Clarithromycin 
Itraconazole 
Ketoconazole 
Nirmatrelvir and ritonavir 
Fluoxetine 
Grapefruit juice 
Ciprofloxacin 
Diltiazem 
Erythromycin 
Fluconazole 
Verapamil 
Sertraline 
Alprazolam 
Atorvastatin 
Amlodipine 
Cimetidine 
Ranitidine 
Roxithromycin 
Ginkgo biloba 
Isoniazid 
10.9 
APPENDIX 8B: EXAMPLES OF DRUGS WITH A POTENTIAL TO CHANGE 
TERIFLUNOMIDE DISPOSITION  
BCRP Inhibitors 
Cyclosporine 
Eltrombopag 
Gefitinib 
10.10 APPENDIX 8C: EXAMPLES OF DRUGS WHICH CAN BE POTENTIALLY AFFECTED 
BY TERIFLUNOMIDE  
Please note that the lists provided are not exhaustive and that the local product information of 
drugs intended for concomitant use should be consulted. If coadministration with the IMP is 
needed, caution needs to be exercised to detect decreased or increased exposure of these drugs and 
participants need to be monitored to detect this in a timely fashion. 
Coadministration of teriflunomide and warfarin may lead to decreased exposure of warfarin. 
Therefore, when warfarin is coadministered with IMP, close INR follow up and monitoring are 
recommended. 
Exposure of drug substances listed below may be increased by teriflunomide: 
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CYP2C8 substrates 
 
Repaglinide 
Pioglitazone 
 
Rosiglitazone 
Oral contraceptives 
 
Ethinylestradiol 
Levonorgestrel 
Organic anion transporter 3 (OAT3) substrates 
Cefaclor 
 
Penicillin G 
 
Ciprofloxacin 
 
Indomethacin 
 
Ketoprofen 
 
Furosemide 
 
Cimetidine 
 
BCRP substrates 
Rosuvastatin 
 
Sulfasalazine 
 
Organic anion transporting polypeptide B1 and B3 (OATP1B1/B3) substrates 
Simvastatin 
 
Atorvastatin 
 
Pravastatin 
 
Repaglinide 
 
Rifampin 
 
Nateglinide 
 
NOTE: exposure may be increased by teriflunomide 
Exposure of drug substances listed below may be decreased by teriflunomide. 
CYP1A2 substrates 
 
Duloxetine 
Theophylline 
Alosetron 
Tizanidine 
Caffeine 
 
10.11 APPENDIX 9: COUNTRY-SPECIFIC REQUIREMENTS  
10.11.1 
Contraception requirements in UK, Germany, and Denmark  
For inclusion criterion I06, the following apply: 
• For UK and Germany only: Acceptable forms of effective contraception include the 
following: 
- 
Established use of oral, injectable, or implantable progestogen-only hormonal 
contraception associated with inhibition of ovulation; 
- 
Placement of an intrauterine device (IUD) or intrauterine hormone-releasing system 
(IUS); 
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- 
Bilateral tubal occlusion; 
- 
Male sterilization (provided that the partner is the sole sexual partner of the WOCBP 
study participant and that the sterilized partner has received medical assessment of the 
surgical success); 
- 
True abstinence: When this is in line with the preferred and usual lifestyle of the 
participant. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods] and withdrawal are not acceptable methods of contraception). 
• For Denmark only: Acceptable methods of effective contraception include the following: 
- 
IUDs; 
- 
Hormonal contraceptives (contraceptive pills, implants, transdermal patches, hormonal 
vaginal devices, or injections with prolonged release). 
10.11.2 
Pregnancy tests in Austria, Czech Republic, Denmark, Finland, Germany, 
Italy, Lithuania, Poland, Romania, Spain, and Sweden  
In Austria, Czech Republic, Denmark, Finland, Germany, Italy, Lithuania, Poland, Romania, 
Spain, and Sweden, pregnancy tests will be performed monthly.  
10.11.3 
Additional requirements for Japan  
• A chest X-ray is required at screening. 
• People with a history of interstitial pneumonia or pulmonary fibrosis are excluded from 
this study. 
• Monthly hematology and ALT/AST monitoring will be continued until to 6 months, will 
then be repeated every 1.5 months for another 6 months, and then will be repeated on 
a quarterly basis. Monitoring will also include KL-6, CRP, and lactate dehydrogenase 
(LDH) at each visit. 
• Temporary IMP interruption will occur for all ALT >5 x ULN events regardless of the 
duration of ALT elevation above 5 x ULN. 
• Temporary IMP interruption will occur if ALT >3 x ULN and INR >1.3 or bilirubin 
>2 x ULN. Monitoring should then occur every 2 to 3 days until ALT and INR/bilirubin 
start down trending, then monitoring can be decreased to weekly until ALT <1.5 x ULN.  
• In any confirmed case of ALT >5 x ULN and recommended for ALT >3 x ULN but ALT 
<5 x ULN, testing of anti-HEV IgA antibody will be performed as part of the workup. The 
remaining components of the ALT algorithm (Appendix 6, Section 10.6) apply for 
participants in Japan. 
• It is strongly recommended to avoid initiating and continuing use of hepatotoxic drugs and 
hepatotoxic herbs/supplements while receiving IMP, due to the risk of hepatotoxicity 
associated with the administration of tolebrutinib. 
• Large, publicly available resources such as the DILIrank reference drug list (42, 43) can be 
a useful guide in identifying hepatotoxic medications. Examples of hepatotoxic 
herbals/supplements determined by the European Association for the Study of Liver 
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Clinical Practice Guidelines for DILI are outlined below (Table 9) (44). Please note that 
the lists provided are not exhaustive and that the product information of drugs intended for 
concomitant use should be consulted. 
Table 9 - Examples of herbal and dietary supplements involved in hepatotoxicity  
Herbal and dietary supplements 
Type of liver injury 
Herbal preparations 
Pyrrolizidine alkaloids, eg, Crotalaria,senecio, heliotrpium, Symphytum 
officinale (comfrey) 
Acute and chronic SOS 
Teucrium chamaedrys (germander) 
AHH, ACH, ALF, chronic hepatitis, cirrhosis, 
cholangitis 
Teucrium polium 
AHH, ACH, ALF 
Atractylis gummifera L. 
AHH, ACH, ALF 
Callilepis laureola L. 
AHH, ALF 
Mentha pulegium 
AHH, ACH, ALF 
Hedeoma pulegioides 
AHH, ACH, ALF 
Chelidonium majus (greater celandine) 
AHH, ACH, chronic hepatitis, cholangitis 
Piper methysticum (kava-kava) 
AHH, ACH, ALF, chronic hepatitis 
Camellia sinensis (green tea extracts) 
AHH, ACH, ALF 
Actaea racemosa (black cohosh) 
AHH, ACH 
Cimicifuga racemosa 
AHH, ACH 
Morinda citrifolia (Noni juice) 
AHH, ACH, ALF 
Serenoa 
ACH 
Azadirachta indica 
Microvesicular steatosis 
Catha edulis (khat) 
AHH, ACH, ALF 
Borago officinalis (borage) 
AHH, ACH 
Cassia angustifolia (senna) 
AHH, ACH 
Larrea tridentata (chaparral) 
AHH, ACH, cholangitis, chronic hepatitis/cirrhosis 
Asian herbal medicine (Chinese, Japanese, ayurvedic medicines) 
Lycopodium serratum (Jin Bu Huan) 
AHH, ACH, ALF 
Ephedra (Ma Huang) 
AHH with autoimmunity 
Sho-Saiko-To (Xiao-Chai-Hu-Tang; complex preparation) 
AHH/chronic hepatitis 
Dai-Saiko-To (complex preparation) 
AHH with autoimmunity 
Chaso and Onshido 
AHH, ACH, ALF 
Boh-Gol-Zhee/Bu Ku Zi 
ACH 
Polygonum multiflorum (Shou-Wu-Pian) 
AHH, ACH 
Ganoderma lucidum (Linghzi) 
AHH 
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Herbal and dietary supplements 
Type of liver injury 
Brena officinalis (Chi R Yun) 
AHH 
Dysosma pleiantha (Boh-Gol-Zhee) 
AHH 
Dietary supplements 
Usnic acid with other ingredients: 
    LipoKinetix® 
AHH, ALF 
    UCP-1® 
AHH, ALF 
    Oxy ELITE® 
AHH, ALF 
Hydroxycut® 
AHH, ACH, ALF, AHH with autoimmunity 
Linoleic acid 
AHH 
Plethoryl® (vitamin A, thyroid hormones) 
AHH, ACH, chronic hepatitis, cirrhosis 
Illicit anabolic androgenic steroids 
AHH, ACH, liver adenoma, HCC, SOS 
ACH, acute cholestatic hepatitis; AHH, acute hepatocellular hepatitis; ALF, acute liver failure; HCC, hepatocellular carcinoma; SOS, sinusoidal 
obstruction syndrome. 
10.11.4 
Country-specific differences for China  
There will be no biological sample exportation from China in this study, and sites in China will 
not participate in the following testing: 
• Pharmacodynamics: assessment of NfL levels in plasma. 
• Genetics: A 6 mL blood sample will be collected for DNA isolation, then be stored. 
Analysis may be performed on genetic variants thought to play a role in MS including, but 
not limited to, specific candidate genes/genome analyses to evaluate their association with 
observed clinical responses to SAR442168. 
• Biomarkers: Samples may be stored for a maximum of 2 years (or according to local 
regulations) following the last participant’s last visit for the study at a facility selected by 
the Sponsor to enable further analysis of biomarker responses to SAR442168. 
10.11.5 
Country-specific provisions for the US  
In addition to refraining from medications that are moderate and potent inducers of CYP3A, 
participants must not take medications that are mild, moderate, and potent inhibitors of CYP3A or 
CYP2C8 hepatic enzymes throughout the conduct of the trial (see Appendix 8A, Section 10.8). 
Participants must refrain from consumption of grapefruit or grapefruit juice (due to inhibition of 
CYP3A4) from 5 days prior to intervention administration and throughout the treatment phase. 
If medications that are mild, moderate, or potent inhibitors of CYP3A or CYP2C8 are clinically 
indicated, alternative options for non-CYP3A or non-CYP2C8 inhibitors should be considered, as 
medically appropriate. For participants not eligible for alternative options, IMP should be 
temporarily discontinued for the duration of treatment on these medications. 
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10.12 APPENDIX 10: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY  
A regional or national emergency declared by a governmental agency (eg, public health 
emergency, natural disaster, pandemic, terrorist attack) may prevent access to the clinical trial site. 
Contingency procedures are suggested below for an emergency that prevents access to the study 
site, to ensure the safety of the participants, to consider continuity of the clinical study conduct, 
protect trial integrity, and assist in maintaining compliance with Good Clinical Practice in 
Conduct of Clinical Trials Guidance. Sponsor agreement MUST be obtained prior to the 
implementation of these procedures for the duration of the emergency; this agreement must be 
provided in writing by the Sponsor and will be kept in the Investigator file. 
During the emergency, if the site will be unable to adequately follow protocol mandated 
procedures, screening and enrollment may be temporarily delayed/halted.  
Attempts should be made to perform all assessments in accordance with the approved protocol to 
the extent possible. In case this is not possible due to a temporary disruption caused by an 
emergency, focus should be given to assessments necessary to ensure the safety of participants 
and those important to preserving the main scientific value of the study. 
10.12.1 
Informed consent  
For a regional or national emergency declared by a governmental agency, contingency procedures 
may be implemented for the duration of the emergency. The participant or their legally authorized 
representative should be verbally informed prior to initiating any changes that are to be 
implemented for the duration of the emergency (eg, study visit delays/treatment extension, use of 
local labs), and the verbal information given to the participant should be documented in the 
participant’s medical record.  
10.12.2 
Study procedures  
Procedures to be considered in the event of a regional or national emergency declared by 
a governmental agency: 
1. New screenings during a regional or national emergency declared by a governmental 
agency can be performed only if allowed by local competent authorities and after 
Sponsor’s agreement is obtained. Rescreening will be permitted when the situation 
normalizes and only if allowed by local competent authorities and after Sponsor’s 
agreement is obtained.  
2. If onsite visits or alternative location (out of participant’s home) are not possible, all visits 
from Week 1 (including those planned to be done onsite) will be performed at home by 
a trained healthcare professional and if allowed by local competent authorities for: 
- 
Treatment administration  
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- 
Blood sampling for safety (at least hematology, hepatic function panel, coagulation 
panel), other safety assessment (at least serum creatinine), and pregnancy test 
(if applicable) 
- 
Measuring vital signs 
- 
Monitoring of injection site reactions, AEs and SAEs  
The use of a local laboratory may be allowed for safety follow up in case the central lab cannot be 
used. 
The Investigator or delegate will perform a phone-call visit at each onsite planned visit to collect 
safety data and concomitant treatment. All data collected remotely will be properly documented in 
the participant’s medical record and the study CRF. 
For all assessments which will not be performed remotely, the assessment windows will be 
extended until participants may access the site.  
If onsite visit and home visit are not possible, a temporary treatment discontinuation may be 
considered. The Investigator or delegate will perform a phone-call visit at each onsite planned 
visit to collect safety data and concomitant treatment. 
Contingencies implemented due to emergency will be documented in the participant’s medical 
record. 
10.12.3 
Temporary discontinuation  
A temporary IMP discontinuation may be considered by the Investigator because of suspected 
AEs or disruption of the clinical trial due to a regional or national emergency declared by 
a governmental agency.  
Reinitiation of study drug can only occur once the Investigator has determined, according to 
his/her best judgement, that the study drug did not contribute to the occurrence of the epidemic 
event (eg, COVID-19). 
For all temporary intervention discontinuations, duration should be recorded by the Investigator in 
the appropriate pages of the CRF or eCRF.  
10.12.4 
Statistical analysis  
The impact of the regional or national emergency declared by a governmental agency on study 
conduct will be summarized (eg, study discontinuation or discontinuation/delay/omission of the 
intervention due to the emergency). Any additional analyses and methods required to evaluate the 
impact on efficacy (eg, missing data due to the emergency) and safety will be detailed in the SAP. 
10.13 APPENDIX 11: ABBREVIATIONS  
 
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ADL: 
activities of daily living 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALT: 
alanine aminotransferase 
ARR: 
annualized adjudicated relapse rate 
AUC: 
area under the curve 
BCRP: 
breast cancer resistance protein 
BTK: 
Bruton’s tyrosine kinase 
CDW: 
confirmed disability worsening 
CFR: 
Code of Federal Regulations 
Chi3L1: 
chitinase-3 like protein-1 
CNS: 
central nervous system 
CPK: 
creatine phosphokinase 
CRF: 
case report form 
CSR: 
clinical study report 
C-SSRS: 
Columbia Suicide Severity Rating Scale 
CYP: 
cytochrome P450 
DILI: 
drug-induced liver injury 
DMC: 
Data Monitoring Committee 
DMT: 
disease-modifying therapy 
DNA: 
deoxyribonucleic acid 
ECG: 
electrocardiogram 
eCRF: 
electronic case report form 
EDSS: 
Expanded Disability Status Scale 
EOS: 
end of study 
EQ-5D-5L: 
EuroQol 5-dimension 5-level questionnaire 
EU: 
European Union 
FSH: 
follicle-stimulating hormone 
GCP: 
Good Clinical Practice 
Gd: 
gadolinium 
HEV: 
hepatitis E virus 
HRT: 
hormone replacement therapy 
ICF: 
informed consent form 
ICH: 
International Council for Harmonisation 
IEC: 
Independent Ethics Committee 
IMP: 
investigational medicinal product 
INR: 
international normalized ratio 
IRB: 
Institutional Review Board 
IRT: 
interactive response technology 
ITT: 
intent to treat 
IUD: 
intrauterine device 
IUS: 
intrauterine hormone-releasing system 
IV: 
intravenous 
JCV: 
John Cunningham virus 
LDH: 
lactate dehydrogenase 
LTS: 
long-term safety 
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MedDRA: 
Medical Dictionary for Regulatory Activities 
MRI: 
magnetic resonance imaging 
MS: 
multiple sclerosis 
MSFC-3: 
Multiple Sclerosis Functional Composite-3 
MSQol-54: 
Multiple Sclerosis Quality of Life-54 
MTR: 
magnetization transfer ratio 
NCI CTCAE: 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NEDA: 
no evidence of disease activity-3 
NfL: 
neurofilament light chain 
NIMP: 
noninvestigational medicinal product 
NMPA: 
National Medical Products Administration 
NSAID: 
nonsteroidal anti-inflammatory drug 
OAT3: 
organic anion transporter3 
PD: 
pharmacodynamic(s) 
PK: 
pharmacokinetic(s) 
PML: 
progressive multifocal leukoencephalopathy 
PPMS: 
primary progressive multiple sclerosis 
QTcF: 
QT interval corrected using Fridericia’s formula 
RMS: 
relapsing multiple sclerosis 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SEL: 
slowly evolving lesion 
SmPC: 
summary of product characteristics 
SoA: 
schedule of activities 
SPMS: 
secondary progressive multiple sclerosis 
Study Manual: 
Study Reference Manual 
SWI: 
susceptibility-weighted imaging 
TEAE: 
treatment-emergent adverse event 
ULN: 
upper limit of normal  
US: 
United States 
USPI: 
United States prescribing information  
WOCBP: 
woman of childbearing potential 
 
10.14 APPENDIX 12: PROTOCOL AMENDMENT HISTORY  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
10.14.1 
Amended protocol 01 (07 May 2020)  
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 
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The primary drivers for this amended protocol are to add exclusion criteria that were previously 
omitted and the regulatory requirement of a benefit/risk evaluation of the study in the context of 
the COVID-19 pandemic. 
Protocol amendment 01 summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
Stratification by age at baseline changed to stratification by 
EDSS score at screening. Statistical details clarified. 
Adjudication added to relapse objectives, endpoints. If locally 
available added to Nfl secondary endpoint. Annualized relapse 
rate changed to annualized adjudicated relapse rate. Relapse 
Adjudication Committee added. Post-trial access to study 
medication clarified. 
Clarity. Health Authority request. 
1.3 Schedule of 
activities 
Timing of MRI scans clarified. Timing of plasma and serum 
samples clarified. Participants who will enter long-term extension 
study and those who need to have the follow-up visit clarified. 
Parameters of physical exam clarified. Potential uses of archival 
samples clarified. Follow-up visit clarified. TB testing option 
clarified. IMP compliance removed from randomization visit. 
Urinalysis corrected to semi-annually. Beta-HCG corrected to 
quarterly. If locally available added to Nfl and Chi3L1 sampling. 
Quarterly lipase testing added. IMP compliance removed at M3 
and M4, added to EOS. Visit window for MRIs performed after 
D1 expanded.  
Clarity. Correction of errors. 
Flexibility because of COVID-19. 
Health Authority request. 
2.1 Study rationale 
Notion of adjudication of relapses added. 
Health Authority request. 
2.3 Benefit/risk 
assessment 
Safety related events clarified: no cardiac arrhythmia clarified to 
no clinically significant cardiac arrhythmia. Investigator 
assessment of relatedness of one AE of temporary ALT increase 
changed to “related” to reflect update in data. Text added to 
address regulatory requirements for COVID-19 risk and 
mitigation. 
Clarity. Regulatory requirement. 
3 Objectives and 
endpoints 
Adjudication added to relapse objectives, endpoints. Annualized 
relapse rate changed to annualized adjudicated relapse rate. 
EDSS-plus endpoint removed. If locally available added to Nfl 
secondary endpoint.  
Health Authority request. 
3.1 Appropriateness of 
measurements 
Justification for EDSS-plus removed. 
Removal of EDSS-plus endpoint. 
4.1 Overall design 
Safety follow-up period clarified. 
Clarity.  
4.2 Scientific rationale 
for study design 
Cholestyramine use for early IMP termination clarified. 
Clarity. 
4.3 Justification for 
dose 
Details added to the description of fed versus fasted participants.  Clarity. 
5.2 Exclusion criteria 
Addition of exclusion criterion for history of infection or risk of 
infection. Combination of former E02 with E06 and deletion of 
duplicate text. Addition of text for sensitivity to study 
interventions, drug, allergies that contraindicate participation in 
the study. Addition of washout period for natalizumab. 
Addition of erroneously omitted 
exclusion criteria. Simplification. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
5.3.1 Meals and 
dietary restrictions 
Time of day of IMP administration will be collected clarified. 
Clarity. 
6.1 Study 
intervention(s) 
administered 
DTP dispensation of IMP added as a possibility. 
Flexibility for COVID-19. 
6.5.1 Rescue 
medication 
Instructions for recording discussion of rescue medication 
removed, as no rescue medication is planned. 
Clarity. 
7.1.1 Definitive 
discontinuation 
Review of ECG findings by a cardiologist clarified. Handling of 
participants after definitive intervention discontinuation clarified. 
Clarity. 
8 Study assessments 
and procedures 
Phone visits modified to include “remote visits” to allow for web-
based visits/potential off-site visits. 
Ease of continuation of study 
during COVID-19 pandemic. 
8.1.1.1 Confirmed 
disability worsening 
Determination of CDW clarified. 
Clarity. 
8.1.2.1 Definition of 
multiple sclerosis 
relapse 
Rewording of MS relapse definition. 
Simplification—matching of 
wording to relapse definition in 
parallel protocols likely to be run 
at the same clinical site. 
8.1.3 Magnetic 
resonance imaging 
Details of MRI assessments added. 
Clarity. 
8.1.7.1 EDSS-Plus 
Section removed. 
Health Authority request. 
8.2.2 Vital signs 
Removal of respiratory rate from vital signs. Oral or tympanic 
body temperature simplified to body temperature. 
Simplification. Not necessary in 
an MS study. 
8.2.3 
Electrocardiograms 
Removal of reference to additional information. 
Consistency within the protocol. 
8.3 Adverse events 
and serious adverse 
events 
Clarified that for the project-specific AESI for ECG of clinically 
significant arrythmia, this pertains to only atrial fibrillation and 
atrial flutter and that confirmation by a cardiologist is not 
required. Clarified that AESI reporting is intended for infections 
that are of severity Grade 3 or above by NCI CTCAE criteria. 
NIMP removed from definition of AESI of overdose. 
Clarity. 
8.3.6 Cardiovascular 
and death events 
Clarification of atrial fibrillation. 
Clarity. 
8.3.7 Multiple sclerosis 
relapse reporting 
MS relapse reporting clarified. 
Clarity. 
8.5 Pharmacokinetics 
Statement that pharmacokinetics of SAR442168 will not be 
systematically/routinely evaluated removed. Blood samples of 
approximately 3 mL clarified as blood samples of approximately 
2 to 3 mL. 
Correction of error. Consistency 
throughout the protocol. 
9.2 Sample size 
determination 
Approximate number of people to be screened added. 
Discontinuation clarified as study discontinuation. 
Clarity. 
9.4.2 Primary endpoint 
Subgroup analysis by baseline EDSS score and sex added. 
Geographic origin corrected to geographic region. Age replaced 
by EDSS score at screening as covariate. 
Clarity. Correction. Health 
Authority request. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
9.4.3 Secondary 
endpoints 
Onset of CDW and 6-month CDW clarified. Geographic origin 
corrected to geographic region. 
Clarity. Correction. 
10.1.5 Committees 
structures 
Relapse Adjudication Committee added. 
Health Authority request. 
10.2 Appendix 2: 
Clinical laboratory 
tests 
Removal of requirement of replicate testing by local and central 
labs. Removal of requirement for central lab testing, if infeasible. 
Simplification. 
10.14.2 
Amended protocol 02 (24 August 2020)  
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 
The primary driver for this amended protocol is to respond to European Health Authorities’ 
requests. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
Correction of dosage of cholestyramine for cases of 
intolerance. 
Correction of error 
 
Addition of SAR442168 relevant metabolite(s) when 
referring to the pharmacokinetic (PK) evaluation. 
Clarity 
1.2 Schema 
Addition of footnote to clarify that ‘Month-1 (D-28 – 
D-1)’ refers to screening period as "Day-28 to Day-1"; 
‘Month 0 (D1)’ refers to randomization on Day 1. 
Clarity 
 
MRI visit at M0 moved to M-1. 
Correction of error 
1.3 Schedule of activities 
Addition of hematology, biochemistry, pregnancy test, 
and the Columbia Suicide Severity Rating Scale 
(C-SSRS) to the follow-up visit. 
Health Authorities’ request 
 
Time period for randomization visit relaxed. Additional 
safety assessments allowed if locally required.  
Health Authorities: COVID-
19 
1.3 Schedule of activities 
10.11.3 Liver function monitoring in 
Austria, Czech Republic, Denmark, 
Finland, Germany, Italy, Lithuania, 
Poland, Romania, Spain, and Sweden 
Modification of the liver function monitoring with 
additional tests for all concerned EU countries. 
Health Authorities’ request 
1.3 Schedule of activities 
8.3.5 Pregnancy 
Monthly pregnancy testing added for all concerned 
EU countries. 
Health Authorities’ request 
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Section # and Name 
Description of Change 
Brief Rationale 
10.11.2 Pregnancy tests in Austria, 
Czech Republic, Denmark, Finland, 
Germany, Italy, Lithuania, Poland, 
Romania, Spain, and Sweden 
2.3 Benefit/risk assessment 
Adverse event (AE) details updated. 
Recent information on Bruton’s tyrosine kinase (BTK) 
inhibitors and COVID-19 added.  
Clarity 
Health Authorities: COVID-
19 
4.1 Overall design 
Addition than a participant is considered to have 
completed the study if he/she has completed all 
phases of the study including the EOS visit, whether 
or not remaining on IMP. 
Clarity 
5.2 Exclusion criteria 
E05: Conditions that may predispose a participant to 
excessive bleeding clarified. 
E09: Investigator’s role in stopping 
anticoagulant/antiplatelet therapies clarified. 
Health Authorities’ request 
5.3.1 Meals and dietary restriction 
Meals and dietary restrictions clarified. 
Clarity 
5.3.2 Caffeine, alcohol, and tobacco 
Amount of alcohol permitted to use for the 
participants added. 
Health Authorities’ request 
6.1.1 Non-investigational medicinal 
product 
Correction of dosage of cholestyramine for cases of 
intolerance. 
Correction of error 
6.3 Measures to minimize bias: 
randomization and blinding 
Contacting of Sponsor for unblinding is removed. 
Health Authorities’ request 
Data access of Treating Investigator clarified. 
Health Authorities’ request 
6.3 Measures to minimize bias: 
randomization and blinding 
8.1.3 Magnetic resonance imaging  
Update of the disclosure of MRI reports to the 
Treating Investigator. 
Health Authorities’ request 
6.5 Concomitant therapy 
Live (attenuated) vaccines prohibited during the 
intervention period. 
Safety 
7.1.1 Definitive discontinuation 
Role of Investigator in treating participant after 
definitive discontinuation clarified. Progressive 
multifocal leukoencephalopathy (PML) added to 
criteria for definitive discontinuation.  
Health Authorities’ request 
7.1.2 Temporary discontinuation 
Suicidal risk as per C-SSRS added. 
Clarity  
8 Study assessments and procedures 
Expansion of visit window allowed. 
Health Authorities: COVID-
19 
Clarification added: “A study reference manual will be 
made available and will include additional details of 
study assessments”. 
Clarity 
8.2.5 Suicidal ideation and behavior 
risk monitoring 
C-SSRS criteria for interruption of study drug clarified. 
Health Authorities’ request 
8.3.4 Regulatory reporting 
requirements for SAEs 
Requirements for reporting of unexpected serious 
adverse reactions (SUSARs) clarified. 
Health Authorities’ request 
8.5 Pharmacokinetics 
Addition of SAR442168 relevant metabolite(s) when 
referring to the PK evaluation. 
Clarity 
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Section # and Name 
Description of Change 
Brief Rationale 
10.1.9 Study and site closures 
The study and site termination have been divided as 
two separate points. 
‘Information about the product leads to doubt as to 
the benefit/risk ratio’ added to reasons for study 
termination. 
‘Total number of participants included earlier than 
expected’ added to reasons for site termination. 
Health Authorities’ request 
10.4 Appendix 4: Contraceptive 
guidance and collection of pregnancy 
information 
Telephone reporting of home pregnancy tests 
allowed.  
Health Authorities: COVID-
19 
10.6 Liver and other safety: suggested 
actions and follow-up assessments 
Diagnostic workup for suspected PML added. 
Health Authorities’ request 
10.13 Appendix 11: Protocol 
amendment history 
Information regarding amended protocol 01 added. 
Update 
11 References 
References updated. 
Update 
Throughout 
Substitution of “long-term extension” for “long-term 
safety” to describe the study that participants will be 
allowed to roll over; substitution of “covid” for “COVID-
19”; for SAR442168 and matching placebo the word 
"film coated" has been added; correction of small 
errors (eg, comma errors, duplication of words); slight 
rewordings for clarity. 
Correction of errors, clarity 
10.14.3 
Amended protocol 03 (28 September 2020)  
This amended protocol (amendment 03) 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 
The primary driver for this amended protocol is to respond to Japanese Health Authorities’ 
requests. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of activities 
Duplicated exam (vital signs) removed. 
Additional safety tests and visits where required 
locally added. Timing of visit assessments 
clarified. References to additional screening and 
testing requirements for Japan added.  
Correction of error. 
Clarification. Health Authority 
request. 
2.3 Benefit/risk assessment 
Reference to Investigator’s Brochure added. 
 
 
Compliance with original 
template.  
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Section # and Name 
Description of Change 
Brief Rationale 
Examples of respiratory effects and reference to 
additional testing requirements for Japan added.  
 
Health Authority request. 
3 Objectives and endpoints 
Clarification of tertiary/exploratory endpoints. 
Clarification 
5.1 Inclusion criteria 
Addition of “preferably” to requiring contraception 
with low user dependency. 
Correction of error. 
5.2 Exclusion criteria 
E02: Clarification of history of infection with HIV; 
clarification of repetition of TB testing. 
 
E07: Clarification of timing of teriflunomide 
washout. Removal of requirement for 
ascertainment of B-cell levels after washout. 
 
 
E17: Potential participants unable to complete 
electronic clinical outcome assessments 
excluded.  
 
E21, reference to additional exclusion 
requirements for Japan, added.  
Clarification.  
 
 
Clarification. 
Advancement in literature 
shows this requirement to be 
unnecessary. 
 
Copyright issue with paper 
clinical outcome assessment 
forms.  
 
Health Authority request. 
5.3.2 Caffeine, alcohol, and tobacco 
Clarification of alcohol recommendations. 
Clarification. 
5.5 Criteria for temporarily delaying 
administration of study intervention 
Section added for contingency measures in the 
case of a regional or national emergency.  
Contingency measures for 
COVID-19. 
6.1 Study intervention(s) administered 
Reference to contingency measures in the case 
of a regional or national emergency added. 
Contingency measures for 
COVID-19. 
6.5 Concomitant therapy 
Clarification of therapies allowed after 
randomization added. 
Clarification. 
7.1.2 Temporary discontinuation 
Reference to contingency measures in the case 
of a regional or national emergency added. 
Contingency measures for 
COVID-19. 
7.1.2.1 Rechallenge 
Reference to contingency measures in the case 
of a regional or national emergency added. 
Contingency measures for 
COVID-19. 
8 Study assessments and procedures 
Reference to contingency measures in the case 
of a regional or national emergency added. 
Contingency measures for 
COVID-19. 
8.1.1.1 Confirmed disability worsening 
MS relapse clarified as adjudicated MS relapse. 
Clarification. 
8.1.3 Magnetic resonance imaging 
Rescheduling of MRI because of corticosteroid 
use clarified. 
Clarification. 
8.2.5 Suicidal ideation and behavior risk 
monitoring 
“Mental health professional” substituted for 
“psychiatrist” for consultation around restarting 
treatment. Alerting families to monitor 
participants for unusual behavior removed. 
Removal of unnecessary 
constraint.  
8.3 Adverse events and serious adverse 
events 
Acute hypersensitivity/anaphylaxis removed from 
list of adverse events of special interest. 
Found to be unnecessary 
because of lack of safety 
signal in previous studies.  
8.3.10 Guidelines for reporting of 
medication errors 
Section removed. 
Template section that does 
not apply to this study was 
erroneously included. 
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Section # and Name 
Description of Change 
Brief Rationale 
8.6 Pharmacodynamics 
Reference to country-specific differences in 
China added. 
Certain tests will not be 
performed in China. 
8.7 Genetics 
Reference to country-specific differences in 
China added. 
Certain tests will not be 
performed in China. 
8.8 Biomarkers 
Reference to country-specific differences in 
China added 
Certain tests will not be 
performed in China. 
9.4.5 Other safety analyses 
Changes in definition of treatment epoch, post-
treatment epoch. 
Clarification. 
9.4.6 Other analyses 
Reference to contingency measures in the case of 
a regional or national emergency added. 
Contingency measures for 
COVID-19. 
10.1.3 Informed consent process 
Reference to contingency measures in the case of 
a regional or national emergency added. 
Contingency measures for 
COVID-19. 
10.1.6 Dissemination of clinical study 
data 
Text on disclosure of information added.  
Change in company policy. 
10.2 Clinical laboratory tests 
Exclusion of studies of hepatic impairment or 
cirrhosis from SAE reporting reversed.  
 
 
Calculation of eGFR removed. 
Potential participants with 
hepatic impairment or 
cirrhosis are excluded from 
this trial.  
 
Cockroft-Gault formula will be 
used instead of eGFR. 
10.6 Liver and other safety: suggested 
actions and follow-up assessments 
PML assessment clarified.  
Clarification. 
10.11.4 Additional requirements for 
Japan 
Section added with additional testing and 
screening requirements for Japan. 
Health Authority request. 
10.11.5 Country-specific differences for 
China 
Section added with test differences for China. 
Certain tests are not to be 
performed in China.  
10.12 Appendix 10: Contingency 
measures for a regional or national 
emergency that is declared by 
a governmental agency 
Section added. 
Contingency measures for 
COVID-19.  
Throughout 
Correction of small errors (eg, comma errors, 
duplication of words); slight rewordings for 
clarity. 
Correction of errors, clarity. 
10.14.4 
Amended protocol 04 (14 April 2021)  
This amended protocol (amendment 04) 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 
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The primary driver for this amended protocol is to update the liver function test frequency in the 
European Union (EU) countries in accordance with the updated teriflunomide (Aubagio) 
summary of product characteristics (SmPC). Alanine aminotransferase exclusion criterion was 
also updated to align with the Aubagio label. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Synopsis 
3 Objectives and endpoints 
Changed the secondary endpoint title from 
“Change in lymphocyte phenotype subsets in 
whole blood at the EOS compared to 
baseline” to “Change in lymphocyte phenotype 
subsets in whole blood at the EOS compared 
to baseline in a subset of population”. 
Lymphocyte phenotype will be 
assessed only for participants who 
were enrolled before 
implementation of protocol 
amendment 04. 
1.3 Schedule of Activities 
6.4 Study intervention compliance 
Added the details about the paper diary. 
Use of the diary was added after 
the release of the initial protocol. 
1.3 Schedule of activities 
8.6 Pharmacodynamics 
Removed the blood collected timepoints for 
lymphocyte phenotypes by flow cytometry 
except randomization and EOS/pEOT visits. 
Added the associated footnote y: Blood 
collection for lymphocyte phenotypes by flow 
cytometry will be performed for a subset of 
participants randomized (approximately 300). 
Lymphocytes phenotypes by flow 
cytometry testing will only be 
performed in the study in a subset 
of participants. The sample 
timepoints have also been reduced. 
Approximately 400 participants, to 
have approximately 200 participants 
randomized to SAR442168, are 
deemed adequate to assess the 
effect at end of treatment. 
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Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of Activities 
The footnotes were updated as follows: 
 
• 
Footnote a: To allow a window of 
1 week (7 days) for screening 
magnetic resonance imaging (MRI) 
if required to be rescheduled or 
repeated (eg, in case of technical 
issues). 
To allow more flexibility for 
screening MRI and safety 
laboratory tests. 
• 
Footnote d: To allow safety 
laboratory tests at Months 1, 2, 4, 
and 5 to be done locally if either 
onsite visit or home health visit is 
not possible. 
To allow more flexibility for the 
laboratory test assessment. 
• 
Footnote e: To clarify the study 
procedures/assessments to be 
performed if a participant 
prematurely permanently 
discontinues treatment with IMP 
Clarity. 
• 
Footnote j: To correct the lipase 
assessment timing. Lipase levels 
will be assessed at screening and 
then quarterly along with other 
biochemistry parameters.  
Correction of error. 
• 
Footnote j: To remove the 
cross-reference to the liver function 
monitoring with additional tests for 
all concerned EU countries.  
As per updated Aubagio SmPC, 
biweekly liver function tests are no 
longer required in EU countries. 
• 
Footnote k: Text added: Serum ß-
HCG pregnancy test at central 
laboratory at screening and urine 
pregnancy tests within 24 hours 
before the first dose of 
investigational medicinal product 
(IMP) and at scheduled times during 
study. 
Clarification of pregnancy tests 
required during study. 
• 
Footnote u: To clarify the details of 
pharmacodynamic/biomarker 
samples for NfL, Chi3L1, and Ig 
levels; these are timed samples only 
at Months 6 and 12. 
Pharmacodynamics/biomarkers 
samples taken at other visits and will 
not be timed. 
Timed pharmacodynamic/biomarker 
sampling is only needed at visits 
when pharmacokinetic (PK) 
samples are also collected at these 
same time points. 
• 
New footnote x: To add requirement 
that samples for hematology and 
biochemistry tests on Day 1 
(randomization) must be collected 
prior to administration of the first 
IMP dose. 
To ensure collection of baseline 
(pre-IMP) values for the safety 
laboratory tests. 
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Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of Activities, footnote 
7.1.1 Definitive discontinuation 
8.5 Pharmacokinetic 
Footnote e: To add that collection of 
pharmacokinetic sample at premature end of 
treatment (pEOT) visit, if the visit can be 
scheduled within a maximum 24 hours from 
the last IMP dose. 
To clarify that the PK sample should 
be collected in case of pEOT only if 
the visit can be scheduled within 
24 hours after the last IMP dose. 
1.3 Schedule of Activities, footnote 
10.2 Appendix 2: Clinical laboratory 
tests 
Footnote j: To clarify that for glucose level 
measurement, fasting is not needed. 
Clarity. 
3. Endpoints and objectives 
Removed tertiary/exploratory endpoint “total 
number of combined unique active lesions 
(CUAL*) as detected by brain MRI at 
Months 18, 24, and the EOS”. The associated 
footnote was also deleted. 
MRI-related endpoints have been 
reassessed for the BTKi program. 
Updated the language of a tertiary/exploratory 
endpoint to add the assessment of cumulative 
number of new T1-hypointense lesions. 
Clarify analysis of T1-hypointense 
lesions. 
4.4 End of study definition 
Text was added to the definition of study 
completion to clarify that a participant is 
considered to have completed the study if 
he/she has completed all periods of the study 
including the EOS visit, whether remaining on 
IMP or not. 
Clarity. 
5.1 Inclusion criteria 
Inclusion criterion 04: Removed the 
requirement of only brain lesion 
(≥1 documented Gd enhancing) on an MRI 
scan within the previous year. 
Spine lesions are also accepted for 
eligibility criteria in accordance with 
clinical practice and similar clinical 
trials in the same indication. 
Inclusion criterion 06: Clarified that a woman 
of childbearing potential must have a negative 
highly sensitive pregnancy test at screening 
and within 24 hours before the first dose of 
study intervention. 
Clarity. 
5.2 Exclusion criteria 
Exclusion criterion 02: Updated the details of 
tuberculosis and hepatitis tests. 
Clarification of these screening 
procedures and harmonization with 
the other studies in the Phase 3 
multiple sclerosis (MS) program. 
Exclusion criterion 03: Clarified that the 
Columbia Suicide Severity Rating Scale 
baseline/screening version will be used for 
assessment of suicidal ideation. 
Clarity. 
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Section # and Name 
Description of Change 
Brief Rationale 
Exclusion criterion 06: 
Removed standalone albumin criterion. 
Changed screening alanine aminotransferase 
(ALT) exclusion threshold to >2 x upper limit of 
normal (ULN) and added criterion that 
confirmed screening ALT>2 x ULN is required. 
 
Align ALT exclusion criteria with the 
Aubagio United States prescribing 
information (USPI) and SmPC. 
Exclusion criterion 07: Added plasma 
exchange with 1 month washout period 
required prior to randomization. 
Previously omitted in error. 
5.3.1 Meals and dietary restrictions 
Clarification of IMP administration details to 
specify that a gap of a minimum of 12 hours 
between 2 doses should be maintained in 
case the mealtime of IMP administration 
needs to be changed. 
Clarification of the minimum time 
between 2 IMP doses. 
Removed the restrictions related to 
consumption of grapefruit or grapefruit juice. 
Update based on outcomes from 
PK results of drug-drug interaction 
studies, investigating concomitant 
use of SAR442168 with drugs such 
as itraconazole. 
6. Study intervention 
6.2 
Preparation/handling/storage/account
ability 
8.3.9 Guidelines for reporting product 
complaints 
Updated the language to remove device from 
the details. 
Correction as no device for study 
intervention. 
6.3 Measures to minimize bias: 
randomization and blinding 
Added the details about randomization. 
Mandatory information as per 
protocol template, previously 
omitted in error. 
6.5 Concomitant therapy 
 
Added the concomitant use of short-term use 
(3 to 5 days) of glucocorticoids (eg, for MS 
relapse treatment or an acute illness) and 
local corticosteroids (eg, topical, nasal, ocular, 
otic, intra-articular). 
Clarification for use of topical 
corticosteroids and short-term 
corticosteroids. 
Guidance added to allow the use of activated 
charcoal in exceptional situations when 
cholestyramine is not tolerated or if 
cholestyramine is not available. 
To align with the current Aubagio 
SmPC, (previously omitted in error). 
Updated the language related to use of 
NSAIDs.  
Clarity. 
5.2 Exclusion criterion 8 
6.5 Concomitant therapy 
10.8 Appendix 8A: Examples of drugs 
with a potential to change SAR442168 
metabolism or absorption 
Updated for antacid drugs: 
Removed the restrictions related to antacid 
drugs as concomitant use of proton-pump 
inhibitors (PPI), H2 receptor antagonists, and 
antacids is allowed. 
Update based on outcomes from 
PK results of drug-drug interaction 
studies, investigating concomitant 
use of SAR442168 with drugs such 
as itraconazole, gemfibrozil, 
rifampicin and pantoprazole. 
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Section # and Name 
Description of Change 
Brief Rationale 
Updated guidance for CYP inhibitors/inducers: 
Potent and moderate inducers of CYP3A or 
potent inhibitors of CYP2C8 hepatic enzymes 
are not permitted throughout the study. 
Clarified concomitant use of potent CYP3A 
inhibitors is allowed. 
7.1.1 Definitive discontinuation 
Updated guidance for the participant 
discontinuation related to laboratory 
abnormalities. 
Removed the Data Monitoring Committee 
(DMC) review of data to determine whether 
AEs should preclude continued treatment with 
study intervention. 
Clarity  
 
 
The DMC has no responsibility to 
review individual data and advice 
for IMP discontinuation of a 
participant.  
8.1.1.1 Confirmed disability worsening 
Rephrased the details of the section for 
clarification. 
Clarity. 
8.1.2.1 Definition of multiple sclerosis 
relapse 
Clarified that MS relapse confirmation will be 
done by the Relapse Adjudication Committee. 
Clarity. 
8.1.3 Magnetic resonance imaging 
Increased the MRI test time from 21 days to 
1 month following last course of systemic 
corticosteroids. 
To be consistent with screening 
MRI requirement and to minimize 
the risk of corticosteroid impact on 
MRI findings. 
8.2.2 Vital signs 
Clarified that blood pressure and heart rate 
measurements will be assessed in a supine or 
sitting position. 
Clarity. 
8.2.3 Electrocardiograms 
Added allowance of manual calculation of QT 
interval corrected using Fridericia’s formula 
(QTcF) and removed the request for 
30 seconds of the rhythm strips. 
To allow some flexibility as some 
automated electrocardiograms do 
not provide these parameters. All 
other electrocardiogram parameters 
will be automatically provided. 
8.3 Adverse events of special interest 
Definition of overdose was clarified. 
Clarity. 
Definition of project-specific adverse events of 
special interest related to infection and 
hemorrhagic events was updated. 
Clarity for the infection and 
hemorrhagic events to be reported 
as adverse events of special 
interest. 
8.4 Treatment of overdose 
Corrected the language to clarify that plasma 
sample for PK analysis is to be obtained within 
24 hours of the last documented IMP dose 
(rather than the last dose of SAR442168). 
Correction of error. 
8.5 Pharmacokinetics 
Updated the section for number of PK 
samples: The five scheduled samples will be 
collected. Additional PK samples may be 
collected (eg, for retest or if clinically 
indicated). 
Clarity, no change in number of 
samples. 
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Section # and Name 
Description of Change 
Brief Rationale 
10.2 Appendix 2: clinical laboratory 
test 
Added details of the serology tests for 
hepatitis B and C and tuberculosis. 
To harmonize with the other 
protocols in the Phase 3 MS 
program. 
Table 5, footnote a was updated to clarify the 
clinical laboratory abnormalities for liver injury. 
Clarity. 
Table 5, footnote c was updated to include 
serum pregnancy test at screening. 
Clarification of pregnancy test. 
Removed the cross-reference to unblinding 
section (Section 6.3). 
Correction of error. 
10.4 Appendix 4: Contraceptive 
guidance and collection of pregnancy 
Information 
Clarified the definition of high 
follicle-stimulating hormone level: >30 IU/L or 
as per laboratory reference ranges. 
Clarification of follicle-stimulating 
hormone level for postmenopausal 
status confirmation as not all 
laboratories use the threshold of 
30 IU/L. 
10.5 Appendix 5: Genetics 
Added the sample retention period. 
Previously omitted in error. 
10.6 Appendix 6: Liver and other 
safety: suggested actions and follow 
up assessments 
Updated the figure related to suspected PML. 
 
Table 6 was updated for clinical history 
manifestations. 
Updated figure to be easier to 
follow. 
Simplification. 
10.6 Appendix 6: Liver and other 
safety: suggested actions and 
follow-up assessments  
Table 6 was updated for clinical history 
manifestations. 
Simplification. 
10.11.3 Liver function monitoring in 
Austria, Czech Republic, Denmark, 
Finland, Germany, Italy, Lithuania, 
Poland, Romania, Spain, and 
Sweden. 
Section removed. 
Biweekly liver function monitoring is 
no longer required per the current 
Aubagio SmPC. 
Appendix 10, 10.12.2 Study 
procedures 
Updated the wording associated with serum 
creatinine test from “efficacy assessment” to 
“other safety assessment”.  
Correction of error. 
10.14.5 
Amended protocol 05 (18 November 2021)  
This amended protocol (amendment 05) 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 
The primary driver for this amended protocol is to update the safety follow-up algorithms for 
ALT increase and thrombocytopenia and the platelet level threshold for definition of an AESI in 
order to harmonize them with the other studies in the Phase 3 program. 
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Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Document History 
Correction of countries that Amended protocol 02 
impacted. 
Correction of error. 
1.1 Synopsis 
9.2 Sample size determination 
Clarification of the total number of participants across 
the 2 RMS studies. 
Clarification. 
1.3 Schedule of activities 
References to Section 7.1 and the Study Manual 
added to footnote c. 
Clarification of the follow up 
after pEOT. 
5.2 Exclusion criteria 
E 07: Update of prior DMTs washout periods and 
addition of DMTs that are newly marketed. 
Clarification to ensure washout 
requirement is based on the 
5 half-life rule for drug 
elimination in participants. 
Update to reflect currently 
marketed DMTs. 
 
E 09: Acetylsalicylic acid (aspirin) ≤81 mg/day 
allowed. 
Update for consistency within 
protocol. 
6.3 Measures to minimize bias: 
randomization and blinding 
8.1 Efficacy assessments 
8.1.1 Expanded disability status 
scale 
8.1.4 Timed 25-foot walk test 
8.1.5 9-hole peg test 
Requirement for Examining Investigator/rater to 
perform all clinical efficacy tests removed. Blinding 
requirements revised for certain data such as 
participant visit number. 
Update to facilitate operational 
feasibility and reduce 
complexity, without 
compromising study integrity. 
6.4 Study intervention compliance 
Proper placement of tear-off label removed. 
Correction of error. The study 
intervention has no tear-off 
label. 
6.5 Concomitant therapy 
Updated the language related to use of NSAIDs and 
symptomatic treatment of MS. 
Clarification. 
 
Added allowed daily maximum dose of aspirin 
81 mg/day. 
With the extensive safety 
monitoring during the study and 
with no bleeding risk identified 
so far for tolebrutinib, the 
Sponsor has relaxed this 
restriction. 
 
Clarified use of substrates of BCRP and members of 
the OATP family. 
Clarification. 
 
Deleted “HMG CoA reductase inhibitors”. 
Correction of error. 
 
Added avasimibe, lumacaftor, rifapentine, and 
rifabutin to list of CYP and transporter inducers that 
should be avoided due to their potential to decrease 
teriflunomide exposure. 
Clarification. 
 
Added “other bile acid sequestrants” to the list of 
drugs to be avoided 
Clarification. 
8.1.3 Magnetic resonance imaging 
Clarification that full MRI report viewing restriction to 
one/year is applicable during the intervention period. 
Clarification. 
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Section # and Name 
Description of Change 
Brief Rationale 
8.3 Adverse events and serious 
adverse events 
AESI thrombocytopenia: platelet count updated from 
<100 x 109/L to <75 x 109/L. 
Modified to align with CTCAE 
guidelines for 
thrombocytopenia. 
9.2 Sample size determination 
Clarification of 24-month ARR. 
Clarification. 
10.4 Appendix 4: Contraceptive 
guidance and collection of 
pregnancy information 
Use of male or female condoms only is not 
considered a highly effective contraceptive method 
and so not permitted as a sole method of 
contraception in this study. 
Clarification. 
10.6 Appendix 6: Liver and other 
safety: actions and follow-up 
assessments 
Clarification of the mandatory and suggested 
flowcharts. 
Clarification. 
 
Update of “Increase in ALT” flowchart. 
To provide clear guidelines for 
safety of participants in case of 
elevated ALT or reduced 
platelet counts. 
 
Update of algorithm for thrombocytopenia. 
Modified to align with CTCAE 
guidelines for 
thrombocytopenia. 
10.10 Appendix 8C: Examples of 
drugs which can be potentially 
affected by teriflunomide  
Added drugs for which concentration can be 
decreased by teriflunomide. Deleted same drugs from 
drugs for which concentration can be increased by 
teriflunomide. 
Correction of error. 
Throughout the document 
Reformatting of existing content when necessary. 
Minor, editorial, stylistic changes as necessary. 
Update table of contents, section numbers, references 
as necessary. 
Update in accordance with 
Sponsor’s standards. 
10.14.6 
Amended protocol 06 (24 May 2022)  
This amended protocol (amendment 06) 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 
The primary driver for this amended protocol is to update liver related exclusion criteria and 
monitoring to mitigate risk of drug-induced liver injury. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Cover page 
Sponsor’s legal address updated. 
Update. 
1.1 Synopsis 
10.1.5 Committees structure 
Independent Hepatology Assessment Committee 
subsection added. 
To evaluate on an ongoing 
basis cases of potential liver 
injury. 
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Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of activities (SOA) 
5.2 Exclusion criteria (E 06) 
10.2 Appendix 2: Clinical laboratory 
tests (Table 5) 
Iron panel at screening and corresponding exclusion 
criteria for genetic liver diseases added. 
Abbreviations under the SoA and Table 5 updated. 
To mitigate the risk of DILI. 
 
Update. 
2.3 Benefit/Risk Assessment 
Text related to drug-induced liver injury identified in 
an ongoing Phase 3 trial added. 
Update. 
5.2 Exclusion criteria (E 03)  
5.3.2 Caffeine, alcohol, and tobacco 
Exclusion criteria for alcohol consumption added. 
Related recommendation for alcohol consumption 
during study updated. 
To mitigate the risk of DILI. 
1.3 Schedule of activities (SOA) 
5.2 Exclusion criteria (E 06)  
10.6 Appendix 6: Liver and other 
safety: actions and follow-up 
assessments 
Liver and safety monitoring plan updated. 
Hepatic monitoring and hepatic exclusion criteria 
added. 
ALT algorithm and related instructions updated. 
To mitigate the risk of DILI. 
Updated monitoring request 
as per new exclusion 
threshold for ALT level. 
10.14: Appendix 12: Protocol 
amendment history 
Updated. 
Update. 
Throughout the document 
Reformatted existing content when necessary. 
Minor, editorial, stylistic changes as necessary. 
Updated table of contents, section numbers, 
references, abbreviations as necessary. 
Update in accordance with 
Sponsor’s standards. 
10.14.7 
Amended protocol 07 (13 September 2022)  
This amended protocol (amendment 07) 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 
The rationale for this protocol amendment is to further reduce the risk of drug-induced liver injury 
(DILI) by increasing the intensity of liver monitoring. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Cover page 
Sponsor disclaimer added. 
Update. 
Document history 
10.14 Appendix 12: Protocol 
amendment history 
Correction of amended protocol 04 approval date. 
Correction of error. 
1.3 Schedule of activities (SOA) 
 
Increased liver laboratory monitoring frequency in 
the first year after the start of the IMP. 
To reduce the risk of DILI. 
 
5.2 Exclusion criteria (E 07) 
“Plasma exchange” deleted under ‘medication’ 
column in the table of prior/concomitant therapy as it 
appeared twice. 
Correction of error. 
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Section # and Name 
Description of Change 
Brief Rationale 
10.6 Appendix 6: Liver and other 
safety: actions and follow-up 
assessments 
Increase in ALT algorithm flowchart and related 
instructions updated. 
Update. 
10.14 Appendix 12: Protocol 
amendment history 
Updated. 
Update. 
Throughout the document 
Reformatted existing content when necessary. 
Minor, editorial, stylistic changes as necessary. 
Updated table of contents, section numbers, 
abbreviations as necessary. 
Update in accordance with 
Sponsor’s standards. 
 
 
10.14.8 
Amended protocol 08 (12 December 2022)  
This amended protocol (amendment 08) 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 
The rationale for this protocol amendment is to clarify information about drug-induced liver 
injury (DILI) and update the ALT increase algorithm in relation to the risk of DILI. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
2.3 Benefit/risk assessment 
Updated information about drug-induced liver injury. 
Update. 
10.1.6 Dissemination of clinical study 
data 
Addition of ‘euclinicaltrials.eu’ in the list of websites 
where Sanofi shares information about clinical trials.  
‘Clinicalstudydatarequest.com’ replaced with 
‘vivli.org’.  
 
Update. 
10.6 Appendix 6: Liver and other 
safety: actions and follow-up 
assessments 
Related instructions of the increase in ALT algorithm 
updated. 
Update. 
10.14 Appendix 12: Protocol 
amendment history 
Updated. 
Update. 
Throughout the document 
Reformatted existing content when necessary. 
Minor, editorial, stylistic changes as necessary. 
Updated table of contents, section numbers, 
abbreviations as necessary. 
Update in accordance with 
Sponsor’s standards. 
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10.14.9 
Amended protocol 09 (17 November 2023)  
This amended protocol (amendment 09) 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 
The rationale for this protocol amendment is to update the testing requirements in the “Increase in 
ALT algorithm” and update the country-specific requirements for Japan with additional guidelines 
in case of ALT increase >3 x ULN as per Health Authorities requests.  
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of activities (SoA) 
 4.1 Overall Design  
 
Safety follow-up visit period changed from ‘4 to 
8 weeks’ to ‘4 weeks’. 
Update. 
10.6 Appendix 6: Liver and other 
safety: actions and follow-up 
assessments 
Increase in ALT algorithm related assessments and 
rechallenge restrictions updated. 
Update. 
10.11.3 Additional requirements for 
Japan 
Updated. 
Health authority request.  
10.14 Appendix 12: Protocol 
amendment history 
Updated. 
Update. 
Throughout the document 
Reformatting of existing content when necessary. 
Minor, editorial, stylistic changes as necessary. 
Updated table of contents, section numbers, 
abbreviations as necessary. 
Update in accordance with 
Sponsor’s standards. 
 
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11 
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15. Sprenger T, Kappos L, Radue EW, Gaetano L, Mueller-Lenke N, Wuerfel J, et al. Association 
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28. Banwell B, Giovannoni G, Hawkes C, Lubin F. Editors’ welcome and a working definition for 
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40. Berger JR, Aksamit AJ, Clifford DB, Davis L, Koralnik IJ, Sejvar JJ, et al. PML diagnostic 
criteria: consensus statement from the AAN Neuroinfectious Disease Section. Neurology. 
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SAP_001.pdf: 
 
 
 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive 
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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: Sanofi eSAP Version 2.0, dated 20-OCT-2021 
 Page 1 
 
 
STATISTICAL ANALYSIS PLAN  
Protocol title: 
Phase 3, randomized, double-blind efficacy and safety 
studies comparing SAR442168 to teriflunomide 
(Aubagio®) in participants with relapsing forms of 
multiple sclerosis (GEMINI 1 and GEMINI 2) 
Protocol number: 
EFC16033 and EFC16034 
Compound number 
(INN/Trademark): 
SAR442168 
(tolebrutinib) 
Study phase: 
Phase 3 
Short Title: 
RMS studies of BTK inhibitor tolebrutinib (SAR442168) 
(GEMINI 1 and GEMINI 2) 
Statistician: 
 
Statistical project leader: 
 
Date of issue: 
10-Jul-2024 
Regulatory agency identifier number(s): 
IND: 
140884 
EudraCT: 
2020-000637-41 
NCT: 
NCT04410978 
WHO: 
U1111-1238-1418 
EUDAMED: 
Not applicable 
Other: 
Not applicable 
 
Date: 
10-Jul-2024 
Total number of pages: 46 
 
 
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF TABLES ........................................................................................................................................... 4 
LIST OF FIGURES .......................................................................................................................................... 4 
VERSION HISTORY ....................................................................................................................................... 5 
1 
INTRODUCTION .............................................................................................................................. 7 
1.1 
STUDY DESIGN .............................................................................................................................. 7 
1.2 
OBJECTIVES AND ENDPOINTS .................................................................................................... 7 
1.2.1 
Estimands ........................................................................................................................................ 9 
2 
ANALYSIS POPULATIONS .......................................................................................................... 11 
3 
STATISTICAL ANALYSES ........................................................................................................... 12 
3.1 
GENERAL CONSIDERATIONS .................................................................................................... 12 
3.2 
PRIMARY ENDPOINT(S) ANALYSIS ............................................................................................ 13 
3.2.1 
Definition of endpoint(s) ................................................................................................................. 13 
3.2.2 
Main analytical approach ............................................................................................................... 13 
3.2.3 
Sensitivity analysis ......................................................................................................................... 14 
3.2.4 
Supplementary analyses ................................................................................................................ 15 
3.2.5 
Subgroup analyses ........................................................................................................................ 15 
3.3 
SECONDARY ENDPOINT(S) ANALYSIS ..................................................................................... 16 
3.3.1 
Key secondary endpoint(s) ............................................................................................................ 16 
3.3.1.1 
Definition of endpoint(s) ................................................................................................................. 16 
3.3.1.2 
Main analytical approach ............................................................................................................... 17 
3.3.1.3 
Multiple imputation for missingness due to CEOS ......................................................................... 18 
3.3.1.4 
Sensitivity analysis (pooled data only) ........................................................................................... 19 
3.3.1.5 
Subgroup analyses (pooled data only) .......................................................................................... 19 
3.3.2 
Supportive secondary endpoint(s) ................................................................................................. 19 
3.3.2.1 
Definition of endpoint(s) ................................................................................................................. 19 
3.3.2.2 
Main analytical approach ............................................................................................................... 20 
3.4 
TERTIARY/EXPLORATORY ENDPOINT(S) ANALYSIS .............................................................. 22 
3.4.1 
Definition of endpoint(s) ................................................................................................................. 22 
3.4.2 
Main analytical approach ............................................................................................................... 23 
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3.5 
MULTIPLICITY ISSUES ................................................................................................................ 25 
3.6 
SAFETY ANALYSES ..................................................................................................................... 26 
3.6.1 
Extent of exposure ......................................................................................................................... 27 
3.6.2 
Adverse events .............................................................................................................................. 27 
3.6.3 
Additional safety assessments ....................................................................................................... 30 
3.6.3.1 
Laboratory variables, vital signs and electrocardiograms (ECGs) ................................................. 30 
3.6.3.2 
Analysis of suicidality assessment ................................................................................................. 32 
3.7 
OTHER ANALYSES....................................................................................................................... 32 
3.7.1 
PK analyses (EFC16033 only) ....................................................................................................... 32 
3.7.2 
Pharmacodynamic (PD) analyses .................................................................................................. 32 
3.8 
INTERIM ANALYSES .................................................................................................................... 33 
4 
SAMPLE SIZE DETERMINATION ................................................................................................ 34 
5 
SUPPORTING DOCUMENTATION .............................................................................................. 35 
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS ..................................................................................... 35 
5.2 
APPENDIX 2 PARTICIPANT DISPOSITION ................................................................................. 36 
5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS .................................................................................................. 37 
5.4 
APPENDIX 4 DATA HANDLING CONVENTIONS ........................................................................ 39 
5.5 
APPENDIX 5 SAS CODE FOR IMPUTATION OF BASELINE GD-ENHANCING T1 
LESION STATUS ........................................................................................................................... 43 
6 
REFERENCES  .............................................................................................................................. 45 
 
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LIST OF TABLES  
Table 1 - Objectives and endpoints ................................................................................................................. 7 
Table 2 - Summary of primary estimand for main endpoints ........................................................................ 10 
Table 3 - Populations for analyses ................................................................................................................ 11 
Table 4 - Sorting of AE tables ....................................................................................................................... 28 
Table 5 - Analyses of adverse events ........................................................................................................... 29 
Table 6 - Selections for AESIs ...................................................................................................................... 30 
Table 7 - Analysis window definition of efficacy variables............................................................................. 39 
Table 8 - Analysis window definition of safety variables ............................................................................... 40 
Table 9 - Analysis window definition of PD variables .................................................................................... 41 
 
LIST OF FIGURES  
Figure 1 - Testing procedure and type 1 error control ................................................................................... 26 
 
 
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VERSION HISTORY  
This statistical analysis plan (SAP) for studies EFC16033 and EFC16034 is based on the EFC16033 
amended protocol 10 dated 20-Dec-2023 and EFC16034 amended protocol 11 dated 20-Dec-2023. 
The first participant was randomized in EFC16033 on 27-Jul-2020 and in EFC16034 on  
25-Jun-2020. This SAP is approved before the first database lock of the two studies. 
Major changes in statistical analysis plan 
SAP Version 
Approval Date 
Changes 
Rationale 
1 for review  
30-Mar-2022 
Not Applicable 
Original version 
1 
17-Aug-2023 
• 
Add non-parametric testing for endpoints 
where there is a potential for deviation from 
the normality assumption. 
Address the feedback 
provided by the FDA 
 
 
• 
Change offset variable from MRI scans to 
patient years. 
Change offset to patient 
years rather than MRI 
scans given that scans are 
not equally spaced. 
 
 
• 
Apply multiple imputation for the primary 
analysis of 6-month CDW only for 
participants that end the study with 3-month 
CDW, but without 6-month confirmation. 
Address the feedback 
provided by the FDA 
2 
23-Apr-2024 
• 
Update and clarify the multiplicity testing 
procedure to control type-1 error in each 
individual study and separately for 
endpoints assessed in the integrated 
dataset. 
Separate testing of 
individual study endpoints 
from those planned to be 
tested in the integrated 
dataset while maintaining 
a control of the type 1 error 
for EFC16033 (GEMINI 1), 
a control for EFC16034 
(GEMINI 2), and a control 
for the integrated studies. 
 
 
• 
Include imputation of missing baseline data 
of Gd-enhancing T1-hypertintense lesion 
presence or absence. Impute as absent if 
all non-missing post baseline values for 
a participant are 0, otherwise assign 
randomly based on the baseline 
proportions in the overall population. 
Baseline Gd-enhancing 
T1-hypertense lesion 
presence or absence is 
used as a covariate in the 
primary analysis of the 
primary endpoint and also 
for analysis of other 
disability related endpoints. 
Baseline imputation is 
included so that all 
participants are included in 
the analyses. The number 
of participants affected is 
minimal with no impact on 
results.  
3 
2-Jul-2024 
• 
Revert back to the original multiplicity 
testing procedure where the key secondary 
endpoint of 6M-CDW using the combined 
FDA feedback 
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SAP Version 
Approval Date 
Changes 
Rationale 
data of EFC16033 and EFC16034 can only 
be tested if both null hypotheses for the 
primary endpoint (ARR) within each study 
have been rejected. 
 
 
• 
Include SAS code to impute baseline Gd-
enhancing T1 lesion status and specify 
random seed. 
FDA feedback 
Additional minor changes have been made to improve clarity and consistency in versions 1, 2 and 3. 
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1 
INTRODUCTION  
1.1 
STUDY DESIGN  
EFC16033 and EFC16034 are Phase 3, randomized, double-blind (DB), double-dummy, 2-arm, 
active-controlled, parallel-group, multicenter, event-driven trials comparing tolebrutinib 
(SAR442168) to teriflunomide in participants with relapsing forms of multiple sclerosis (RMS). 
The treatment duration is variable ranging from approximately 24 to 48 months. See Section 4 for 
details. 
After a screening phase of up to 28 days (up to 35 days in exceptional situations), participants will 
be randomized within study at a 1:1 ratio to receive a daily dose of 60 mg oral tolebrutinib as well 
as placebo to match the teriflunomide tablet or 14 mg oral teriflunomide as well as placebo to 
match the tolebrutinib tablet. Randomization is stratified by the Expanded Disability Status Scale 
(EDSS) score at screening (<4 versus ≥4) and geographic region (US versus non-US).  
A month is defined as a period of 28 days by convention. As such, 6 months is defined as 
24 weeks and 24 months as 96 weeks. 
Participants completing the planned DB treatment period can enroll in a separate long-term safety 
(LTS) study with 60 mg tolebrutinib oral daily dosing. For participants that complete the DB 
treatment and do not enter the LTS study, a final follow-up visit to collect safety data is performed 
4 weeks after the last dose of investigational medicinal product (IMP). A participant is considered 
to have completed the study if he/she has completed all periods of the study including the end of 
study (EOS) visit, whether remaining on IMP or not. 
1.2 
OBJECTIVES AND ENDPOINTS  
Table 1 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
• 
To assess efficacy of daily SAR442168 compared 
to a daily dose of 14 mg teriflunomide (Aubagio) 
measured by annualized adjudicated relapse rate in 
participants with relapsing forms of MS 
• 
Annualized relapse rate during the study period 
assessed by confirmed protocol-defined adjudicated 
relapses 
Secondary 
• 
To assess efficacy of SAR442168 compared to 
teriflunomide (Aubagio) on disability progression, 
magnetic resonance imaging (MRI) lesions, 
cognitive performance, and quality of life 
• 
Time to onset of confirmed disability worsening 
(CDW), confirmed over at least 6 months, defined 
as follows: 
- 
increase of ≥1.5 points from the baseline 
Expanded Disability Status Scale (EDSS) score 
when the baseline score is 0, OR 
- 
increase of ≥1.0 point from the baseline EDSS 
score when the baseline score is 0.5 to ≤5.5, 
OR 
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Objectives 
Endpoints 
- 
increase of ≥0.5 point from the baseline EDSS 
score when the baseline score is >5.5 
• 
Time to onset of CDW, assessed by the EDSS 
score and confirmed over at least 3 months  
• 
Total number of new and/or enlarging 
T2-hyperintense lesions as detected by MRI, 
defined as the sum of the individual number of new 
and/or enlarging T2 lesions at all scheduled visits 
starting after baseline up to and including the End-
of-Study (EOS) visit and number of new and/or 
enlarging T2-hyperintense lesions by visit over time  
• 
Total number of new gadolinium- (Gd-) enhancing 
T1-hyperintense lesions as detected by MRI, 
defined as the sum of the individual number of new 
Gd-enhancing T1-hyperintense lesions at all 
scheduled visits starting after baseline up to and 
including the EOS visit 
• 
Time to confirmed disability improvement (CDI), 
defined as a ≥1.0 point decrease on the EDSS from 
the baseline EDSS score confirmed over at least 
6 months  
• 
Percent change in brain volume loss as detected by 
brain MRI scans at the EOS compared to Month 6  
• 
Change in cognitive function at the EOS compared 
to baseline as assessed by the Symbol Digit 
Modalities Test (SDMT) 
• 
Change in cognitive function at the EOS compared 
to baseline as assessed by the CVLT-II, where 
available 
• 
Change in Multiple Sclerosis Quality of Life 54 
(MSQoL-54) questionnaire score at the EOS 
compared to baseline 
• 
To evaluate the safety and tolerability of daily 
SAR442168 
• 
Adverse events (AEs), serious AEs, AEs leading to 
permanent study intervention discontinuation, AEs 
of special interest, and potentially clinically 
significant abnormalities in laboratory tests, safety 
scales, ECG, and vital signs during the study period 
• 
To evaluate population pharmacokinetics (PK) of 
SAR442168 and relevant metabolite(s) and its 
relationship to efficacy and safety (EFC16033 only) 
• 
Plasma concentration of SAR442168 and relevant 
metabolite(s) (population PK assessment) at 
Months 6, 9, and 12 
• 
To evaluate pharmacodynamics (PD) of 
SAR442168 
• 
Change in plasma neurofilament light chain (NfL) 
levels at the EOS compared to baseline, where 
available 
• 
Change in lymphocyte phenotype subsets in whole 
blood at the EOS compared to baseline in a subset 
of participants (EFC16033 only) 
• 
Changes in serum immunoglobulin level at the EOS 
compared to baseline  
• 
Change in serum Chi3L1 levels at the EOS 
compared to baseline 
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Objectives 
Endpoints 
Tertiary/exploratory 
• 
To evaluate the efficacy of SAR442168 on disease 
activity as measured by additional clinical, brain 
MRI, and composite measurements 
• 
EDSS score change from baseline at scheduled 
visits starting after baseline and including the EOS 
visit 
• 
Proportion of adjudicated relapse-free participants 
from randomization until the EOS visit 
• 
Time to onset of 20% worsening in the 9-hole peg 
test (9-HPT) confirmed over at least 3 and 6 months 
• 
Time to onset of 20% worsening in the timed 
25-foot walk (T25-FW) test confirmed over at least 
3 and 6 months 
• 
Time to onset of 4-point decrease in Symbol Digit 
Modalities Test (SDMT) confirmed over at least 
3 and 6 months 
• 
Change from baseline of total volume of 
T2-hyperintense lesions as detected by brain MRI 
at Months 18, 24, and the EOS 
• 
Magnetization transfer ratio recovery at the EOS in 
new magnetization transfer ratio lesions detected at 
Months 6 and 12 
• 
Change in number of phase rim lesions in 
susceptibility-weighted imaging (SWI) MRI from 
baseline by visit over time (subset of centers with 
capacity of 3T MRI) 
• 
Proportion of participants with no evidence of 
disease activity (NEDA-3) at Months 18, 24, and the 
EOS 
• 
Change from baseline to Months 12, 18, and 24 and 
to the EOS in modified Multiple Sclerosis Functional 
Composite 3 (MSFC-3), assessed as the composite 
of the T25-FW test, 9-HPT, and SDMT 
• 
Change from baseline by visit over time in volume 
of T1-hypointense lesions, and cumulative number 
of new T1-hypointense lesions 
• 
Number and volume of slowly evolving lesions 
(SELs) 
• 
Normalized T1 intensity evolution in SELs 
• 
To evaluate the treatment effect of SAR442168 via 
changes in participants’ health-related quality of life 
(HRQoL), and working capacity 
• 
Change in EuroQol 5-dimension 5-level 
questionnaire (EQ-5D-5L) from baseline by visit 
over time 
 
 
1.2.1 Estimands  
Primary estimands for the primary and key secondary endpoints are defined in Table 2. Complete 
details are provided in Section 3. For all estimands, the comparison of interest is tolebrutinib 
versus teriflunomide. 
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Table 2 - Summary of primary estimand for main endpoints  
Endpoint 
Category 
(estimand) 
Estimands 
Endpoint 
Population 
Intercurrent event(s) handling 
strategy 
Population-level summary  
(Analysis and missing data handling) 
Primary objective: To assess efficacy of daily tolebrutinib compared to a daily dose of 14 mg teriflunomide (Aubagio) measured by annualized adjudicated relapse rate (ARR) in 
participants with relapsing forms of MS 
Primary endpoint  
(treatment policy 
estimand) 
Annualized adjudicated 
relapse rate during 
study period. 
ITT 
Regardless of study intervention 
discontinuation (treatment policy) 
Relative reduction in the annualized adjudicated relapse rate as 
derived from the negative binomial model with treatment group, 
Gd-enhancing T1 lesions at baseline (presence, absence), 
geographical region (US, non-US) and EDSS strata (<4, ≥4) as 
covariates; log transformed observation duration as the offset 
variable.  
Missing data will not be imputed. 
Secondary objective: To assess efficacy of tolebrutinib compared to teriflunomide (Aubagio) on disability progression 
Key Secondary 
endpoint  
(treatment policy 
estimand) 
Time from 
randomization to onset 
of 6-month confirmed 
disability worsening 
ITT (EFC16033 and 
EFC16034 pooled 
data) 
Regardless of study intervention 
discontinuation (treatment policy) 
Hazard ratio from Cox proportional hazards model with terms for 
treatment group, Gd-enhancing T1 lesions at baseline (presence, 
absence), geographical region (US, non-US), EDSS strata (<4, ≥4) 
and study (EFC16033, EFC16034). The statistical comparison will 
be performed using the log-rank test stratified by the geographical 
region (US, non-US), EDSS strata (<4, ≥4) and study. 
Incomplete data will be imputed only for participants who complete 
the study, meet 3-month CDW criteria, and continue to meet criteria 
for EDSS disability worsening through the final study assessment, 
but did not reach 6-month confirmation. For other participants 
without a confirmed 6-month CDW or with premature study 
discontinuation prior to 6-month confirmation after onset of an event, 
the participants will be censored at the date of last EDSS 
measurement. 
ITT: intention to treat 
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2 
ANALYSIS POPULATIONS  
Table 3 - Populations for analyses  
Population 
Description 
Enrolled 
All participants who sign the ICF. 
Randomly assigned to study 
intervention / randomized 
All participants with a treatment kit number allocated and recorded in the IRT database, 
regardless of whether the treatment kit was used or not. 
Participants treated without being randomized will not be considered randomized and will 
not be included in any efficacy population. 
ITT 
The primary efficacy population will be the ITT population, defined as all randomly assigned 
participants. All 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 and exposed to study treatment, regardless of the 
amount of exposure, analyzed according to the treatment actually received.  
Randomized participants for whom it is unclear whether they took the study medication will 
be included in the safety population as randomized. 
The pharmacodynamic (PD) analyses will be performed on the safety population. 
PK 
All participants in the safety population with at least one non-missing PK sample after first 
dose of the study treatment. Participants will be analyzed according to the treatment actually 
received. 
ICF: informed consent form; IRT: interactive response technology; ITT: intention to treat; PD: pharmacodynamlic(s); PK: pharmacokinetic(s) 
The PK population applies only to study EFC16033.  
Participants exposed to study IMP before or without being randomized will not be considered 
randomized and will not be included in any analysis population. The safety experience of 
these participants will be reported separately. 
For any participant randomized more than once, only the data associated with the 
first randomization will be used in any analysis population. The safety experience associated with 
any later randomization will be reported separately. 
For participants receiving more than one study intervention during the study, the treatment group 
for as-treated analyses will be the treatment the participant received for the longest duration.  
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3 
STATISTICAL ANALYSES  
3.1 
GENERAL CONSIDERATIONS  
The baseline values of efficacy parameters are generally defined as the last available value prior to 
the first dose of study medication unless otherwise specified. For the EDSS, the baseline value 
will be taken as the average of the screening and randomization visit values. If one of the values is 
missing, the non-missing value will be used as baseline. The baseline value of safety parameters is 
defined as the last available value prior to the first dose of IMP. For the C-SSRS, the baseline 
value will be the worst assessment between the past 6 months evaluation at screening and the 
since last visit evaluation on Day 1. For participants randomized but not treated, the baseline 
value is defined as the last available value before randomization. Unless otherwise indicated, 
2-sided p-values and 95% confidence intervals [CI(s)] will be provided for assessment of 
treatment differences. 
To include all participants in analyses where baseline Gd-enhancing T1-hyperintense lesion 
presence or absence is used as a covariate, baseline status (present or absent) will be imputed for 
participants with a missing baseline count: if subsequent post-baseline counts for a participant are 
all 0, then impute baseline status as absent, otherwise, impute baseline status randomly based on 
the proportion of presence/absence at baseline in the overall population (Section 5.5). The random 
seed used for imputation will be the study number, ie, 16033 for imputation in EFC16033 and 
16034 for imputation in EFC16034. Of note, the number of participants affected is minimal with 
no impact on results. 
In general, continuous data will be summarized using the number of observations available, mean, 
standard deviation (SD), median, interquartile range (Q1, Q3), minimum, and maximum. 
Categorical and ordinal data will be summarized using the count and percentage of participants. 
Efficacy data will be analyzed in the ITT population, and safety data will be analyzed in the safety 
population, unless otherwise specified. 
Unless otherwise specified, analyses will be performed by treatment group (and overall for 
baseline and demographics characteristics). For endpoints to be analyzed in pooled 
EFC16033+EFC16034 data [confirmed disability worsening (CDW) and confirmed disability 
improvement (CDI)], pooled data will be mentioned in the analyses. If no such specification is 
included, the analysis is within the individual study. 
The primary analysis of each study and the analyses of pooled study data will be conducted after 
the completion and database lock of both studies. 
Observation period  
The observation periods for safety will be divided into 3 epochs:  
• The screening (pre-treatment) period is defined as the period from the signed informed 
consent date up to first IMP administration.  
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• The treatment period (ie, treatment-emergent (TE) period) is defined as the period from 
the first IMP administration to the earliest of 1) last IMP administration + 10 days, 
2) death date, or 3) last contact date. 
• The post-treatment period, if applicable, is defined as the period from the last day of the 
treatment period to the participant’s final study contact date.  
The on-study period is defined as the time from the randomization until the end of the study, 
defined as the last scheduled visit for those participants who complete the study and the 
end-of-study date collected on the electronic case report form (eCRF) page “Completion of 
End of Study” for those who did not complete the study. If death is the end-of-study reason, 
date of death will be used. 
Contingency measures for a regional or national emergency that is declared by a governmental 
agency 
For participants in Ukraine, Russia, and Belarus who are impacted by national events and likely 
lost to follow-up (LFU) as of 24 February 2022, their data will be handled as follows: 
• For the primary endpoint of annualized adjudicated relapse rate, all observed events, if 
any, up to the last contact date for the participant will be included in the analysis, and the 
observation duration will be from randomization to the last contact date. No imputation 
will be performed for the unobserved events that may happen after being LFU. 
• For time to event secondary and tertiary endpoints, participants will be treated as 
prematurely discontinuing the study and will be censored at the date of last corresponding 
assessment (eg, last EDSS assessment). 
• For all other secondary and tertiary endpoints as well as all safety endpoints, all observed 
data up to the last contact date will be included for analyses.  
3.2 
PRIMARY ENDPOINT(S) ANALYSIS  
3.2.1 Definition of endpoint(s)  
The primary endpoint is the ARR (this refers to the adjudicated ARR herein, unless otherwise 
specified) during the study period assessed by confirmed protocol-defined adjudicated relapses.  
3.2.2 Main analytical approach  
The purpose of the primary analysis of ARR is to assess the efficacy of tolebrutinib in an ITT 
setting. The null hypothesis for the primary efficacy endpoint of ARR is that there is no treatment 
difference between tolebrutinib and teriflunomide, and the alternative is that there is 
a between-treatment difference.  
In this primary approach, off-treatment events of participants who prematurely discontinue study 
intervention will be included for analysis as per the ITT principle. Participants who permanently 
discontinue study intervention will be asked and encouraged to return to the clinic for 
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all remaining study visits. In this case, all events during the planned treatment period will be 
included and the observation duration will be from randomization to the EOS. If a participant 
withdraws from the study prior to the common end of study (CEOS), all observed events up to the 
last contact date will be included in the analysis, and the observation duration will be from 
randomization to the last contact date. No imputation will be performed for the unobserved events 
that may happen after study discontinuation. This estimand compares the rate of relapse for the 
participants randomized to tolebrutinib versus teriflunomide, regardless of what treatment 
participants actually received. It assesses the benefit of the treatment policy or strategy relative to 
teriflunomide. The study will be declared positive if the null hypothesis for ARR for tolebrutinib 
versus teriflunomide is rejected at the 2-sided 0.05 significance level. 
ARR will be analyzed using a negative binomial regression model with robust variance estimation 
(1). The robust variance can be estimated by specifying the participant identifier in the repeated 
statement using SAS PROC GENMOD (version 9.4 or later). The model will include the total 
number of adjudicated relapses per participant occurring during the observation period as the 
response variable, with treatment group, gadolinium (Gd)-enhancing T1 lesions at baseline 
(presence, absence), EDSS strata (<4, ≥4) and geographic region (US, non-US) as covariates. Log 
transformed observation duration will be the offset variable. 
The estimated ARR for each treatment group and corresponding 2-sided 95% confidence interval 
will be derived from the negative binomial model where the adjusted mean value within treatment 
group is based on a sample size dependent weight within each categorical covariate (ie, weight by 
overall proportion of participants in each stratum or categorical factor, also called “population 
weight”). The relative reduction in ARR with tolebrutinib compared to teriflunomide, its 2-sided 
95% confidence interval and p-value will be provided.  
The absolute difference in ARR between tolebrutinib and teriflunomide, two-sided 95% 
confidence interval and associated p-value derived using the delta method will also be provided as 
supportive information.  
The unadjusted ARR (total number of adjudicated relapses during the study period divided by the 
total participant years on study) will also be presented by treatment group. Mean cumulative 
function plot will be provided for descriptive purposes. 
3.2.3 Sensitivity analysis  
The following sensitivity analyses will be performed to assess the robustness of the conclusion of 
the main analytical approach:  
• ARR based on all Investigator-reported relapses, regardless of adjudication status, based 
on the ITT population.  
• ARR for the first 24-month study period (from randomization; fixed 24-month duration) 
based on the participants completing at least 24 months on study, regardless of treatment 
status. All adjudicated relapses occurring from randomization through Month 24, 
including data collected after premature treatment discontinuation if applicable, will be 
used for analysis.  
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• ARR on-treatment analysis based on the randomized and exposed participants. This model 
will include adjudicated relapses occurring during treatment (first administration of IMP to 
last administration inclusive) as the response variable and the log transformed duration of 
treatment as the offset variable. Data collected after premature treatment discontinuation 
will not be included in this analysis. 
In each case, a negative binomial model with the same set of covariates as specified in the primary 
analysis will be used.  
3.2.4 Supplementary analyses  
The time to first adjudicated relapse for tolebrutinib versus teriflunomide will be compared via 
a log-rank test stratified by EDSS strata (<4, ≥4) and geographic region (US, non-US). 
Participants without an adjudicated relapse event during the study will be censored at their 
last contact date. Kaplan-Meier (KM) plots of the cumulative incidence rate will be provided by 
treatment group. The proportion of participants with events at given time points (eg, Month 12, 
18, 24, 30, …) will be calculated using the KM estimates. The hazard ratio (95% CI) will be 
estimated by a Cox proportional hazards model with terms for treatment, Gd-enhancing T1 lesions 
at baseline (presence, absence), EDSS strata (<4, ≥4), and geographic region (US, non-US). 
3.2.5 Subgroup analyses  
To assess the homogeneity of the treatment effect, analyses will be performed on the primary 
endpoint (ARR) across the following subgroups (categories with too few participants for the 
model to converge will be combined with another category; for factors with only two categories, 
no subgroup analysis will be performed if fewer than 5 participants in one category): 
• Age (≤40, >40 years) 
• Sex (Male, Female) 
• Race (White, Black or African American, Asian, Other) 
• EDSS strata (<4, ≥4) 
• Gd-enhancing T1 lesions at baseline (presence, absence) 
• Geographic region (US, non-US) 
• Region (Eastern Europe [EU], Western EU, North America, rest of the world [ROW]) 
• Highly active disease (HAD) at baseline (Yes, No) 
• Prior disease modifying therapy (DMT) use (Yes, No) 
• Relapses in the one year prior to screening (<2, ≥2)  
• Time since symptom onset in years (<5, 5 to <10, >=10) 
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Participants with HAD are defined as having 1 relapse in the previous year AND one of the 
following: at least 1 Gd enhancing T1-hyperintense lesion; or 9 or more T2-hyperintense lesions 
at baseline for participants who were already treated with DMT (any treatment with DMTs would 
be considered, if documented, during the prior year) or who had 2 or more relapses in the previous 
year, whether treated with DMTs or not.  
Treatment by subgroup interaction and its p-value will be derived from a negative binomial 
model. This model will include the total number of adjudicated relapses occurring during the 
observation period as the response variable with treatment group, Gd-enhancing T1 lesions at 
baseline (presence, absence), EDSS strata (<4, ≥4), geographic region (US, non-US), subgroup 
(if different than the aforementioned covariates), and treatment by subgroup interaction as 
covariates. Log transformed observation duration will be the offset variable. If quantitative 
treatment by subgroup interaction is detected with nominal p-value <0.1 for any subgroup factor, 
a further investigation will be performed to evaluate possible qualitative interaction. The ARR 
(95% CI) within each subgroup separately will be provided from similar negative binomial 
models excluding the subgroup and treatment by subgroup interaction terms. Forest plots of 
relative risks and corresponding 95% CIs, and forest plots of risk differences and corresponding 
95% CIs comparing tolebrutinib to teriflunomide within each subgroup will be provided.  
3.3 
SECONDARY ENDPOINT(S) ANALYSIS  
The secondary endpoints detailed in this section are for assessing efficacy of tolebrutinib 
compared to teriflunomide on disability progression, lesion counts and volumes obtained via 
magnetic resonance imaging (MRI), cognitive performance, and quality of life.  
Other secondary endpoint analyses are defined in Section 3.6.2 (AE, SAE), Section 3.6.3.1 
(laboratory abnormalities), Section 3.7.1 (PK) and Section 3.7.2 (PD).  
3.3.1 Key secondary endpoint(s)  
3.3.1.1 Definition of endpoint(s)  
Time to onset of 6-month CDW is defined as the time from randomization to the onset of 
a confirmed, sustained increase from baseline in EDSS score (of ≥1.5 points when the baseline 
score is 0, of ≥1.0 point when the baseline score is 0.5 to ≤5.5, of ≥0.5 points when the baseline 
EDSS score is >5.5) over at least 6 months that is not attributable to another etiology (eg, fever, 
concurrent illness, or concomitant medication).  
• The initial onset increase from baseline EDSS score can be from a scheduled or 
unscheduled assessment. 
• All intermediate EDSS scores (EDSS scores obtained after onset of disability and before 
the confirmatory assessment), if any, must maintain at least the minimum increase. 
• Confirmatory EDSS assessment must be obtained at least 6 months after onset, at a routine 
quarterly visit, at least 30 days after any confirmed clinical relapse, and not be associated 
with an ongoing relapse. 
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Note: 6-month confirmation must be ≥154 days after onset. Given that visits are scheduled 
every 12 weeks with a time window of ±7 days for conducting EDSS assessment, the minimum 
per protocol allowed time between 2 EDSS assessments scheduled 24 weeks apart is 154 days 
(6 months=24 weeks=168 days minus a 7-day window for each of the 2 visits, ie, 168-14=154).  
3.3.1.2 Main analytical approach  
The primary analysis of the key secondary endpoint, time to onset of 6-month CDW, will be 
performed on the pooled ITT population from studies EFC16033 and EFC16034. The null 
hypothesis is the same as for the primary endpoint analysis, ie, no treatment difference between 
tolebrutinib and teriflunomide versus the alternative of a between-treatment difference. 
In this primary ITT analysis: 
• For participants who complete the study without an initial onset of disability worsening, 
the participant will be censored at the date of last EDSS assessment. 
• For participants who have an initial onset of disability worsening but complete the study at 
the common study end without 3-month confirmation, the participant will be censored at 
the date of last EDSS assessment. 
• For participants who complete the study, meet 3-month CDW criteria, and continue to 
meet criteria for EDSS disability worsening through the final study assessment, but do not 
reach 6-month confirmation, the 6-month CDW event status of the participant will be 
determined by an imputation approach. Since in this setting the partial missing data can 
reasonably be assumed to be missing at random, this approach leverages the partial 
information and follows the ITT principle. The details of this imputation approach are 
provided in Section 3.3.1.3. 
If a participant dies due to MS, it will be considered a confirmed disability worsening regardless 
of the baseline EDSS or the change in EDSS. The time to onset will be calculated as (date of 
EDSS assessment at a tentative onset of the event – date of randomization + 1) or (date of death – 
date of randomization + 1) if a tentative onset date does not exist. Death for other reasons than 
MS will not be considered a disability worsening.  
The time to onset of 6-month CDW for tolebrutinib versus teriflunomide will be compared via 
a log-rank test stratified by EDSS strata (<4, ≥4), geographic region (US, non-US), and study 
(EFC16033, EFC16034). KM plots of the cumulative incidence rate will be provided by treatment 
group to depict the course of onset of 6-month CDW over time. The proportion of participants 
with events at given time points (eg, Month 12, 18, 24, 30, …) will be calculated using the KM 
estimates. The hazard ratio (95% CI) will be estimated by a Cox proportional hazards model with 
robust variance estimation (1). The covariates are treatment group, Gd-enhancing T1 lesions at 
baseline (presence, absence), EDSS strata (<4, ≥4), geographic region (US, non-US), and study 
(EFC16033, EFC16034). An expanded model with a treatment-by-study interaction will be fit to 
the data, and between-study heterogeneity will be tested (type-3); the corresponding p-value will 
be provided.  
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3.3.1.3 Multiple imputation for missingness due to CEOS  
For participants who met 3-month CDW criteria, and continued to meet criteria for EDSS 
disability worsening through the final study assessment, but do not reach 6-month confirmation, 
the event status (ie, confirmed or not confirmed) of the participant will be determined by a logistic 
regression model as follows: 
𝑌𝑖~𝐵𝑒𝑟𝑛𝑜𝑢𝑙𝑙𝑖(𝑝𝑖𝑗), 𝑖= 1, … , 𝑛𝑗 ;  𝑗= 1,2 
𝑙𝑜𝑔𝑖𝑡(𝑝𝑖𝑗) = 𝑙𝑛(
𝑝𝑖𝑗
1 −𝑝𝑖𝑗
) = β0𝑗+ β1𝑗𝑥1𝑖𝑗+ β2𝑗𝑥2𝑖𝑗+ β3𝑗𝑥3𝑖𝑗 
where 𝑌𝑖𝑗 is the indicator for event status of 6-month CDW for participant 𝑖 from group 𝑗; 
1 = 6-month CDW, 0 = no 6-month CDW, 𝑝𝑖𝑗 is the probability that participant 𝑖 from group 𝑗 has 
a 6-month CDW event, 𝑥1𝑖𝑗 is the EDSS strata (<4, ≥4), 𝑥2𝑖𝑗 is the geographic region (US, non-
US), 𝑥3𝑖𝑗 is the Gd-enhancing T1 lesion status at baseline (absence, presence), β𝑘𝑗 are the model 
parameters (𝑘= 0,1,2,3; 𝑗= 1,2). The logistic model parameters β𝑘𝑗 will be estimated from 
participants who do not have missing value due to CEOS. Separate logistic models will be 
estimated within each treatment arm. Then, these estimates will be used to calculate the predicted 
probability for participants who meet 3-month CDW criteria, and continue to meet criteria for 
EDSS disability worsening through the final study assessment, and missingness due to CEOS. 
Finally, the missing value for those participants with an initial onset of disability worsening and 
missingness due to CEOS will be imputed via a randomly generated value from a Bernoulli 
distribution with 𝑝𝑖𝑗.  
Using the above methodology, 1000 complete data sets will be generated with imputed missing 
data via PROC MI in SAS. Each of the data sets will be analyzed using the Cox proportional 
hazards model as described above. Log-rank test and KM plot will also be provided based on 
1000 complete data sets based on the method in (2). The SAS MIANALYZE procedure will be 
used to generate statistical inferences by combining results from the 1000 analyses using Rubin’s 
formula. 
Sample SAS code is provided below: 
PROC MI data=DATAIN out=DATAOUT nimpute=1000; 
  by  Treatment_group; 
  var EDSS_strata geographic_region Gd_T1; 
  fcs logistic(Confirmation = EDSS_strata geographic_region Gd_T1/ link=glogit); 
run; 
 
PROC MIANALYZE data= DATAOUT; 
    modeleffects Estimate; 
    stderr StdErr; 
run; 
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DATAIN only includes participants who meet the imputation criteria mentioned above. Details of 
multiple imputation can be found in SAS support document (3). 
In addition to the analysis using pooled data, time to onset of 6-month CDW will also be analyzed 
within each study separately using the same statistical methods as for the primary analysis, but 
without study included in the model and without any treatment-by-study interaction analysis.  
3.3.1.4 Sensitivity analysis (pooled data only)  
To assess robustness of the primary analysis, a sensitivity analysis will be performed based on the 
observed confirmed 6-month CDW where missing or incomplete 6-month CDW will be treated 
censored at their last EDSS assessment. The analysis methods will be the same as those for the 
primary analysis of 6-month CDW but without imputation. 
3.3.1.5 Subgroup analyses (pooled data only)  
To assess the homogeneity of the treatment effect, analyses will be performed on the key 
secondary endpoint for the same subgroups as specified in Section 3.2.5. There will be no 
imputation for incomplete/missing data for these subgroup analyses.  
Treatment by subgroup interaction and its p-value will be derived from a Cox proportional 
hazards model with terms for treatment, Gd-enhancing T1 lesions at baseline (presence, absence), 
EDSS strata (<4, ≥4), geographic region (US, non-US), study (EFC16033, EFC16034), subgroup 
(if different than the aforementioned covariates) and treatment by subgroup interaction as 
covariates. The HR (95% CI) comparing tolebrutinib to teriflunomide within each subgroup 
separately (Cox models without subgroup and treatment by subgroup interaction terms) will be 
provided and displayed in forest plots. 
3.3.2 Supportive secondary endpoint(s)  
3.3.2.1 Definition of endpoint(s)  
Other secondary endpoints are listed in Table 1.  
SDMT is used to assess divided attention, visual scanning, tracking and motor speed. The number 
of correct substitutions and number of items completed within a 90 second interval (max = 110) 
are recorded. The baseline mean and standard deviation of all participants are used to create the 
Z-score for SDMT number of correct substitutions: Z = {(SDMT score – baseline mean 
SDMT)/baseline SD SDMT)}. Z-scores will be used for analysis. 
California verbal learning test-II (CVLT-II) is a verbal learning and memory test. It consists of 
recall and recognition of a list of 16 words. For each assessment, 5 trials are completed. The total 
correct, total intrusions, and total repetitions across the 5 trials combined are recorded and 
converted to a standardized score by sex within each of 7 age groups (4). Total Correct Recall 
Trials 1–5 is scaled to a normalized T–score metric, which has a mean of 50 and standard 
deviation of 10, with higher values indicating better performance. Total intrusions and total 
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repetitions are normed on a linear Z-score metric, with a mean of 0, standard deviation of 1.0, and 
increment values of plus or minus 0.5. Higher positive Z-scores on these measures reflect greater 
deficits. Standardized scores will be used for analysis.  
MSQoL-54 is a multidimensional health-related quality of life measure that combines both 
generic and MS-specific items into a single instrument (5). The recall time, when relevant, is for 
the last 4 weeks. There are 2 derived summary scores, physical health composite and mental 
health composite, and 12 subscale scores: physical function, role limitations-physical, role 
limitations-emotional, pain, emotional well-being, energy, health perceptions, social function, 
cognitive function, health distress, overall quality of life, and sexual function, and 2 single-item 
measures: satisfaction with sexual function and change in health. The total number of items in 
each subscale is listed as the divisor for each subtotal. Due to missing data, the divisor can be less 
than that if not every item within a given scale has been answered. All scores are transformed 
linearly to a common 0 (worst) to 100 (best) score range.  
3.3.2.2 Main analytical approach  
Time to onset of 3-month CDW will be analyzed using the same statistical methods as for the 
primary analysis of time to onset of 6-month CDW. Primary analyses will be in the pooled 
EFC16033 and EFC16034 ITT population. Analysis within each study separately will also be 
provided.  
Note: 3-month confirmation must be ≥70 days after onset. Given that visits are scheduled 
every 12 weeks with a time window of ± 7 days for conducting EDSS assessment, the minimum 
per protocol allowed time between 2 EDSS assessments scheduled 12 weeks apart is 70 days 
(3 months=12 weeks=84 days minus a 7-day window for each of the 2 visits, ie, 84-14=70).  
Time to onset of 6-month CDI will be analyzed using similar statistical methods as for the 
primary analysis of time to onset of 6-month CDW, but without imputation. Participants with 
6-month CDI onset without confirmation will be treated censored at the last EDSS assessment. 
Primary analyses will be in the pooled EFC16033 and EFC16034 ITT population. Analysis within 
each study separately will also be provided.  
For categorical efficacy endpoints with count data (annualized rate of new/enlarging 
T2-hyperintense lesions and average number of new gadolinium- (Gd-) enhancing 
T1-hyperintense lesions per scan), similar negative binomial regression analyses as for the 
primary analysis of ARR will be performed in the ITT population. The response variable in 
this case will be the total count of the respective type of lesion across all scheduled MRI scans 
during the study period and the offset variable will be the log transformed study duration for T2 
lesions and number of MRI scans for T1 lesions. Randomization stratification factors will remain 
as covariates in the model. For analysis of new Gd-enhancing T1 lesions, Gd-enhancing T1 
lesions at baseline (presence, absence) will remain as a covariate, but for analysis of 
new/enlarging T2 lesion count, this covariate will be replaced by baseline T2 lesion count. The 
average number of lesions per scan (95% CI) for each treatment group will be estimated from the 
model along with the relative risk (95% CI, p-value) for tolebrutinib compared to teriflunomide. 
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Percent change in brain volume loss at the EOS compared to Month 6 will be analyzed using 
a mixed-effect model with repeated measures (MMRM) approach in the ITT population for 
estimating the treatment effect with appropriate transformation if necessary (eg, log-transform). 
Estimates derived from the MMRM approach will be weighted by overall proportion of 
participants in each stratum or categorical factor. The model will include percent change from 
Month 6 values at scheduled visits up to and including the end of study visit as the response 
variable, and treatment, EDSS strata (<4, ≥4), geographic region (US, non-US), visit, treatment 
by-visit interaction, Month 6 brain volume, and Month 6 brain volume-by-visit interaction as 
covariates; have an unstructured variance-covariance matrix and be fitted using restricted 
maximum likelihood estimation. If this model fails to converge, the following variance-
covariance structures will be tested in this order:  
• Heterogeneous Toeplitz (TOEPH) 
• Heterogeneous first-order autoregressive (ARH(1)) 
• Heterogeneous compound symmetry (CSH) 
• Toeplitz (TOEP) 
• AR(1) 
• CS 
The first (co)variance structure yielding convergence will be used as the primary analysis. 
Comparisons between treatment arms will be made using least squares mean contrasts at the EOS 
with denominator degrees of freedom estimated using the Kenward-Roger approximation (6). 
When a variance-covariance structure other than unstructured is used, the denominator degrees of 
freedom will be estimated using the between within method (DDFM=BW in SAS PROC MIXED) 
(7). 
Example SAS code for the MMRM is: 
ods output Diffs = out1 
           LSMeans = out2; 
proc mixed data = DATAIN method = reml; 
  class TRTPN VISIT USUBJID; 
  model PCHG = EDSS REGION TRTPN VISIT TRTPN*VISIT M6 M6*VISIT /  
          s ddfm=kr; 
  repeated VISIT / type = un subject = USUBJID  r; 
  lsmeans TRTPN TRTPN*VISIT / OM cl diff; 
run; 
where TRTPN = treatment group, VISIT refers to the protocol scheduled visits for the endpoint up 
to and include the EOS, USUBJID = unique participant ID, PCHG is the percent change from 
Month 6 in brain volume, M6 is the Month 6 brain volume, EDSS refers to the EDSS strata, and 
REGION refers to the geographic region strata. Type specifies the variance-covariance structure 
and can take on a value of UN, TOEPH, ARH(1), CSH, TOEP, AR(1) or CS as described above. 
Change from baseline in SDMT number of correct substitutions, CVLT-II total correct and 
MSQoL-54 physical and mental health composite scores at EOS will be analyzed using 
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an analogous MMRM approach in the ITT population with the change from baseline values for 
the respective endpoint at scheduled visits up to and including the end of study visit as response 
variables, and treatment, EDSS strata (<4, ≥4), geographic region (US, non-US), visit, treatment 
by-visit interaction, baseline value for the endpoint being assessed and baseline value by-visit 
interaction as covariates. 
For each endpoint, difference in least squares means, the corresponding 95% CI, and p-value will 
be provided for the comparison of tolebrutinib versus teriflunomide. Plots of least squares means 
(LSM) [±standard error (SE)] over time will be provided. Participants who discontinue study 
treatment before the common study end will be asked and encouraged to return for all remaining 
study visits and the additional off-treatment values measured up through the EOS visit will be 
included in the primary analysis. For participants who withdraw from the study before the CEOS, 
values will be missing after study discontinuation and no imputation will be performed. In order 
to assess the impact of deviation from the normality assumption, a sensitivity analysis using rank 
ANCOVA with the same covariates as for the MMRM analysis except visit and related interaction 
terms, will be performed for these continuous supportive secondary endpoints to provide the 
p-value for the comparison between the treatment groups. No other sensitivity, supplementary, or 
subgroup analyses will be performed for these supportive secondary endpoints. 
3.4 
TERTIARY/EXPLORATORY ENDPOINT(S) ANALYSIS  
3.4.1 Definition of endpoint(s)  
Tertiary/exploratory endpoints are listed in Table 1.  
The T25-FW is a quantitative mobility and leg function performance test based on a timed 25-foot 
walk; time in seconds to walk 25 feet (lower bound: 2.2 sec; upper bound: 180 sec). For 
each assessment, 2 trials are performed. The score is the average of the times from the 2 trial 
(or single score if only 1 completed). The baseline mean and standard deviation of all participants 
are used to create Z-scores: Z = -{(Average 25-FW - Baseline Mean T25-FW) /Baseline SD 
T25-FW}. The negative of the Z-score is used so that improvement is a positive number and 
worsening a negative number. For a participant who could not complete the 25-FW due to 
a “physical limitation”, the maximum time (180 sec) will be used. Missing values for other 
reasons will not be imputed. In case of values below (above) the lower (upper) bound, the value 
will be set to the respective bound.  
The 9-HPT is a brief, standardized, quantitative test of upper extremity function (lower bound: 
10 sec; upper bound: 300 sec). Two consecutive trials with the dominant hand are immediately 
followed by two consecutive trials with the non-dominant hand. The total time to complete the 
task is recorded. To transform the data so that higher Z-scores correspond to an improved 
outcome and lower Z-scores correspond to deterioration, the inverse of the test values are taken 
prior to computing the Z-score. The baseline mean and standard deviation of all participants are 
used to create Z-scores: Z = {(1/trialarm,left + 1/trialarm,right ) / 2.0 – Baseline mean (1/9-HPT)} 
/ Baseline SD(1/9-HPT). The two trials for each hand are averaged, converted to the reciprocals of 
the mean times for each hand and then the two reciprocals are averaged. Where 1/trialarm,left = 
(1/average of the two times of the left arm trials); if one is missing then use the one available. For 
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a participant who could not complete the 9-HPT due to a “physical limitation”, the maximum time 
(300 sec) will be used. Investigators will be reminded that missing data should be avoided. 
However, in case of missing data for other reason than inability to complete the test, missing data 
will be treated as follows: 
• In case only 1 trial was done for a hand, the average of the two trials will be replaced by 
the time for the available trial. 
• In case 9-HPT was assessed for only one hand, the overall 9-HPT will not be calculated 
and considered missing. 
Missing values for other reasons will not be imputed. In case of values below (above) the lower 
(upper) bound, the value will be set to the respective bound. 
MSFC-3 is a multidimensional, three-component performance scale to assess the degree of 
impairment in MS patients. Here, the MSFC-3 score is defined as the average of the T25-FW, 
9-HPT and SDMT Z-scores. 
EQ-5D-5L is a standardized health-related quality of life questionnaire that provides a simple, 
generic measure of health for clinical and economic appraisal. It consists of 2 pages, the EQ-5D 
descriptive system and the EQ visual analogue scale (VAS). The EQ-5D descriptive system 
comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort and 
anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate 
problems, severe problems, and extreme problems. EQ-5D-5L health status will be converted into 
a single index value by using the value sets based on UK population and according to the 
crosswalk algorithm developed by B. van Hout (8). The index score is anchored at 1 (full health) 
with 0 (negative values) corresponding to states being as bad or worse than dead. The EQ VAS 
records the respondent’s self-rated health on a vertical VAS ranging from 0 (worst imaginable 
health state) at the bottom to 100 (best imaginable health state) at the top. Overall, higher scores 
indicate high health utility. 
3.4.2 Main analytical approach  
Summary statistics including mean, standard deviation, median, interquartile range (Q1, Q3), 
minimum, and maximum will be provided for the following continuous data endpoints at 
scheduled visits over the study period including the EOS. Only non-missing data will be included. 
For change from baseline, only participants with baseline and post-baseline data will be 
summarized.  
• EDSS score and change from baseline 
• Number of Gd-enhancing T1 lesions and change from baseline 
• Number of new Gd-enhancing T1 lesions 
• Number of new/enlarging T2 lesions per 6-month interval 
• T2 lesion volume and change from baseline 
• Cumulative number of new T1-hypointense lesions 
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• T1-hypointense lesion volume and change from baseline. 
• Number of phase rim lesions and change from baseline 
• Normalized brain volume at screening and percent change in brain volume at post baseline 
time points 
• Number of slowly evolving lesions at EOS compared to screening 
• Volume of slowly evolving lesions at EOS compared to screening 
• SDMT number of correct substitutions Z-score and change from baseline 
• SDMT number of completed items and change from baseline 
• CVLT-II standardized scores for total number correct and change from baseline 
• CVLT-II standardized scores for total number of intrusions and change from baseline 
• CVLT-II standardized scores for total number of repetitions and change from baseline 
• MSFC-3 and change from baseline 
• T25-FW raw score and Z-score for leg function/ambulation and change from baseline 
• 9-HPT raw score and Z-score for arm/hand function and change from baseline 
• MSQoL-54 score and change from baseline for the 2 derived composite scores, 
12 subscale scores and 2 single item scores 
• EQ-5D-5L health state utility value score and change from baseline 
• EQ VAS score and change from baseline 
Plots of mean (±SD) and/or mean change (±SD) and/or median over time will also be provided for 
better visualization. 
No evidence of disease activity-3 (NEDA-3) is defined as absence of all of the following: 
• 6-month CDW 
• Active MRI lesions (both new or enlarged T2-hyperintense lesions and Gd-enhancing 
T1-hyperintense lesions) 
• MS relapses 
The proportion of adjudicated relapse-free participants at the EOS and the proportion of 
participants with NEDA-3 at Months 18, 24, and the EOS will be analyzed in the ITT population 
via a stratified Cochran-Mantel-Haenszel (CMH) test, stratified by EDSS strata (<4, ≥4) and 
geographical region (US, non-US). The relative ratio for tolebrutinib versus teriflunomide, 
95% confidence interval, and p-value will be provided.  
Time-to-event endpoints confirmed over 3 and 6 months (20% worsening in 9-HPT, 
20% worsening in T25-FW, 4-point decrease in SDMT) will be analyzed using similar statistical 
methods as for the primary analysis of time to onset of 6-month CDW (key secondary endpoint) 
in the pooled EFC16033 and EFC16034 ITT population, but without multiple imputation for 
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incomplete/missing data (ie, censoring at last assessment). Analysis within each study separately 
will also be provided.  
Change from baseline in total volume of T2 hyperintense lesions (M18, M24, and EOS), MSFC-3 
Z-score (M12, M18, M24, and EOS), and EQ-5D-5L index and VAS scores (by scheduled visit) 
will be analyzed in the ITT population using a similar MMRM approach as described for the 
continuous supportive secondary endpoints in Section 3.3.2. Analysis of T2 lesion volume will be 
performed with appropriate transformation if necessary (eg, log-transform). In order to assess the 
impact of deviation from the normality assumption, a sensitivity analysis using rank ANCOVA 
with the same covariates as for the MMRM analysis except visit and related interaction terms, will 
be performed for these continuous tertiary endpoints to provide the p-value for the comparison 
between the treatment groups. 
The participant/lesion time courses for magnetization transfer ratio (MTR) recovery in 
Gd-enhancing lesions detected at Months 6 and 12 and normalized T1 intensity evolution in 
slowly evolving lesions will be listed. 
Missing data will not be imputed in the analysis of tertiary endpoints, nor will other sensitivity or 
subgroup analyses be conducted.  
3.5 
MULTIPLICITY ISSUES  
To strongly control the type 1 error rate at the level of the individual studies and at the level of the 
pooled studies, the testing strategy in (9) illustrated in Figure 1 will be implemented.  This allows 
for sequential, hierarchical testing of selected endpoints within each study given the null 
hypothesis for the primary endpoint (ARR) of the study is rejected at 2-sided 0.05.  Additionally, 
given the null hypothesis for the primary endpoint (ARR) is rejected in both studies (each at 
2-sided 0.05), it allows for sequential, hierarchical testing of selected disability endpoints in the 
pooled EFC16033 and EFC16034 study population.  Hypotheses can only be tested in sequential 
order as indicated by the arrows. A specific hypothesis can only be tested if all proceeding null 
hypotheses in the sequence have been rejected. The number associated with each hypothesis 
(α and α-α2) indicates the significance level at which the hypothesis can be tested. The testing is 
performed at 2-sided α=0.05 within each study, but the corresponding efficacy claim can be made 
only if both studies demonstrate statistical significance for the associated endpoint. The family-
wise type I error rate for each study is controlled at 2-sided α=0.05. The type I error rate for the 
primary endpoint (H1, H1’) and secondary endpoints (H5, H5’; H6, H6’; H7, H7’; H8, H8’; H9, 
H9’) is controlled at 2-sided α2 (0.052). For all secondary endpoints, including those based on the 
pooled data (H2, H2’), (H3, H3’) and (H4, H4’), the family-wise type I error is controlled at 
2-sided 0.05.  
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Figure 1 - Testing procedure and type 1 error control   
 
 
3.6 
SAFETY ANALYSES  
All safety analyses will be performed for each study on the safety population as defined in  
Section 2, unless otherwise specified, using the following common rules: 
• The analysis of the safety variables will be descriptive, and no testing is planned. The 
summary of safety results will be presented by treatment group. 
• Safety data in participants who do not belong to the safety population (eg, exposed but not 
randomized) will be provided separately. 
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3.6.1 Extent of exposure  
The extent of IMP exposure will be assessed by the duration of IMP exposure and summarized 
within the safety population. 
Duration of IMP exposure 
Duration of IMP exposure is defined as last IMP administration date – first IMP administration 
date + 1 day, regardless of unplanned intermittent discontinuations. If the date of the last dose of 
IMP is missing, the duration of IMP will be left as missing. 
Duration of IMP exposure will be summarized quantitatively and categorically:  
• >0 and <24 weeks 
• ≥24 and <48 weeks 
• ≥48 and <72 weeks 
• ≥72 and <96 weeks 
• … (24-week intervals) 
Additionally, the cumulative duration of treatment exposure (expressed in participant-years) will 
be provided. 
Treatment compliance 
A given administration will be considered non-compliant if the participant did not take the 
planned dose of treatment as required by the protocol, ie, once daily oral dose. No imputation will 
be made for participants with missing or incomplete data. 
Percentage of compliance for a participant will be defined as the number of days that the 
participant was compliant divided by the total number of days of planned administration during 
the treatment period. 
Treatment compliance will be summarized quantitatively and categorically: <80%, ≥80%. 
3.6.2 Adverse events  
General common rules for adverse events 
All adverse events (AE(s)) will be graded according to National Cancer Institute Common 
Terminology for Adverse Events (NCI-CTCAE version 5.0, 27 Nov 2017) and coded to a lower-
level term (LLT), preferred term (PT), high-level term (HLT), high-level group term (HLGT), and 
associated primary system organ class (SOC) using the Medical Dictionary for Regulatory 
Activities (MedDRA) version currently in effect at Sanofi at the time of database lock. 
The AEs will be analyzed in the following 3 categories: 
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• Pre-treatment AEs: AEs that developed, worsened, or became serious during the pre-
treatment period. 
• Treatment-emergent adverse events (TEAE(s)): AEs that developed, worsened, or became 
serious during the treatment period 
• Post-treatment AEs: AEs that developed, worsened, or became serious during the post-
treatment period  
Similarly, if occurring, deaths will be analyzed in the pre-treatment, treatment-emergent, and post-
treatment period.  
The primary focus of AE reporting will be on TEAEs. Pre-treatment and post-treatment AEs will 
be described separately.  
An AE with incomplete or missing date/time of onset (occurrence, worsening, or becoming 
serious) will be classified as a TEAE unless there is definitive information to determine it is a pre-
treatment or a post-treatment AE.  
If the assessment of the relationship to IMP is missing for an AE, this AE will be assumed as 
related to the IMP. If the grade is missing for 1 of multiple treatment-emergent occurrences of 
a specific AE for a participant, the grade will be imputed with the maximal grade of the other 
occurrences. If the grade is missing for all the occurrences, the grade will be left as missing. 
Multiple occurrences of the same event in the same participant will be counted only once in the 
tables within a treatment period, using the maximum (worst) grade by treatment period.  
The AE tables will be sorted as indicated in Table 4. 
Table 4 - Sorting of AE tables  
AE presentation 
Sorting rules 
SOC and PT 
By the internationally agreed SOC order and decreasing frequency of PTsa 
PT 
By decreasing frequency of PTsa 
AESI category and PT 
By AESI category (protocol order) and decreasing frequency of PTsa 
a Sorting will be based on the tolebrutinib treatment group incidence; alphabetic order in case of equal frequency. 
Analysis of all adverse events 
The overview of TEAEs will be generated presenting the number (%) of participants with: 
• Any TEAE  
• Any treatment emergent SAE 
• A TEAE leading to death 
• Any TEAE leading to permanent discontinuation of IMP 
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• Any treatment emergent AESI 
• Any TEAE considered by the investigator as related to IMP 
An additional overview summary including the number and rate of events will be provided. 
The AE summaries of Table 5 will be generated with number (%) of participants experiencing at 
least one event. 
Listings of SAEs from randomized participants, AEs leading to treatment/study discontinuation 
and severe AEs will be provided. 
Table 5 - Analyses of adverse events  
Type of AE 
MedDRA levels 
All TEAEs 
Primary SOC and PT 
 
PT (incidence ≥ 2%) 
Severe (grade ≥3) TEAEs 
Primary SOC and PT 
 
PT 
TEAEs related to IMP as per Investigator’s judgment 
Primary SOC and PT 
 
PT 
Treatment-emergent SAEs 
Primary SOC and PT 
 
PT 
Treatment emergent SAEs related to IMP as per Investigator’s 
judgment 
Primary SOC and PT 
Treatment emergent AESIs 
AESI category and PT 
TEAEs leading to permanent treatment discontinuation 
Primary SOC and PT 
 
PT 
TEAEs leading to death (death as an outcome of the AE as 
reported by the Investigator in the AE page) 
Primary SOC and PT 
Pre-treatment AEs 
Overviewa 
 
Primary SOC and PT 
Post-treatment AEs 
Overviewa 
 
Primary SOC and PT 
a Will include the following AE categories: any AEs, any severe (grade ≥ 3) AE, any serious AEs, any AEs leading to death 
Analysis of deaths 
In addition to the analyses of deaths included in Table 5, the number (%) of participants in the 
following categories will be provided: 
• Deaths during the treatment-emergent and post-treatment periods 
• Deaths in non-randomized participants or randomized but not treated participants 
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Analysis of adverse events of special interest (AESIs)  
Adverse events of special interest (AESIs) are as described in Table 6. Number (%) of participants 
experiencing at least one event will be provided. Tables will be sorted as indicated in Table 4. 
A listing of AESIs will also be provided. 
Table 6 - Selections for AESIs  
AESIs 
Selection 
Pregnancy of a female participant or female partner of 
a male participant 
Dedicated CRF page (AECAT=”PREGNANCY DATA”) 
Symptomatic overdose (serious or non-serious) with IMP 
Dedicated CRF page (AECAT=”OVERDOSE DATA”); must be 
symptomatic and related to IMP 
Increase of ALT > 3xULN (confirmed) 
Dedicated CRF page (AECAT=”ALT INCREASE DATA”) and 
AESI marked “Y” 
ECG observation of atrial fibrillation/atrial flutter 
CMQ30003 for selection and AESI check box marked 
Severe infection (NCI CTCAE grade 3 or above), that 
may or may not meet seriousness criteria (eg, a grade 3 
opportunistic infection) 
SOC of Infections and Infestations, grade 3 or above and AESI 
marked “Y” 
Moderate or severe hemorrhagic events (NCI CTCAE 
grade 2 or above), including, but not limited to, 
symptomatic bleeding, bleeding in a critical area or organ 
such as the CNS, or intraocular bleeding 
SMQNAME='Haemorrhage terms (excl laboratory terms)” for 
selection, grade 2 or above, and AESI marked “Y” 
Thrombocytopenia, platelet count <75 x 109/L 
PT=”Thrombocytopenia” and AESI marked “Y” 
 
 
3.6.3 Additional safety assessments  
3.6.3.1 Laboratory variables, vital signs and electrocardiograms (ECGs)  
The following laboratory variables, vital signs, and electrocardiogram (ECG) variables will be 
analyzed. They will be converted into standard international units [and conventional unit, if 
applicable]. 
• Hematology: 
- 
Red blood cells and platelets: red blood cell count, platelet count, hemoglobin, 
hematocrit 
- 
White blood cells: white blood cell count, neutrophils, lymphocytes, monocytes, 
basophils, eosinophils 
• Clinical chemistry: 
- 
Metabolism: glucose, total protein, albumin, creatine phosphokinase, lipase 
- 
Electrolytes: sodium, potassium, chloride, calcium, bicarbonate 
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- 
Renal function: creatinine, creatinine clearance, blood urea nitrogen. Creatinine 
clearance will be derived with the equation of Cockcroft and Gault using weight 
assessed at the same visit as creatinine. 
- 
Liver function: alanine aminotransferase, aspartate aminotransferase, alkaline 
phosphatase, total and direct bilirubin 
• Urinalysis for quantitative analysis: pH, specific gravity 
• Vital signs: heart rate, systolic and diastolic blood pressure, weight, temperature 
• ECG variables: heart rate, PR, QRS, QT, and corrected QTcF (according to Fridericia) 
For laboratory data reported as <xx or >yy, a numeric value of xx/2 or yy, respectively, will be 
used for quantitative analysis.  
Quantitative analyses 
For all laboratory variables, vital signs, and ECG variables above, descriptive statistics for results 
and changes from baseline will be provided for each analysis visit window during the treatment 
period. These analyses will be performed using central measurements only for laboratory 
variables.  
For each laboratory parameter, vital sign parameter and ECG parameter, mean changes from 
baseline with the corresponding standard error will be plotted over time.  
Analyses according to PCSA 
Potentially clinically significant abnormality (PCSA) analyses will be performed based on the 
PCSA list currently in effect at Sanofi at the time of the database lock. For parameters for which 
no PCSA criteria are defined, similar analyses will be done using the normal range.  
Analyses according to PCSA (normal range) will be performed based on the worst value during 
the treatment-emergent period, using all measurements (either local or central, either scheduled, 
nonscheduled or repeated). 
For laboratory variables, vital signs, and ECG variables above, the incidence of participants with 
at least one PCSA during the treatment-emergent period will be summarized regardless of the 
baseline level and according to the following baseline status categories: 
• Normal/missing 
• Abnormal according to PCSA (normal range) criterion or criteria 
Additional analyses for drug-induced liver injury 
The following additional analyses will be performed for drug-induced liver injury:  
• Time to onset of the initial ALT elevation (>3 x ULN, >5 x ULN, >8 x ULN, >10 x ULN), 
the initial AST elevation (>3 x ULN, >5 x ULN, >8 x ULN, >10 x ULN), and the initial 
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ALT or AST elevation >3 x ULN with total bilirubin elevation >2 x ULN will be 
presented by treatment group with KM curves. 
• A graph of the distribution of peak values of ALT versus peak values of total bilirubin 
during the treatment-emergent period will be provided. 
• The normalization (to ≤1 x ULN or return to baseline) of elevated liver function tests of 
ALT will be summarized by categories of elevation (3 x ULN, 5 x ULN, 10 x ULN, 
20 x ULN for ALT), with the following categories of normalization: never normalized, 
normalized before study intervention discontinuation, and normalized after study 
intervention discontinuation. Note that a participant will be counted only under the 
maximum elevation category.  
3.6.3.2 Analysis of suicidality assessment  
The number (%) of participants with suicidal ideation, suicidal behavior, and self-injurious 
behavior without suicidal intent based on the C-SSRS during treatment will be summarized. 
A shift table for baseline versus during treatment responses will be provided according to the 
categories of no suicidal ideation or behavior, suicidal ideation and suicidal behavior. 
3.7 
OTHER ANALYSES  
3.7.1 PK analyses (EFC16033 only)  
Tolebrutinib and M2 metabolite PK individual parameters (at least Cmax, tmax, AUC0-24) and 
corresponding descriptive statistics (mean, geometric mean, median, standard deviation, 
coefficient of variation, minimum, and maximum) will be determined by POP PK analysis by 
PKDM department using sampling times on Month 6, 9 and 12. 
Tolebrutinib and M2 metabolite PK parameters will be reported in a standalone report outside of 
the CSR. 
3.7.2 Pharmacodynamic (PD) analyses  
Blood samples for lymphocyte phenotyping (EFC16033 only) will be collected during the study 
for a subset of participants randomized (approximately 400). Flow cytometry will be used for 
evaluation of change (and % change) from baseline in lymphocyte count and phenotype subsets. 
Additional pharmacodynamics evaluations will include assessment of neurofilament light chain 
(NfL) levels in plasma, Chi3L1, and Ig levels in serum. 
These parameters will be summarized by actual treatment group on the safety population using the 
following descriptive statistics: mean, geometric mean, median, standard deviation, coefficient of 
variation, minimum, and maximum.  
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3.8 
INTERIM ANALYSES  
No formal efficacy interim analysis is planned. 
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4 
SAMPLE SIZE DETERMINATION  
While the primary endpoint for each study is ARR, the studies have been sized and are event 
driven based on the secondary endpoint of 6M-CDW.  
Approximately 1200 people will be screened to achieve 900 (±10%) participants per study 
randomly assigned to the study intervention: approximately half to each treatment group, 
tolebrutinib and teriflunomide. This study sample size provides greater than 90% power to detect 
a 45% relative reduction of ARR (primary endpoint) with tolebrutinib compared to teriflunomide, 
based on a negative binomial distribution for the number of relapses with the following 
assumptions: 
• ARR of 0.29 for teriflunomide  
• 1:1 randomization 
• variance inflation factor (defined as variance divided by mean) of 1.5 for each arm 
• 20% study discontinuation by Month 24 
These calculations are based on 2-sided α = 0.05. For the primary ITT analysis, study duration 
will be variable (approximately 18 to 36 months) given the event-driven trial design based on the 
key secondary efficacy endpoint (confirmed 6-month CDW). All randomized participants are 
expected to have at least an 18-month study duration, with more than 60% (approximately 
550 participants) having at least 24 months. In this subset of participants, the study will also have 
90% power to detect a 45% reduction for the analysis of 24-month ARR (analysis of ARR during 
a fixed 24-month period from randomization). 
Studies EFC16033 and EFC16034 pooled together will have a total sample size of at least 
1800 participants. EFC16033 along with EFC16034 are planned as an event-driven trials to have 
90% power, by pooling the two studies, for assessing the key secondary efficacy endpoint of time 
to onset of 6-month CDW. Each study will continue until approximately 162 events are projected 
to have occurred in the pooled data, to ensure approximately 90% power to detect a 40% risk 
reduction in 6-month CDW in participants treated with tolebrutinib compared to those treated 
with teriflunomide, based on an assumed 24-month event rate of 12% in the teriflunomide arm. 
Without pooling (ie, approximately 81 events per study), each study will have more than 
60% power to detect a 40% risk reduction in 6-month CDW. These calculations are based on 
2-sided testing and α = 0.05. 
Event rates in the tolebrutinib arm are assumed to be similar to those observed in the ocrelizumab 
arms of RMS trials (9) The forecast of CDW risk reduction by 40% is based on current 
knowledge of SAR442168, similar to that of ocrelizumab. The forecast of the event rates in the 
teriflunomide group is based on observations in previous teriflunomide trials, taking into account 
tendencies of event rate decrease in recent trials of other MS DMTs such as those that have been 
observed in beta-interferon groups in ocrelizumab pivotal trials (9, 10).  
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5 
SUPPORTING DOCUMENTATION  
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS  
 
AE(s): 
adverse event(s) 
AESIs: 
adverse events of special interest 
ARR: 
annualized relapse rate 
ATC: 
anatomic therapeutic category 
CDI: 
confirmed disability improvement 
CDW: 
confirmed disability worsening 
CEOS: 
common end of study 
CI(s): 
confidence interval(s) 
CMH: 
Cochran Mantel Haenszel 
CVLT-II: 
California verbal learning test-II 
DB: 
double-blind 
DMT: 
disease modifying therapy 
eCRF: 
electronic Case Report Form 
EDSS: 
Expanded Disability Status Scale 
EOS: 
end of study 
EU: 
Europe 
Gd: 
gadolinium 
HAD: 
highly active disease 
HLGT: 
high-level group term 
HLT: 
high-level term 
IC: 
informed consent 
IMP: 
investigational medicinal product 
KM: 
Kaplan-Meier 
LFU: 
lost to follow-up 
LLT: 
lower-level term 
LSM: 
least squares means 
LTS: 
long-term safety 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MMRM: 
mixed-effect model with repeated measures 
MTR: 
magnetization transfer ratio 
NCI-CTCAE: 
National cancer institute common terminology for adverse events 
PCSA: 
potentially clinically significant abnormality 
PD: 
pharmacodynamic 
PT: 
preferred term 
RMS: 
relapsing forms of multiple sclerosis 
ROW: 
rest of the world 
SAP: 
statistical analysis plan 
SD: 
standard deviation 
SE: 
standard error 
SOC: 
system organ class 
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TE: 
treatment emergent 
TEAE(s): 
treatment-emergent adverse event(s) 
VAS: 
visual analogue scale 
WHO-DD: 
World Health Organization-drug dictionary 
 
5.2 
APPENDIX 2 PARTICIPANT DISPOSITION  
The number (%) of participants included in each of the analysis populations listed in Table 3 will 
be summarized.  
Screened participants are those with a signed informed consent. Screen failures are defined as 
participants who consent to participate in the study but are not subsequently randomized. The 
number of screened participants will be summarized along with the number (%) of screen failures 
overall and by reason(s). 
The number (%) of participants in the following categories will be provided:  
• Exposed but not randomized, if applicable 
• Randomized but not exposed, if applicable 
• Randomized and exposed  
- 
Completed the study intervention period  
- 
Did not complete the study intervention period including main reason for intervention 
discontinuation and reason for intervention withdrawal by participant 
• Completed the study period 
• Did not complete the study period including main reason for study discontinuation 
• Status at last contact (alive, dead) 
• Entered LTS study 
Reasons for permanent study intervention and study discontinuation, “adverse event”, and “other 
reasons” will be split as related versus not related to COVID-19, if applicable. 
For all categories of participants (except for nonrandomized) percentages will be calculated using 
the number of randomized participants as the denominator.  
In addition, the number (%) of participants screened, screened-failed, randomized, with 
permanent intervention discontinuation and with early study discontinuation will be provided by 
country and site. Listings of other reasons for intervention discontinuation, and participants who 
are exposed but not randomized will be provided. 
Protocol deviations 
Critical and major protocol deviations (automatic or manual) will be summarized in the 
randomized population as well as displayed separately as related versus not related to COVID-19 
if applicable. A listing of critical and major protocol deviations will be provided. 
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5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS  
Demographics, baseline characteristics, medical surgical history 
The following demographic and baseline characteristics, smoking and alcohol history, disease 
characteristics at baseline, and medical and surgical history will be summarized using descriptive 
statistics in the randomized population.  
Demographic and baseline characteristics  
• age in years as a quantitative variable and in categories (≤40, >40; 18 to 55) 
• sex (Male, Female) 
• race (White, Black or African American, Asian, American Indian or Alaska Native, Native 
Hawaiian or Other Pacific Islander, Multiple, Unknown, Not reported) 
• ethnicity (Hispanic or Latino, Not Hispanic or Latino, Unknown, Not reported) 
• region (US, non-US; North America, Western Europe, Eastern Europe, ROW) 
• weight in kg as a quantitative variable 
• BMI in kg/m2 as a quantitative variable and in categories (<25, ≥25 to <30, ≥30) 
Smoking and alcohol habits 
• smoking history (Never, Current, Former) 
• cessation prior to screening for Former smokers in months 
• cigarettes per day for smokers 
• frequency of alcohol drinking in the past 12 months (Never, Occasional, At least monthly, 
At least weekly, At least daily) 
• # standard alcohol drinks on typical day when drinking (1 or 2, >2) 
Disease characteristics at baseline 
• prior DMT (0, 1, 2, >2) 
• MS type (Relapsing remitting, Secondary progressive) 
• time since symptom onset in years 
• time since diagnosis in years as a quantitative variable and in categories  
(<1, ≥1 to 5, ≥5 to 10, ≥10) 
• time since most recent relapse in months 
• number of relapses within the past 1 year as a quantitative variable and in categories  
(0, 1, 2, ≥3) 
• number of relapses within the past 2 years as a quantitative variable and in categories  
(0, 1, 2, ≥3) 
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• baseline EDSS score as a quantitative variable (average of screening and baseline scores 
when both available) 
• time since most recent MRI prior to screening in months 
• number of active Gd-enhancing lesions on last MRI prior to screening as a quantitative 
variable and in categories (0, 1, 2, ≥3) 
• screening EDSS score (<4, ≥4). 
• EDSS strata (<4, ≥4). 
• Gd-enhanced T1 lesions at baseline as a quantitative variable and in categories  
(presence, absence). 
• HAD at baseline (Yes, No). 
Baseline safety and efficacy parameters (apart from those listed above) will be presented along 
with the safety and efficacy summaries.  
Relevant medical (or surgical) history collected in the eCRF will be coded to a LLT, PT, HLT, 
HLGT, and associated primary SOC using the MedDRA version currently in effect at Sanofi at 
the time of database lock and will be summarized by primary SOC and HLT (internationally 
agreed SOC order and decreasing frequency of HLTs in the Overall group). 
Prior or concomitant medications 
All medications will be coded using the version of the World Health Organization-Drug 
Dictionary (WHO-DD) currently in effect at Sanofi at the time of database lock.  
• Prior medications are those the participant used prior to first IMP intake. Prior medications 
can be discontinued before first administration or can be ongoing during treatment period. 
• Concomitant medications are any interventions received by the participant concomitantly 
to IMP during the treatment period. 
• Post-treatment medications are those the participant took in the period running from the 
end of the concomitant medications period up to the end of the study, if applicable.  
• A given medication can be classified as a prior medication and/or as a concomitant 
medication and/or as post-treatment medication. If it cannot be determined whether 
a given medication was taken prior or concomitantly or post, it will be considered as prior, 
concomitant, and post-treatment medication. 
Any prior DMT use will be summarized by the standardized medication name in the randomized 
population, sorted by decreasing frequency in the Overall group. Additionally, prior, concomitant, 
and post-treatment (if applicable) medications will be summarized for the randomized and 
exposed population by anatomic and therapeutic level. The summaries will be sorted by 
decreasing frequency of anatomic category (ATC) based on incidence in the tolebrutinib group. In 
case of equal frequency, alphabetical order will be used. Participants will be counted once in each 
ATC category (anatomic or therapeutic) linked to the medication. 
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5.4 
APPENDIX 4 DATA HANDLING CONVENTIONS  
Analysis windows for time points 
The following analysis windows will decide how the scheduled and/or unscheduled visits will be 
used in the by-visit analyses of efficacy, safety, and PD variables. 
A measurement (scheduled or unscheduled) will be used if it is available and measurement date is 
within the analysis window.  
After applying these time windows, if multiple assessments are associated to the same time point, 
the closest from the targeted study day will be used. If the difference is a tie, the value after the 
targeted study day will be used. If multiple valid values exist within a same day, then the first 
value of the day will be selected.  
If there is no measurement for a given parameter in an analysis window, data will be considered 
missing for the corresponding visit and similar quarterly windows will be applied if the treatment 
period extends beyond 36 months. 
Table 7 - Analysis window definition of efficacy variables  
Visits 
Target 
Day 
EDSS 
MRI 
T25FW, 9-HPT, 
SDMT, CVLT-II 
MSQoL-54, 
EQ-5D-5L 
 
 
Start 
Day 
End 
Day 
Start 
Day 
End 
Day 
Start 
Day 
End 
Day 
Start 
Day 
End 
Day 
Baseline 
1 
-40 
1 
-120 
1 
-40 
1 
-40 
1 
Month 3 
84 
2 
126 
 
 
2 
126 
 
 
Month 6 
168 
127 
210 
2 
252 
127 
210 
2 
252 
Month 9 
252 
211 
294 
 
 
211 
294 
 
 
Month 12 
336 
295 
378 
253 
420 
295 
378 
253 
420 
Month 15 
420 
379 
462 
 
 
379 
462 
 
 
Month 18 
504 
463 
546 
421 
588 
463 
546 
421 
588 
Month 21 
588 
547 
630 
 
 
547 
630 
 
 
Month 24 
672 
631 
714 
589 
840 
631 
714 
589 
756 
Month 27 
756 
715 
798 
 
 
715 
798 
 
 
Month 30 
840 
799 
882 
 
 
799 
882 
757 
924 
Month 33 
924 
883 
966 
 
 
883 
966 
 
 
Month 36 
1008 
967 
1050 
841 
1176 
967 
1050 
925 
1092 
EOS 
 
Start Day: last visit window upper limit +1 
End Day: EOS visit date 
Nominal visit (9000) 
FU for participants who 
completed treatment to 
EOS but do not enter LTS 
 
≥(Date of EOS+1) 
Nominal visit (8010) 
 
 
pEOT 
 
Start Day: date of discontinuation+1 
End Day: start of the next scheduled visit window 
Map to the closest scheduled visit 
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Table 8 - Analysis window definition of safety variables  
AVISIT 
Target 
Day 
Hematology, 
biochemistry  
Vital Signs, C-
SSRS, B-HCG Test 
Weight 
ECG 
Urinalysis 
Coagulation 
  
  
Start 
Day 
End 
Day 
Start 
Day 
End 
Day 
Start 
Day 
End 
Day 
Start 
Day 
End 
Day 
Start 
Day 
End 
Day 
Start 
Day 
End 
Day 
Screening 
-1 
-40 
-1 
-40 
-1 
-40 
-1 
-40 
-1 
-40 
-1 
-40 
-1 
Day 1 
1 
1 
1 
1 
1 
1 
1 
  
  
  
  
  
  
Month 1 
28 
2 
42 
  
  
 
 
  
  
  
  
  
  
Month 2 
56 
43 
70 
  
  
 
 
  
  
  
  
  
  
Month 3 
84 
71 
98 
2 
126 
2 
126 
1 
126 
1 
210 
  
  
Month 4 
112 
99 
126 
  
  
 
 
  
  
  
  
  
  
Month 5 
140 
127 
154 
  
  
 
 
  
  
  
  
  
  
Month 6 
168 
155 
210 
127 
210 
127 
252 
127 
210 
  
  
  
  
Month 9 
252 
211 
294 
211 
294 
 
 
211 
294 
  
  
  
  
Month 12 
336 
295 
378 
295 
378 
253 
420 
295 
504 
211 
420 
  
  
Month 15 
420 
379 
462 
379 
462 
 
 
  
  
  
  
  
  
Month 18 
504 
463 
546 
463 
546 
421 
588 
  
  
421 
588 
  
  
Month 21 
588 
547 
630 
547 
630 
 
 
  
  
  
  
  
  
Month 24 
672 
631 
714 
631 
714 
589 
756 
505 
840 
589 
756 
  
  
Month 27 
756 
715 
798 
715 
798 
 
 
  
  
  
  
  
  
Month 30 
840 
799 
882 
799 
882 
757 
924 
  
  
757 
924 
  
  
Month 33 
924 
883 
966 
883 
966 
 
 
  
  
  
  
  
  
Month 36 
1008 
967 
1050 
967 
1050 
925 
1050 
841 
1050 
925 
1050 
  
  
EOS 
 
Start Day: last visit window upper limit +1; End Day: EOS visit date; Nominal visit (9000) 
 
 
Liver function tests 
 
Nominal visit at Month 0.5, 1.25, 1.5, 1.75, 2.25, 2.5, 2.75, 7, 8, 10, 11. 
 
 
FU for participants who completed 
treatment to EOS but do not enter 
LTS 
 
>= Date of EOS+1 
Nominal visit (8010) 
 
 
 
 
 
 
pEOT 
 
Start Day: date of discontinuation+1; End Day: start of the next scheduled visit window 
Map to the closest scheduled visit 
 
 
 
 
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Table 9 - Analysis window definition of PD variables  
AVISIT 
Target 
Day 
Plasma samples (NfL), serum 
samples (Chi3L1) 
Serum samples (Ig levels) 
Lymphocyte phenotypes by 
flow cytometry 
Blood sample for 
archiving 
  
  
Start Day 
End Day 
Start Day 
End Day 
Start Day 
End Day 
Start Day 
End Day 
Screening 
-1 
 
 
 
 
 
 
-40 
-1 
Day 1 
1 
1 
1 
1 
1 
1 
1 
  
  
Month 1 
28 
 
 
  
  
 
 
 
 
Month 2 
56 
 
 
 
 
 
 
 
 
Month 3 
84 
2 
126 
 
 
 
 
 
 
Month 4 
112 
 
 
 
 
 
 
 
 
Month 5 
140 
 
 
 
 
 
 
 
 
Month 6 
168 
127 
252 
2 
252 
 
 
 
 
Month 9 
252 
 
 
 
 
 
 
 
 
Month 12 
336 
253 
420 
253 
420 
 
 
 
 
Month 15 
420 
 
 
 
 
 
 
 
 
Month 18 
504 
421 
672 
421 
672 
 
 
 
 
Month 21 
588 
 
 
 
 
 
 
 
 
Month 24 
672 
 
 
 
 
 
 
 
 
Month 27 
756 
 
 
 
 
 
 
 
 
Month 30 
840 
673 
924 
673 
924 
 
 
 
 
Month 33 
924 
 
 
 
 
 
 
 
 
Month 36 
1008 
925 
1050 
925 
1050 
 
 
 
 
EOS 
 
Start Day: last visit window upper limit +1; End Day: EOS visit date 
Nominal visit (9000) 
 
 
pEOT 
 
Start Day: date of discontinuation+1; End Day: start of the next scheduled visit window 
Map to the closest scheduled visit 
 
 
 
Lymphocyte testing will be done for selected participant at EOS or pEOT whichever comes first. 
 
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Unscheduled visits 
Unscheduled visit measurements of laboratory data, vital signs, and ECG will be used for 
computation of baseline, the last on-treatment value, analysis according to PCSAs, and the shift 
summaries for safety. They will also be included in the by-visit summaries (central lab only for 
laboratory data) if they are re-allocated to scheduled visits based on the analysis windows defined 
above.
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5.5 
APPENDIX 5 SAS CODE FOR IMPUTATION OF BASELINE GD-ENHANCING T1 
LESION STATUS  
 
/*select subjects with missing baseline GD-enhancing T1 lesion*/ 
 data pt_list; 
   set _adsl_5; 
   if gdt1bl=''; 
   keep usubjid gdt1bl; 
 run; 
 
 /*get all Nb of Gad Enhanc T1 Hyperintense Lesions for those subjects*/ 
 data gd; 
    merge pt_list(in=a)  
               add.admr; 
   by usubjid; 
   if a; 
   if paramcd='T1GDLNUM' and avisitn>0 and anl01fl='Y'; 
   keep usubjid paramcd param aval avisit avisitn anl01fl; 
 run; 
  
/*get ITT population and subjects with non-missing baseline GD-enhancing T1 lesion*/ 
 data itt; 
   set _adsl_5; 
   where ittfl='Y' and gdt1bl^=''; 
 run; 
  
proc freq data=itt ; 
  table gdt1bl /missing out=pct; 
run; 
 
/*get observed rate of presence subjects*/ 
 proc sql; 
   select (percent)/100 into:pct 
   from pct 
   where gdt1bl='presence'; 
 quit; 
  
proc sql; 
  create table gd1 as 
  select usubjid, sum(aval) as sum  
  from gd 
  group by usubjid; 
quit; 
  
data ptlist; 
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  set gd1; 
  if sum=0; 
run; 
  
/* randomly assign value to patients with missing IGDT1BL based on observed rate*/ 
data _adsl_6; 
  merge _adsl_5  
             ptlist(in=b); 
  by usubjid; 
  if ittfl="Y" then do; 
     call streaminit(16034);/*specify random seed as study id, for study EFC16033 random seed 
will be 
                                          16033*/ 
    if gdt1bl ne '' then IGDT1BL=gdt1bl; 
    else if b then IGDT1BL = 'absence'; 
    else do; 
       p=RAND("Bernoulli", &pct.); 
       if p=0 then IGDT1BL = 'absence'; 
       if p=1 then IGDT1BL = 'presence'; 
    end; 
  end; 
 run; 
 
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6 
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sensitivity analyses of time-to-event data with possibly informative censoring. J Biopharm 
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3. Yuan YC. Multiple imputation for missing data: Concepts and new development. Proceedings 
of the Twenty-Fifth Annual SAS Users Group International Conference; 2000. 
4. Delis DC, Kramer JH, Kaplan E, Ober BA. (2000). CVLT-II, California verbal learning test: 
Adult version: manual. 
5. Vickrey BG, Hays RD, Harooni R, Myers LW, Ellison, GW. A Health-Related Quality of Life 
Measure for Multiple Sclerosis. Quality Life Res. 1995;4(3):187-206. 
6. Kenward MG, Roger JH. Small sample inference for fixed effects from restricted maximum 
likelihood. Biometrics. 1997;53(3):983-97. 
7. Kaifeng L, Devan V. Mehrotra. Specification of covariance structure in longitudinal data 
analysis for randomized clinical trials. Statistics in Medicine. 2010;29:474-88. 
8. Van Hout B, Janssen MF, Feng YS, Kohlmann T, Busschbach J, Golicki D, et al. Interim 
scoring for the EQ-5D-5L: mapping the EQ-5D-5L to EQ-5D-3L value sets. Value Health. 
2012;15(5):708-15. 
9. Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung HP, Hemmer B, et al. Ocrelizumab 
versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med. 2017;376(3):221-34. 
10. O'Connor P, Wolinsky JS, Confavreux C, Comi G, Kappos L, Olsson TP, et al. Randomized 
trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011;365(14):1293-
303. 
 
 
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