Clinical trial NCT04411641
Conditions: Non-relapsing Secondary Progressive Multiple Sclerosis
Sponsor: Sanofi
Start date: 2020-09-24; Completion date: 2024-08-29
Enrollment: 1131 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objective:

To determine the efficacy of SAR442168 compared to placebo in delaying disability progression in NRSPMS

Secondary Objective:

To evaluate efficacy of SAR442168 compared to placebo on clinical endpoints, magnetic resonance imaging (MRI) lesions, cognitive performance, physical function, and quality of life To evaluate safety and tolerability of SAR442168 To evaluate population pharmacokinetics (PK) of SAR442168 and relevant metabolites in NRSPMS and its relationship to efficacy and safety To evaluate pharmacodynamics (PD) of SAR442168

Detailed description:
This was an event-driven (6-month CDP) trial with a variable treatment duration (end-of-study \[EOS\] duration: up to approximately 47months).

Participants with 6-month confirmed disability progression (CDP) had an option to receive tolebrutinib in the open-label (OL).

Arms: arm 1: 60 mg of oral SAR442168 once daily arm 2: Placebo tablet to match SAR442168 once daily
Interventions: intervention 1: Tolebrutinib intervention 2: Placebo to match Tolebrutinib
Intervention descriptions: intervention 1: Pharmaceutical form: Film-coated tablet Route of administration: Oral intervention 2: Pharmaceutical form: Film-coated 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 
Based on Template: Sanofi OneDocument Version 2.0, dated 14-OCT-2019 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 12  
Protocol title: 
A Phase 3, randomized, double-blind, efficacy and safety 
study comparing SAR442168 to placebo in participants 
with nonrelapsing secondary progressive multiple 
sclerosis (HERCULES) 
Protocol number: 
EFC16645 
Amendment number: 12 
Compound number 
(INN/Trademark): 
SAR442168  
(tolebrutinib/not applicable) 
Study phase: 
Phase 3 
Short title: 
NRSPMS study of BTK inhibitor tolebrutinib (SAR442168) 
HERCULES 
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: 
2020-000647-30  
NCT: 
NCT04411641 
WHO: 
U1111-1246-7768 
EUDAMED: 
Not applicable 
Other: 
Not applicable 
Date: 
20-Dec-2023 
Total number of pages: 149 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY  
Document 
Country/countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial Protocol 12 
All 
20 December 2023, version 1 (electronic 21.0) 
Amended Clinical Trial Protocol 11 
All 
20 November 2023, version 1 (electronic 20.0) 
Amended Clinical Trial Protocol 10 
All 
28 September 2023, version 1 (electronic 17.0) 
Amended Clinical Trial Protocol 09 
France 
12 July 2023, version 1 (electronic 16.0) 
Amended Clinical Trial Protocol 08 
All 
14 December 2022, version 1 (electronic 14.0) 
Amended Clinical Trial Protocol 07 
All 
13 September 2022, version 1 (electronic 13.0) 
Amended Clinical Trial Protocol 06 
All 
23 May 2022, version 1 (electronic 12.0) 
Amended Clinical Trial Protocol 05 
All 
21 December 2021, version 1 (electronic 11.0) 
Amended Clinical Trial Protocol 04 
All 
26 July 2021, version 1 (electronic 10.0) 
Amended Clinical Trial Protocol 03  
All 
03 November 2020, version 1 (electronic 7.0) 
Amended Clinical Trial Protocol 02 
Austria, Czech Republic, 
Denmark, Finland, Germany, 
Greece, Hungary, Italy, 
Lithuania, Netherlands, 
Norway, Poland, Portugal, 
Romania, Spain, United 
Kingdom, Belgium, France, 
Bulgaria 
28 August 2020, version 1 (electronic 5.0) 
Amended Clinical Trial Protocol 01 
All 
15 May 2020, version 1 (electronic 2.0) 
Original Clinical Trial Protocol 
 
28 February 2020, version 1 (electronic 1.0) 
Amended protocol 12 (20 December 2023) 
This amended protocol (amendment 12) 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 update the liver function test monitoring 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. 
10.9 Appendix 9: Example of drugs 
with a potential to change 
SAR442168 metabolism or 
absorption 
Table 8: removed ‘rifabutin’ from the list of potent 
CYP3A inducers. Table 9: 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. 
10.14 Appendix 14: 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 12 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 4 
LIST OF TABLES ......................................................................................................................................... 10 
LIST OF FIGURES ........................................................................................................................................ 10 
1 
PROTOCOL SUMMARY ............................................................................................................... 11 
1.1 
SYNOPSIS ..................................................................................................................................... 11 
1.2 
SCHEMA ........................................................................................................................................ 18 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 19 
2 
INTRODUCTION ............................................................................................................................ 30 
2.1 
STUDY RATIONALE...................................................................................................................... 30 
2.2 
BACKGROUND ............................................................................................................................. 32 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 33 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 37 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 39 
4 
STUDY DESIGN ............................................................................................................................ 40 
4.1 
OVERALL DESIGN ........................................................................................................................ 40 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 40 
4.2.1 
Justification for participant’s age and study duration ..................................................................... 40 
4.2.2 
Justification for the use of placebo................................................................................................. 41 
4.2.3 
Participant input into design ........................................................................................................... 41 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 41 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 42 
5 
STUDY POPULATION .................................................................................................................. 43 
5.1 
INCLUSION CRITERIA .................................................................................................................. 43 
5.2 
EXCLUSION CRITERIA ................................................................................................................ 44 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 49 
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5.3.1 
Meals and dietary restrictions ........................................................................................................ 49 
5.3.2 
Caffeine, alcohol, and tobacco ....................................................................................................... 49 
5.3.3 
Activity ............................................................................................................................................ 49 
5.4 
SCREEN FAILURES...................................................................................................................... 50 
5.5 
CRITERIA FOR TEMPORARILY DELAYING ADMINISTRATION OF STUDY 
INTERVENTION ............................................................................................................................ 50 
6 
STUDY INTERVENTION ............................................................................................................... 51 
6.1 
CRITERIA FOR TEMPORARILY DELAYING ENROLLMENT AND ADMINISTRATION OF 
STUDY INTERVENTION ............................................................................................................... 51 
6.2 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 51 
6.2.1 
Noninvestigational medicinal product ............................................................................................ 51 
6.3 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 52 
6.4 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 52 
6.5 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 54 
6.6 
CONCOMITANT THERAPY .......................................................................................................... 55 
6.6.1 
Open-label treatment ..................................................................................................................... 56 
6.7 
DOSE MODIFICATION .................................................................................................................. 57 
6.8 
INTERVENTION AFTER THE END OF THE STUDY ................................................................... 57 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 58 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 58 
7.1.1 
Definitive discontinuation ............................................................................................................... 58 
7.1.2 
Temporary discontinuation ............................................................................................................. 60 
7.1.2.1 
Rechallenge ................................................................................................................................... 60 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 61 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 62 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 63 
8.1 
EFFICACY ASSESSMENTS ......................................................................................................... 63 
8.1.1 
Expanded disability status scale .................................................................................................... 64 
8.1.1.1 
Confirmed disability progression .................................................................................................... 64 
8.1.1.2 
Confirmed disability improvement .................................................................................................. 65 
8.1.2 
Magnetic resonance imaging ......................................................................................................... 65 
8.1.3 
Multiple sclerosis relapse assessment ........................................................................................... 66 
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8.1.3.1 
Definition of multiple sclerosis relapse ........................................................................................... 66 
8.1.3.2 
Unscheduled assessment visits ..................................................................................................... 67 
8.1.4 
Timed 25-foot walk test .................................................................................................................. 67 
8.1.5 
9-hole peg test ............................................................................................................................... 68 
8.1.6 
Cognitive tests ................................................................................................................................ 68 
8.1.7 
Composite analyses ....................................................................................................................... 68 
8.1.7.1 
Modified Multiple Sclerosis Functional Composite-3 ..................................................................... 68 
8.1.7.2 
Assessment of no evidence of disease activity ............................................................................. 68 
8.1.8 
Clinical outcome assessments and health-related quality of life parameters ................................ 69 
8.2 
SAFETY ASSESSMENTS ............................................................................................................. 69 
8.2.1 
Physical examinations ................................................................................................................... 69 
8.2.2 
Vital signs ....................................................................................................................................... 70 
8.2.3 
Electrocardiograms ........................................................................................................................ 70 
8.2.4 
Clinical safety laboratory assessments .......................................................................................... 70 
8.2.5 
Suicidal ideation and behavior risk monitoring .............................................................................. 71 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........................................................... 71 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 72 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 72 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 72 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 72 
8.3.5 
Pregnancy ...................................................................................................................................... 73 
8.3.6 
Cardiovascular and death events .................................................................................................. 73 
8.3.7 
Multiple sclerosis relapse reporting ................................................................................................ 74 
8.3.8 
Magnetic resonance imaging ......................................................................................................... 74 
8.3.9 
Adverse event of special interest ................................................................................................... 74 
8.3.10 
Guidelines for reporting product complaints .................................................................................. 75 
8.4 
TREATMENT OF OVERDOSE ...................................................................................................... 75 
8.5 
PHARMACOKINETICS .................................................................................................................. 76 
8.6 
PHARMACODYNAMICS ............................................................................................................... 76 
8.7 
GENETICS ..................................................................................................................................... 77 
8.8 
BIOMARKERS ............................................................................................................................... 77 
8.9 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 77 
8.10 
MEDICAL RESOURCE UTILIZATION AND HEALTH ECONOMICS ........................................... 77 
8.11 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH ................................ 78 
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9 
STATISTICAL CONSIDERATIONS .............................................................................................. 79 
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 79 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................. 79 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 80 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 80 
9.4.1 
General considerations .................................................................................................................. 80 
9.4.2 
Primary endpoint ............................................................................................................................ 81 
9.4.3 
Secondary endpoint(s) ................................................................................................................... 82 
9.4.4 
Tertiary/exploratory endpoint(s) ..................................................................................................... 82 
9.4.5 
Other safety analyses .................................................................................................................... 83 
9.4.6 
Other analyses ............................................................................................................................... 84 
9.5 
INTERIM ANALYSES .................................................................................................................... 84 
9.6 
DATA MONITORING COMMITTEE (DMC) ................................................................................... 84 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 85 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 85 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 85 
10.1.2 
Financial disclosure........................................................................................................................ 86 
10.1.3 
Informed consent process .............................................................................................................. 86 
10.1.4 
Data protection ............................................................................................................................... 87 
10.1.5 
Committee structures ..................................................................................................................... 89 
10.1.5.1 Data Monitoring Committee ........................................................................................................... 89 
10.1.5.2 Scientific Advisory Committee ....................................................................................................... 89 
10.1.5.3 Eligibility Adjudication Committee .................................................................................................. 90 
10.1.5.4 Relapse Adjudication Committee ................................................................................................... 90 
10.1.5.5 Independent Hepatology Assessment Committee ......................................................................... 90 
10.1.6 
Dissemination of clinical study data ............................................................................................... 90 
10.1.7 
Data quality assurance .................................................................................................................. 91 
10.1.8 
Source documents ......................................................................................................................... 92 
10.1.9 
Study and site start and closure ..................................................................................................... 92 
10.1.10 Publication policy ........................................................................................................................... 93 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 93 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ................................................ 95 
10.3.1 
Definition of AE .............................................................................................................................. 95 
10.3.2 
Definition of SAE ............................................................................................................................ 97 
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10.3.3 
Recording and follow up of AE and/or SAE ................................................................................... 98 
10.3.4 
Reporting of SAEs........................................................................................................................ 100 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION ............................................................................................................................ 100 
10.5 
APPENDIX 5: GENETICS ........................................................................................................... 103 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: ACTIONS AND FOLLOW-UP 
ASSESSMENTS .......................................................................................................................... 104 
10.7 
APPENDIX 7: MEDICAL DEVICE ADVERSE EVENTS (AES), ADVERSE DEVICE 
EFFECTS (ADES), SERIOUS ADVERSE EVENTS (SAES) AND DEVICE DEFICIENCIES: 
DEFINITION AND PROCEDURES FOR RECORDING, EVALUATING, FOLLOW-UP, AND 
REPORTING ................................................................................................................................ 112 
10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS ............................................................ 112 
10.8.1 
Contraception requirements in UK, Germany, and Denmark ...................................................... 112 
10.8.2 
Country-specific differences for China ......................................................................................... 113 
10.8.3 
Country-specific provisions for France and Japan ....................................................................... 113 
10.8.4 
Country-specific provisions for Japan .......................................................................................... 115 
10.8.5 
Country-specific provisions for the US ......................................................................................... 115 
10.8.6 
Country-specific provisions for the US, Israel, and sites following FDA partial clinical hold 
conditions ..................................................................................................................................... 115 
10.9 
APPENDIX 9: EXAMPLE OF DRUGS WITH A POTENTIAL TO CHANGE SAR442168 
METABOLISM OR ABSORPTION .............................................................................................. 115 
10.10 
APPENDIX 10: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................. 117 
10.10.1 Informed consent ......................................................................................................................... 117 
10.10.2 Study procedures ......................................................................................................................... 117 
10.10.3 Temporary discontinuation ........................................................................................................... 118 
10.10.4 Statistical analysis ........................................................................................................................ 118 
10.11 
APPENDIX 11: IMMUNOPHENOTYPING (TOLEDYNAMIC SUBSTUDY) ................................ 119 
10.12 
APPENDIX 12: ACTIGRAPHY SUBSTUDY ................................................................................ 121 
10.13 
APPENDIX 13: ABBREVIATIONS ............................................................................................... 122 
10.14 
APPENDIX 14: PROTOCOL AMENDMENT HISTORY .............................................................. 124 
10.14.1 Amended protocol 01 (15 May 2020)........................................................................................... 124 
10.14.2 Amended protocol 02 (28 August 2020) ...................................................................................... 128 
10.14.3 Amended protocol 03 (03 November 2020) ................................................................................. 130 
10.14.4 Amended protocol 04 (26 July 2021) ........................................................................................... 132 
10.14.5 Amended protocol 05 (21 December 2021) ................................................................................. 137 
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10.14.6 Amended Protocol 06 (23 May 2022) .......................................................................................... 139 
10.14.7 Amended protocol 07 (13 September 2022) ................................................................................ 139 
10.14.8 Amended protocol 08 (14 December 2022) ................................................................................. 140 
10.14.9 Amended protocol 09 (12 July 2023) ........................................................................................... 141 
10.14.10 Amended protocol 10 (28 September 2023) ................................................................................ 142 
10.14.11 Amended protocol 11 (20 November 2023) ................................................................................. 144 
11 
REFERENCES ............................................................................................................................. 146 
 
 
 
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LIST OF TABLES  
Table 1 - Objectives and endpoints ............................................................................................................... 37 
Table 2 - Overview of study interventions administered ............................................................................... 51 
Table 3 - Populations for analysis ................................................................................................................. 80 
Table 4 - Safety analyses .............................................................................................................................. 83 
Table 5 - Protocol-required laboratory assessments .................................................................................... 94 
Table 6 - Clinical and MRI features suggestive of PML .............................................................................. 111 
Table 7 - Examples of herbal and dietary supplements involved in hepatotoxicity ..................................... 113 
Table 8 - Potent and moderate CYP3A inducers and potent CYP2C8 inhibitors ....................................... 116 
Table 9 - Mild, moderate, and potent inhibitors of CYP3A and CYP2C8, and moderate and potent inducers 
of CYP3A ..................................................................................................................................................... 116 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................. 18 
 
 
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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 placebo in participants with nonrelapsing secondary progressive 
multiple sclerosis (HERCULES) 
Short title: 
NRSPMS study of BTK inhibitor tolebrutinib (SAR442168) (HERCULES) 
Rationale: 
The advent of disease-modifying therapies for relapsing forms of multiple sclerosis (MS) has led 
to significant strides in reducing relapse frequency and the attendant morbidity. However, chronic 
disability accumulation remains a significant unmet need for people living with MS. Individuals 
with progressive disease, including secondary progressive MS (SPMS), need therapies to reduce 
the accumulation of disability. The recent approval of siponimod has led to a broad relabeling of 
existing disease-modifying therapies, with an indication “for the treatment of relapsing forms of 
MS, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary 
progressive disease, in adults”. This label reflects the perception that drugs like ocrelizumab and 
siponimod that were tested in patients with progressive disease benefits patients with “active 
disease”, ie, they reduced acute inflammatory activity rather than directly reducing “Progression 
Independent of Relapse Activity” or PIRA. 
Data from the Phase 3 EXPAND trial of siponimod, a S1P receptor modulator, in a SPMS 
population demonstrated reduced risk (hazard ratio [HR]=0.79) of 3-month confirmed disability 
progression (CDP) (1). However, in the subgroup without activity at baseline (defined by the 
occurrence of relapses in the 24-month period prior to enrollment), the effect on 3-month CDP 
was limited (HR=0.87). Likewise, data from ORATORIO, the pivotal Phase 3 trial of ocrelizumab 
in a primary progressive MS (PPMS) population, demonstrated that this anti-CD20 monoclonal 
antibody that depletes B lymphocytes provided a small but statistically significant (HR=0.76) 
benefit in reducing the risk of disability progression (2). As with EXPAND, analysis of 
a subgroup defined by activity (in this case, the presence or absence of gadolinium (Gd) 
contrast-enhancing lesions at baseline, which amounted to 199 or 533 of 732 participants, 
respectively) revealed a smaller, non-significant effect size (HR=0.84) in patients without this 
inflammatory magnetic resonance imaging (MRI) activity at enrollment. According to these data, 
and to our working hypothesis, effective management of MS disease activity will require 
additional interventions beyond immunomodulation of peripheral immunity. Our focus is on 
targeting innate immunity, including monocytes and macrophages peripherally, as well as B cells 
in the central nervous system (CNS) and microglial cells that represent the resident innate immune 
system within the CNS. 
BTK inhibitors do not result in chronic B-cell depletion; SAR442168 (tolebrutinib) inhibits 
B-cell-receptor signaling by blocking Bruton’s tyrosine kinase (BTK) activity. Furthermore, 
abundant evidence suggests that innate immunity, and specifically CNS-resident microglial cell 
activity, is a significant driver of disability accumulation in all forms of MS. The dual working 
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hypothesis driving development of SAR442168 is based on the following: 1) modulating B cells 
to render them inert to antigenic stimulation will have an effect similar to B-cell depletion on 
progressive MS disability accumulation, and 2) CNS penetrance will provide a potential added 
benefit of modulating innate immunity mediated by macrophages and microglial cells to suppress 
maladaptive neuroinflammatory processes associated with chronic disability progression. 
The ability of SAR442168 to reduce the formation of acute brain lesions in MS was assessed in 
a Phase 2b dose-finding trial in participants with relapsing MS (RMS) (DRI15928). Patients with 
progressive forms of MS may also present with acute focal inflammatory activity in the CNS. 
This activity manifests on MRI as T1 hyperintense Gd+ lesions and new or enlarging T2 lesions. 
SAR442168 has proven to be effective in reducing both types of CNS lesions. The SAR442168 
Phase 2b results showed that SAR442168 reduced the number of new T1 hyperintense Gd+ 
lesions by 85% and the number of new or enlarged T2 lesions by 89% in the 60 mg group 
(the dose to be used in the Phase 3 program) compared to placebo. 
Reduction in number of T1-hyperintense (gadolinium-enhanced) lesions has been established as 
a highly reliable predictive biomarker for clinical efficacy in pivotal studies in MS including 
Phase 3 RMS studies (3). While there is no comparable radiographic biomarker to predict clinical 
efficacy on disability progression, the assumption has been that doses effective at preventing 
relapses can be used to assess disability progression in PPMS or SPMS (2, 4, 5, 6, 7). SAR442168 
was shown to achieve pharmacologically relevant concentrations in cerebrospinal fluid (CSF) 
after a single oral administration, with the potential to inhibit microglia and infiltrating bone-
marrow-derived macrophages that are believed to drive neuroinflammation linked to disease 
progression. 
The goal of this Phase 3 clinical trial is to demonstrate the efficacy and safety of SAR442168 
compared to placebo in participants with nonrelapsing secondary progressive multiple sclerosis 
(NRSPMS). The primary endpoint is time to onset of 6-month CDP assessed via the Expanded 
Disability Status Scale (EDSS) score.  
The EDSS is widely used to measure neurological disability in clinical trials and routine settings 
(8). It will be used to assess 6-month CDP, as is standard practice in many clinical trials and as is 
recommended by guidelines (2, 4) and considered as more stable than 3-month CDP. Electronic 
EDSS score collection will be employed to ensure completeness and consistency of measurement. 
Magnetic resonance imaging outcomes will include change in brain volume, which is considered 
as a marker of the CNS degenerative process and therefore recommended for use in progressive 
MS trials (9). 
Together with additional evaluation of secondary and exploratory endpoints, this study will 
provide a comprehensive evaluation of the efficacy and safety of SAR442168 in people with 
NRSPMS. 
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Objectives and endpoints 
Objectives 
Endpoints 
Primary 
• 
To determine the efficacy of SAR442168 
compared to placebo in delaying disability 
progression in NRSPMS 
• 
Time to onset of 6-month CDP defined as follows: 
- 
Increase of ≥1.0 point from the baseline EDSS score 
when the baseline score is ≤5.0, OR 
- 
Increase of ≥0.5 point when the baseline EDSS score 
is >5.0 
Secondary 
• 
To evaluate efficacy of SAR442168 compared to 
placebo on clinical endpoints, MRI lesions, 
cognitive performance, physical function, and 
quality of life 
• 
Time to onset of sustained 20% increase in the 9-HPT for at 
least 3 months 
• 
Time to onset of sustained 20% increase in the T25-FW for 
at least 3 months 
• 
Time to onset of 3-month CDP as assessed by the EDSS 
score 
• 
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 
• 
Time to onset of CDI defined as a ≥1.0 point decrease on 
the EDSS score from baseline confirmed over at least 
6 months 
• 
Percent change in brain volume loss (BVL) as detected by 
MRI scans at the EOS compared to Month 6 
• 
Change in cognitive function at the EOS compared to 
baseline as assessed by SDMT 
• 
Change in cognitive function at the EOS compared to 
baseline as assessed by CVLT-II, where available 
• 
Change in MSQoL-54 questionnaire score from baseline 
through the EOS 
• 
To evaluate safety and tolerability of 
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 of 
SAR442168 and relevant metabolite(s) in 
NRSPMS 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 NfL levels at the EOS compared to 
baseline 
• 
Change in lymphocyte phenotype subsets in whole blood at 
the EOS compared to baseline in a subset of participants 
• 
Change in serum immunoglobulin level at baseline 
compared to the EOS 
• 
Change in serum Chi3L1 levels at baseline compared to the 
EOS 
Abbreviations: 9-HPT, 9-hole peg test; AE, adverse event; AESI, adverse event of special interest; CDI, confirmed disability improvement; CDP, 
confirmed disability progression; Chi3L1, chitinase-3-like protein 1; ECG, electrocardiogram; EDSS, Expanded Disability Status Scale; EOS, end 
of study; MRI, magnetic resonance imaging; MSQoL-54, Multiple Sclerosis Quality of Life-54 Questionnaire; NfL, neurofilament light chain; PD, 
pharmacodynamic; PK, pharmacokinetic; nrSPMS, non-relapsing secondary progressive multiple sclerosis; T25-FW, timed 25-foot walk. 
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Overall design: 
This is a Phase 3, randomized, double-blind, 2-arm, placebo-controlled, parallel group, 
multicenter, event-driven (6-month CDP) trial with a variable treatment duration ranging from 
approximately 24 to 48 months in participants with NRSPMS. 
Disclosure Statement: This is a parallel treatment study with 2 arms that is blinded/masked for 
participants, the Investigator, any Investigator site staff, and the Sponsor. 
Number of participants: 
Approximately 1700 people will be screened to achieve up to 1290 participants randomly 
assigned to study intervention. 
Enrolled participants will be randomly assigned at a ratio of 2:1 to 60 mg (established from 
dose-finding Study DRI15928) of oral, daily SAR442168 or daily matching placebo. 
Randomization will be stratified by age at screening (>40 versus ≤40 years) and geographic 
region (US versus non-US). 
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.  
Intervention groups and duration: 
Study intervention(s) 
Investigational medicinal product(s) 
• Formulation: SAR442168 film coated tablet 
• Route(s) of administration: oral 
• Dose regimen: 60 mg once daily 
Investigational medicinal product(s) 
• Formulation: placebo to match SAR442168 film coated tablet 
• Route(s) of administration: oral 
• Dose regimen: once daily 
Noninvestigational medicinal product(s)  
• Formulation: MRI contrast-enhancing preparations 
• Route(s) of administration: intravenous (IV) 
• Dose regimen: per respective label 
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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 and the risk of bleeding. 
Devices 
Not applicable. 
Long-term safety study  
After the end of this study, participants who complete the trial and are taking the IMP treatment 
until the end of the trial (double-blind or open-label SAR442168 if meeting 6-month CDP) may 
be offered the option to participate in a long-term safety (LTS) study for an additional 2 years, or 
until SAR442168 is approved in their respective country, whichever comes first. Details of the 
LTS study will be described in a separate protocol.  
Duration of study (per participant)  
The duration of treatment will vary for individual participants, depending on the time of 
recruitment. Considering the recruitment period of approximately 24 months and an assumed 
event rate (discussed below), the duration of the study should be approximately 48 months. All 
recruited participants will be followed in the study until the common study end, which will be 
estimated and announced by the Sponsor to ensure that approximately 288 events of 6-month 
CDP have been observed before the study end.  
Statistical considerations: 
• Primary endpoint: 
The primary estimand will be the treatment difference between SAR442168 and placebo in time 
to onset of 6 month-CDP regardless of completion of the treatment period. This estimand 
corresponds to a “treatment policy strategy”. This estimand will be considered primary for 
supporting regulatory decision making.  
The time to onset of 6-month CDP will be analyzed by a Cox proportional hazards model with 
terms for treatment, age at screening (>40, ≤40 years), geographic region (US, non-US), baseline 
EDSS score, and baseline Gd-enhancing T1 lesions (0, ≥1). A log-rank test stratified by age at 
screening (>40, ≤40 years) and geographic region (US, non-US) to compare SAR442168 to 
placebo will also be examined.  
In this primary intent-to-treat (ITT) analysis: 
• For participants who complete the study without an initial disability progression, the 
participant’s event time will be censored at the date of last EDSS assessment.  
• For participants who have an initial onset of disability progression but complete the study 
at the common study end date without 3-month confirmation, the participant will be 
censored at the date of last EDSS assessment. 
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• For participants who prematurely discontinue the study before 6-month confirmation of 
an onset of disability progression, regardless of having an initial onset, the participant will 
be censored at the date of last EDSS assessment. 
• For participants who meet 3-month CDP but complete the study at the common study end 
date without 6-month confirmation, the event status of the participant will be determined 
by an imputation approach only if all additional EDSS assessments after 3-month 
confirmation to participant’s end of study also meet the criteria for disability progression. 
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 age at screening (>40, ≤40 years), geographic region (US, 
non-US), baseline EDSS score, and baseline Gd-enhancing T1 lesions (0, ≥1) will be used 
to determine the event status as the imputation model within each treatment. A multiple 
imputation approach will be used to summarize the results.  
Only EDSS assessments measured more than 90 days after the onset of an adjudicated relapse will 
be used to determine onset of disability progression. In addition, for the purpose of confirmation, 
only EDSS scores measured more than 90 days after the onset of an adjudicated relapse will be 
used. In case of such MS relapse, the next quarterly EDSS assessment >90 days after relapse onset 
will be used for CDP confirmation. The minimum increase in score required for progression must 
also be maintained for any non-confirmatory (ie, intervening) EDSS assessment(s) between the 
initial (onset) and confirmation EDSS scores. 
• Main secondary endpoints: 
For other time-to-event endpoints (time to onset of sustained 20% increase in the 9-HPT, of 
sustained 20% increase in the T25-FW, of 3-month CDP, and of CDI), similar analysis as for the 
primary analysis of the primary efficacy endpoint will be performed in the ITT population, but 
without imputation.  
Continuous endpoints (percent change in brain volume loss, change in cognitive function, change 
in physical function, and change in MSQoL-54 at EOS) will be analyzed using a mixed-effect 
model with repeated measures (MMRM) approach. The model will include change/percent 
change values for the respective endpoint at each scheduled visit as response variables, and 
treatment, age at screening (>40, ≤40 years), 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.  
Categorical efficacy endpoints with count data (new and/or enlarging T2 hyperintense over the 
study period after baseline) will be analyzed using a negative binomial regression model. The 
model will include the total lesion count across all post-randomization MRI scans during the study 
period as the response variable, with treatment group, age at screening (>40, ≤40 years), 
geographic region (US, non-US), baseline EDSS score, and baseline T2 lesions as covariates. 
Log-transformed observation duration from screening MRI to last available MRI will be the offset 
variable.  
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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, electrocardiograms [ECGs], and vital signs). 
TEAEs are defined as adverse events (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. 
Data Monitoring Committee: Yes 
Scientific Advisory Committee: Yes 
Eligibility Adjudication Committee: Yes 
Relapse Adjudication Committee: Yes 
Independent Hepatology Assessment Committee: Yes 
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Page 18 
1.2 
SCHEMA  
Figure 1 - Graphical study design  
 
 
Abbreviations: CDP, confirmed disability progression; 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 : 24 to 48 months
All patients continue in the study until the 288 events of 6-month CDP are observed before the study end
0
12
24
15
18
Months
Placebo
Oral
1:2 randomization ratio 
SAR442168
60 mg Oral
2:1 randomization ratio 
3
6
9  
21
-1
1 Tablet Daily (SAR442168)
MRI Scan:
Disability
assessments:
End of Study and start of Long-term Safety Study
1 Tablet Daily (matched placebo)
27
33
30
EOS
36
Participants with 6-month CDP 
will have an option to receive 
open-label SAR442168 treatment
Quarterly
Yearly MRI
R
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Page 19 
1.3 
SCHEDULE OF ACTIVITIES (SOA)  
 
Procedure 
Screeninga 
Randomization/ start of IMP 
To Year 2 (M24)b 
From M27 to EOSb 
Only for participants who 
prematurely discontinue IMP 
For all participants 
Only for participants who 
completed treatment 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 
M15 
M18 
M21 
M24 
Quarterly 
visits 
(M27, M30, 
M33, M36, 
M39, M42, 
M45, 
M48…) 
Semi-
annual 
visits 
(M30, M36, 
M42, 
M48…) 
pEOTe 
EOS 
“Common 
study end 
date” visitf 
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, 
V19, V20, 
V21, V22 
V16, V18, 
V20, V22 
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 
X 
X 
X 
X 
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20-Dec-2023 
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Page 20 
Procedure 
Screeninga 
Randomization/ start of IMP 
To Year 2 (M24)b 
From M27 to EOSb 
Only for participants who 
prematurely discontinue IMP 
For all participants 
Only for participants who 
completed treatment 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 
M15 
M18 
M21 
M24 
Quarterly 
visits 
(M27, M30, 
M33, M36, 
M39, M42, 
M45, 
M48…) 
Semi-
annual 
visits 
(M30, M36, 
M42, 
M48…) 
pEOTe 
EOS 
“Common 
study end 
date” visitf 
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, 
V19, V20, 
V21, V22 
V16, V18, 
V20, V22 
pEOTe 
EOS 
FUV 
Study treatment 
administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP dispensation 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
IMP Compliance 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Xe 
X 
 
Paper diary 
dispensation/collection 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Safetyy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationh 
and vital signs 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
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Amended Clinical Trial Protocol 12  
SAR442168-EFC16645 - tolebrutinib 
20-Dec-2023 
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Page 21 
Procedure 
Screeninga 
Randomization/ start of IMP 
To Year 2 (M24)b 
From M27 to EOSb 
Only for participants who 
prematurely discontinue IMP 
For all participants 
Only for participants who 
completed treatment 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 
M15 
M18 
M21 
M24 
Quarterly 
visits 
(M27, M30, 
M33, M36, 
M39, M42, 
M45, 
M48…) 
Semi-
annual 
visits 
(M30, M36, 
M42, 
M48…) 
pEOTe 
EOS 
“Common 
study end 
date” visitf 
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, 
V19, V20, 
V21, V22 
V16, V18, 
V20, V22 
pEOTe 
EOS 
FUV 
Serology tests for 
hepatitis B and C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 
X 
X 
X 
X 
12-lead ECGj 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
yearly 
X 
X 
 
Hematology, 
biochemistryk 
X 
Xz 
 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Amended Clinical Trial Protocol 12  
SAR442168-EFC16645 - tolebrutinib 
20-Dec-2023 
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Page 22 
Procedure 
Screeninga 
Randomization/ start of IMP 
To Year 2 (M24)b 
From M27 to EOSb 
Only for participants who 
prematurely discontinue IMP 
For all participants 
Only for participants who 
completed treatment 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 
M15 
M18 
M21 
M24 
Quarterly 
visits 
(M27, M30, 
M33, M36, 
M39, M42, 
M45, 
M48…) 
Semi-
annual 
visits 
(M30, M36, 
M42, 
M48…) 
pEOTe 
EOS 
“Common 
study end 
date” visitf 
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, 
V19, V20, 
V21, V22 
V16, V18, 
V20, V22 
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 
X 
X 
 
Pregnancy test (if 
applicable)m 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Amended Clinical Trial Protocol 12  
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20-Dec-2023 
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Page 23 
Procedure 
Screeninga 
Randomization/ start of IMP 
To Year 2 (M24)b 
From M27 to EOSb 
Only for participants who 
prematurely discontinue IMP 
For all participants 
Only for participants who 
completed treatment 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 
M15 
M18 
M21 
M24 
Quarterly 
visits 
(M27, M30, 
M33, M36, 
M39, M42, 
M45, 
M48…) 
Semi-
annual 
visits 
(M30, M36, 
M42, 
M48…) 
pEOTe 
EOS 
“Common 
study end 
date” visitf 
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, 
V19, V20, 
V21, V22 
V16, V18, 
V20, V22 
pEOTe 
EOS 
FUV 
Serum FSHn 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Suicidality 
assessment by 
C-SSRS 
X 
X 
 
 
 
 
 
X 
 
X 
 
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 
X 
X 
X 
X 
 
Timed 25-foot walk 
test 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
9-hole peg test 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
SDMT and CVLT-II, 
where availableo 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
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Page 24 
Procedure 
Screeninga 
Randomization/ start of IMP 
To Year 2 (M24)b 
From M27 to EOSb 
Only for participants who 
prematurely discontinue IMP 
For all participants 
Only for participants who 
completed treatment 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 
M15 
M18 
M21 
M24 
Quarterly 
visits 
(M27, M30, 
M33, M36, 
M39, M42, 
M45, 
M48…) 
Semi-
annual 
visits 
(M30, M36, 
M42, 
M48…) 
pEOTe 
EOS 
“Common 
study end 
date” visitf 
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, 
V19, V20, 
V21, V22 
V16, V18, 
V20, V22 
pEOTe 
EOS 
FUV 
Basic or expanded 
MRIp 
Xq 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
yearly 
X 
X 
 
Actigraphy (optional 
for subset of 
participants)r  
X 
Clinical outcome assessmentss 
MSQoL-54 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
EQ-5D-5L 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
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Amended Clinical Trial Protocol 12  
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Procedure 
Screeninga 
Randomization/ start of IMP 
To Year 2 (M24)b 
From M27 to EOSb 
Only for participants who 
prematurely discontinue IMP 
For all participants 
Only for participants who 
completed treatment 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 
M15 
M18 
M21 
M24 
Quarterly 
visits 
(M27, M30, 
M33, M36, 
M39, M42, 
M45, 
M48…) 
Semi-
annual 
visits 
(M30, M36, 
M42, 
M48…) 
pEOTe 
EOS 
“Common 
study end 
date” visitf 
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, 
V19, V20, 
V21, V22 
V16, V18, 
V20, V22 
pEOTe 
EOS 
FUV 
Pharmacokinetics 
SAR442168 and 
relevant metabolite(s) 
pharmacokinetic 
plasma samplest 
 
 
 
 
 
 
 
 
 
Xu 
 
Xu 
 
Xu 
 
 
 
 
 
 
Xe 
 
 
Pharmacogenetics 
DNA sample 
(optional)w 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacodynamics/biomarkers 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for 
archivingx 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Procedure 
Screeninga 
Randomization/ start of IMP 
To Year 2 (M24)b 
From M27 to EOSb 
Only for participants who 
prematurely discontinue IMP 
For all participants 
Only for participants who 
completed treatment 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 
M15 
M18 
M21 
M24 
Quarterly 
visits 
(M27, M30, 
M33, M36, 
M39, M42, 
M45, 
M48…) 
Semi-
annual 
visits 
(M30, M36, 
M42, 
M48…) 
pEOTe 
EOS 
“Common 
study end 
date” visitf 
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, 
V19, V20, 
V21, V22 
V16, V18, 
V20, V22 
pEOTe 
EOS 
FUV 
Immunophenotyping/ 
RNA sequencing 
(ToleDYNAMIC/optiona
l substudy at selected 
sites)aa 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Lymphocyte 
phenotyping by flow 
cytometry in whole 
blood (subset of 
participants)bb  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Plasma samples (NfL), 
serum samples 
(Chi3L1)v 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
yearly 
X 
X 
 
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Procedure 
Screeninga 
Randomization/ start of IMP 
To Year 2 (M24)b 
From M27 to EOSb 
Only for participants who 
prematurely discontinue IMP 
For all participants 
Only for participants who 
completed treatment 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 
M15 
M18 
M21 
M24 
Quarterly 
visits 
(M27, M30, 
M33, M36, 
M39, M42, 
M45, 
M48…) 
Semi-
annual 
visits 
(M30, M36, 
M42, 
M48…) 
pEOTe 
EOS 
“Common 
study end 
date” visitf 
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, 
V19, V20, 
V21, V22 
V16, V18, 
V20, V22 
pEOTe 
EOS 
FUV 
Serum samples (Ig 
levels)v 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
yearly 
X 
X 
 
aPTT, activated partial thromboplastin time; β-HCG, β-human chorionic gonadotropin; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Chi3L1, chitinase-3-like protein 1; 
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 instrument; FSH, follicle stimulation hormone; FUV, follow-up visit; ICF, informed consent form; Ig, immunoglobulin; IRT, interactive response technology; HIV, human immunodeficiency 
virus; IMP, investigational medicinal product; INR, international normalized ratio; LTS, long term safety study; M, month; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; MRI: magnetic 
resonance imaging; MS: multiple sclerosis; SDMT, Symbol Digit Modalities Test; CVLT-II, California Verbal Learning Test-II; MSQoL-54: Multiple Sclerosis Quality of Life-54; NfL: neurofilament light chain; pEOT: 
premature end of treatment; PK: pharmacokinetic; PT: prothrombin time; RBC, red blood cell; SWI, susceptibility weighted imaging; TB, tuberculosis; TIBC: total iron-binding capacity; V: visit; WBC, white blood cell. 
Note: All assessments should 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 of 
any delay to screening (MRI rescheduling, lab retests, etc), an additional period of up to 2 weeks is allowed.  
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 on as needed basis to evaluate the participant in 
accordance with the Investigator’s best judgement 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. 
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c At the EOS, the participants who have completed treatment with IMP (double blind or open label if meeting CDP) may be offered participation in LTS study. Follow-up visit assessment only performed for those 
participants who completed treatment and are not willing to take part in the LTS 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 (it is 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 pEOT 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 the common 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). Additional information is provided in the Study Manual. 
f 
For participants continuing in the study, the common EOS visit will be done when the prespecified number of events for 6-month CDP 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 needs to be reported in the eCRF; 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 (M12, M24, M36, M48) and at EOS; brief physical examination is sufficient for the rest of the visits (complete and brief physical examinations will 
include neurological examination and collection of the following vital signs: arterial blood pressure, heart rate, temperature). 
i 
To be performed at screening for all participants. Tuberculosis examination will be repeated based on clinical judgment, borderline results, or clinical suspicion of TB infection. For further details, refer to E 01. 
Screening tests for TB are described in Appendix 2 (Section 10.2). 
j 
ECG and 30 second rhythm strips will be obtained locally. 
k Hematology (platelet count, RBC count, hemoglobin, hematocrit, MCV, MCH, reticulocytes, WBC count with differential: neutrophils, lymphocytes, monocytes, eosinophils, basophils).  
Biochemistry (blood urea nitrogen [BUN], creatinine, glucose, sodium, potassium, bicarbonate, calcium, liver function tests [AST, ALT, ALP, albumin, total and direct bilirubin], total protein; creatine phosphokinase. 
Lipase will be tested at the Screening Visit, then quarterly. Monthly visits (M1, M2, M4, and M5) will include hematology and full liver panel only. Additional safety assessments can be performed if required by local 
regulations. Such testing shall be performed at local laboratories. 
Note: a one-time retest at screening may be performed if laboratory test abnormality is considered temporary. Additional safety assessments can be performed if required by local regulations; such testing shall be 
performed locally whenever possible. Additional visits may be added if required by local regulations. 
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; a window of ±3 days is permitted for 
weekly liver function test (LFT) timepoints and ±7 days for the other timepoints. Additional information is provided in the Study Manual. For participants switching to open-label treatment, please refer to 
Section 6.6.1. 
m At screening, perform the serum ß-hCG pregnancy test at the central laboratory. At randomization and other scheduled visits during the study, urine pregnancy tests should be performed. At randomization, 
a pregnancy test should be performed prior to the first dose of IMP. 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).  
n Only in female participants, if needed to establish menopausal status. 
o The 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 central MRI manual.  
q A visit window of ±21 days is acceptable for MRIs performed after D1. For systemic corticosteroids and adrenocorticotropic hormone, 1-month wash-out required prior to the MRI scans. 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 only after it has been established that the participant meets 
all inclusion and no exclusion criteria. 
r 
A noninvasive activity monitor (actigraphy) may be optionally implemented by the Sponsor in a subset of participants during the course of the study if results from pilot assessment demonstrate feasibility. 
s 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 where 
available per local regulations. 
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t 
On days of PK sampling, the IMP needs to be taken at the study site after a “regular meal”. In case a participant forgot IMP at home or took IMP prior to arriving at the site on the day of visits with PK sampling, 
he/she will be asked to have a repeat 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 M6 and M12: Two samples: one sample between 30 to 90 minutes and one sample between 2.5 to 5 hours after IMP administration. M9: one sample 30-90 minutes after IMP. 
v Pharmacodynamics and biomarkers samples will be collected only if permitted per local regulations. 
w DNA testing will be allowed at any time after signature of consent (in case it could not be done for some reason at Day 1). Participation is optional. Participants who do not wish to participate in the genetic research 
may still participate in the study. A separate consent is required for the genetic analysis component of the study.  
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 Additional safety assessments can be performed if required by local regulations; such testing shall be performed locally whenever possible. Additional visits may be added if required by local regulations. 
z Samples for hematology and biochemistry tests on Day 1 (randomization) must be collected prior to administration of the first IMP dose. 
aa Samples must be shipped within 24 hours. For detailed instructions see Appendix 11 (Section 10.11) and the Study Manual. 
bb Blood sample collection for lymphocyte phenotyping by flow cytometry will be performed in a subset of randomized participants. Participants who did not have a baseline sample collected, will no longer have this 
test performed; participants who had a baseline sample collected will have a second sample collected at EOT/pEOT. 
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2 
INTRODUCTION  
SAR442168, a brain penetrant inhibitor of Bruton’s tyrosine kinase (BTK), is being developed for 
the indication of treatment of patients with MS. This study is designed to collect evidence of 
SAR442168 efficacy and safety in the nonrelapsing SPMS (NRSPMS) population. 
2.1 
STUDY RATIONALE  
The goal of this Phase 3 clinical trial is to demonstrate the efficacy and safety of SAR442168 
compared to placebo in participants with NRSPMS. SAR442168 is a small molecule administered 
as a once daily oral treatment that is an irreversible, covalent inhibitor of BTK. SAR442168 is 
a brain-penetrant compound that modulates the pro-inflammatory activity of B cells in the 
periphery and in the CNS as a result of the BTK inhibition. The proposed mechanism of action for 
SAR442168 is to inhibit the coupling of the B cell receptor to downstream signaling in B cells, 
thereby modulating B cells without depleting them. Additionally, it is also known that activated 
B cells are key players in the pathogenesis of MS, specifically in the progressive form of the 
disease. 
The immune complex receptor FcγRII, found in macrophages and microglial cells and that also 
signals through BTK, will similarly be modulated. The Sponsor hypothesizes that this action will 
result in a decrease of inflammatory activity in the CNS, diminishing brain lesions as detected by 
MRI as well as reducing the accumulation of disability progression. 
The advent of disease-modifying therapies for relapsing forms of MS has led to significant strides 
in reducing relapse frequency and the attendant morbidity for people with MS. However, chronic 
disability accumulation remains a significant unmet need for people living with MS. Individuals 
with progressive disease, including SPMS, need therapies to reduce the accumulation of 
disability. With several drugs approved for active secondary progressive disease, there is still no 
treatment available for NRSPMS. 
Data from the recent pivotal trial of siponimod, a S1P receptor modulator, in SPMS patients 
demonstrated reduced risk of 3-month confirmed disability progression (HR=0.79) (1). Data from 
ORATORIO, the pivotal Phase 3 trial of ocrelizumab in a PPMS population, demonstrated that 
this anti-CD20 monoclonal antibody that depletes B lymphocytes could provide a small but 
statistically significant benefit (HR=0.76) in reducing the risk of disability progression (2).  
Furthermore, abundant evidence suggests that innate immunity, and specifically CNS-resident 
microglial cell activity, is a significant driver of disability accumulation in all forms of MS. The 
dual working hypothesis driving development of SAR442168 is based on the following: 
1) modulating B cells inert to antigenic stimulation will have an effect similar to B-cell depletion 
on progressive MS disability accumulation, and 2) CNS penetrance will provide a potential added 
benefit of modulating innate immunity mediated by macrophages and microglial cells to suppress 
maladaptive neuroinflammatory processes associated with chronic disability progression. 
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The ability of SAR442168 to reduce the formation of acute brain lesions in MS was assessed in 
a Phase 2b dose-finding trial in participants with RMS (DRI15928). Patients with progressive 
forms of MS may also present with acute focal inflammatory activity in the CNS. This activity 
manifests on MRI as T1 hyperintense Gd+ lesions and new or enlarging T2 lesions. SAR442168 
has proven to be effective in reducing both types of CNS lesions. The SAR442168 Phase 2b 
results showed that SAR442168 reduced the number of new T1 hyperintense Gd+ lesions by 85% 
and the number of new or enlarged T2 lesions by 89% in the 60 mg group (the dose to be used in 
the Phase 3 program) compared to placebo. These data also support the use of this compound in 
progressive forms of MS. 
Reduction in number of T1-hyperintense (Gd-enhanced) lesions has been established as a highly 
reliable predictive biomarker for clinical efficacy in pivotal studies in MS including Phase 3 RMS 
studies (3). While there is no comparable radiographic biomarker to predict clinical efficacy on 
disability progression, the assumption has been that doses effective at preventing relapses can be 
used to assess disability progression in PPMS or SPMS (2, 4, 5, 6, 7, 10, 11). SAR442168 was 
shown to achieve pharmacologically relevant concentrations in CSF after a single oral 
administration, with the potential to inhibit microglia and infiltrating bone-marrow-derived 
macrophages that are believed to drive neuroinflammation linked to disease progression. 
The primary endpoint is time to onset of 6-month CDP assessed via EDSS score. The EDSS is 
widely used to measure neurological disability in clinical trials and routine settings (8). Six-month 
CDP is standard practice in many clinical trials and is recommended by guidelines (2, 4) and 
considered clinically more meaningful than 3-month CDP. 
The CDI over at least 6 months measured by the EDSS score will be used as a secondary endpoint 
due to its clinical importance.  
Magnetic resonance imaging outcomes will include change in brain volume, which is considered 
as a marker of the CNS degenerative process and therefore recommended for use in progressive 
MS trials (9). 
Population pharmacokinetics (PK) will be performed in order to obtain a larger and more diverse 
population to evaluate the PK of SAR442168 in the NRSPMS population, to assess sources of PK 
variability (ethnicity, special populations), and to establish exposure correlation to clinical 
efficacy, biomarkers, and safety endpoints. Soft lock of the population PK data may be performed 
as soon as all participants have finished the Month 12 visit (a separate unblinded team will be 
used to preserve blinding integrity). 
This study will employ other secondary outcome measures to collect additional data in an effort to 
assess the benefit of SAR442168 for people with NRSPMS.  
Although no enrolled participants are expected to have MS relapses, their occurrence cannot be 
ruled out completely. Relapse data will be carefully collected and adjudicated, and their impact on 
the primary endpoint will be assessed (see also statistical considerations). 
Exploratory assessments are expected to provide additional evidence for SAR442168 activity on 
neuroinflammation and neurodegeneration. 
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2.2 
BACKGROUND  
Immunomodulatory drugs are 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). Targeting B cells is 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 (12). However, the 
importance of immune cells residing in the CNS is also well known (13) and needs to be 
considered in MS pathogenesis. 
Evidence of inflammation and presence of activated T and B cells in the brain have also been 
confirmed in PPMS and SPMS, especially in the early stages (14). Inflammatory activity in RMS 
has been attenuated to different degrees with a variety of immunomodulatory therapies; however, 
historically these therapies have shown very little effect on disease activity in people with 
progressive MS despite the evidence for inflammatory activity. This may relate to conditions in 
the CNS, especially the integrity of the blood brain barrier (BBB), but also to the potency and 
mechanism of action of the agents. 
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, PPMS and SPMS) (15). Even the most 
recent high-efficacy disease-modifying therapies act mainly on adaptive immunity in the 
periphery with only modest or temporary ability to slow neuroinflammatory and 
neurodegenerative processes and stop disease progression (2, 3). Therefore, development of MS 
treatments with new modes of action is of interest. This is particularly true for individuals with 
progressive disease, including SPMS, occurring in more than 50% of patients with relapsing-
remitting multiple sclerosis (RRMS) within 15 to 20 years. 
The disease progression for patients with PMS is not driven by relapse but by smoldering 
inflammation within the brain mediated by activated microglial cells. During this time, MRI signs 
associated with smoldering neuroinflammation and neurodegeneration mediated by resident 
innate immunity (maladaptive microglia) have become more prominent. In this context, brain 
tissue loss (atrophy), slowly evolving lesions (SEL) and paramagnetic rim lesions, are important 
features in progressive forms of MS (16, 17). 
SAR2442168 is thought to have the potential to address “outside-in” and “inside-out” MS 
pathological mechanisms. In the periphery, SAR442168 inhibits antigen-induced B cell 
activation, while, due to its property of brain penetrance, SAR442168 modulates maladaptive 
microglial cells in the CNS. Microglial cells express Fc-gamma receptors that couple to BTK 
signaling pathways which result in the secretion of pro-inflammatory cytokines in the CNS. This 
pro-inflammatory activity, which is continuous, gradual, and chronic, is believed to drive 
neuroinflammation linked to progressive tissue damage in the brain and spinal cord that occurs in 
the absence of clinical relapses and MRI Gd-enhancing lesions. This smoldering 
neuroinflammation has, as pathophysiological consequences, axonal loss, lack of remyelination, 
and myelin damage, all believed to be closely related to clinical disability progression. In other 
words, a brain-penetrant compound that crosses the blood-brain barrier, acts directly on 
maladaptive reactive microglial cells, and modulates smoldering inflammatory activity may result 
in less tissue damage, resulting in less disability progression over time. 
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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. 
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 progression (as expressed by 
an increase in the Expanded Disability Status Scale [EDSS] score). 
• 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, paramagnetic rim lesions) 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.  
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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. 
• 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.  
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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), including severe DILI (risk 
of liver transplantation or death) as an identified risk, were reported in the ongoing Phase 3 
trials; cases occurred in Months 1 to 3, with potential confounders identified for some of 
the cases.  
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 (18, 19). 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.  
Infections are an important potential risk for SAR442168, and severe infections are being 
monitored as an AESI in all ongoing and future clinical trials. In the completed Phase 2b trial in 
130 participants 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. 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 
coronavirus disease 2019 (COVID-19), without discernable toxicity, over a 10- to 14-day 
treatment course (20). Randomized studies with acalabrutinib and ibrutinib in COVID-19 are 
ongoing (21, 22, 23, 24). 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 (18). 
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. 
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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. 
Last, 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.  
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 participants with RMS, 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, including severe DILI (risk of liver transplantation or death) as 
an identified risk, 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. 
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 determine the efficacy of SAR442168 compared 
to placebo in delaying disability progression in 
NRSPMS 
• 
Time to onset of 6-month CDP defined as follows: 
- 
Increase of ≥1.0 point from the baseline EDSS 
score when the baseline score is ≤5.0, OR 
- 
Increase of ≥0.5 point when the baseline EDSS 
score is >5.0 
Secondary 
• 
To evaluate efficacy of SAR442168 compared to 
placebo on clinical endpoints, MRI lesions, 
cognitive performance, physical function, and 
quality of life 
• 
Time to onset of sustained 20% increase in the 
9-HPT for at least 3 months 
• 
Time to onset of sustained 20% increase in the 
T25-FW for at least 3 months 
• 
Time to onset of 3-month CDP as assessed by the 
EDSS score 
• 
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 
• 
Time to onset of CDI defined as a ≥1.0 point 
decrease on the EDSS score from baseline 
confirmed over at least 6 months 
• 
Percent change in BVL as detected by MRI scans at 
the EOS compared to Month 6 
• 
Change in cognitive function at the EOS compared 
to baseline as assessed by SDMT 
• 
Change in cognitive function at the EOS compared 
to baseline as assessed by CVLT-II, where available 
• 
Change in MSQoL-54 questionnaire score from 
baseline through the EOS 
• 
To evaluate safety and tolerability of 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 of 
SAR442168 and relevant metabolite(s) in NRSPMS 
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 NfL levels at the EOS compared 
to baseline 
• 
Change in lymphocyte phenotype subsets in whole 
blood at the EOS compared to baseline in a subset 
of participants 
• 
Change in serum immunoglobulin level at baseline 
compared to the EOS 
• 
Change in serum Chi3L1 levels at baseline 
compared to the EOS 
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Objectives 
Endpoints 
Tertiary/exploratory 
• 
To evaluate efficacy of SAR442168 on disease 
progression and activity in NRSPMS, assessed by 
other clinical and imaging measures and by self-
reported assessment 
• 
Time to onset of sustained 20% increase in the 
9-HPT for at least 6 months 
• 
Time to onset of sustained 20% increase in the 
T25-FW for at least 6 months 
• 
Time to onset of a 4-point decrease in the SDMT, 
confirmed over at least 3 and 6 months  
• 
The proportion of participants with CDI confirmed 
over at least 6 months 
• 
The proportion of participants with CDI confirmed 
over at least 6 months and maintained until the EOS 
• 
Change from baseline to Months 12, 18, and 24 and 
to the EOS in the EDSS score, T25-FW test, 9-HPT, 
SDMT, and CVLT-II 
• 
Change from baseline to Months 12, 18, and 24 and 
to the EOS in modified MSFC-3, assessed as the 
composite of the T25-FW test, 9-HPT, and SDMT 
• 
Proportion of participants with NEDA-3 at 
Months 18, 24, 30, 36, and the EOS 
• 
The annualized adjudicated relapse rate (ARR) 
• 
Actigraphic analysis of activity counts and indices of 
change from baseline to the EOS summarized over 
time (in a subset of participants) 
• 
Change from baseline of total volume of 
T2-hyperintense lesions as detected by brain MRI at 
Months 18, 24, and the EOS 
• 
Total number of new 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  
• 
Change from baseline by visit in the volume of 
T1-hypointense lesions and cumulative number of 
new T1 hypointense lesions 
• 
MTR recovery at EOS in new MTR lesions detected 
at months 6 and 12 
• 
Change in number of phase rim lesions in SWI MRI 
from baseline through the EOS (subset of centers 
with capacity of 3T MRI) 
• 
Number and volume of slowly evolving lesions 
(SELs) 
• 
Normalized T1 (nT1) 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 EQ-5D-5L from baseline by visit over 
time 
Abbreviations: 9-HPT, 9-hole peg test; AE, adverse event; AESI, adverse event of special interest; ARR, annualized adjudicated relapse rate; BVL, brain volume 
loss; CDI, confirmed disability improvement; CDP, confirmed disability progression; Chi3L1, Chitinase-3 like protein-1; ECG, electrocardiogram; EDSS, Expanded 
Disability Status Scale; EQ-5D-5L, EuroQol 5-dimension 5-level instrument; EOS, end of study; Gd, gadolinium; HRQoL, health related quality of life; MRI, 
magnetic resonance imaging; MTR, magnetization transfer ratio; MSFC-3, Multiple Sclerosis Functional Composite 3; MSQoL-54, Multiple Sclerosis Quality of Life-
54 Questionnaire; NEDA-3, no evidence of disease activity-3; NfL, neurofilament light chain; NRSPMS, non-relapsing secondary progressive multiple sclerosis; 
PD, pharmacodynamic; PK, pharmacokinetic; SAE, serious adverse event; SDMT, Symbol Digit Modalities Test; SEL, slowly evolving lesions; SWI, susceptibility 
weighted imaging; T25-W, timed 25-foot walk 
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3.1 
APPROPRIATENESS OF MEASUREMENTS  
Nonrelapsing SPMS is defined as an MS phenotype with progressive disability in the absence of 
relapse, after an initial variable period of a relapsing-remitting course. Hence, delaying the 
progression of disability is a clinically relevant outcome and is an aim of any disease-modifying 
treatment in NRSPMS. Measurement of delay of disability progression is an important clinical 
endpoint and is endorsed by regulatory guidance (9). The EDSS is widely used to measure 
neurological disability in clinical trials and routine settings (8). Due to known fluctuation in EDSS 
scores, CDP confirmed after 3- or 6 months is used as an endpoint in clinical trials of progressive 
MS (1, 2). Confirmed disability progression lasting for at least 6 months is considered to be more 
clinically relevant and superior in ruling out EDSS score fluctuations and is therefore chosen as 
the primary efficacy endpoint in this trial. 
Confirmed disability improvement over at least 6 months as measured by the EDSS score will be 
a secondary endpoint due to its clinical importance. Magnetic resonance imaging measurements 
will include change in brain volume, which is considered to be a marker of the CNS degenerative 
process and is therefore recommended in progressive MS (9). Magnetic resonance imaging at 
Month 6 will serve as the baseline for analyses of MTR and brain atrophy to exclude the potential 
confounding effect of transient changes in brain volume associated with resolution of 
inflammation after introduction of treatment (so-called pseudoatrophy) (25). The MRI markers of 
inflammatory activity in the brain observed in previous clinical trials of progressive MS (1, 2) will 
also be measured. The number of active T2-hyperintense lesions and change in their volume at the 
EOS are selected as secondary endpoints, as they reliably reflect accumulating MS lesion load 
over time.  
In addition, MRI measurements will include analysis of brain volume loss over time. Several MS 
drugs are known for their capacity to slow down brain volume loss, which will be assessed in 
search of a possible signal. 
Clinical outcome assessments are considered important for understanding the impact of treatment 
on function and well-being (26). In both progressive and relapsing MS, the increasing limitation 
and loss of physical function are prevalent and among the most debilitating signs and symptoms 
of the disease (5). Physical function limitations are associated with decrements in quality of life 
due to diminishing productivity and ability to perform daily activities, maintain employment, and 
maintain social roles and emotional wellbeing. Reduction of disease impact on patient-reported 
physical function is therefore important to assess in addition to the clinician assessment and 
constitutes a direct measure of treatment effectiveness, ie, whether a treatment influences how 
a participant feels or functions (27). MS relapses may occur infrequently in a small part of the 
study population (1, 2). Relapse data will be carefully collected and adjudicated, and their impact 
on the primary endpoint will be assessed. 
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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
This is a Phase 3, randomized, double-blind, 2-arm, placebo-controlled, parallel-group, 
multicenter, event-driven (6-month CDP) trial with a variable treatment duration ranging from 
approximately 24 to 48 months in participants with NRSPMS. 
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 2:1 ratio to 
receive oral SAR442168 (60 mg) daily or matching placebo daily. 
Intervention period: Double-blind treatment period for assessment of efficacy and safety up to the 
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 treatment [double blind or open-label, if initiated after 6-month CDP] and not 
entering the LTS study) to collect safety data.  
EOS: 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. 
Participants with 6-month CDP are eligible for open-label active treatment (SAR442168) 
(Section 6.6.1). 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
This is a Phase 3 study for which a double-blind, randomized, placebo-controlled design has been 
selected to minimize possible biases in the study outcome. 
4.2.1 Justification for participant’s age and study duration  
Male and female participants with a diagnosis of NRSPMS between 18 and 60 years inclusive 
will be selected for this study. The age range is limited to participants who are ≤60 years to reduce 
confounding neurological conditions prevalent in older individuals (eg, degenerative pathology of 
the spine, vascular disorders, other neurodegenerative processes). Besides, since the SPMS 
phenotype is more prevalent in an older population, it was considered appropriate to set the upper 
age limit to 60 years. 
The duration of the treatment period will vary for individual participants, depending on the time 
of recruitment and study end as described below. All recruited participants will be followed in the 
study until approximately 288 events of 6-month CDP are observed. Considering the recruitment 
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period of approximately 24 months and an assumed event rate (see Section 9.2), the duration of 
the study should be approximately 48 months, with estimated mean treatment duration of 33 to 
36 months. 
Participants will be encouraged to remain in the study and comply with all study visits until the 
EOS in the case that they discontinue the study intervention early. 
To minimize possible biases in the study outcome, the study is double blinded. The blind of 
initial treatment will be kept from participants, any Investigator site staff, and the Sponsor until 
the study end. 
4.2.2 Justification for the use of placebo  
This study will explore the efficacy and safety of SAR442168 in participants that are not routinely 
included in MS clinical trials: NRSPMS patients. This study will allow for a proper controlled 
data driven approach in a subset of MS patients who do not have approved therapeutic options.  
Data obtained in recent MS clinical trials also support the use of placebo as a comparator in this 
target population. The results from the Phase 3 EXPAND study (4), that explored the efficacy and 
safety of siponimod in SPMS participants, did not show a significant impact of this compound on 
disability progression in the sub-population of participants without relapses. For this reason, EMA 
approved siponimod only for active SPMS, characterized by recent relapse or MRI activity.  In 
addition, ocrelizumab, the only DMT approved for primary progressive MS, has not been studied 
in NRSPMS (2, 28). Despite the off-label use of other DMTs for NRSPMS patients, clinical 
experience has confirmed a relative lack of efficacy for patients with low or absent clinical or 
MRI activity. 
With the current study design, participants will be allocated 2:1, SAR442168 to placebo, in order 
to minimize the exposure to placebo and maximize the chance of receiving active therapy. The 
participants who enroll in the study and achieve disease progression (6-month CDP) will be 
offered treatment with open-label SAR442168 or the possibility to switch to another DMT, if 
available for NRSPMS in their country. All participants who successfully complete the study will 
additionally be offered the possibility to enroll in a long-term safety study where open label 
SAR442168 will be provided. 
4.2.3 Participant input into design  
No impact to study design is anticipated. 
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 
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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. 
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. 
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. Overall, no new risks were identified in this trial. 
The Phase 2b trial tested efficacy and safety in a population that comprised people with RMS. 
One final consideration regarding dose selection is whether doses that were effective in an RMS 
population would also be optimal for treating progressive disease. This question has been 
confronted by sponsors of previous trials in progressive forms of MS. Without exception, those 
trials have tested the same dose as that approved to treat relapsing forms of MS, including Avonex 
(IMPACT), Betaseron (North American Study Group on Interferon beta-1b in Secondary 
Progressive MS), Copaxone (PROMiSe), Rebif (SPECTRIMS), Tysabri (ASCEND), Gilenya 
(INFORMS), Ocrevus (ORATORIO), and Mayzent (EXPAND). The main issue with dose 
selection for progressive forms of disease is that there is no clear predictive biomarker to explore 
doses in Phase 2b trials. The data from the Phase 2b trial support 60 mg dose as the best means to 
evaluate efficacy and safety in the progressive MS trials planned. 
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 EOS visit, whether remaining on IMP or not. 
This study will end when approximately 288 primary endpoint events of 6-month CDP have been 
observed which is expected to provide sufficient follow up for safety and secondary efficacy 
endpoint evaluation. Considering the recruitment period of approximately 24 months and 
an assumed event rate as discussed in Section 9.2, the duration of the study should be 
approximately 48 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. Participant must be 18 to 60 years of age inclusive, at the time of signing the informed 
consent. 
Type of participant and disease characteristics 
I 02. The participant must have a previous diagnosis of RRMS in accordance with the 
2017 revised McDonald criteria (5). 
I 03. The participant must have a current diagnosis of SPMS in accordance with the clinical 
course criteria (11) revised in 2013 (10) and endorsed by an Adjudication Committee.  
I 04. The participant must have documented evidence of disability progression observed during 
the 12 months before screening. Eligibility will be analyzed by an Adjudication Committee 
(to evaluate source data for disability confirmation; details see Section 10.1.5.3).  
I 05. Absence of clinical relapses for at least 24 months. 
I 06. The participant must have an EDSS score at screening from 3.0 to 6.5 points, inclusive. 
I 07. Deleted in Amended Protocol 03. 
Weight  
I 08. Not applicable. 
Sex 
I 09. Male and/or female 
Contraceptive use should be consistent with local regulations regarding the methods of 
contraception for those participating in clinical studies. 
A) Male participants 
Not applicable. 
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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 applies: 
- 
Is not a woman of childbearing potential (WOCBP).  
OR 
- 
Is a WOCBP and agrees to use an acceptable contraceptive method as described in 
Appendix 4 (Section 10.4) during the intervention period. WOCBP must use reliable 
means of contraception as described in Appendix 4 (Section 10.4) at a minimum. If 
local requirements are more stringent than what is described in Appendix 4 
(Section 10.4), they should be followed.  
- 
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations) (Appendix 2 [Section 10.2]) at screening and 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. 
- 
Requirements for pregnancy testing during and after study intervention are located in 
the SoA (Section 1.3). 
• Additional requirements for pregnancy testing during and after study intervention are 
located in Appendix 2 (Section 10.2). 
• 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. 
Informed consent 
I 10. The participant is capable of giving signed informed consent as described in Appendix 1 of 
the protocol which includes compliance with the requirements and restrictions listed in the 
informed consent form (ICF) and in this protocol. In countries where the legal age of 
majority is above 18 years, a specific ICF 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 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. 
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• 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). 
• A history of active or latent tuberculosis (TB); TB testing should be performed at 
screening and again during the study, if clinically indicated and maybe repeated based on 
clinical judgment, borderline results, or clinical suspicion of TB infection. In case of 
confirmed active or latent TB the patient can be re-screened after full completion of 
anti-tuberculosis treatment. Further details are described in the Study Manual (see 
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 the source 
data and may then randomize the participant. 
• Persistent chronic or active or recurring system infection that may adversely affect 
participation or IMP administration in this study, as judged by the Investigator. 
• 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: results at screening 
for serological markers for hepatitis B and C indicating acute or chronic infection. See the 
Study Manual for further details. 
E 02. 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). 
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E 03. The following findings obtained during the Screening Visit considered in the Investigator’s 
judgment to be clinically significant in the context of this trial: 
• Any screening laboratory values outside normal limits.  
• Abnormal ECG.  
E 04. 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. 
E 05. Conditions that would adversely affect participation in the study or make the primary 
efficacy endpoint non-evaluable: 
• 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, 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 × ULN OR aspartate aminotransferase (AST) >1.5 × ULN 
OR alkaline phosphatase (ALP) >2 × ULN (unless caused by non-liver-related disorder or 
explained by a stable chronic liver disorder) OR total bilirubin >1.5 × 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 nonevaluable for 
the primary efficacy endpoint or that would adversely affect participation in this study, as 
judged by the Investigator. 
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Prior/concomitant therapy 
E 06. A requirement for concomitant treatment that could bias the primary evaluation, such as 
any of the following medications/treatments within the specified time frame before any 
randomization assessment (no wash out is required for dimethyl fumarate, interferon beta 
or glatiramer acetate treatments although use is not permitted on or after Day 1): 
 
Medication 
Wash-out period duration 
Systemic corticosteroids, adrenocorticotropic hormone 
1 month prior to screening MRI scan 
Siponimod, ponesimod 
1 week before randomization with MRI and clinical 
assessment for PML prior to randomization 
Plasma exchange 
1 month prior to randomization 
IV immunoglobulin 
2 months prior to randomization 
Fingolimod, ozanimod 
6 weeks before randomization with MRI and clinical 
assessment for PML 
Teriflunomidea mildly to moderately 
immunosuppressive/chemotherapeutic medications such 
azathioprine, mycophenolate mofetil, and methotrexate 
3 months prior to randomization 
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  
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 therapies 
5 half-lives or until end of pharmacodynamics 
activity, whichever is longer 
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 
No patient who has received any of these treatments 
at any time is eligible. 
IV: intravenous, MRI: magnetic resonance imaging, MS: multiple sclerosis, PML: progressive multifocal leukoencephalopathy  
a No time restriction if accelerated elimination procedure is done.  
Prior/concurrent clinical study experience 
E 07. The participant is receiving potent and moderate inducers of CYP3A or potent inhibitors of 
CYP2C8 hepatic enzymes as listed in Appendix 9 (Section 10.9). 
E 08. The participant is receiving anticoagulant/antiplatelet therapies; those that are not 
permitted to be taken concomitantly with the IMP, include the following: 
• Acetylsalicylic acid (aspirin) >81 mg/day. 
• Antiplatelet drugs (eg, clopidogrel). 
• Warfarin (vitamin K antagonist). 
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• 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 randomization. 
If however the participant has a chronic underlying medical condition (stroke, coronary or 
carotid artery disease, valvular heart disease etc) requiring continued use of these 
medications, the participant cannot be enrolled in the study. 
E 09. The participant has sensitivity to any of the study interventions, or components thereof, or 
has a drug or other allergy that, in the opinion of the Investigator, contraindicates 
participation in the study. 
E 10. The participant was previously exposed to any BTK inhibitor, including SAR442168. 
E 11. The participant has taken other investigational drugs within 3 months or 5 half-lives, 
whichever is longer, before the Screening Visit. 
Diagnostic assessments 
E 12. The participant has a 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. 
Note: People with a contraindication to Gd can be enrolled into the study but cannot 
receive Gd contrast dyes during their MRI scan. 
Other exclusions 
E 13. Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or participants who are legally institutionalized. 
E 14. Any country-related specific regulation that would prevent the participant from entering 
the study. See Appendix 8 (Section 10.8) (country-specific requirements). 
E 15. The participant is 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. 
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E 16. 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 (in 
conjunction with Section 1.61 of the International Council for Harmonisation [ICH] - 
Good Clinical Practice [GCP] Ordinance E6). 
E 17. Any other situation during study implementation/course that may raise ethics 
considerations. 
Note: a one-time retest at screening may be performed if an abnormal laboratory test value 
is considered temporary. 
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 needs to be 
changed for IMP administration, 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. 
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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 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 
reasons, 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 participants should be assigned a different participant 
number. More information on rescreening procedures is provided in the Study Manual. 
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 (see Section 10.10) should be considered for screening, enrollment, randomization, 
and 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 
CRITERIA FOR TEMPORARILY DELAYING ENROLLMENT AND 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 10.10) should be considered for screening, enrollment, randomization, and 
administration of the study intervention. 
6.2 
STUDY INTERVENTION(S) ADMINISTERED  
Table 2 - Overview of study interventions administered  
ARM name 
SAR442168 
Placebo 
Intervention name 
SAR442168 
Placebo 
Type  
Drug 
Drug 
Dose formulation 
Film coated tablet 
Film coated tablet 
Unit dose strength(s) 
60 mg 
0 mg 
Dosage level(s) 
Once daily 
Once daily 
Route of administration 
Oral 
Oral 
Use 
Experimental 
Placebo 
IMP and NIMP 
IMP 
IMP 
Packaging and labeling 
Study intervention will be provided in 
wallet blister packaging. Each wallet 
blister packaging will be labeled as per 
country requirements. 
Study intervention will be provided in 
wallet blister packaging. Each wallet 
blister packaging will be labeled as per 
country requirements. 
Current name 
SAR442168 
Not applicable 
IMP: investigational medicinal product; NIMP: noninvestigational medicinal product. 
Between the protocol-scheduled on-site visits, interim visits may be required for IMP dispensing. 
As an alternative to these visits or to replace on-site IMP dispensation, if needed, SAR442168 
may be supplied from the site to the participant via a Sponsor-approved courier company 
(direct-to-patient [DTP]) where allowed by local regulations and approved by the Sponsor. 
6.2.1 Noninvestigational medicinal product  
MRI contrast-enhancing preparations 
• Route(s) of administration: IV 
• Dose regimen: as per respective label 
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6.3 
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 (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) must be promptly notified to the Sponsor. 
Some deficiencies may be recorded through a complaint procedure (see Section 8.3.10). 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall the IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party (except for DTP 
shipment, for which a courier company has been approved by the Sponsor), allow the IMP to be 
used other than as directed by this clinical trial protocol, or dispose of IMP in any other manner. 
6.4 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
All participants will be centrally assigned to randomized study intervention using an interactive 
response technology (IRT). Randomization will be stratified by age at screening (>40, ≤40 years) 
and geographic region (US versus 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. 
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 
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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 assignment of SAR442168 and placebo. Tablets of SAR442168 and 
placebo will appear identical. 
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/rater (blinded). The study 
site personnel designated to conduct efficacy assessments (Examining Investigators/raters or other 
qualified site staff) must be different than 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 Examining Investigator/rater during the study. 
The Treating Investigator is the physician responsible for participant’s 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 but will receive 
alerts on 6-month CDP. The Treating Investigator will have access to the participant’s other 
collected data and will follow the participant, collect safety events, and make treatment decisions 
based on the participant’s clinical response and laboratory findings. Once the participant has been 
randomly assigned to treatment, the Treating Investigator will use a 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 of 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 
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 prior EDSS 
assessments. Whenever possible, the same individual should perform the 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 co-medication used or symptoms unless requested by the 
Examining Investigator/rater for efficacy evaluation. 
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A 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. 
6.5 
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 on-site visits). 
• Measures taken to ensure study intervention accountability include the following: 
- 
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. A new paper diary should be provided to the study participant at 
each visit when study medication will be dispensed. In case of DTP 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. 
When participants self-administer study intervention(s) at home, compliance with study 
intervention will be assessed at each visit. Compliance will be assessed by counting returned 
tablets during the site visits and documented in the source documents and eCRF. Deviation(s) 
from the prescribed dosage regimen should be recorded in the eCRF. 
A record of the number of SAR442168 tablets dispensed to and taken by each participant must be 
maintained and reconciled with study intervention and compliance records. Intervention start and 
stop dates, including dates for intervention delays and/or dose reductions will also be recorded in 
the eCRF. 
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6.6 
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. 
Any live (attenuated) vaccine within 2 months before the first treatment visit and during the 
intervention period is prohibited. 
Therapies for MS noted in the exclusion criterion E 06 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. 
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 and Sponsor, the 
medication will not interfere with the study.  
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 the following: 
• 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). 
Paracetamol/acetaminophen, at doses of ≤3 grams/day, is permitted for use at any time during 
the study. Short courses (up to 5 days) of 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. 
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CYP Inhibitors and Inducers: 
Potent and moderate inducers of CYP3A or potent inhibitors of CYP2C8 hepatic enzymes are not 
permitted throughout the study (Appendix 9 [Section 10.9]). 
Based on nonclinical drug metabolism studies, SAR442168 is a substrate of the CYP3A 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 
(Study INT16385) and potent CYP2C8 inhibitor (gemfibrozil 600 mg twice daily for 6 days) 
increased SAR442168 AUC exposure 8.4-fold (Study INT16726). 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 SAR442168 once daily for 14 days under fed conditions 
(Study TDR16862), 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 
(Study INT16726). 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 9 (Section 10.9) for the list of drugs to be avoided. 
The Sponsor should be contacted if there are any questions regarding concomitant or prior 
therapy. 
6.6.1 Open-label treatment  
If a participant achieves the primary endpoint (6-month CDP), they may, in conjunction with the 
Treating Investigator, choose to receive one of the following:  
1. To switch to open-label SAR442168 treatment; OR 
2. To switch to a non-study treatment approved for NRSPMS in their respective country. In 
this case, the participant will permanently discontinue the IMP and will be encouraged to 
remain in the study for planned clinical visits (see Section 7.1.1) until common study end. 
In case the participant switches to open-label SAR442168 treatment, he/she will need to be 
monitored for liver function tests after the first open-label dose at Weeks 2, 3, 4, 5, 6, 7, 8, 9, 10, 
11, and 12, and then monthly for the next 9 months. After that, the schedule visits timepoints per 
SoA will be resumed (ie, every 3 months), until the common study end. Whenever a timepoint 
will coincide with a scheduled visit as per SoA (Section 1.3), the full scheduled visit assessments 
will be performed instead of the liver monitoring testing alone.  
For participants achieving 6-month CDP, the Investigator must ensure that the participant does not 
meet any of the following criteria prior to the switch to open-label SAR442168 treatment:  
• 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). 
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• Acute liver disease, cirrhosis, chronic liver disease (unless considered stable for 
>6 months). 
• Confirmed ALT >1.5 × ULN OR AST >1.5 × ULN OR ALP >2 × ULN (unless caused by 
non-liver-related disorder or explained by a stable chronic liver disorder) OR total 
bilirubin >1.5 × ULN (unless due to Gilbert syndrome or non-liver-related disorder). 
Liver function tests will be performed for all participants prior to the start of open-label treatment.  
Should the participant and Investigator opt for the provision of open-label medicine, they will 
remain blinded to the original treatment assignment. 
All individual blinded data will be reviewed and all queries resolved, if possible, before the switch 
to the open-label treatment to ensure data integrity for primary assessment. Prior to initiation of 
open-label treatment, the Investigator shall confirm that there has been no adjudicated relapse 
within 90 days prior to the onset or confirmation of 6-month CDP. Based on individual symptoms 
and assessed risk of further progression, the Investigator and participant may choose for the 
participant to remain on the initial double-blind treatment after achieving 6-month CDP. 
The initial treatment assignment will be kept blinded from participants, any Investigator site staff, 
and the Sponsor until the study end.  
The supply of SAR442168 as open-label medication will be specified at the country level.  
Multiple sclerosis relapses are not frequent in the NRSPMS population, but their occurrence 
during the study cannot be ruled out completely. In the case of MS relapse, treatments are allowed 
as per local routine practice (eg, high dose IV methylprednisolone for 3 to 5 days). The date and 
time of relapse treatment administration as well as the name and dosage regimen of the 
medication must be recorded. 
6.7 
DOSE MODIFICATION  
Dose modification is not foreseen in this study. Treatment might need to be interrupted or 
permanently discontinued if deemed necessary due to an AE (Section 7 and Section 8.3). 
6.8 
INTERVENTION AFTER THE END OF THE STUDY  
After the end of this study, participants who complete the IMP treatment (double-blind or 
open-label SAR442168 if meeting 6-month CDP) may be offered the option to participate in 
an LTS study for an additional 2 years, or until SAR442168 is approved in their respective 
country, whichever comes first. Details of the LTS study will be described in a separate protocol.  
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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 by 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 will be asked to 
remain in the study to be evaluated until the EOS visit. For this set of participants (participants 
who discontinued the IMP and/or switched to other DMTs), no PK or biomarker samples will be 
collected after the pEOT visit, and MRI assessments will be performed only annually using the 
next annual visit as the starting point.   
This will be important to continue to evaluate for safety and efficacy. 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 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 the guidance for the follow up of laboratory 
abnormalities (Appendix 2 [Section 10.2]). 
• The participant is no longer deriving a therapeutic/clinical benefit in the opinion of the 
Investigator. 
• If a female participant becomes pregnant or wishes to become pregnant during the study. 
• At participant’s request, ie, withdrawal of the consent for treatment. 
• Any serious opportunistic infections (eg, PML [see Appendix 6 {Section 10.6}], HIV) 
• Continued need for/chronic use of prohibited a concomitant medication (see Appendix 9 
[Section 10.9]). 
• Use of open-label SAR442168 or non-study disease modifying therapy approved for 
NRSPMS in their respective countries (eg, after 6-month CDP).  
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Discontinuation of study intervention for abnormal liver function is required 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 best interest of the participant.  
Any clinically significant abnormal laboratory value or ECG parameter will be 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 using Fridericia’s formula [QTcF]) after enrollment, the 
Investigator or qualified designee will determine if the participant can continue in the study and if 
any change in participant management is needed. Review of ECG findings by a cardiologist may 
be considered for a decision of a definitive discontinuation of study intervention because of ECG 
changes. This review of the ECG printed at the time of collection must be documented. Any new 
clinically relevant finding should be reported as an AE. 
See the SoA (Section 1.3) for data to be collected at the time of intervention discontinuation and 
follow-up and for any further evaluations that need to be completed. 
Handling of participants after definitive intervention discontinuation 
Participants will be followed 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 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 per SoA (Section 1.3), if possible 
until the end of the study. If the participant does not agree to the full visit schedule after a decision 
for permanent end of treatment, 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 end of study.  
For participants with definitive discontinuation of study drug who do not agree to remain in the 
study after the premature end of treatment visit, if the premature end of treatment 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.  
Participants who are treated with open label IMP who decide to prematurely and permanently 
discontinue the open label IMP prior to the common study end date should be assessed as soon as 
possible using the procedures normally planned for the premature end of treatment visit. 
Participants who prematurely and permanently discontinue open label IMP who do not agree to 
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remain in the study after performing a visit analogous to the premature end of treatment visit, 
should have an additional visit performed with assessments normally planned for the follow-up 
visit if the last study visit was less than 3 weeks after the last dose of the open label IMP.  
Participants who prematurely and permanently end treatment for a reason other than 6-month 
CDP will not be eligible for open-label IMP. 
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 10.10]: 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. 
If surgery is needed during the study, the benefit-risk of withholding the IMP for at least 3 to 
7 days pre- and post-surgery and the risk of bleeding should be considered.  
The following shall lead to temporary treatment discontinuation: 
• Cytopenias: algorithm for neutropenia and thrombocytopenia as per Appendix 6 
(Section 10.6) should be followed. 
• Serum creatinine, creatine phosphokinase (CPK) and liver enzyme increase: follow 
corresponding 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. 
If needed, temporary treatment discontinuation can be considered by the Investigator or by the 
participant for any other reason, including due to any safety concerns because of disruption of the 
clinical trial due to a regional or national emergency declared by a governmental agency such as 
COVID-19 (Appendix 10 [Section 10.10]) 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. 
7.1.2.1 Rechallenge  
Reinitiation of intervention with the IMP will be done under close and appropriate clinical and/or 
laboratory monitoring once the Investigator will have considered, according to his/her best 
medical judgment, that the responsibility of the IMP(s) in the occurrence of the concerned event 
was unlikely, there are no safety concerns and if the criteria for permanent treatment 
discontinuation have not been met (refer to Section 5). 
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For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 10 (see Section 10.10). 
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. See SoA (Section 1.3) for data to be collected at the time 
of study discontinuation and follow-up and for any further evaluations that need to be 
completed. 
• The participant will be permanently discontinued both from the study intervention and 
from the study at that time. 
• 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 EOS Visit. 
The Investigators should discuss with them 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 rerandomized (treated) in the study. 
Their inclusion and intervention numbers must not be reused. 
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7.3 
LOST TO FOLLOW UP  
A participant will be considered lost to follow up if he or 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 recontacted again at the time of the end of study 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). 
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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 
(Section 1.3), 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 will be recorded on the 
designated field in the eCRF.  
• 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 Section 10.10, Appendix 10: 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 a blinded Examining Investigator/rater or blinded 
imaging raters who are not otherwise involved in the management of participants in this study. 
Key assessments of disability (EDSS score) will be performed by a blinded Examining 
Investigator/rater who will have no access to laboratory and AE reports. Magnetic resonance 
imaging 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 assessment (8). All Examining 
Investigators/raters will be trained and certified to perform the EDSS assessment 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 be aware of which visit a participant is 
completing, 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 6.4). 
A screening EDSS assessment must be completed to confirm eligibility, and it must be repeated at 
the randomization visit.  
EDSS scores, except for screening EDSS scores, will not be communicated to any study staff 
including the Treating Investigator. The Treating Investigator will be notified if the participant 
meets the EDSS criteria for 6-month CDP. Participants will not be informed of their EDSS scores. 
They will be informed of 6-month CDP by the Treating Investigator in order to make decisions as 
defined in Section 6.6.1. 
8.1.1.1 Confirmed disability progression  
Three- and 6-month CDPs are defined as an increase in EDSS score (defined as an increase of 
≥1.0 point from the baseline EDSS score when the baseline score is ≤5.0 or an increase of 
≥0.5 points from the baseline EDSS score when the baseline score is >5.0) confirmed after 
a minimum of 3- and 6-month interval, respectively. 
EDSS scores used for potential onset of disability progression may be observed by the Examining 
Investigator/rater during routine quarterly visits or unscheduled visits. However, confirmation of 
CDP (at least 3 or 6 months later) must be at a routine quarterly visit. Results of all EDSS 
assessments obtained during routine or unscheduled visits throughout the minimum 3- or 6-month 
period (for the primary endpoint) will serve as the basis for conclusion. Once confirmation is 
achieved, the potential onset becomes the actual onset for time to onset of CDP. 
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Only EDSS assessments measured more than 90 days after the onset of an adjudicated relapse will 
be used to determine onset of disability progression. In addition, for the purpose of confirmation, 
only EDSS scores measured more than 90 days after the onset of an adjudicated relapse will be 
used. In case of such MS relapse, the next quarterly EDSS assessment will be used for CDP 
confirmation. The minimum increase in score required for progression must also be maintained 
for any non-confirmatory (ie, intervening) EDSS assessment(s) between the initial (onset) and 
confirmation EDSS scores. 
Confirmed disability improvement is defined as a ≥1 point decrease from baseline in the EDSS 
score lasting at least 6 months. 
8.1.1.2 Confirmed disability improvement  
Confirmed disability improvement is defined as a ≥1 point decrease from baseline in the EDSS 
score lasting at least 6 months. 
8.1.2 Magnetic resonance imaging  
Cranial (brain) MRI before and after administering the 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 
magnetization transfer ratio (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-hypoinense lesion, brain volume loss rate, volume, number and 
intensity (T1) of SEL, and Gd-enhancing T1-hyperintense lesion count (see Section 3). 
The expanded MRI protocol will be used to evaluate Gd enhancement recovery (MTR) 
and phase rim lesions (SWI). 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 (29).  
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 
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 
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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, the Treating Investigator can access MRI reports 
during the blinded intervention period 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. 
8.1.3 Multiple sclerosis relapse assessment  
8.1.3.1 Definition of multiple sclerosis relapse  
For the purposes of this study, MS relapse is defined as monophasic, acute or subacute onset of, 
new neurological symptoms or worsening of previous neurological symptoms with 
an objective change on neurological examination. Symptoms must: 
1. Be attributable to MS,  
2. Last for ≥24 hours, with or without recovery, 
3. Be present at normal body temperature (ie, no infection, excessive exercise, or excessively 
high ambient temperature), and 
4. 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 (8) (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). 
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Confirmation of MS relapse for analysis and study report purposes is detailed in Section 9.4.2.  
Refer to Section 8.3.7 for details regarding MS relapse reporting and Appendix 1 
(Section 10.1.5.4) for details regarding the Relapse Adjudication Committee. 
8.1.3.2 Unscheduled assessment visits  
Participants must be instructed to immediately report new neurological symptoms and recurring or 
worsening of previous symptoms to the Investigator. Any reported symptoms will be collected. 
If a participant reports symptoms that may be consistent with relapse, an unscheduled assessment 
visit to the Treating Investigator and the Examining Investigator/rater (blinded) 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. 
Diagnosing MS relapses during the study: The Treating Investigator will assess whether the 
reported episode is consistent with the definition of MS relapse. If it is consistent with the 
definition of MS relapse or if there is any doubt and 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 EDSS assessment, this will be documented 
with an explanation of the reason. Whenever possible, the Examining Investigator/rater should 
perform the EDSS rating the same day 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 must 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 or 
medically unexpected, or matches definition of an 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 will apply. 
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 (30). The mean walk time will be used for assessment of the 
participant’s walking ability. An increase of >20% from the baseline in the T25-FW test is 
considered meaningful worsening (31). The Examining Investigator/rater or qualified study staff 
will perform this test. 
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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 (32). The mean time to test completion 
will serve for assessment of the participant’s hand dexterity. An increase of >20% from the 
baseline in the 9-HPT is considered meaningful worsening (31). 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 (33) 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 (34). The Examining Investigator/rater or qualified study staff 
will perform this test. 
The CVLT-II (35) measures verbal learning and memory by using a 16-item word list. The list is 
read by the examiner, and patients listen to the list and report as many of the items as possible. 
Five successive trials are scored. The Examining Investigator/rater or qualified study staff will 
perform this test. 
8.1.7 Composite analyses  
Data from the clinical assessments described above will be utilized in various composite analyses 
and endpoints to assess effects of SAR442168 on a 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 modified Multiple Sclerosis Functional Composite-3 (MSFC-3) tool is the composite of the 
T25-FW test, 9-HPT, and SDMT (32, 36). 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 (37): 
• 6-month CDP. 
• Active MRI lesions (both new or enlarged T2-hyperintense lesions and Gd-enhancing 
T1-hyperintense lesions). 
• Adjudicated MS relapse. 
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8.1.8 Clinical outcome assessments and health-related quality of life parameters  
Participants will be provided with a handheld electronic device to record clinical outcome 
assessments and health-related quality of life parameters during onsite visits. Prior to the 
first attempt to complete the clinical outcome assessments, the study coordinator will train the 
participant in the use of the device and how to answer the questions. Participants must record 
clinical outcome assessments 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 (38, 39) 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 disease-modifying therapies 
(eg, teriflunomide). This 54-item instrument generates 12 subscales and 2 single-item 
measures. The 12 subscales are as follows: physical health (10 items), emotional 
well-being (5 items), cognitive function (4 items), role limitation 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 (1 item) and change in health (1 item). 
A linguistically validated MSQoL-54 is available in multiple languages.  
• EuroQoL 5-Dimension 5-Level Instrument: The EQ-5D-5L is a generic quality of life 
instrument used for measuring utility (40) and some of the regulatory bodies’ 
requirements. It consists of 2 parts: a descriptive part (5 questions) and a visual assessment 
scale. It is used in the majority of MS (41), (eg, daclizumab NCT01797965) and non-MS 
clinical studies routinely. The EQ-5D-5L is available in multiple languages. 
All clinical outcome assessments are quantitative tools; they do not collect tolerability data. No 
information that could be a potential safety signal is expected, so clinical outcome assessments 
data will be analyzed at the end of the study. 
8.2 
SAFETY ASSESSMENTS  
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1 Physical examinations  
A physical examination will be performed at the time points specified in the SoA (Section 1.3). 
• A 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. Height (at screening) and weight will also be measured and recorded. Further 
details will be provided in the Study Manual. 
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• A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, neurological examination, and abdomen (liver and spleen). 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
• Any clinically significant new finding or worsening of previous finding should be reported 
as an AE, per Investigator’s judgement. 
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. 
8.2.2 Vital signs  
• Body temperature, heart rate, and blood pressure will be assessed. 
• Blood pressure and pulse measurements will be assessed with the participant in a supine or 
sitting position with a completely automated device. Manual techniques will be used only 
if an automated device is not available. 
• Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions (eg, television, cell phones). 
• Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 heart 
rate and 3 blood pressure measurements (3 consecutive blood pressure readings will be 
recorded at intervals of at least 1 minute).  
8.2.3 Electrocardiograms  
• 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTcF 
intervals. Refer to Section 7 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 
• ECG and 30 second 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. Per 
the SoA, serology tests for hepatitis B and C will be performed during screening; testing 
for other infectious disease should be performed during screening if required locally.  
• 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. 
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• 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 values do not return to normal/baseline within a period of time 
judged reasonable by the Investigator, the etiology should be identified and the 
Sponsor notified. 
• All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), 
must be conducted in accordance with the laboratory manual and the SoA. 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 as well 
as treatment-emergent suicidal ideation and behavior will be monitored during Study EFC16645 
using the C-SSRS. For safety reasons, C-SSRS will be administered throughout the study by the 
Treating Investigator or delegated to an individual who is certified for to administer the scale. 
Study drug administration must be interrupted if a participant scores “yes” on items 4 or 5 of the 
Suicidal Ideation Section of the C-SSRS, or “yes” on any item of the Suicidal Behavior Section. 
A psychiatrist will be consulted and decide whether the study drug 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  
The definitions of an AE or SAE can be found in Appendix 3 (Section 10.3).  
AEs 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).  
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8.3.1 Time period and frequency for collecting AE and SAE information  
All SAEs will be collected from the signing of the ICF until the follow-up visit/EOS visit at the 
time points specified in the SoA (Section 1.3). 
All AE will be collected from the signing of the ICF at the time points specified in the SoA 
(Section 1.3). 
All SAEs and AESI 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 SAE data to the Sponsor within 24 hours of it being 
available. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the 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 AE and SAE 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 
non-leading 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 pre-specified study end-date, all SAEs, and AESIs 
(as defined in Section 8.3.9), 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 provided in Appendix 3 (Section 10.3). 
8.3.4 Regulatory reporting requirements for SAEs  
• Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.  
• The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
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• Reporting of suspected unexpected serious adverse reactions (SUSARs) will be in 
accordance with Directive 2001/20/EC or as per national regulatory requirements in 
participating countries. SUSARs are reported to regulatory authorities, Investigators, and 
IRBs/IECs as follows: 
- 
For SUSARs that are life-threatening or result in death, reporting is no later than 
7 days after first knowledge by the Sponsor, with all relevant follow-up information 
subsequently reported within an additional 8 days, 
- 
For SUSARs, other than those that are life-threatening or result in death, reporting is 
no later than 15 days after first knowledge by the Sponsor. 
• Adverse events that are considered expected will be specified in the reference safety 
information (see the Investigator’s brochure [IB]).  
• An Investigator who receives an Investigator safety report describing an SAE, SUSAR or 
any 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. It is the responsibility of the Sponsor to assess whether 
an event meets the criteria for a SUSAR, and therefore, is expedited to regulatory 
authorities. 
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 follow-up/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. 
• 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, and ectopic pregnancy) are considered SAEs. 
• AEs that occur to study participants who become pregnant are to be reported according to 
the relevant portion of Appendix 3 (Section 10.3). 
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 DMC).  
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Death events will be reported per standard SAE reporting rules. Every effort will be made 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 8.1.3, as with all 
efficacy endpoints, will be exempt from being reported as AEs except when they meet the 
definition of an SAE or are medically severe or medically unexpected. Hospitalization for MS 
relapse, if done routinely at the site (eg, for high dose IV methylprednisolone), will not be 
considered as a seriousness criterion for this study. 
Multiple sclerosis relapses will be collected on the eCRF and be analyzed as part of the efficacy 
analysis. Other worsening of neurological symptoms that do not meet the definition of MS relapse 
will be reported as AEs according to general safety reporting rules. 
8.3.8 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 on MRI do not need to be reported unless they are deemed unusual and 
thus a distinct safety finding. 
8.3.9 Adverse event of special interest  
Adverse event of special interest 
An AESI is an AE (serious or nonserious) of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and immediate notification by the 
Investigator to the Sponsor is required. Such events may require further investigation in order to 
characterize and understand them. Adverse events of special interest may be added, modified, or 
removed during a study by protocol amendment. 
• 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, 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]). 
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• 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).  
• Increase in alanine transaminase (ALT) >3 × ULN  
- 
ALT increase >3 × ULN confirmed by retest within 72 hours or in the absence of 
a retest within 72 hours. 
• Other project specific AESI(s) 
- 
ECG observation of atrial fibrillation or atrial flutter, 
- 
Severe infection (NCI CTCAE Grade 3 or above) infection, 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, 
- 
Thrombocytopenia, platelet count <75 000/mm3 (see Appendix 6 [Section 10.6] for 
management flow chart). 
8.3.10 Guidelines for reporting product complaints  
Any defect in the IMP must be reported as soon as possible by the Investigator to the monitoring 
team that will complete a product complaint form within required timelines. 
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE. 
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: 
1. Contact the Sponsor immediately. 
2. Closely monitor the participant for any AE/SAE and abnormal laboratory test values. 
3. Obtain a plasma sample for PK analysis within 24 hours of the last documented IMP dose. 
4. Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF. 
5. Decisions regarding dose interruptions will be made by the Investigator in consultation 
with the Sponsor based in the clinical evaluation of the participant. 
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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 timepoints during the 
study (for participants who discontinued IMP, no PK samples are collected after pEOT 
visit). If warranted and agreed upon between the Investigator and the Sponsor, additional 
PK samples may be collected (eg, for retesting, pEOT, or if clinically indicated). The PK 
sample collection/storage is strongly recommended for events of confirmed ALT increase 
>5 × ULN (recommended for ALT >3 × ULN) and thrombocytopenia (platelets 
<75 000/mm3), and is recommended for events of neutropenia (neutrophils <1500/mm3), 
serum creatinine increase (confirmed increase >1.7 × ULN or decrease clearance >50%, 
cannot be rapidly reversed), and CPK increase (confirmed >10 × ULN) (see Section 10.6 
for more details). 
• 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, other analyses, and 
a back-up]). 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. 
• Population PK analysis will be performed using SAR442168 and relevant metabolite(s) 
concentration and will be reported in a standalone report. 
Drug concentration information that would unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded. 
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 up to 200 randomized participants. Flow cytometry will be used 
for evaluation of change from baseline in lymphocyte count and phenotype in a subset of 
participants. Additional PD evaluations will include assessment of NfL levels in plasma, Chi3L1, 
and Ig levels in serum. For lymphocyte phenotyping, participants who did not have a baseline 
sample collected will no longer need to have this test performed; participants who had a baseline 
sample collected will have a second sample collected at EOT/pEOT. For additional PD 
evaluations (NfL levels and Chi3L1 and Ig levels), sample collections are no longer needed for 
participants who discontinued IMP or switched to other DMTs. For participants in China, 
see Appendix 7 (Section 10.7). 
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8.7 
GENETICS  
A 6 mL blood sample for DNA isolation will be collected from participants who have consented 
to participate in the genetic analysis component of the study. Participation is optional. Participants 
who do not wish to participate in the genetic research may still participate in the study. 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. For participants in China, see Appendix 7 
(Section 10.7). 
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. 
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 plasma and serum samples for biomarker research is also part of this study.  
• Samples will be tested to evaluate biomarkers and 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, plasma or serum analytes to 
evaluate their association with observed clinical responses to SAR442168. 
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 participants in China, see Appendix 7  
(Section 10.7). 
8.9 
IMMUNOGENICITY ASSESSMENTS  
Not applicable. 
8.10 
MEDICAL RESOURCE UTILIZATION AND HEALTH ECONOMICS  
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study. 
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8.11 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH  
Future research may help further the understanding of disease and the development of new 
medicines. Reuse of coded data and biological samples (leftover) will be limited to future 
scientific research conducted under a research plan for the purpose of diagnosing, preventing or 
treating diseases. The future research projects will be conducted under the Sponsor’s and/or its 
affiliates’ and/or, if applicable, the partner of the Sponsor which has licensed the study drug to the 
Sponsor or which is co-developing the study drug with the Sponsor’s control, acting alone or in 
collaboration with research partners such as universities, research institutions or industrial 
partners with whom the coded data may be shared.  
Data and biological samples will be stored and used for future research only when consented to by 
participants (see Section 10.1.3) and, when applicable, further information on the future research 
has been provided to the study participant, unless prohibited by local laws or IRBs/IECs (in such 
case, consent for future use of data/sample will not be included in the local ICF). The conditions 
for reuse will be adapted locally with the appropriate language in the ICF.  
In any case, a specific consent will be collected for the performance of genetic analyses on 
leftover samples.  
Data protection – Processing of coded clinical data  
The study participant will be provided will all mandatory details of the data processing in Part 2 
of the core ICF.   
The Sponsor adopts safeguards for protecting participant confidentiality and personal data 
(see Section 10.1.4). 
Use of leftover samples for future research 
Remaining leftover samples will be used only after the study ends, ie, end of study as defined in 
the study protocol. 
The study participant will be provided with all mandatory details of the use of the human 
biological samples (leftover) in Section 2 of the Core ICF.  
Study participant data will be stored for up to 25 years for regulatory purposes and future 
research. Biological samples for future use will be stored for up to 25 years after the end of the 
study. Any samples remaining at the end of retention period will be destroyed. If a participant 
requests destruction of his/her samples before the end of the retention period, the Investigator 
must notify the Sponsor (or its contract organization) in writing. In such case, samples will be 
destroyed and related coded data will be anonymized unless otherwise required by applicable 
laws. 
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9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES  
The null hypothesis for the primary efficacy endpoint of time to onset of 6-month CDP is that 
there is no treatment difference between SAR442168 and placebo, and the alternative hypothesis 
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 or any interim 
analysis, if applicable. The study will be declared positive if the null hypothesis for the primary 
endpoint of 6-month CDP for SAR442168 versus placebo is rejected. 
9.2 
SAMPLE SIZE DETERMINATION  
Approximately 1700 participants will be screened to achieve up to 1290 randomly assigned to 
study intervention (2:1 randomization ratio of SAR442168 to placebo). This study is planned as 
an event-driven trial based on 6-month CDP. The study will continue until approximately 
288 events are projected to have occurred to provide 80% power to detect a 30% risk reduction in 
6-month CDP with SAR442168 compared to placebo (2-sided α=0.05). The following 
assumptions were used for the calculations: 2-year placebo event rate of 23.6%; annual 
discontinuation rate of 10%; constant hazard rates using a log-rank test; estimated enrollment 
period of 24 months with last randomized participant followed for 24 months. 
Actual recruitment and disability event rates may vary; therefore, it is possible to stop with 
a reduced sample size of around 1100 and still maintain study power by extending the duration of 
the trial, if needed, to reach approximately the same number of events. For example, it could be 
that the last randomized participant is followed for around 30 months instead of 24, if necessary. 
Additional recruitment of participants will not substantially reduce the trial duration. In any case, 
the power is based on the number of events, and the actual trial duration will be dependent on the 
observed placebo rate and treatment effect. 
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.  
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9.3 
POPULATIONS FOR ANALYSES  
For purposes of analysis, the following populations are defined (Table 3): 
Table 3 - Populations for analysis  
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. 
Pharmacokinetics 
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 prior to database lock or before any interim analysis, if 
applicable, 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. 
9.4.1 General considerations  
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, all statistical hypotheses for the primary and 
secondary endpoints and other treatment comparisons will be tested at the 5% significance level 
(α=0.05) against 2-sided alternatives. 
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9.4.2 Primary endpoint  
The primary estimand will be the treatment difference between SAR442168 and placebo in time 
to onset of 6 month-CDP regardless of completion of the treatment period. This estimand 
corresponds to a “treatment policy strategy”. This estimand will be considered primary for 
supporting regulatory decision making.  
The time to onset of 6-month CDP will be analyzed by a Cox proportional hazards model with 
terms for treatment, age at screening (>40, ≤40 years), geographic region (US, non-US), baseline 
EDSS score, and baseline Gd-enhancing T1 lesions (0, ≥1). A log-rank test stratified by age at 
screening (>40, ≤40 years) and geographic region (US, non-US) to compare SAR442168 to 
placebo 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 CDP 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 progression, the 
participant’s event time will be censored at the date of last EDSS assessment. 
• For participants who have an initial onset of disability progression but complete the study 
at the common study end date without 3-month confirmation, the participant will be 
censored at the date of last EDSS assessment. 
• For participants who prematurely discontinue the study before 6-month confirmation of 
an onset of disability progression, regardless of having an initial onset, the participant will 
be censored at the date of last EDSS assessment. 
• For participants who meet 3-month CDP but complete the study at the common study end 
date without 6-month confirmation, the event status of the participant will be determined 
by an imputation approach only if all additional EDSS assessments after 3-month 
confirmation to participant’s end of study also meet the criteria for disability progression. 
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 age at screening (>40, ≤40 years), geographic region (US, 
non-US), baseline EDSS score, and baseline Gd-enhancing T1 lesions (0, ≥1) will be used 
to determine the event status as the imputation model within each treatment. A multiple 
imputation approach will be used to summarize the results. Details will be provided in the 
SAP.  
Only EDSS assessments measured more than 90 days after the onset of an adjudicated relapse will 
be used to determine onset of disability progression. In addition, for the purpose of confirmation, 
only EDSS scores measured more than 90 days after the onset of an adjudicated relapse will be 
used. In case of such MS relapse, the next quarterly EDSS assessment >90 days after relapse onset 
will be used for CDP confirmation. 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.  
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Additionally, subgroup analyses will be explored to assess consistency of treatment effect. The 
subgroup factors include geographic region (US, non-US; Eastern EU, Western EU, North 
America, Rest of the World), age strata (ie, age at screening; >40, ≤40 years), sex (male, female), 
baseline Gd-enhancing T1 lesions (0, ≥1), baseline EDSS score ( ≤4.5 versus >4.5 and ≤5.5 versus 
>5.5), prior disease modifying therapy use (0, 1, ≥2), duration since RRMS symptom onset 
(≤5, >5 to ≤10, >10 years) and adjudicated relapse during the study. The detailed list of subgroups 
and additional details of the subgroup analyses will be provided in the SAP. 
9.4.3 Secondary endpoint(s)  
For other time-to-event endpoints (time to onset of sustained 20% increase in the 9-HPT, of 
sustained 20% increase in the T25-FW, of 3-month CDP, and of CDI), similar analysis as for the 
primary analysis of the primary efficacy endpoint will be performed in the ITT population but 
without imputation.  
Continuous endpoints (percent change in brain volume loss, change in cognitive function, change 
in physical function, and change in MSQoL-54 at EOS) will be analyzed using a mixed-effect 
model with repeated measures (MMRM) approach. The model will include change/percent 
change values for the respective endpoint at each scheduled visit as response variables, and 
treatment, age at screening (>40, ≤40 years), 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 LS means, the corresponding 95% CI, and p-value will be 
provided for the comparison of SAR442168 versus placebo. For percent change in brain volume 
loss, log transformation will be applied in the MMRM model. 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 endpoints to provide the p-value for the comparison between the 
treatment groups. 
Categorical efficacy endpoints with count data (new and/or enlarging T2 hyperintense over the 
study period after baseline) will be analyzed using a negative binomial regression model. The 
model will include the total lesion count across all post-randomization MRI scans during the study 
period as the response variable, with treatment group, age at screening (>40, ≤40 years), 
geographic region (US, non-US), baseline EDSS score, and baseline T2 lesions as covariates. 
Log-transformed observation duration from screening MRI to last available MRI will be the offset 
variable. In order to assess the impact of open-label therapy, sensitivity analysis excluding the 
data after initiation of open-label therapy will be performed for the key secondary endpoints that 
will be pre-specified in the SAP. Further details including details of missing data handling and 
subgroup analyses for secondary endpoints will also be detailed in the SAP. 
9.4.4 Tertiary/exploratory endpoint(s)  
Methods for analysis of tertiary/exploratory endpoints will be included in the SAP. 
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9.4.5 Other safety analyses  
All safety analyses will be performed on the safety population. 
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. 
The observation period will be divided into 4 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 for participants not receiving SAR442168 open-label treatment. 
- 
The first administration of SAR442168 open-label treatment for participants switching 
to open-label therapy. 
• The open-label epoch, applicable only for participants switching to SAR442168 open-
label treatment, is defined as the time from first administration of SAR442168 open-label 
treatment to the earlier of last administration of open-label treatment plus 10 days or first 
IMP in the LTS study. 
• If applicable, the post-treatment epoch is defined as the time from the end of treatment 
epoch (or end of open-label epoch, if applicable) 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 AEs, TEAEs, 
SAEs, AEs leading to 
treatment 
discontinuation, AEs 
leading to death and 
AESIs 
 
The number and percentage of participants with at least one TEAE, treatment-emergent SAE, 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, 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; ECG: electrocardiography; SAE: serious adverse event; TEAE: treatment-
emergent adverse event 
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9.4.6 Other analyses  
Pharmacokinetic, pharmacodynamic (PD), and biomarker exploratory analyses that will be 
included in the study report will be described in the SAP. Biomarker research will not be part of 
statistical analysis in this study and will not be reported in the clinical study report (CSR). 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 10.10, Appendix 10: Contingency measures for a regional or national 
emergency that is declared by a governmental agency.  
9.5 
INTERIM ANALYSES  
An optional, non-binding interim futility analysis may be performed when approximately 50% of 
the primary endpoint events are observed. The futility interim analysis will be conducted by 
an independent statistics group and reviewed by the DMC. Neither the Sponsor’s team nor the 
Investigator’s staff will have access to the treatment information at the individual participant level 
or group level before the study is formally unblinded after study completion or after the DMC 
recommendation/Sponsor agreement for stopping the trial.  
9.6 
DATA MONITORING COMMITTEE (DMC)  
For details on the DMC, refer to Appendix 1 (Section 10.1.5). 
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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 (eg, data protection law as General Data Protection 
Regulation - GDPR). 
• 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. Determining whether an incidental finding should be 
returned to a participant and, if it meets the appropriate criteria, to ensure the finding is 
returned (an incidental finding is a previously undiagnosed medical condition that is 
discovered unintentionally and is unrelated to the aims of the study for which the tests 
are being performed). The following should be considered when determining the return 
of an incidental finding: 
- 
The return of such information to the study participant (and/or his/her designated 
healthcare professional, if so designated by the participant) is consistent with all 
applicable national, state, or regional laws and regulations in the country where the 
study is being conducted, and, 
- 
The finding reveals a substantial risk of a serious health condition or has 
reproductive importance, AND has analytical validity, AND has clinical validity,  
- 
The participant in a clinical study has the right to opt out of being notified by the 
Investigator of such incidental findings. In the event that the participant has opted 
out of being notified and the finding has consequences for other individuals, eg, the 
finding relates to a communicable disease, Investigators should seek independent 
ethical advice before determining next steps. 
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- 
In case the participant has decided to opt out, the Investigator must record in the 
site medical files that she/he does not want to know about such findings. 
- 
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 Regulation (CFR), ICH guidelines, the IRB/IEC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations. 
As applicable, according to Directive 2001/20/EC, the Sponsor will be responsible for obtaining 
approval from the Competent Authorities of the EU Member States and/or Ethics Committees, as 
appropriate, for any amendments to the clinical trial that are deemed as “substantial” (ie, changes 
which are likely to have a significant impact on the safety or physical or mental integrity of the 
clinical trial participants or on the scientific value of the trial) prior to their implementation. 
10.1.2 Financial disclosure  
Investigators and sub-Investigators 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. 
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.  
• Participant who is rescreened is required to sign a new ICF. 
• The ICF contains a separate section that addresses the use for research of participants’ data 
and/or samples (remaining mandatory ones). Future research is to be defined in Core 
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Study Informed Consent Form (CSICF) Part 2: consent for use of leftover samples and 
associated coded data for future research, and consent for performance of genetic analyses 
on biological samples. Each option is subject to an independent consent and must be 
confirmed by ticking a checkbox in CSICF Part 3. The Investigator or authorized designee 
will explain to each participant the objectives of the exploratory research and why data and 
samples are important for future 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. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 10 (see Section 10.10). 
10.1.4 Data protection  
All personal data collected related to participants, Investigators, or any person involved in the 
study will be handled in compliance with all applicable Privacy & Data Protection laws and 
regulations, including the General Data Protection Regulation (GDPR). The study Sponsor is the 
Sanofi company responsible for ensuring compliance with this matter, when processing data from 
any individual who may be included in the Sanofi databases, including Investigators, nurses, 
experts, service providers, Ethics Committee members, etc.  
When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor takes all appropriate measures to safeguard and prevent access to this 
data by any unauthorized third party. 
• 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 regulatory agencies (eg, on Afro American population for the FDA or on Chinese 
population for the China Food and Drug Administration in China) (42, 43). Participant 
race and ethnicity will not be collected in the countries where this is prohibited by local 
regulation. 
• 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. 
• 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 to the Sponsor. 
• 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 as described in the informed consent.  
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• 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 will take all appropriate measures to safeguard and prevent 
access to this data by any unauthorized third party. 
• Participants must be informed that their study-related data will be used for the whole “drug 
development program”, ie, for this trial as well as for the following steps necessary for the 
development of the investigational product, including to support negotiations with payers 
and publication of results. 
Protection of data related to professionals involved in the study  
• Personal data (eg, contact details, affiliation(s) details, job title and related professional 
information, role in the study, professional resume, training records) are necessary to 
allow Sanofi to manage involvement in the study and/or the related contractual or pre-
contractual relationship. They may be communicated to any company of the Sanofi group 
(“Sanofi”) or to Sanofi service providers, where needed. 
• Personal data can be processed for other studies and projects. At any time, objection to 
processing can be made by contacting the Sanofi Data Protection Officer (link available at 
Sanofi.com). 
• In case of refusal to the processing of personal data by or on behalf of Sanofi, it will be 
impossible to involve the professionals in any Sanofi study. In case the professionals have 
already been involved in a Sanofi study, they will not be able to object to the processing of 
their personal data as long as they are required to be processed by applicable regulations. 
The same rule applies in case the professionals are listed on a regulatory agencies 
disqualification list. 
• Personal data can be communicated to the following recipients:  
- 
Personnel within Sanofi or partners or service providers involved in the study.  
- 
Judicial, administrative, and regulatory authorities, in order to comply with legal or 
regulatory requirements and/or to respond to specific requests or orders in the 
framework of judicial or administrative procedures. Contact details and identity may 
also be published on public websites in the interest of scientific research transparency. 
• Personal data may be transferred towards entities located outside the Economic European 
Area, in countries where the legislation does not necessarily offer the same level of data 
protection or in countries not recognized by the European Commission as offering 
an adequate level of protection. Those transfers are safeguarded by Sanofi in accordance 
with the requirement of European law including, notably:  
- 
The standard contractual clauses of the European Commission for transfers towards 
our partners and service providers. 
- 
Sanofi’s Binding Corporate Rules for intra-group transfers.  
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• Professionals have the possibility to lodge a complaint with Sanofi leading Supervisory 
Authority, the “Commission Nationale de l’Informatique et des Libertés” (CNIL) or with 
any competent local regulatory authority. 
• Personal data of professionals will be retained by Sanofi for up to 30 years unless further 
retention is required by applicable regulations. 
• In order to facilitate the maintenance of Investigators personal data, especially if they 
contribute to studies sponsored by several pharmaceuticals companies, Sanofi participates 
in the Shared Investigator Platform (SIP) and in the TransCelerate Investigator Registry 
(IR) project (https://transceleratebiopharmainc.com/initiatives/investigator-registry/). 
Therefore, personal data will be securely shared by Sanofi with other pharmaceutical 
company members of the TransCelerate project. This sharing allows Investigators to keep 
their data up to date once for all across pharmaceutical companies participating in the 
project, with the right to object to the transfer of the data to the TransCelerate project.  
Professionals have the right to request the access to and the rectification of their personal data, as 
well as their erasure (where applicable) by contacting the Sanofi Data Protection Officer: Sanofi 
DPO - 46 Avenue de la Grande Armée - 75017 Paris - France (to contact Sanofi by email, visit 
https://www.sanofi.com/en/our-responsibility/sanofi-global-privacy-policy/contact). 
10.1.5 Committee structures  
10.1.5.1 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 assess futility through an interim analysis during the trial 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. 
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The responsibilities of the Scientific Advisory Committee are provided in the Scientific Advisory 
Committee charter. 
10.1.5.3 Eligibility Adjudication Committee  
Before randomization, an adjudication committee of MS experts will evaluate anonymized data of 
participants to endorse the diagnosis of NRSPMS and disability progression during the last 
12 months. Details of the workflow between the adjudication committee and Investigators will be 
provided in the Study Manual. 
Any increase in EDSS score is sufficient to confirm disability progression. If an EDSS score is 
unavailable or disability progression is not confirmed by EDSS assessment, disability progression 
can be further explained by a functional systems assessment. In addition, objective neurologic 
findings can also be used to support disability progression (a validated checklist for trial eligibility 
will be provided to the site). 
10.1.5.4 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 be trained on study 
procedures. Relapses, as adjudicated by the committee, need to meet protocol criteria 
(Section 8.1.3.1). 
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. 
10.1.5.5 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, EU clinicaltrialregister (eu.ctr), euclinicaltrials.eu, and 
sanofi.com, as well as some national registries. 
In addition, results from clinical trials in patients are required to be submitted to peer-reviewed 
journals following internal company review for accuracy, fair balance, and intellectual property. 
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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, the Sponsor will continue to protect the privacy of 
participants in their 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.  
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 eCRF unless transmitted to 
the Sponsor or designee electronically (eg, laboratory data). The Investigator is responsible for 
verifying that data entries are accurate and correct by physically or electronically signing the 
eCRF.  
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 on-site 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). 
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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 study report unless local 
regulations or institutional policies require a longer retention period. No records may be destroyed 
during the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.  
10.1.8 Source documents  
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
Data entered in the eCRF that are transcribed from source documents must be consistent with the 
source documents or the discrepancies must be explained. The Investigator may need to request 
previous medical records or transfer records, depending on the study. Also, current medical 
records must be available. 
Definition of what constitutes source data can be found in the Study Manual.  
10.1.9 Study and site start and closure  
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first site open and will be the study start date. 
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 the following: 
• For study termination: 
- 
Information on the product leads to doubt as to the benefit/risk ratio. 
- 
Discontinuation of further study intervention development. 
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• 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. 
If the study is prematurely terminated or suspended, the Sponsor will promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator will promptly inform the participant and should assure 
appropriate participant therapy and/or follow up. 
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. 
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 in the event that the central laboratory results are not 
available in time for either 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. 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. 
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Table 5 - Protocol-required laboratory assessments  
Laboratory assessments 
Parameters 
Hematology 
 
 
Platelet count 
 
RBC count 
 
Hemoglobin 
 
Hematocrit 
 
RBC indices: 
 
MCV 
 
MCH 
 
%Reticulocytes 
 
WBC count with differential: 
 
Neutrophils 
 
Lymphocytes 
 
Monocytes 
 
Eosinophils 
 
Basophils 
Clinical chemistrya 
 
 
BUN 
 
Creatinine 
 
Glucose 
 
Potassium 
 
Sodium 
 
Calcium 
 
Chloride 
 
AST/SGOT 
 
ALT/SGPT 
 
Alkaline phosphatase 
 
Total and direct bilirubin 
 
Creatine phosphokinase 
 
Albumin 
 
Bicarbonate  
 
Total protein 
 
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) 
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Laboratory assessments 
Parameters 
Other screening tests 
• 
Follicle-stimulating hormone (if needed in female participants to confirm 
postmenopausal status) 
• 
Highly sensitive serum or urine hCG pregnancy test (as needed for women of 
childbearing potential)b 
• 
Serology test for hepatitis B (HBs Ag, anti-HBc IGM and total, anti- HBs) and C 
(anti HCV); in case these results are inconclusive (eg, anti-HBs negative and anti-
HBc positive or anti-HC IgG positive), HBV-DNA and/or HCV-RNA should be done, 
respectively, for confirmation. HIV and other infectious disease, if locally required 
• 
Coagulation: PT/international normalized ratio (INR), aPTT 
• 
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 T-SPOT can also be performed, if availablec  
• 
Iron panel (serum): iron, ferritin, transferrin saturation, TIBC. 
The results of each test must be entered into the eCRF. 
ALT: alanine aminotransferase; anti-HBc: antibody to hepatitis B core antigen; anti-HBs: hepatitis B surface antibody; AST: aspartate 
aminotransferase; aPTT: activated partial thromboplastin time; BUN: blood urea nitrogen; eCRF: electronic case report form; hCG: human 
chorionic gonadotropin; HIV: human immunodeficiency virus; IEC: 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 hemoglobin; PT: prothrombin time; RBC: red blood 
cell; SAE: serious adverse event; SGOT: serum glutamic-oxaloacetic transaminase; SGPT: serum glutamic-pyruvic transaminase; 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 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 that may suggest severe liver injury and must be reported as an SAE.  
b Local urine testing will be standard for the protocol (except for the Screening Visit when serum pregnancy test is required) unless serum 
testing is required by local regulation or IRB/IEC. 
c Further details are given in E 01. 
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 other 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  
10.3.1 Definition of AE  
AE definition 
• An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
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Events meeting the AE definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the Investigator (ie, not related to progression of underlying 
disease), eg:  
- 
Symptomatic and/or  
- 
Requiring either corrective treatment or consultation, and/or  
- 
Leading to IMP discontinuation or modification of dosing, and/or  
- 
Fulfilling a seriousness criterion, and/or  
- 
Defined as an AESI. 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. 
• “Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they 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. 
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10.3.2 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. 
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. 
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10.3.3 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’s representative. In this case, all participant identifiers, with the exception of 
the participant number, will be redacted on the copies of the medical records before 
submission to the Sponsor’s representative. 
• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of 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 Activity of Daily Living (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: 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. 
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Any life-threatening AE or death must be reported as an SAE. Any other AE event can be defined 
as “serious” if it meets at least 1 of the predefined outcomes as described in the definition of 
an SAE in Section 10.3.2. 
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. 
• There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to the Sponsor’s representative. However, it is 
very important that the Investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to the Sponsor’s 
representative. 
• The Investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor’s 
representative to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide the Sponsor’s representative with a copy of any post-
mortem findings including histopathology. 
• New or updated information will be recorded in the originally completed eCRF. 
• The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
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10.3.4 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 Section 10.3.4) 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 Section 10.3.4) 
or to the Sponsor’s representative by telephone. 
• 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. 
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3. Postmenopausal female 
- 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
- 
A high follicle stimulating hormone (FSH) level (eg, >30 IU/L or as per the 
laboratory reference range) in the postmenopausal range may be used to confirm 
a postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, 
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 acceptable 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 ovulationb 
- 
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.) 
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ACCEPTABLE METHODSd 
1. 
Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary mode of action 
2. 
Male or female condom with or without spermicidee 
3. 
Cervical cap, diaphragm, or sponge with spermicide 
4. 
A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide (double-barrier 
methods)c 
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. 
d Considered effective, but not highly effective - failure rate of ≥1% per year. Periodic abstinence (calendar, symptothermal, post-ovulation 
methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of 
contraception.  
e Male condoms and female condoms should not be used together (due to risk of failure with friction). 
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 24 hours of learning of the partner’s pregnancy.  
• The female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor.  
• Generally, the follow up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure.  
Female participants who become pregnant  
• The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information 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 24 hours of learning of a participant’s pregnancy.  
• The participant will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the participant and the neonate, and the 
information will be forwarded to the Sponsor. Generally, follow up will not be required for 
longer than 6 to 8 weeks beyond the estimated delivery date. Any termination of 
pregnancy will be reported, regardless of fetal status (presence or absence of anomalies) or 
indication for the procedure. 
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• Any pregnancy complication or elective termination of a pregnancy for medical reasons 
will be reported as an AE or SAE.  
• A spontaneous abortion (occurring at <22 weeks gestational age) or still birth (occurring at 
>22 weeks gestational age) 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. While the Investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting.  
• The participant will be invited to remain in the study in any case. 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 NRSPMS and related 
diseases. They may also be used to develop tests/assays including diagnostic tests related 
to SAR442168 and NRSPMS. 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 for 15 years in a secure storage space with 
adequate measures to protect confidentiality. 
• The samples will be retained while research on SAR442168 for NRSPMS or other period 
as per local requirements. 
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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.  
 
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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Abbreviations: aPTT: activated partial thromboplastin time; EDTA: Ethylenediaminetetraacetic acid; INR: international normalized ratio; 
PK: pharmacokinetic; 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); 
o 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; CPK, creatine phosphokinase; DIC, disseminated intravascular coagulation; ECG, electrocardiogram; 
PK, pharmacokinetic(s); ULN, upper limit of normal 
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 drug; 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 [44] and [45]). 
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. 
In the event that PML is suspected based on imaging results, the local radiologist will directly 
inform the Investigator and a central review of the MRI will not be required. The Investigator will 
obtain additional plasma, urine, and CSF samples for John Cunningham virus (JCV) analysis. 
Samples will be analyzed upon receipt and the results will be provided directly to the 
investigational site and to the Sponsor. Further management will be deferred to the Treating 
Investigator. However, next steps will include discontinuation of study treatment. Additional 
imaging will be at the discretion of the Investigator depending on the diagnostic workup and 
treatment plan. 
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• The detection of JCV DNA in the CSF of a participant with clinical and MRI features 
suggestive of PML establishes the diagnosis of PML. 
• If JCV DNA is not detected in CSF and if clinical suspicion of PML remains high, another 
lumbar puncture should be performed. 
• 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 ADVERSE EVENTS (AES), ADVERSE DEVICE 
EFFECTS (ADES), SERIOUS ADVERSE EVENTS (SAES) AND DEVICE 
DEFICIENCIES: DEFINITION AND PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW-UP, AND REPORTING  
Not applicable. 
10.8 
 APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS  
10.8.1 Contraception requirements in UK, Germany, and Denmark  
For inclusion criterion I 09, 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); 
- 
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, 
post-ovulation methods] and withdrawal are not acceptable methods of contraception). 
• For Denmark Only: Acceptable methods of effective contraception include the following: 
- 
IUD; 
- 
Hormonal contraceptives (contraceptive pills, implants, transdermal patches, hormonal 
vaginal devices, or injections with prolonged release). 
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10.8.2 Country-specific differences for China  
There will be no biological sample exportation from China in this study, and the sites in China 
will not participate in the following testing: 
• Pharmacodynamic: 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. 
10.8.3 Country-specific provisions for France and Japan  
Temporary IMP interruption will occur for all ALT >5 x ULN events regardless of the duration of 
ALT elevation above 5 x ULN. The remaining components of the ALT algorithm (Appendix 6, 
Section 10.6) apply for participants in France and Japan. 
For participants starting IMP/open-label tolebrutinib, liver testing will occur at Weeks 1 and 3 in 
addition to the frequent liver monitoring outlined in the Schedule of Activities (Section 1.3). 
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 (46, 47) can be 
a useful guide in identifying hepatotoxic medications. Examples of hepatotoxic 
herbals/supplements determined by the European Association for the Study of Liver Clinical 
Practice Guidelines for DILI are outlined below (Table 7, 48). Please note that the lists provided 
are not exhaustive and that the product information of drugs intended for concomitant use should 
be consulted. 
Table 7 - 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 
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Herbal and dietary supplements 
Type of liver injury 
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 
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. 
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10.8.4 Country-specific provisions for Japan  
Temporary IMP interruption will occur if ALT >3 × ULN and INR >1.3 or bilirubin >2 × ULN. 
Monitoring should then occur every 2 to 3 days until ALT and INR/bilirubin start downtrending, 
then monitoring can be decreased to weekly until ALT <1.5 × ULN.  
The remaining components of the ALT algorithm (Appendix 6, Section 10.6) and Appendix 8, 
Section 10.8.3 apply for participants in Japan. 
10.8.5 Country-specific provisions for the US  
Participants who previously discontinued IMP within 60 days of trial start due to the partial 
clinical hold and are now restarting IMP, will require liver function test monitoring at Weeks 2, 3, 
4, 5, 6, 7, 8, 9, 10, 11, and 12 (M3), and then monthly for the next 9 months until M12. After that, 
the schedule visit timepoints per SoA (Section 1.3) will be resumed (ie, every 3 months), until the 
study end. Whenever a timepoint will coincide with a scheduled visit as per SoA, the full 
scheduled visit assessments will be performed instead of the liver monitoring testing alone. 
10.8.6 Country-specific provisions for the US, Israel, and sites following FDA partial 
clinical hold conditions  
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 9, Section 10.9). 
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. 
10.9 
APPENDIX 9: EXAMPLE OF DRUGS WITH A POTENTIAL TO CHANGE SAR442168 
METABOLISM OR ABSORPTION  
The following drugs should not be taken during the study concomitantly with 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 8). 
Additionally, participants in the US, Israel, and any other sites following FDA partial clinical hold 
conditions must not take medications that are mild, moderate, or potent inhibitors of CYP3A or 
CYP2C8 (Table 9).  
Please note that the lists provided in Table 8 and Table 9 are not exhaustive and that the product 
information of drugs intended for concomitant use should be consulted. 
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Table 8 - 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 
Table 9 - 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 
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10.10 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 patients, 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. 
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. 
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 patients and 
those important to preserving the main scientific value of the study. 
10.10.1 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 
subject’s medical record.  
10.10.2 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.  
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2. If onsite visits or alternative location (out of subject’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  
- 
Blood sampling for safety (at least hematology, hepatic function panel, coagulation 
panel) and other safety assessments (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 subject’s medical record and the study CRF. 
For all assessments which will not be performed remotely, the assessment windows will be 
extended until subjects 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. 
10.10.3 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.  
10.10.4 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. 
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10.11 APPENDIX 11: IMMUNOPHENOTYPING (TOLEDYNAMIC SUBSTUDY)  
Title 
An immunological substudy to better understand the mechanism of action of the BTK inhibitor 
tolebrutinib in participants with multiple sclerosis and to correlate immunological changes with 
clinical/paraclinical responses (ToleDYNAMIC). 
Introduction/Study rationale  
Bruton’s tyrosine kinase mediates B cell receptor signaling and is also expressed in innate 
immune cells such as monocytes, macrophages, and microglial cells. BTK inhibitors exhibit well 
characterized effects in (autoreactive) B cells as one of the key target cell population in MS. 
However, nonclinical models also indicate indirect effects on T cell subsets due to the intricate, 
reciprocal B cell and T cell crosstalk, which is particularly interesting in light of their role in the 
pathogenesis of MS.  
The second target population of BTK inhibitors is myeloid lineage cells. BTK inhibition alters 
macrophage phagocytic capacity and reduces secretion of proinflammatory and cytotoxic 
cytokines and mediators. In the context of MS pathophysiology, these effects on innate immune 
cells have been proposed to contribute to control of progression. This concept is supported by 
recent neuropathologic findings that the “mixed active-inactive” MS lesions exhibiting absence of 
signs of relevant remyelination depict a pronounced rim of infiltrating macrophages, implicating 
this cell population in this “repair-hostile” environment. 
We propose to elucidate the impact of BTK inhibition via tolebrutinib on the peripheral immune 
regulatory network beyond B cells and to characterize its effects on functional properties and 
transcriptional signatures of peripheral blood monocyte populations in patients with PMS. In light 
of existing nonclinical data, it can be hypothesized that tolebrutinib exerts distinct effects on 
peripheral immune signatures exceeding its direct immune-modulatory effects on B cells and 
monocytes and which may restore immune-regulatory network function. 
Objectives  
The major advantage of the multicenter substudy is that several key immunological questions can 
be addressed in context with available clinical/MRI data in order to gain knowledge about the 
potential correlation between key immunological changes and treatment response. 
In light of the limited amount of blood available and to ensure sufficient participant recruitment, 
we will focus on the following: 
1. Highly standardized functional multiparameter (13 colors per panel) flow cytometry of 
peripheral blood of tolebrutinib-treated participants with PMS before and at different time 
points after onset of tolebrutinib treatment. We will focus on a characterization of T and B 
cell subsets as well as monocyte populations, ie, 
• T cells: CD4, CD8, CD4-CD8-, CD4+CD8+, naive, central memory, effector memory, 
TEMRA, RTE, Treg 
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• CD4 memory: Th1, Th2, Th 17, IL, Tfh, IFNγ, TNFα, GM-CSF, IL4, IL22, IL17A, GrA, 
GrB, GrK, GrM, perforin, MCAM 
• CD8 memory: Cytolytic activity, IFNγ, TNFα, GM-CSF, IL4, IL22, IL17A, GrA, GrB, 
GrK, GrM, perforin 
• Treg: pTreg, tTreg, RTE Treg, CD39, DNAM-1, TIGIT 
• B cells: naïve, class switch memory, Breg, unusual, transitional, marginal-zone-like, IgM 
only 
• Monocytes: classical, intermediate, nonclassical subsets 
Classical, intermediate, nonclassical:  
- 
Chemokine receptor expression (CCR2, CCR5, CX3CR1) 
- 
Activation markers (CD80, CD86, CD116, CD39) 
- 
Pro-inflammatory markers (CD69, CD54, CD68, CD40, CD64, CD32) 
- 
Anti-inflammatory markers (S100A9, CD93, CD36, CD163, PD-1, CD106, CD206, 
CD124, CD121b) 
- 
Adhesion and migratory capacities (CCR7, CD31)  
The frequency will be determined as well as activation status and functional properties such as 
cytokine production and cytolytic profile. Simultaneous assessment of peripheral blood cell 
counts within the main study will allow for quantification of each immune cell subset in 
peripheral blood. 
2. The second set of experiments will focus on functional properties of peripheral blood 
monocytes. Cytokine profile of ex vivo and short-term stimulated CD14 monocytes will 
be determined using Luminex technology.  
• Isolated CD14 monocytes: cytokine/chemokine production (IFNα, IFNγ, TNFα, IL6, 
IL1α, IL1β, IL1RA, IL2, IL4, IL6, IL8, IL10, IL15, IL33, CCL2C) 
• Isolated CD14 monocytes: capacity to phagocytose myelin as determined by flow 
cytometry  
• Production of reactive oxygen species by CD14 monocytes as determined by flow 
cytometry 
• Analysis of key metabolic properties of CD14 monocytes by Seahorse technology 
The effect of tolebrutinib on transcriptional profiles of peripheral blood B cells and CD14 
monocytes using unbiased RNA sequencing of magnetic-bead-sorted cells will be determined. 
This approach will provide a detailed overview of therapy-induced changes within the T cell 
monocyte compartments to potentially identify immune cell subsets as well as transcriptional 
networks affected by tolebrutinib. This approach may identify transcriptional markers which 
might be used in the future as biomarkers for treatment response. 
Statistical analysis will be described in a separate SAP. 
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Study duration  
This substudy will take place during the main study. There will be 3 sampling points (baseline, 
Months 3 and 12) to collect approximately 40 mL of blood per sample/per visit for the 3 visits. 
A total of approximately 120 mL blood will be collected from each participant for this substudy. 
Study design  
• Inclusion/exclusion criteria are those for the main study. 
• Multicenter substudy in participants with PMS sampled at baseline (before treatment) and 
Months 3 and 12 (after initiation of tolebrutinib). 
• Clinical endpoints and MRI measures are from the main study. 
• This substudy will be performed in 80 participants total (40 participants from both 
PERSEUS and HERCULES, respectively). RNA sequencing will be performed in a subset 
of participants. 
• Blood sampling, handling, and shipment. 
• Each blood sample is approximately 40 mL (3 samples of approximately 120 mL for the 
substudy). 
• Special procedures for collection, storage and shipping of blood samples will be described 
in the operational Study Manual for handling samples. 
• Shipment to the central laboratory must be within 24 hours of sampling.  
• Bulk RNA-sequencing will be performed from frozen and subsequently thawed peripheral 
blood mononuclear cells and monocytes. 
Participating centers 
Selected sites. 
10.12 APPENDIX 12: ACTIGRAPHY SUBSTUDY  
A subset of participants may perform actigraphy (a noninvasive activity monitor) to assess disease 
symptoms and progression in the participant’s free-living environment. The objective of this 
assessment is to test the hypothesis that the increased sensitivity and ecological validity of 
an actigraphy device will reflect changes in the participant’s condition more accurately and more 
comprehensively than occasional in-clinic assessments. If implemented based on pilot assessment, 
the Sponsor will provide participants with an actigraphy device. Participants will be required to 
wear the device during waking hours for 14 days on and 14 days off every month from enrollment 
into the substudy until the end of the sub-study, as specified in the schedule of activities 
(Section 1.3). Additional details can be found in the Study Reference Manual.  
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10.13 APPENDIX 13: ABBREVIATIONS  
 
ADL: 
activity of daily living 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALP: 
alkaline phosphatase 
ALT: 
alanine transaminase 
aPTT: 
activated partial thromboplastin time 
AST: 
aspartate aminotransferase 
BTK: 
Bruton’s tyrosine kinase 
CD: 
cluster of differentiation 
CDP: 
confirmed disability progression 
CFR: 
Code of Federal Regulation 
Chi3L1: 
chitinase-3 like protein-1 
CIOMS: 
Council for International Organization of Medical Sciences 
CNS: 
central nervous system 
COVID-19: 
Coronavirus Disease 2019 
CPK: 
creatine phosphokinase 
CSF: 
cerebrospinal fluid 
CSR: 
clinical study report 
C-SSRS: 
Columbia-suicide severity rating scale 
DDI: 
drug-drug interaction 
DILI: 
drug-induced liver injury 
DMC: 
data monitoring committee 
DNA: 
deoxyrebonucleic acid 
DNAM-1: 
DNAX accessory molecule 1 
DTP: 
direct-to-patient 
EC: 
ethics committee 
eCRF: 
electronic case report form 
EDSS: 
expanded disability status scale 
EU: 
European Union 
FSH: 
follicle stimulating hormone 
GCP: 
Good Clinical Practice 
Gd: 
gadolinium 
GM-CSF: 
granulocyte-macrophage-colony stimulating factor 
GrA: 
human granzyme A 
GrB: 
human granzyme B 
GrK: 
human granzyme K 
GrM: 
human granzyme M 
HIV: 
human immunodeficiency virus 
HR: 
hazard ratio 
HRT: 
hormonal replacement therapy 
ICF: 
informed consent form 
ICH: 
International Council for Harmonisation 
IEC: 
Independent Ethics Committees 
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IFNγ: 
Interferon γ 
IL: 
interleukin 
IMP: 
investigational medicinal product 
INR: 
international normalized ratio 
IRB: 
Institutional Review Boards 
IRT: 
interactive response technology 
ITT: 
intent-to-treat 
IUD: 
intrauterine device 
IUS: 
intrauterine hormone-releasing system 
IV: 
intravenous 
IWRS: 
interactive web response system 
JCV: 
John Cunningham virus 
LTS: 
long-term safety 
MCAM: 
melanoma cell adhesion molecule 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MMRM: 
model with repeated measures 
MRI: 
magnetic resonance imaging 
MS: 
multiple sclerosis 
MSFC-3: 
multiple sclerosis functional composite 3 
MTR: 
magnetization transfer ratio 
NCI CTCAE: 
National Cancer Institute Common Terminology Criteria for Adverse Event 
NEDA: 
no evidence of disease activity-3 
NfL: 
neurofilament light chain 
NRSPMS: 
nonrelapsing secondary progressive multiple sclerosis 
NSAIDs: 
nonsteroidal anti-inflammatory drugs 
PCSA: 
potentially clinically significant abnormality 
PD: 
pharmacodynamic(s) 
PK: 
pharmacokinetics 
PML: 
progressive multifocal leukoencephalopathy 
PPMS: 
primary progressive multiple sclerosis 
pTreg: 
peripheral regulatory T cells 
RMS: 
relapsing multiple sclerosis 
RRMS: 
relapsing-remitting multiple sclerosis 
RTE: 
recent thymic emigrant 
SAP: 
statistical analysis plan 
SEL: 
slowly evolving lesions 
SoA: 
schedule of activities 
SPMS: 
secondary progressive multiple sclerosis 
SUSAR: 
suspected unexpected serious adverse reaction 
SWI: 
susceptibility-weighted imaging 
TB: 
tuberculosis 
TEAE: 
treatment-emergent adverse event 
Tfh: 
T follicular helper 
Th 17: 
T helper 17 cells 
Th1: 
T helper 1 cells 
Th2: 
T helper 2 cells 
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TIGIT: 
T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif 
(ITIM) domain 
TNFα: 
tumor necrosis factor α 
Treg: 
regulatory T cell 
tTreg: 
thymically derived Foxp3(+) regulatory T cells 
ULN: 
upper limit of normal 
WBC: 
white blood cells 
WOCBP: 
women of childbearing potential 
 
10.14 APPENDIX 14: 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 (15 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 
The primary driver for this amended protocol consists of regulatory requirements including addition 
of a Relapse Adjudication Committee, change in stratification factor, removal of an endpoint and 
addition of a benefit-risk evaluation of the study in the context of the COVID-19 pandemic. 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
Expanded Disability Status Scale (EDSS)-plus endpoint removed. 
Time to onset of sustained 20% increase in the timed 25 foot walk 
(T25-FW) and the 9-hole peg test (9-HPT) for at least 3 months 
maintained as secondary endpoints. Stratification by 
absence/presence of gadolinium (Gd) enhancing T1 lesions at 
baseline changed to stratification by age at screening. Geographic 
origin corrected to geographic region. Mention that investigational 
medicinal products (IMPs) are film coated tablets. Relapse 
Adjudication Committee added. Post-trial access to study medication 
clarified. Statistical considerations updated for consistency with rest 
of document.  
Accuracy. Clarity. 
Consistency. Health authority 
request. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
1.3 Schedule of 
activities 
Removal of dispensation of IMP and matching placebo from 
premature end of treatment (pEOT) visit. Removal of investigational 
medicinal product (IMP) compliance check from randomization visit. 
Parameters of physical examination clarified. Clarification of 
tuberculosis (TB) testing. Timing of plasma and serum samples 
clarified. Participants who will enter long-term extension study was 
clarified. Quarterly lipase testing added. Mention that additional 
safety assessments may be performed locally if required. Visit 
window for magnetic resonance imaging (MRI) performed after D1 
expanded. Clarification of potential uses of archival sample. 
Accuracy. Clarity. 
2.1 Study rationale 
Removal of paragraph on EDSS-Plus. Mention that relapse data will 
be adjudicated 
EDSS-Plus is removed from 
secondary and 
tertiary/exploratory endpoints. 
Health authority request. 
2.3 Benefit/risk 
assessment 
In potential benefits, “reduction in the accumulation of confirmed 
disability worsening” changed to “reduction in the accumulation of 
confirmed disability progression” for clarity. Investigator assessment 
of relatedness of one adverse event (AE) of temporary alanine 
transaminase (ALT) increase changed to “related” to reflect update in 
data. “No cardiac arrhythmia was observed” was changed to “No 
clinically significant cardiac arrhythmia was observed” for clarity. Text 
added to address regulatory requirements for COVID-19 risk and 
mitigation. 
Clarity. Accuracy. Response 
to regulatory requirement. 
3 Objectives and 
endpoints 
Adjudication added to relapse tertiary/exploratory endpoint. EDSS-
plus endpoint removed. Time to onset of sustained 20% increase in 
the T25-FW and the 9-HPT for at least 3 months moved from 
tertiary/exploratory to secondary endpoints. Change from baseline to 
Months 12, 18, and 24 and to the end of study (EOS) in California 
Verbal Learning Test-II (CVLT-II) added in tertiary/exploratory 
endpoints.  
Accuracy. Clarity. 
Consistency. Health authority 
request. 
3.1 Appropriateness 
of measurements 
Removal of paragraph on EDSS-Plus. Mention that relapse data will 
be adjudicated 
EDSS-Plus is removed from 
secondary and 
tertiary/exploratory endpoints. 
Health authority request. 
4.1 Overall design 
Safety follow-up period clarified.  
Clarity. 
4.2 Scientific 
rationale for study 
design 
Clarification of statistical issue. 
Clarity. 
4.3 Justification for 
dose 
Text about external trials added.  
Clarity. Addition of 
accidentally omitted text. 
5.1 Inclusion criteria 
Move country specificities to Appendix 8. 
Clarity. 
5.2 Exclusion criteria 
In E01, wording “baseline” was change to “screening”. 
Removal of E18 as E09 is a similar criterion.  
In E06, timing of washout for concomitant medications changed from 
“before any baseline” to “before any randomization”, and table 
clarified. 
Clarity.  
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Section # and 
Name 
Description of Change 
Brief Rationale 
5.3.1 Meals and 
dietary restrictions 
Timing of IMP administration clarified. 
Clarity. 
6.1 Study 
intervention(s) 
administered 
Mention that IMPs are film coated tablets. Direct-to-patient (DTP) 
dispensation of IMP added as a possibility. 
Accuracy. Flexibility for 
COVID-19. 
6.2 
Preparation/handling/ 
storage/accountability 
Mention of responsibility in case of DTP shipment 
Flexibility for COVID-19. 
6.3 Measures to 
minimize bias: 
randomization and 
blinding 
Stratification by absence/presence of Gd enhancing T1 lesions at 
baseline changed to stratification by age at screening. Geographic 
origin corrected to geographic region. 
Clarity. Health authority 
request. 
6.5 Concomitant 
therapy 
Mention that live (attenuated) vaccines are prohibited. 
Clarity 
6.5.1 Rescue 
medicine 
“A non-study treatment available for NRSPMS in their respective 
country” changed to “a non-study treatment approved for NRSPMS 
in their respective country”. Clarification that there can be no 
adjudicated relapse within 90 days prior to onset or confirmation of 
6-month CDP. 
Clarity. 
6.7 Intervention after 
the end of the study 
Participants who will enter long-term extension study was clarified. 
Clarity. 
7.1.1 Definitive 
discontinuation 
Clarification of discontinuation reason related to non-study disease 
modifying therapy. Recommendation for cardiologist review of 
electrocardiograms (ECGs) clarified. Last visit for participants with 
definitive discontinuation and participants who decide to discontinue 
open-label IMP clarified. Last visit for participants who decide to 
discontinue the IMP clarified. Participants who prematurely and 
permanently end treatment for a reason other than 6-month CDP will 
not be eligible for open-label IMP 
Clarity. 
7.1.2 Temporary 
discontinuation 
Text added to address regulatory requirements for COVID-19 risk 
and mitigation. 
Consistency. 
8 Study assessments 
and procedures 
“Phone visits” changed to “telephone/remote visits” to allow for web-
based visits. 
Ease of continuation of study 
during COVID-19 pandemic. 
8.1.1.1 Confirmed 
disability progression 
Definition of confirmed disability progression clarified. 
Clarity. 
8.1.2 Magnetic 
resonance imaging 
Details of MRI assessments added. 
Clarity. 
8.1.3.1. Definition of 
MS relapse 
Clarification of MS relapse confirmation definition. Crosslinks added. 
Clarity. 
8.1.7.1 EDSS plus 
Section removed 
EDSS-plus is not an endpoint 
anymore. 
8.1.7.2 Assessment 
of no evidence of 
disease activity 
Mention that MS relapse is adjudicated 
Health Authority requirement. 
8.1.8 Actigraphy 
Actigraphy device must be worn for 14 days after screening for 
baseline assessment. 
Clarity. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
8.2.2 Vital signs 
Removed 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 
Removed reference to additional information. 
Consistency within the 
protocol. 
8.3.6 Cardiovascular 
and death events 
Clarification that only atrial fibrillation and atrial flutter are AESIs in 
this study. 
Clarity. 
8.3.7 MS relapse 
reporting 
MS relapse reporting criteria clarified. 
Clarity. 
8.3.9 Adverse events 
of special interest 
Clarified that the project-specific adverse event of special interest 
(AESI) for ECG pertains to atrial fibrillation and atrial flutter only 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 National Cancer Institute Common Terminology Criteria for 
Adverse Event (NCI CTCAE). 
Clarity. 
8.5 Pharmacokinetics 
Blood samples of approximately 3 mL clarified as blood samples of 
approximately 2 to 3 mL. 
Accuracy. 
8.6 
Pharmacodynamics 
Clarification of the number of participants expected to participate in 
the pharmacodynamics part of the study. 
Clarity. 
9.1 Statistical 
hypotheses 
Addition of details on hypotheses. 
Clarity. 
9.1 Statistical 
hypotheses 
Details added for clarification. 
Clarity. 
9.4.2 Primary 
endpoint 
Clarification of definition of confirmed disability progression. 
Stratification by absence/presence of Gd enhancing T1 lesions at 
baseline changed to stratification by age at screening. Geographic 
origin corrected to geographic region. Subgroup analyses clarified. 
Clarity. Health Authority 
request. 
9.4.3 Secondary 
endpoint(s) 
Stratification by absence/presence of Gd enhancing T1 lesions at 
baseline changed to stratification by age at screening. Geographic 
origin corrected to geographic region 
Clarity. Health Authority 
request. 
9.5 Interim analyses 
The futility criteria or boundary will be predefined in the data 
monitoring committee (DMC) charter. 
Correction of error. This 
definition belongs in the DMC 
statistical analysis plan 
(SAP). 
10.1.5.4 Relapse 
Adjudication 
Committee 
Section added. All relapses are to be adjudicated. 
Clarity. Health Authority 
request. 
10.2 Appendix 2: 
Clinical laboratory 
tests 
Removal of requirement of replicate sampling for local and central 
labs. Removal of requirement for central lab testing, if infeasible. 
Simplification.  
10.8 Appendix 8: 
Country-specific 
requirements 
Country specificities in inclusion criteria moved here. 
Clarity 
Whole document 
Minor format changes and typos correction. 
Accuracy. Consistency. 
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10.14.2 Amended protocol 02 (28 August 2020)  
This amended protocol 02 (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. The amendment also added Phase 2b results with regard to SAR442168 potential benefit 
for non-relapsing secondary progressive multiple sclerosis (NRSPMS). 
Protocol amendment summary of changes table 
Section # and Name Description of Change 
Brief Rationale 
Title page 
Added NCT number. 
Administrative change 
Section 1.1 Synopsis - 
objectives and endpoints, 
Section 1.3 Schedule of 
Activities (SoA), Section 3 
Objectives and Endpoints, 
and Section 8.5 
Pharmacokinetics 
Addition of SAR442168 relevant metabolite(s) when referring to the 
pharmacokinetic (PK) evaluation. 
Clarity 
Section 1.1 Synopsis - 
Rationale, Section 2.1 
Study rationale 
Updated text in these sections. 
Health Authorities’ request 
1.3 Schedule of Activities 
(SoA) 
Addition of hematology, biochemistry, pregnancy test, and 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: 
Coronavirus disease 2019 
(COVID-19) 
 
Repeated vital signs assessment row and checkmark for the same 
deleted. 
Correction 
 
Due to revision of footnotes, sequencing of footnotes has been 
updated 
Updation 
1.3 Schedule of Activities 
(SoA), 10.4 Appendix 4 
Contraceptive guidance 
and collection of 
pregnancy information 
Telephone reporting of home pregnancy tests allowed.  
Health Authorities: 
COVID-19 
2.3 Benefit/risk 
assessment 
Adverse events (AEs) details updated. 
Recent information on Bruton’s tyrosine kinase (BTK) inhibitors and 
COVID-19 added. 
Clarity 
Health Authorities: 
COVID-19 
4.1 Overall design 
"whether or not remaining on IMP" was added to EOS definition 
Clarity 
4.2.2 Justification for the 
use of placebo 
Added a new sub-heading- Justification for the use of placebo, and 
relevant text. 
Health Authorities’ request, 
clarity 
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Section # and Name Description of Change 
Brief Rationale 
5.1 Inclusion criteria 
I09B was updated by adding “women of childbearing potential 
(WOCBP) must use reliable means of contraception as described in 
Appendix 4 (Section 10.4) at a minimum. If local requirements are 
more stringent than what is described in Section 10.4, they should be 
followed”.  
Health Authorities’ request 
5.2 Exclusion criteria 
E04: Conditions that may predispose the patient to excessive 
bleeding clarified. 
E08: Investigator’s role in stopping anticoagulant therapies clarified. 
Health Authorities’ request 
 
E18: Deleted the placeholder for already deleted exclusion criteria 
E18 
Clarity 
 
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 
6.5 Concomitant therapy 
“Therapies for MS noted in the exclusion criterion E06 (Section 5.2) 
are not permitted after randomization while the patient is on study 
treatment” was added.  
Health Authorities’ request. 
Clarity. To address the 
issues around use of 
ocrelizumab and siponimod 
both prior to enrolment and 
during the trial. 
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, 
7.1.2.1 Rechallenge, 
8.0 Study assessments 
and procedures, 
10.1.3 Informed consent 
process, and 
10.12 Appendix 12 
Contingency Measures for 
a regional or national 
emergency that is 
declared by a 
governmental agency.  
Contingency measures for a regional or national emergency were 
added. 
Include flexibility and ease of 
continuation of study during 
regional or national 
emergency such as 
COVID-19. 
7.1.2 Temporary 
discontinuation 
Suicidal risk as per C-SSRS added. 
Clarity  
8.1.2 Magnetic resonance 
imaging 
Added provision for study manual to be provided to all sites for MRI 
related procedure. 
Clarity 
 
Update of the disclosure of MRI reports to the Treating Investigator. 
Health Authorities’ request 
8.2.5 Suicidal ideation and 
behavior risk monitoring 
Columbia-suicide severity rating scale (C-SSRS) criteria for 
interruption of study drug clarified. 
Health Authorities’ request 
8.3.4 Regulatory reporting 
requirements for SAEs 
Requirements for reporting of suspected unexpected serious adverse 
reactions (SUSARs) clarified. 
Health Authorities’ request 
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Section # and Name Description of Change 
Brief Rationale 
10.6 Liver and other 
safety: suggested actions 
and follow-up 
assessments 
Diagnostic workup for PML suspicion added. 
Health Authorities’ request 
10.8 Appendix 8: Country-
specific requirements 
A new sub-heading was added "10.8.1 Contraception requirements 
in UK, Germany and Denmark" 
Updation 
10.11 Appendix 11 
Protocol amendment history with the change that the section was 
updated with amended protocol01 history 
Updation 
Throughout 
Substitution of “long term safety (LTS)” for “long term extension 
(LTE)” to describe the study that participants will be allowed to roll 
over to; correction of small errors (eg, comma errors, duplication of 
words); slight rewordings for clarity, addition of abbreviations, covid-
19 changed to COVID-19. 
New references have been added and sequence numbering have 
been changed throughout the document. 
Correction of errors, clarity 
10.14.3 Amended protocol 03 (03 November 2020)  
This amended protocol 03 (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 the feedback from Investigators with 
regard to the inclusion/exclusion criteria.  
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
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. 
Clarification 
 
M1 corrected to M0. MRI visit at M0 moved to M-1. 
“Long-term extension study” changed to “Long-term 
safety study”.  
Correction of error 
1.3 Schedule of activities (SoA) 
Timing of visit assessments clarified. Reference to E01 
added in footnote “I”. Timing of MRI scans clarified 
(footnote “p” added and duplicated text removed from 
footnote “o”). Sequencing of footnotes has changed due 
to the addition of footnote “p”. 
Clarification 
3 Objectives and endpoints 
Tertiary/exploratory endpoints: Clarification of the MTR 
recovery and slowly evolving lesions (SELs) endpoints. 
Clarification 
5.1 Inclusion criteria 
I07: Deletion of existing criteria. 
Update and clarification 
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Section # and Name 
Description of Change 
Brief Rationale 
5.2 Exclusion criteria 
E01: Clarification of repetition of TB testing. Clarification 
of hepatitis testing. 
Clarification. 
 
E06: Changes of the wash-out period header of the 
table. Removal of requirement for ascertainment of 
B-cell levels after washout. 
Clarification. To allow earlier 
treatment that may potentially 
reduce the progression of 
disability and it is routine 
practice to continue certain MS 
treatments for participants on 
anti-CD20 antibody treatments 
with low B-cell counts. 
 
E15: Potential participants unable to complete 
electronic clinical outcome assessments excluded. 
Copyright issue with paper 
clinical outcome assessment 
forms. 
Section 5.5 Criteria for temporarily 
delaying administration of study 
intervention 
Section 6.1 Criteria for temporarily 
delaying enrollment and 
administration of study intervention 
Sections added to allow flexibility in case of a regional 
or national emergency declared by a governmental 
agency. 
Contingency measures for 
COVID-19. 
Section 8 Study assessments and 
procedures. 
Section 9.4.6 Other analyses 
Reference to contingency measures in the case of 
a regional or national emergency added. 
Contingency measures for 
COVID-19. 
8.1.2 Magnetic resonance imaging 
Rescheduling of MRI because of systemic 
corticosteroid use clarified. 
Clarification. 
8.2.5 Suicidal ideation and behavior 
risk monitoring 
Alerting families to monitor participants for unusual 
behavior removed. 
Removal of unnecessary 
constraint. 
8.3.9 Adverse event of special 
interest 
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. 
8.3.11 Guidelines for reporting of 
medication errors 
Section removed. 
Template section that does not 
apply to this study was 
erroneously included. 
9.4.5 Other safety analyses 
Changes in definition of treatment and post-treatment 
epochs. 
Clarification. 
10.1.5.3 Eligibility Adjudication 
Committee 
Clarification of the assessment of disability progression. Clarification. 
10.1.6 Dissemination of clinical study 
data 
Text on disclosure of information added.  
Change in company policy. 
10.2 Appendix 2: Clinical laboratory 
tests 
Clarification of repetition of TB testing and reference to 
E01 added. 
Clarification. 
 
Template wording regarding hepatic impairment and 
cirrhosis removed. 
Template wording not applicable 
to this study. 
10.6 Liver and other safety: 
suggested actions and follow-up 
assessments 
PML assessment clarified.  
Clarification. 
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Section # and Name 
Description of Change 
Brief Rationale 
10.11 Appendix 11: Protocol 
amendment history 
Protocol amendment history updated. 
Update. 
10.12 Appendix 12: Contingency 
measures for a regional or national 
emergency that is declared by 
a governmental agency 
Additional measures added. 
Contingency measures for 
COVID-19. 
Throughout the document 
Correction of small errors (eg, comma errors, 
duplication of words); slight rewordings for clarity, 
addition of abbreviations.  
New references have been added and sequence 
numbering has been changed throughout the 
document. Table of contents has been updated. 
In-text references updated in relation to update of 
sections. 
Correction of errors, clarity. 
10.14.4 Amended protocol 04 (26 July 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 
The primary reason for this amendment is the availability of new information from drug-drug 
interaction studies. 
Protocol amendment summary of changes 
Section # and Name 
Description of Change 
Brief Rationale 
Synopsis 
3 Objectives and endpoints 
Changed a secondary endpoint from 
“Change in lymphocyte phenotype subsets in 
whole blood at the EOS compared to 
baseline” to “Change in lymphocyte 
phenotyping subsets in whole blood at the 
EOS compared to baseline in a subset of 
participants.” 
Lymphocyte phenotyping will be 
assessed only for participants who 
were sampled before implementation 
of amended protocol 04. 
1.3 Schedule of Activities, footnotes 
The footnotes were updated as follows: 
 
 
• 
Footnote a: To allow a window of 
1 additional 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. 
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Section # and Name 
Description of Change 
Brief Rationale 
 
• 
Footnote e: To clarify the study 
procedures/assessments to be 
performed if a participant prematurely 
permanently discontinues treatment 
with the IMP. 
Clarity. 
 
• 
Footnote i: Text added: Screening 
tests for TB are described in Appendix 
2 (Section 10.2). 
Clarity. 
 
• 
Footnote k: Text added: Lipase will be 
tested at the Screening Visit, then 
quarterly. Also clarified that additional 
safety assessments can be performed 
at local laboratories, if required by local 
regulations. 
Clarity. 
 
• 
Footnote l: Text updated as: A serum 
ß-hCG pregnancy test will be analyzed 
at a central laboratory at screening and 
urine pregnancy tests before the first 
dose of investigational medicinal 
product (IMP) and at scheduled times 
during the study. 
Clarification of pregnancy tests 
required during the study. 
 
• 
Footnote u: Clarified the details of 
pharmacodynamic/biomarker samples 
are not timed at pEOT and EOS. 
Timed pharmacodynamic/biomarker 
sampling is only needed at visits when 
pharmacokinetic (PK) samples are 
also collected at these same time 
points.  
 
• 
New footnote y added 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. 
 
• 
New footnote z added to clarify 
immunophenotyping/RNA sequencing 
samples shipping details. 
Clarity. 
1.3 Schedule of activities, footnote e 
8.5 Pharmacokinetics 
To add the collection of a 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 due to short t1/2 after the last 
IMP dose. 
1.3 Schedule of Activities 
Immunophenotyping/RNA sequencing 
(ToleDYNAMIC/optional substudy at 
selected sites) added.  
Additional substudy to investigate 
immunological changes over the 
treatment duration. 
1.3 Schedule of Activities 
8.6 Pharmacodynamics 
Updated footnote aa for lymphocyte 
phenotyping blood collection: Blood sample 
collection for lymphocyte phenotyping by 
flow cytometry will be performed in a subset 
of randomized participants. Participants who 
did not have a baseline sample collected, will 
no longer have this test performed; 
participants who had a baseline sample 
collected will have a second sample 
collected at EOT/pEOT. 
Lymphocytes phenotyping by flow 
cytometry will be determined only in 
a subset of participants. Sample time 
points have also been reduced. 
Approximately up to 200 participants 
will be randomized to SAR442168, as 
deemed adequate to assess the effect 
at end of treatment. 
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Section # and Name 
Description of Change 
Brief Rationale 
3. Objectives and endpoints 
Updated the language of a tertiary/exploratory 
endpoint to add the assessment of 
cumulative number of new T1-hypointense 
lesions. 
To clarify analysis of T1 hypointense 
lesions. 
4.1 Overall design 
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 09: Clarified that a woman 
of childbearing potential must have a 
negative highly sensitive pregnancy test at 
screening and before the first dose of study 
intervention. 
Clarity. 
5.2 Exclusion criteria 
Exclusion criterion 01: 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 participants. 
 
Exclusion criterion 02: Clarified that the 
Columbia Suicide Severity Rating Scale 
baseline/screening version will be used for 
assessment of suicidal ideation 
Clarity. 
 
Exclusion criterion 03: Updated language to 
clarify Investigator’s judgement to be 
clinically significant in the context of this trial. 
Clarity. 
 
Exclusion criterion 05: Removed standalone 
albumin criterion. 
Clarity. 
 
Exclusion criterion 06: Added plasma 
exchange with a 1-month washout period 
required prior to randomization with MRI and 
clinical assessment for PML. Updated 
washout period for fingolimod and 
natalizumab and in addition provided the 
washout period for ofatumumab and 
ozanimod. 
Clarification to ensure washout 
requirement is based on the 5 half-life 
rule for drug elimination in participants. 
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 needs to be changed for 
IMP administration. 
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 (DDI) 
studies, investigating concomitant use 
of SAR442168 with drugs such as 
itraconazole. 
6. Study intervention 
Updated language to remove device from 
the details. 
Correction as no device for study 
intervention. 
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Section # and Name 
Description of Change 
Brief Rationale 
6.4 Measures to minimize bias: 
Randomization and blinding 
Added text: A participant cannot be 
randomized more than once in the study. 
Clarity. 
1.3 Schedule of activities 
6.5 Study intervention compliance 
Added details of paper diary provision to all 
participants, to capture all study-related 
details. 
Clarity. 
6.6 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. 
 
Updated the language related to use of 
NSAIDs and symptomatic treatment of MS. 
Clarity. 
 
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 to improve patient 
engagement. 
5.2 Exclusion criterion 7 
6.6 Concomitant therapy 
10.9 Appendix 9: 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. 
 
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. 
New information from DDI studies. 
 
Clarified concomitant use of potent CYP3A 
inhibitors is allowed. 
New information from DDI studies. 
6.6.1 Rescue medicine 
Updated language to clarify options of 
medicines that participants may choose to 
receive if they achieve primary endpoint.   
Clarity. 
7.1.1 Definitive discontinuation 
Updated guidance for the participant 
discontinuation related to laboratory 
abnormalities. 
Clarification for participants who 
discontinued IMP will have not need 
PK, biomarker and will have reduced 
MRI schedules. 
 
Removed the Data Monitoring Committee 
(DMC) review of data to determine whether 
AEs should preclude continued treatment 
with study intervention. 
The DMC has no responsibility to 
review individual data and advice for 
IMP discontinuation for a participant. 
 
To add collection of a 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 due to short t1/2 after the last 
IMP dose. 
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Section # and Name 
Description of Change 
Brief Rationale 
7.1.2 Temporary discontinuation 
Text updated to clarify contingency 
measures in case of temporary intervention 
discontinuation because of AEs or regional 
or national emergency declared by 
a government agency. 
Clarity. 
8.1.2 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. 
8.1.3.1 Definition of multiple sclerosis 
relapse 
Clarified that MS relapse confirmation will be 
done by the Relapse Adjudication 
Committee. 
Clarity. 
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). 
To allow some flexibility as some 
automated electrocardiograms do not 
provide these parameters. All other 
electrocardiogram parameters will be 
automatically provided. 
8.3.8 reporting of safety findings from 
magnetic resonance imaging 
Text updated to “In case of clinically relevant 
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.” 
Clarity. 
8.3.9 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. 
 
Thrombocytopenia, platelet count updated 
from <100 000/mm3 to <75 000/mm3 
Modified to align with CTCAE 
guidelines for thrombocytopenia 
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. 
8.6 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. 
10.2 Appendix 2: Clinical laboratory 
test 
Added details of the serology tests for 
hepatitis B and C. 
To harmonize with other protocols in 
Phase 3 MS program. 
 
Table 5, footnote a was updated to clarify the 
clinical laboratory abnormalities for liver 
injury. 
Clarity. 
 
Table 5, footnote b was updated to include 
serum pregnancy test at screening. 
Clarification of pregnancy test. 
 
Removed the cross-reference to unblinding 
section (Section 6.3). 
Clarification of error. 
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Section # and Name 
Description of Change 
Brief Rationale 
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. 
10.6 Appendix 6: Liver and other 
safety: required actions and follow up 
assessments 
Table 6 was updated for clinical history 
manifestations. 
Simplification. 
 
Updated ‘Increase in ALT’ flowchart. 
To provide clear guidelines for safety 
of participants in case of elevated ALT 
or reduced platelet counts. 
 
Updated algorithm for thrombocytopenia. 
To align with CTCAE guidelines for 
thrombocytopenia. 
10.8.2 Country-specific differences 
for China 
Added text to clarify that China will not 
participate in pharmacodynamic, genetic, 
and biomarker testing. 
Previously omitted in error. 
10.10.2 Study procedures 
Updated the wording associated with serum 
creatinine test from “efficacy assessment” to 
“other safety assessments. 
Correction of error. 
10.11 Appendix 11 
Immunophenotyping/ToleDYNAMIC 
substudy 
Added appendix for immunophenotyping 
substudy. 
Additional substudy to investigate 
immunological changes over the 
treatment duration  
Throughout the document 
Correction of small errors (eg, comma errors, 
duplication of words); slight rewordings for 
clarity, addition of abbreviations.  
New references have been added and 
sequence numbering has been changed 
throughout the document. Table of contents 
has been updated. 
In-text references updated in relation to 
update of sections. 
Correction of errors, clarity. 
10.14.5 Amended protocol 05 (21 December 2021)  
This amended protocol (amendment 05) was 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 reason for this amendment was to facilitate operational feasibility and reduce 
complexity, without compromising study integrity.  
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Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Document History 
Countries impacted by amendment changed 
for Amended protocol 02. 
Correction of error. 
1.3 Schedule of activities 
PK sampling added to pEOT visit. 
Footnote a: additional week of flexibility 
allowed for broadened scheduling.  
Footnote c: added references to Section 7.1 
and the Study Reference Manual. 
Footnote t updated, added to M9 PK 
sampling. 
Footnote u: clarification of pharmacodynamics 
and biomarkers sampling.  
Correction of error. 
Additional flexibility in case of 
logistical issues.  
Clarification. 
5.2 Exclusion criteria 
E 01: Text inserted to allow for rescreening 
after TB treatment. 
Flexibility. 
6.4 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 
8.1.6 Cognitive tests 
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. 
6.5 Study intervention compliance 
Proper placement of tear-off label removed. 
Correction of error. This study has 
no tear-off label. 
6.6 Concomitant therapy 
Updated the language related to use of 
NSAIDs. 
Clarification. 
8.1.1.1 Confirmed disability 
progression 
Clarification of timing of observation of EDSS 
scores used for confirmed disability 
progression. 
Clarification. 
8.1.2 Magnetic resonance imaging 
Clarification that full MRI report viewing 
restriction to one/year is applicable during the 
intervention period. 
Clarification. 
8.1.8 Actigraphy 
Section 8.1.8 moved to appendices. 
 
Reference to Study Reference Manual added. 
Timing of requirement for wearing device 
clarified. 
Compliance with requirement that 
substudies be listed as appendices. 
Clarification. 
8.2.1 Physical examinations 
Clarification of reporting of AEs. 
Clarification. 
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. 
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10.14.6 Amended Protocol 06 (23 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. 
1.3 Schedule of activities (SoA) 
5.2 Exclusion criteria (E 05) 
10.2 Appendix 2: Clinical laboratory 
tests (Table 5) 
Iron panel at screening and corresponding exclusion 
criteria for genetic liver diseases added. 
To mitigate the risk of DILI. 
Abbreviations under the SoA and Table 5 updated. 
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 02)  
5.3.2 Caffeine, alcohol, and tobacco 
Exclusion criteria for alcohol consumption added. 
Related recommendation for alcohol consumption 
during study and PK/PD visits updated. 
To mitigate the risk of DILI. 
1.3 Schedule of activities (SoA) 
5.2 Exclusion criteria (E 05)  
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 14: 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, 
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. 
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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. 
1.3 Schedule of activities (SOA) 
 
Increased liver laboratory monitoring frequency in 
the first year after the start of the IMP. Footnote ‘l’ 
updated. 
Albumin’ added in footnote ‘k’. 
Footnote ‘s’ next to ‘Pharmacokinetics’, 
‘Pharmacogenetics’, and 
‘Pharmacodynamics/biomarkers’ removed.  
To reduce the risk of DILI. 
 
Correction of error. 
Correction of error. 
6.6.1 Rescue medicine 
Increased liver laboratory monitoring added for 
participants switching to open-label SAR442168 
treatment after 6-month CDP confirmation. 
To reduce the risk of DILI. 
 
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 14: 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, 
references, abbreviations as necessary. 
Update in accordance with 
Sponsor’s standards. 
10.14.8 
Amended protocol 08 (14 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. 
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Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
1.2 Schema 
Number of participants removed and replaced by 
the ratio in Figure 1 - Graphical study design. 
Clarification. 
9.2 Sample size determination 
Updated to clarify that with a reduced sample size, 
study power can be maintained by extending 
follow-up duration. 
Sample size is adjusted 
based on actual recruitment 
and event rates. The target 
number of events is 
unchanged. 
1.3 Schedule of activities (SOA) 
Removal of actigraphy wording from footnote ‘r’. 
Update. 
10.12 Appendix 12: Actigraphy 
substudy 
Updated to allow performing actigraphy in 
participants from enrollment into the substudy 
instead of screening. 
 
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 14: 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, 
references, abbreviations as necessary. 
Update in accordance with 
Sponsor’s standards. 
10.14.9 
Amended protocol 09 (12 July 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 incorporate country-specific guidelines for France.  
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Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Document history 
Countries impacted by amendment added for 
Amended protocol 02. 
Correction of error. 
10.8.3 Country-specific differences for 
France 
Section created. 
Health Authority request. 
10.14 Appendix 14: Protocol 
amendment history 
Updated. 
Update. 
11 References 
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. 
10.14.10 
Amended protocol 10 (28 September 2023)  
This amended protocol (amendment 10) 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 the language and requirements for the use 
of open-label SAR442168 in participants who have achieved 6-month confirmed disability 
progression, and to update the testing requirements in the “Increase in ALT algorithm” in 
accordance with the Council for International Organization of Medical Sciences (CIOMS) 
working group on DILI consensus report.   
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
Changed the subtitle of “Post-trial access to study 
medication” to “Long-term safety study”. 
Clarification. 
1.1 Synopsis, 1.3 Schedule of 
activities (SoA), and 6.8 Intervention 
after the end of the study 
Revised “will be offered” to “may be offered”. 
Clarification.  
1.1 Synopsis and 9.4.2 Primary 
endpoint 
Added “baseline EDSS score” and “baseline 
Gd-enhancing T1 lesions (0, ≥1)” as a covariate of 
the Cox proportional hazards model.  
Updated the censoring and imputation algorithm for 
analyzing the time to onset of 6-month CDP. 
Update. 
 
 
Update primary ITT analyses 
based on the feedback from 
the health authority. 
1.1 Synopsis and 9.4.3 Secondary 
endpoint(s) 
Added “baseline EDSS score” and “baseline number 
of T2 lesions” as covariates and update the offset 
variable based on the different duration of times 
between MRI scans.   
Update secondary endpoint 
analyses. 
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Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of activities (SoA) 
Updated footnote ‘e’ to include reference to the Study 
Manual. 
Updated footnote ‘l’ to include permitted time window 
for liver function tests. 
Clarification. 
2.2 Background 
2.3 Benefit/risk assessment 
Changed “T2 phase rims” to “paramagnetic rim 
lesions”. 
Update. 
2.3 Benefit/risk assessment  
Removed “all” for the identified risk for tolebrutinib 
and removed “to mitigate risk of hepatic injury”. 
Update to keep consistency 
with the Investigator’s 
Brochure. 
Updated “drug-induced liver injury (DILI)” to “DILI, 
including severe DILI (risk of liver transplantation or 
death), as an identified risk”. 
 
4.1 Overall Design 
Replaced “rescued” with “initiated”. Removed “as 
rescued”. 
Clarification. 
6.6.1 Open-label treatment 
 
Replaced the term ‘rescue treatment’ with ‘open-label 
treatment’. Replaced the term “rescue medication” 
with “relapse treatment”. 
Clarification. 
Updated requirements related to the exclusion criteria 
for participants switching to open-label treatment. 
Clarification. 
 
7.1.1 Definitive discontinuation 
Replaced “should be considered” with “is required”. 
Clarification. 
8.5 Pharmacokinetics  
Clarified PK sample collection/storage requirements 
and recommendations for liver and other safety 
events. Added cross-reference to Section 10.6 for 
more details. 
Clarification. 
8.11 Use of biological samples and 
data for future research 
Added details about the future use of participant’s 
biological samples and data. 
To keep consistency with ICF 
and Sponsor standards 
related to data privacy 
guidelines. 
9.4.2 Primary endpoint 
Updated the subgroup analyses on the primary 
endpoint, including geographic region, baseline 
EDSS score, prior disease modifying therapy use, 
and duration since relapsing-remitting multiple 
sclerosis (RRMS) symptom onset.   
Clarification on the subgroup 
factors. 
9.4.3 Secondary endpoint(s) 
Updated the handling of the impact of deviation from 
normality. 
Updated the estimate as annualized rate based on 
the different duration of times between MRI scans. 
Clarification.  
 
Update the secondary 
endpoint analyses. 
10.1.3 Informed consent process 
Clarification of informed consent process. 
To keep consistency with ICF 
and Sponsor standards 
related to data privacy 
guidelines. 
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Section # and Name 
Description of Change 
Brief Rationale 
10.1.4 Data protection 
Sponsor’s data privacy and protection responsibilities 
clarified. Data protection for professionals involved in 
the study clarified. 
To be compliant with data 
privacy guidelines. 
10.3.3 Recording and follow up of AE 
and/or SAE 
Updated requirement for reporting SAEs in case of 
life-threatening or death events. 
Clarification.  
10.6 Appendix 6: Liver and other 
safety: actions and follow-up 
assessments  
Increase in ALT algorithm related assessments 
updated. 
Update, for consistency with 
the CIOMS consensus 
report. 
10.8.3 Country-specific provisions for 
France and Japan 
Added Japan to this section. 
Health authority request. 
10.8.4 Country-specific provisions for 
Japan 
Section created. 
Health authority request. 
10.9 Appendix 9: Example of drugs 
with a potential to change 
SAR442168 metabolism or 
absorption 
Removed “(per the lists of the Drug Interaction 
Database Program of the University of Washington)” 
and “modafinil”. 
Correction of error as, 
according to the labels, 
modafinil is a weak CYP3A 
inducer, and therefore not 
prohibited; also, only keeping 
the recommendation for the 
sites to refer to the drug label 
for metabolic interactions. 
10.14 Appendix 14: Protocol 
amendment history 
Updated. 
Update. 
11 References 
Updated. 
Update. 
Throughout the document 
Reformatting of 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. 
Replaced the word ‘rescue treatment’ with ‘open-label 
treatment’. 
Clarification. 
10.14.11 
Amended protocol 11 (20 November 2023)  
This amended protocol (amendment 11) 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. 
 
 
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Page 145 
OVERALL RATIONALE FOR THE AMENDMENT 
The rationale for this protocol amendment is to clarify the liver function monitoring requirements, 
update the testing requirements in the “Increase in ALT algorithm”, and update the concomitant 
medications that are prohibited during the conduct of the study as per health authority request. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis, 9.4.3 Secondary 
endpoints 
Clarification of statistical descriptions. 
Clarification. 
1.3 Schedule of activities (SOA) 
Safety follow-up visit period changed from 4 to 
8 weeks to 4 weeks. 
Update. 
6.6.1 Open-label treatment 
Liver function test monitoring provided.  
Update. 
10.6 Appendix 6: Liver and other 
safety: actions and follow up 
assessments 
Liver function test monitoring guidance provided. 
Increase in ALT algorithm related assessments 
updated. Rechallenge restrictions updated. 
Update. 
10.8.5 Country specific provisions for 
US 
New section added to address liver function 
monitoring for participants restarting IMP after 
discontinuing due to partial clinical hold. 
Update. 
10.8.6 Country specific provisions for 
US, Israel, and sites under FDA 
partial clinical hold conditions 
New section added to reflect the prohibited use of 
CYP3A and CYP2C8 inhibitors and the restriction of 
grapefruit/grapefruit juice (a CYP3A4 inhibitor). 
Update. 
10.9 Appendix 9: Example of drugs 
with a potential to change 
SAR442168 metabolism or 
absorption 
Update to provide guidance to US, Israel, and any 
other sites that may be under FDA partial clinical 
hold. 
Update to provide guidance. 
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 
REFERENCES  
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36. Drake AS, Weinstock-Guttman B, Morrow SA, Hojnacki D, Munschauer FE, Benedict RH. 
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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 
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: Sanofi eSAP Version 2.0, dated 20-OCT-2021 
 Page 1 
 
 
STATISTICAL ANALYSIS PLAN  
Protocol title: 
A Phase 3, randomized, double-blind, efficacy and 
safety study comparing SAR442168 to placebo in 
participants with nonrelapsing secondary progressive 
multiple sclerosis (HERCULES) 
Protocol number: 
EFC16645 
Compound number 
(INN/Trademark): 
SAR442168 
tolebrutinib/not applicable 
Study phase: 
Phase 3 
Short Title: 
NRSPMS study of BTK inhibitor tolebrutinib (SAR442168) 
HERCULES 
Statistician: 
Statistical project leader: 
Date of issue: 
30-Apr-2024 
Regulatory agency identifier number(s): 
IND: 
140884 
EudraCT: 
2020-000647-30 
NCT: 
NCT04411641 
WHO: 
U1111-1246-7768 
EUDAMED: 
Not applicable 
Other: 
Not applicable 
 
Date: 
30-Apr-2024 
Total number of pages: 45 
 
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Statistical Analysis Plan  
30-Apr-2024 
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Version number: 3 
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Page 2 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF TABLES ........................................................................................................................................... 4 
VERSION HISTORY ....................................................................................................................................... 5 
1 
INTRODUCTION .............................................................................................................................. 7 
1.1 
STUDY DESIGN .............................................................................................................................. 7 
1.2 
OBJECTIVES AND ENDPOINTS .................................................................................................... 7 
1.2.1 
Estimands ...................................................................................................................................... 10 
2 
ANALYSIS POPULATIONS .......................................................................................................... 12 
3 
STATISTICAL ANALYSES ........................................................................................................... 13 
3.1 
GENERAL CONSIDERATIONS .................................................................................................... 13 
3.2 
PRIMARY ENDPOINT(S) ANALYSIS ............................................................................................ 14 
3.2.1 
Definition of endpoint(s) ................................................................................................................. 14 
3.2.2 
Main analytical approach ............................................................................................................... 15 
3.2.3 
Multiple imputation for missingness due to end of study ............................................................... 16 
3.2.4 
Sensitivity analysis ......................................................................................................................... 17 
3.2.5 
Subgroup analyses ........................................................................................................................ 18 
3.3 
SECONDARY ENDPOINT(S) ANALYSIS ..................................................................................... 18 
3.3.1 
Secondary endpoint(s) ................................................................................................................... 19 
3.3.1.1 
Definition of endpoint(s) ................................................................................................................. 19 
3.3.1.2 
Main analytical approach ............................................................................................................... 21 
3.4 
TERTIARY/EXPLORATORY ENDPOINT(S) ANALYSIS .............................................................. 23 
3.4.1 
Definition of endpoint(s) ................................................................................................................. 23 
3.4.2 
Main analytical approach ............................................................................................................... 24 
3.5 
MULTIPLICITY ISSUES ................................................................................................................ 27 
3.6 
SAFETY ANALYSES ..................................................................................................................... 27 
3.6.1 
Extent of exposure ......................................................................................................................... 27 
3.6.2 
Adverse events .............................................................................................................................. 28 
3.6.3 
Additional safety assessments ....................................................................................................... 31 
3.6.3.1 
Laboratory variables, vital signs and electrocardiograms (ECGs) ................................................. 31 
3.6.3.2 
Analysis of suicidality assessment ................................................................................................. 33 
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3.7 
OTHER ANALYSES....................................................................................................................... 33 
3.7.1 
Other variables and/or parameters ................................................................................................ 33 
3.7.1.1 
PK analyses ................................................................................................................................... 33 
3.7.2 
Pharmacodynamic (PD) analyses .................................................................................................. 33 
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 DISPOSITIONS .............................................................................. 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 ANALYSES SUPPORTING THE INTEGRATED SUMMARY OF SAFETY ............ 43 
6 
REFERENCES ............................................................................................................................... 45 
 
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Statistical Analysis Plan  
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Page 4 
LIST OF TABLES  
Table 1 - Objectives and endpoints ................................................................................................................. 7 
Table 2 - Summary of primary estimand for main endpoints ........................................................................ 11 
Table 3 - Populations for analyses ................................................................................................................ 12 
Table 4 - Sorting of AE tables ....................................................................................................................... 29 
Table 5 - Analyses of adverse events ........................................................................................................... 29 
Table 6 - Selections for AESIs ...................................................................................................................... 30 
Table 7 - Analyses window definition of efficacy variables ........................................................................... 40 
Table 8 - Analysis window definition of safety variables ............................................................................... 41 
Table 9 - Analysis window definition of PD variables .................................................................................... 42 
 
 
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Statistical Analysis Plan  
30-Apr-2024 
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Page 5 
VERSION HISTORY  
This amended statistical analysis plan (SAP) for study EFC16645 is based on the amended 
protocol 11 dated 20 November 2023. The first participant was randomized on 23 October 2020. 
The initial SAP V1 was approved before the interim analysis for futility was conducted. Amended 
SAP V2 reflected statistical section changes incorporated in amended protocol 10 versus amended 
protocol 8 and any major changes since amended protocol 10. This amended SAP specifies rule 
for imputation of missing baseline Gd-enhancing T1-hypertintense lesion presence or absence 
status and additional analyses to support integrated safety summary. 
Major changes in statistical analysis plan 
SAP Version 
Approval Date 
Changes 
Rationale 
1 
10-Feb-2023 
Original version changes from protocol 
amendment 8 
 
 
 
More covariates, ie, baseline EDSS score and Gd-
enhancing T1 lesions at baseline are specified in 
the Cox model for the primary endpoint and other 
related time-to-event endpoints 
Based on clinical input 
Censoring approach is different: imputation of 
6-month confirmation event status is performed 
only for participants who have an initial onset of 
disability progression but complete the study at 
the common study end date with 3-month 
confirmation and without 6-month confirmation. 
Based on FDA feedback  
For subgroup analysis of prior therapy use, the 
categories are 0, 1, ≥2 
Clarification 
Actigraphic analysis baseline is defined at time of 
enrollment in substudy 
Clarification 
2 
30-Oct-2023 
Changes already incorporated in Amended 
protocol 10: 
Update the imputation approach for primary 
analysis: imputation of 6-month confirmation event 
status is performed only for participants who meet 
3-month CDP criteria and continue to meet the 
criteria for EDSS disability progression through 
the final study assessment, but do not reach 
6-month confirmation. 
Based on FDA feedback 
 
 
Changes from Amended protocol 10: 
Change offset variable for analysis of 
new/enlarging T2 lesions to time from screening 
MRI to last available MRI scan rather than 
observation duration. 
Clarification 
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Statistical Analysis Plan  
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Page 6 
SAP Version 
Approval Date 
Changes 
Rationale 
3 
30-Apr-2024 
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.  
 
 
Specify additional analyses in Section 5.5 to 
support the integrated summary of safety  
For completeness 
Additional minor changes have been made to improve clarity and consistency in both versions 2 and 3 
 
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1 
INTRODUCTION  
1.1 
STUDY DESIGN  
This is a Phase 3, randomized, double-blind (DB), 2-arm, placebo-controlled, parallel group, 
multicenter, event-driven (6-month confirmed disability progression [CDP]) trial with a variable 
treatment duration (minimum of approximately 18 to 24 months) in participants with nonrelapsing 
secondary progressive multiple sclerosis (NRSPMS). 
Approximately 1700 participants will be screened to achieve up to 1290 participants randomly 
assigned to study intervention.  
After a screening period of up to 28 days, participants will be randomly assigned at a 2:1 ratio to 
receive 60 mg oral tolebrutinib or matching placebo daily. Randomization will be stratified by age 
at screening (>40 versus ≤40 years) 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, 24 months as 96 weeks, and 48 months as 192 weeks. 
Participants who complete the study intervention period (DB or open-label [OL] tolebrutinib if 
meeting 6-month CDP) may be offered the option to participate in a long-term safety (LTS) study. 
For participants who complete the study intervention period (DB or OL, if meeting 6-month CDP) 
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 study intervention. 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 study intervention or not. 
Study primary analysis will be conducted after study completion, when approximately 288 events 
of 6-month CDP have been observed, and final database lock.  
1.2 
OBJECTIVES AND ENDPOINTS  
Table 1 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
• 
To determine the efficacy of tolebrutinib compared 
to placebo in delaying disability progression in 
NRSPMS 
• 
Time to onset of 6-month CDP defined as follows: 
- 
Increase of ≥1.0 point from the baseline 
EDSS score when the baseline score is ≤5.0, 
OR 
- 
Increase of ≥0.5 point when the baseline 
EDSS score is >5.0 
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Objectives 
Endpoints 
Secondary 
• 
To evaluate efficacy of tolebrutinib compared to 
placebo on clinical endpoints, MRI lesions, cognitive 
performance, physical function, and quality of life 
• 
Time to onset of sustained 20% increase in the 
9-HPT for at least 3 months 
• 
Time to onset of sustained 20% increase in the 
T25-FW for at least 3 months 
• 
Time to onset of 3-month CDP as assessed by the 
EDSS score 
• 
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 
• 
Time to onset of CDI defined as a ≥1.0 point 
decrease on the EDSS score from baseline 
confirmed over at least 6 months 
• 
Percent change in brain volume loss (BVL) as 
detected by MRI scans at the EOS compared to 
Month 6 
• 
Change in cognitive function at the EOS compared 
to baseline as assessed by SDMT 
• 
Change in cognitive function at the EOS compared 
to baseline as assessed by CVLT-II, where 
available 
• 
Change in MSQoL-54 questionnaire score from 
baseline through the EOS 
• 
To evaluate safety and tolerability of tolebrutinib 
• 
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 of 
tolebrutinib and relevant metabolite(s) in NRSPMS 
and its relationship to efficacy and safety 
• 
Plasma concentration of tolebrutinib and relevant 
metabolite(s) (population PK assessment) at 
Months 6, 9, and 12 
• 
To evaluate pharmacodynamics (PD) of tolebrutinib 
• 
Change in plasma NfL levels at the EOS compared 
to baseline 
• 
Change in lymphocyte phenotype subsets in whole 
blood at the EOS compared to baseline in a subset 
of participants 
• 
Change in serum immunoglobulin level at baseline 
compared to the EOS 
• 
Change in serum Chi3L1 levels at baseline 
compared to the EOS 
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Objectives 
Endpoints 
Tertiary/exploratory 
• 
To evaluate efficacy of tolebrutinib on disease 
progression and activity in NRSPMS, assessed by 
other clinical and imaging measures and by self-
reported assessment 
• 
Time to onset of sustained 20% increase in the 
9-HPT for at least 6 months 
• 
Time to onset of sustained 20% increase in the 
T25-FW for at least 6 months 
• 
Time to onset of a 4-point decrease in the SDMT, 
confirmed over at least 3 and 6 months  
• 
The proportion of participants with CDI confirmed 
over at least 6 months 
• 
The proportion of participants with CDI confirmed 
over at least 6 months and maintained until the 
EOS 
• 
Change from baseline to Months 12, 18, and 24 and 
to the EOS in the EDSS score, T25-FW test, 
9-HPT, SDMT, and CVLT-II 
• 
Change from baseline to Months 12, 18, and 24 and 
to the EOS in modified MSFC-3, assessed as the 
composite of the T25-FW test, 9-HPT, and SDMT 
• 
Proportion of participants with NEDA-3 at 
Months 18, 24, 30, 36, and the EOS 
• 
The annualized adjudicated relapse rate (ARR) 
• 
Actigraphic analysis of activity counts and indices of 
change from baseline to the EOS summarized over 
time (in a subset of participants) 
• 
Change from baseline of total volume of 
T2-hyperintense lesions as detected by brain MRI 
at Months 18, 24, and the EOS 
• 
Total number of new Gd-enhancing T1hyperintense 
lesions as detected by MRI, defined as the sum of 
the individual number of new Gd-enhancing 
T1hyperintense lesions at all scheduled visits 
starting after baseline up to and including the EOS 
visit  
• 
Change from baseline by visit in the volume of 
T1-hypointense lesions and cumulative number of 
new T1 hypointense lesions 
• 
MTR recovery at EOS in new MTR lesions detected 
at Months 6 and 12 
• 
Change in number of phase rim lesions in SWI MRI 
from baseline through the EOS (subset of centers 
with capacity of 3T MRI) 
• 
Number and volume of slowly evolving lesions 
(SELs) 
• 
Normalized T1 (nT1) intensity evolution in SELs 
• 
To evaluate the treatment effect of tolebrutinib via 
changes in participants’ health-related quality of life 
(HRQoL), and working capacity 
• 
Change in EQ-5D-5L from baseline by visit over 
time 
 
 
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1.2.1 Estimands  
The primary estimand for the primary endpoint is summarized in Table 2. More details are 
provided in Section 3. 
In all analyses, the comparison of interest will be the comparison of tolebrutinib versus placebo. 
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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 evaluate the efficacy of tolebrutinib compared to placebo in delaying disability progression in NRSPMS 
Primary endpoint 
(treatment policy 
estimand) 
Time from randomization 
to onset of 6-month CDP 
ITT 
Regardless of completion of the treatment period 
(treatment policy) 
Treatment effect on time to onset of 6-month CDP, as 
measured by the hazard ratio for tolebrutinib 
compared to placebo, analyzed by a Cox proportional 
hazards model with terms for treatment group, age at 
screening (>40, ≤40 years), geographical region 
(US, non-US), baseline EDSS score and baseline 
Gd-enhancing T1 lesions (present, absent). The 
comparison of treatment groups will also be assessed 
using the log-rank test stratified by age at screening 
(>40, ≤40 years) and geographical region (US, non-
US).  
Incomplete data will be imputed only for participants 
who complete the study, meet 3-month CDP criteria, 
and continue to meet criteria for EDSS disability 
progression through the final study assessment, but 
do not reach 6-month confirmation. For other 
participants without a confirmed 6-month CDP 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. 
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2 
ANALYSIS POPULATIONS  
The following populations for analyses are defined:  
Table 3 - Populations for analyses  
Population 
Description 
Enrolled 
All participants who signed 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 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. 
Pharmacokinetics 
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); IRT: interactive response technology 
Participants exposed to study intervention 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 tolebrutinib 60 mg. 
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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. In most cases the assessment should 
be prior to the randomization call, but it is possible that some assessments are performed between 
the actual randomization call and the first intake of investigational medicinal product (IMP). For 
the Expanded Disability Status Scale (EDSS) score, 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 C-SSRS 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 (CIs) will be provided for treatment comparisons.  
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 with seed 
= 16645 based on the proportion of presence/absence at baseline in the overall population. 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 specified otherwise. 
Unless otherwise specified, analyses will be performed by treatment group and overall for 
baseline and demographics characteristics. 
Observation period  
The observation periods for safety will be divided into 4 epochs:  
• The screening (pre-treatment) period is defined as the period from the signed informed 
consent date up to first administration of the study intervention.  
• The treatment period (ie, treatment-emergent (TE) period) is defined as the period from 
the first administration of study intervention to  
- 
The earlier of last administration of the study intervention + 10 days or first IMP in the 
LTS study for participants not receiving tolebrutinib OL treatment, 
- 
The first administration of tolebrutinib OL treatment for participants switching to OL 
therapy  
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• The OL period (ie, OL TE period), applicable only for participants switching to 
tolebrutinib OL treatment, is defined as the time from first administration of tolebrutinib 
OL treatment to the earlier of last administration of OL treatment + 10 days or first IMP in 
the LTS study 
• The post-treatment period, if applicable, is defined as the period from the end of 
treatment period (or end of OL period, if applicable) to the participant’s final post-
treatment study contact date. 
Summaries of OL period data will be presented by original randomized treatment group and 
overall. 
The on-study period is defined as the time from randomization until the end of the study defined 
as the last scheduled visit for those who completed the study and the end-of-study date collected 
on electronic case report form (e-CRF) 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 
Participants in Ukraine, Russia and Belarus who are lost to follow-up due to national emergency 
will be considered as prematurely discontinuing the study at the date of last contact (or start of 
war). For the primary endpoint of time to onset of 6M-CDP, unless already having a confirmed 
event at the time of last follow-up, participants will be censored at the date of the last EDSS 
assessment for the primary analysis. Other time-to-event endpoints will be handled similarly. For 
continuous endpoints as well as safety data, all observed data up to the last contact date will be 
included for assessment. For count data, all observed data up to the last contact date will be 
included in the analysis. No imputation will be performed for unobserved data/events that may 
happen after being lost to follow-up. 
3.2 
PRIMARY ENDPOINT(S) ANALYSIS  
3.2.1 Definition of endpoint(s)  
Time to onset of 6-month CDP is defined as the time from randomization to the onset of 
a sustained increase from baseline in EDSS score (of ≥1.0 point from the baseline EDSS score 
when the baseline score is ≤5.0, of ≥0.5 points when the baseline EDSS score is >5.0) confirmed 
after a minimum 6-month interval. 
EDSS scores used for potential onset of disability progression may be observed by the Examining 
Investigator during routine quarterly visits or unscheduled visits. However, confirmation of CDP 
(after at least 6 months) must be at a routine quarterly visit (with the potential exception in case of 
contingency measures for a regional or national emergency). Results of all EDSS assessments 
obtained during routine or unscheduled visits throughout the minimum 6-month period (for the 
primary endpoint) will serve as the basis for conclusion. Once confirmation is achieved, the 
potential onset becomes the actual onset for time to onset of CDP. 
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In case of occurrence of adjudicated relapse, only EDSS assessments measured more than 90 days 
after relapse onset will be used to determine onset of disability progression. In addition, for the 
purpose of confirmation, only EDSS scores measured more than 90 days after the onset of 
an adjudicated relapse will be used. In case of such multiple sclerosis (MS) relapse, the next 
quarterly EDSS assessment >90 days after relapse onset will be used for CDP confirmation. The 
minimum increase in score required for progression must also be maintained for any non-
confirmatory (ie, intervening) EDSS assessment(s) between the initial (onset) and confirmation 
EDSS scores. 
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).  
3.2.2 Main analytical approach  
The primary analysis of the primary endpoint, time to onset of 6-month CDP, will be performed 
on the ITT population. The null hypothesis is no treatment difference between tolebrutinib and 
placebo, and the alternative hypothesis is that there is a between-treatment difference. The study 
will be declared positive if the null hypothesis for the primary endpoint of 6-month CDP for 
tolebrutinib compared to placebo is rejected at the 2-sided 0.05 significance level. 
In this primary ITT analysis: 
• For participants who complete the study without an initial onset of disability progression, 
the participant will be censored at the date of last EDSS assessment. 
• For participants who have an initial onset of disability progression but complete the study 
without 3-month confirmation, the participant will be censored at the date of last EDSS 
assessment. 
• For participants who prematurely discontinue the study before 6-month confirmation of 
an onset of disability progression, regardless of having an initial onset, the participant will 
be censored at the date of last EDSS assessment.  
• For participants who complete the study, meet 3-month CDP criteria, and continue to meet 
criteria for EDSS disability progression through the final study assessment, but do not 
reach 6-month confirmation, the 6-month CDP event status of the participant will be 
determined by an imputation approach. The details of this imputation approach are 
provided in Section 3.2.3. 
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Death 
If a participant dies due to MS, it will be considered a confirmed disability progression regardless 
of the baseline EDSS or the change in EDSS. The time to event will be calculated as  
• (date of EDSS assessment at a tentative onset of disability progression – date of 
randomization + 1), or  
• (date of death – date of randomization + 1) if a tentative onset date does not exist.  
If a participant dies for other reasons before a 6-month CDP, the participant’s event time will be 
censored at the date of last EDSS assessment. 
Analytical Approach 
The time to onset of 6-month CDP will be modeled by a Cox proportional hazards model with 
robust variance estimation (1). The covariates included in the model are treatment group, age at 
screening (>40, ≤40), region (US, non-US), baseline EDSS score and baseline gadolinium 
(Gd)-enhancing T1 lesions (present, absent). The hazard ratio, its 95% confidence interval and the 
p-value for comparing tolebrutinib to placebo will be estimated from this model. Comparison 
between tolebrutinib and placebo will also be assessed by a log-rank test stratified by age at 
screening (>40, ≤40 years) and region (US, non-US). Kaplan-Meier (KM) plots of the cumulative 
incidence rate will be provided by treatment group to depict the course of onset of 6-month CDP 
over time. The proportion of participants with events at given time points (eg, Months 6, 12, 18, 
24, 30, …) and median time to 6-month CDP will be calculated using the KM estimates.  
3.2.3 Multiple imputation for missingness due to end of study  
For participants who meet 3-month CDP criteria, and continue to meet the criteria for EDSS 
disability progression through the final study assessment, but do not reach 6-month confirmation, 
the 6-month CDP 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+ β4𝑗𝑥4𝑖𝑗 
where 𝑌𝑖𝑗 is the indicator for event status for participant 𝑖 from group 𝑗; 1 = 6-month CDP, 0 = no 
6-month CDP, 𝑝𝑖𝑗 is the probability that participant 𝑖 from group 𝑗 with a 3-month CDP has 
a 6-month CDP event, 𝑥1𝑖𝑗 is the age at screening (>40, ≤40 years), 𝑥2𝑖𝑗 is the geographic region 
(US, non-US), 𝑥3𝑖𝑗 is the baseline EDSS score, 𝑥4𝑖𝑗 is baseline Gd-enhancing T1 lesions (present, 
absent), and β𝑘𝑗 are the model parameters (𝑘= 0,1,2,3,4;  𝑗= 1,2). The logistic model 
parameters β𝑘𝑗 will be estimated from participants with a 3-month CDP and who do not have 
missing value due to end of study. 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 CDP criteria and continue to meet criteria for EDSS disability 
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progression through the final study assessment, and missingness due to end of study. Finally, the 
missing value for participants with an initial onset of disability progression and missingness for 
6-month CDP due to end of study 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 seed=16645 nimpute=1000; 
  by  Treatment_group; 
  var age_strata geographic_region EDSS_base Gd_T1; 
  fcs logistic (Confirmation = age_strata geographic_region EDSS_base Gd_T1/ 
link=glogit); 
run; 
 
PROC MIANALYZE data= DATAOUT; 
    modeleffects Estimate; 
    stderr StdErr; 
run; 
DATAIN only includes participants who meet the imputation criteria mentioned above. Details of 
multiple imputation can be found in SAS support document (3). 
3.2.4 Sensitivity analysis  
The following sensitivity analyses, without any imputation, will be performed to evaluate the 
impact of missing data to the primary analysis results: 
1. Participants with a potential onset of disability progression but without 6-month 
confirmation due to missing data, regardless of reason, will be considered to have 
confirmed progression with the time to onset being the time to the initial EDSS increase. 
Of note, a potential onset is invalidated if there is any non-confirmatory EDSS in the 
confirmation period that does not meet the minimum change required for progression.  
2. Participants with missing or incomplete 6-month CDP will be treated as censored at the 
last EDSS assessment date.  
For the above analyses, the same Cox proportional hazards model as described in Section 3.2.2, 
without imputation, will be used to estimate the hazard ratio, 95% CI, and p-value on tolebrutinib 
compared to placebo. 
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3.2.5 Subgroup analyses  
To assess the homogeneity of the treatment effect across various subgroups, analyses will be 
performed on the primary endpoint across the following (no subgroup analysis will be performed 
if fewer than 5 participants in one category): 
• Geographic region (US, non-US; Eastern Europe, Western Europe, North America, rest of 
the world [ROW]) 
• Age at screening (>40, ≤40 years) 
• Sex (Male or Female) 
• Race (White, Black or African American, Asian, Other). 
• Baseline Gd-enhancing T1 lesions (present, absent) 
• Baseline EDSS score (≤4.5, >4.5; ≤5.5, >5.5) 
• Prior disease modifying therapy use (0, 1, ≥2) 
• Duration since relapsing-remitting multiple sclerosis (RRMS) symptom onset (≤5, >5 to 
≤10, >10 years) 
• Adjudicated relapse during the study (yes, no)  
Since adjudicated relapse during the study is a post randomization event, this subgroup analysis is 
purely exploratory. 
The treatment effect (tolebrutinib compared to placebo) for the primary endpoint will be provided, 
as well as the corresponding 95% CI, for each subgroup separately, using the same methods as 
described in Section 3.2.2. Forest plots of hazard ratios and the corresponding 95% CIs will be 
provided.  
Treatment by subgroup interaction and its p-value will be derived from a Cox proportional 
hazards model with terms for treatment group, age at screening (>40, ≤40), region (US, non-US), 
baseline EDSS score, baseline Gd-enhancing T1 lesions (present, absent), subgroup (if different 
than the aforementioned covariates) and treatment by subgroup interaction as covariates. 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. 
3.3 
SECONDARY ENDPOINT(S) ANALYSIS  
The secondary endpoints detailed in this section are for assessing efficacy of tolebrutinib 
compared to placebo. Other secondary endpoints analyses are defined in Section 3.6.2 (AE, SAE), 
Section 3.6.3.1 (laboratory abnormalities), Section 3.7.1.1 (PK) and Section 3.7.2 (PD).  
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3.3.1 Secondary endpoint(s)  
3.3.1.1 Definition of endpoint(s)  
The 9-hole peg test (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. An increase of >20% from the baseline in the 9-HPT is considered 
meaningful worsening (4). 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
2 (
1
𝑡𝑟𝑖𝑎𝑙𝑎𝑟𝑚, 𝑙𝑒𝑓𝑡+
1
𝑡𝑟𝑖𝑎𝑙𝑎𝑟𝑚, 𝑟𝑖𝑔ℎ𝑡) −𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑀𝑒𝑎𝑛
𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑆𝐷 
 
The times from 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, for example,  
1
𝑡𝑟𝑖𝑎𝑙𝑎𝑟𝑚, 𝑙𝑒𝑓𝑡=
1
𝑎𝑣𝑒𝑟𝑎𝑔𝑒 𝑜𝑓 𝑡ℎ𝑒 𝑡𝑤𝑜 𝑡𝑖𝑚𝑒𝑠 𝑜𝑓 𝑡ℎ𝑒 𝑙𝑒𝑓𝑡 𝑎𝑟𝑚 𝑡𝑟𝑎𝑖𝑙𝑠 
In case one of the two times for the same arm is missing, the available time will be used. In case 
9-HPT was assessed for only one hand for reason other than “physical limitation”, then the 
Z-score will be set to missing. For a participant who could not complete the 9-HPT due to 
a “physical limitation”, the maximum time (300 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 Timed 25-Foot Walk (T25-FW) test 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 trials (or single score if only 1 completed). An increase of >20% from baseline in the 
T25-FW test is considered meaningful worsening (4). The baseline mean and SD of 
all participants are used to create Z-scores: 
𝑍= (−1) × 𝐴𝑣𝑒𝑟𝑎𝑔𝑒 𝑠𝑐𝑜𝑟𝑒−𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑀𝑒𝑎𝑛
𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑆𝐷
 
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. If results from both trials are missing due to reasons other than “physical limitation”, the 
Z-score will be set to missing. In case of values below (above) the lower (upper) bound, the value 
will be set to the respective bound.  
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Time to onset of 3-month CDP is defined as the time from randomization to the onset of 
a sustained increase from baseline in EDSS score (of ≥1.0 point from the baseline EDSS score 
when the baseline score is ≤5.0, of ≥0.5 points when the baseline EDSS score is >5.0) confirmed 
after a minimum 3-month interval. The confirmation of 3-month CDP follows the same criteria as 
that of 6-month CDP. 
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).  
Confirmed disability improvement is defined as a ≥1 point decrease from baseline in the EDSS 
score lasting at least 6 months. 
Symbol Digit Modalities Test (SDMT) is used to assess processing speed, 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. A decrease of 4 points 
from baseline on the SDMT is considered meaningful worsening (5). 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 
𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑆𝐷
 
Z-scores will be used for analysis. 
The 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 (6). Total 
Correct Recall Trials 1–5 is scaled to a normalized T-score metric, which has a mean of 50 and 
SD of 10, with higher values indicating better performance. Total intrusions and total repetitions 
are normed on a linear Z-score metric, with a mean of 0, SD 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. 
Multiple Sclerosis Quality of Life-54 (MSQoL-54) is a multidimensional health-related quality of 
life measure that combines both generic and MS-specific items into a single instrument (7). The 
recall time, when relevant, is for the previous 4 weeks. It is composed of 54 items. There are 
2 derived summary scores, physical health composite and mental health composite, 12 subscale 
scores: physical function, role limitations-physical, role limitations-emotional, pain, emotional 
wellbeing, 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. Each subscale score can then be calculated by summing the non-missing 
item responses and dividing by the number of non-missing item responses. Physical health 
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composite score is calculated as a weighted sum of physical function (weight = 0.17), health 
perceptions (weight = 0.17), energy (weight = 0.12), role limitations-physical (weight = 0.12), 
pain (weight = 0.11), sexual function (weight = 0.08), social function (weight = 0.12) and health 
distress (weight = 0.11). Mental health composite score is calculated as a weighted sum of health 
distress (weight = 0.14), overall quality of life (weight = 0.18), emotional well-being  
(weight = 0.29), role limitations-emotional (weight = 0.24) and cognitive function  
(weight = 0.15). All scores are transformed linearly to a common 0 (worst) to100 (best) score 
range. 
3.3.1.2 Main analytical approach  
3.3.1.2.1 Time to event endpoints  
Time to onset of 3-month CDP will be analyzed using the same statistical methods as for the 
primary analysis of time to onset of 6-month CDP without imputation.  
Time to onset of sustained 20% increase in the 9-HPT (T25-FW) for at least 3 months and time to 
onset of 6-month confirmed disability improvement (CDI) will be analyzed using similar 
statistical methods as for the primary analysis of time to onset of 6-month CDP, but without 
imputation. Participants with onset without confirmation will be treated as censored at the 
last endpoint assessment. 
3.3.1.2.2 Number of new and/or enlarging T2 lesions  
Number of new and/or enlarging T2 hyperintense lesions over the study period will be analyzed 
using a negative binomial regression model with robust variance estimation in the ITT population. 
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 
lesion count across all magnetic resonance imaging (MRI) scans at all scheduled 
post-randomization visits during the study period as the response variable, with treatment group, 
age at screening (>40, ≤40 years), geographic region (US, non-US), baseline EDSS score, and 
baseline number of T2 lesions as covariates. Log transformed observation duration from screening 
MRI to last available MRI scan will be the offset variable. The estimated mean number of lesions 
per year for each treatment group and the corresponding two-sided 95% CI will be estimated 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 on tolebrutinib compared to placebo, its 95% CI, and p-value will be provided. No 
imputation for missing data due to early study withdrawal will be performed.  
3.3.1.2.3 Continuous endpoints  
Percent change in brain volume 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 
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each stratum or categorical factor. The model will include percent change from Month 6 values at 
scheduled visits up to and including the EOS visit as the response variable, and treatment group, 
age at screening (>40, ≤40 years), 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 (Toeplitz with non-equal variances) 
• Heterogeneous AR(1) (first-order autoregressive with non-equal variances) 
• Heterogeneous CS (compound symmetry with non-equal variances) 
• Toeplitz (equal variances and a separate correlation for each level of separation between 
the time points) 
• AR(1) (first-order autoregressive, equal variances and exponentially decreasing 
correlations) 
• CS (compound symmetry, equal variances and equal pairwise correlations across fixed 
time points).  
The first (co)variance structure yielding convergence will be used as the primary analysis. 
Comparisons between treatment arms will be made using least squares means (LSM) contrasts at 
the EOS with denominator degrees of freedom estimated using the Kenward-Roger 
approximation (8). 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) (9). 
Change from baseline in SDMT number of correct substitutions, CVLT-II total correct and 
MSQoL-54 physical and mental health composite scores at the EOS will be analyzed using 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 EOS visit as response variables, 
and treatment group, age at screening (>40, ≤40 years), 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 LSM, the corresponding 95% CI, and p-value will be estimated 
from the MMRM model for the comparison of tolebrutinib to placebo using weights for each 
stratum equal to the overall proportion of participants in each stratum (ie, “Population weight”). 
Plots of LSM [±standard error (SE)] over time will be provided. Participants who discontinue 
study intervention before the 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 will be included 
in the primary analysis. For participants who withdraw from the study before the EOS, values will 
be missing after study discontinuation and no imputation will be performed.  
SDMT, CVLT-II and MSQoL-54 data are assumed a priori to be normally distributed. Given the 
large sample size, the impact of violation of normality should not be great. In order to assess the 
impact of deviation from the normality assumption, a sensitivity analysis using rank analysis of 
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covariance (ANCOVA), with the same covariates as for the MMRM analysis except VISIT and 
related interaction terms, will be performed to test the significance of the treatment effect. 
Given that participants who reach the primary endpoint of 6M-CDP are eligible to switch to OL 
tolebrutinib, including data after the switch could impact the analysis of secondary endpoints: 
number of new/enlarging T2 lesions per year, time to onset of sustained 20% increase in the 
9-HPT (T25-FW) for at least 3 months, and percent change in brain volume at EOS compared to 
Month 6. Sensitivity analyses excluding data after initiation of OL therapy will be performed for 
these endpoints. 
No other sensitivity, supplementary, or subgroup analyses will be performed for the secondary 
endpoints. 
3.4 
TERTIARY/EXPLORATORY ENDPOINT(S) ANALYSIS  
3.4.1 Definition of endpoint(s)  
Multiple Sclerosis Functional Composite (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. If any one of the T25-FW, 
9-HPT, and SDMT Z-scores is missing, then MSFC-3 score is set to missing. 
No evidence of disease activity-3 (NEDA-3) is defined as absence of all of the following: 
• 6-month CDP 
• Active MRI lesions (both new or enlarged T2-hyperintense lesions and Gd-enhancing 
T1-hyperintense lesions) 
• Adjudicated MS relapse 
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 (10). 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. 
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: 
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1. be attributable to MS, 
2. last for ≥24 hours, with or without recovery, 
3. be present at normal body temperature (ie, no infection, excessive exercise, or excessively 
high ambient temperature), and 
4. be preceded by ≥30 days of clinical stability (including no previous MS relapse). 
Confirmation of MS relapse will be based on EDSS score (provided by the Examining 
Investigator), 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, 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). 
3.4.2 Main analytical approach  
Summary statistics including mean, SD, 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 
• 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 
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• CVLT-II standardized scores for total number of repetitions and change from baseline 
• MSFC-3 score 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. 
Time-to-event endpoints  
Time-to-event endpoints include: 
• Time to onset of sustained 20% increase in the 9-HPT for at least 6 months,  
• Time to onset of sustained 20% increase in the T25-FW for at least 6 months 
• Time to onset of a 4-point decrease in the SDMT confirmed over at least 3 months 
• Time to onset of a 4-point decrease in the SDMT confirmed over at least 6 months 
Participants with no event will be censored at the date of the last assessment for the endpoint. No 
imputation will be performed for missing data. These endpoints will be analyzed using similar 
statistical methods as for the primary analysis of time to onset of 6-month CDP.  
Binary endpoints 
Binary endpoints include: 
• Proportion of participants with CDI confirmed over at least 6 months  
• Proportion of participants with CDI confirmed over at least 6 months and maintained until 
the EOS 
• Proportion of participants with NEDA-3 at Months 18, 24, 30, 36, and EOS 
A Cochran–Mantel–Haenszel (CMH) test stratifying by age at screening (>40, ≤40 years) and 
region (US, non-US) will be used and the relative risk ratio on tolebrutinib compared to placebo 
with 95% CI will be estimated.  
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Count endpoints 
Count endpoints include:  
• Annualized adjudicated relapse rate 
• Total number of new Gd-enhancing T1-hyperintense lesions 
A negative binomial model will be used to analyze total count occurring during the observation 
period, adjusting for treatment group, age at screening (>40, ≤40 years), region (US, non-US), 
baseline EDSS score and baseline Gd-enhancing T1 lesion (present, absent). Log transformed 
post-randomization observation duration or number of scans will be the offset variable. The 
estimated mean rates/numbers for each treatment group with the corresponding 95% CI, and the 
relative reduction on tolebrutinib compared to placebo with the 95% CI will be estimated. 
Continuous endpoints 
Continuous endpoints include: 
• Change from baseline in MSFC-3 Z-score at Months 12, 18, 24, and EOS 
• Change from baseline in total volume of T2-hyperintense lesions at Months 18, 24, and 
EOS 
• Change from baseline in EQ-5D-5L descriptive system index score and VAS score by visit 
An MMRM method will be used for these endpoints, including covariates of treatment group, age 
at screening (>40, ≤40 years), region (US, non-US), visit, treatment-by-visit interaction, the 
baseline score, and baseline-by-visit interaction. Least squares means ± SE for each treatment 
group, as well as LSM difference with the 95% CI will be estimated.  
Since volume data are often non-normally distributed, analysis of T2 lesion volume will be 
performed on log-transformed volume data. MSFC-3 and EQ-5D-5L data are assumed a priori to 
be normally distributed. Given the large sample size, the impact of violation of normality should 
not be great. 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 to test the significance of the 
treatment effect. 
Other endpoints 
Data for magnetization transfer ratio (MTR) recovery at EOS in new MTR lesions detected at 
Months 6 and 12 and normalized T1 intensity in SELs will be listed. 
Actigraphy sub-study data will be collected and processed by an external vendor, Koneksa. 
Analysis and reporting of this sub-study will be performed separately from the CSR.  
Missing data will not be imputed in the analysis of tertiary endpoints, nor will sensitivity or 
subgroup analyses be conducted.  
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3.5 
MULTIPLICITY ISSUES  
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 statistical significance is achieved for the primary 
endpoint, a selective set of secondary endpoints will be tested following the hierarchical testing 
procedure shown below: 
• Time to onset of 3-month CDP as assessed by the EDSS score 
• Number of new and/or enlarging T2 hyperintense lesions per year 
• Time to onset of sustained 20% increase in the 9-HPT for at least 3 months 
• Time to onset of sustained 20% increase in the T25-FW for at least 3 months 
• Time to onset of CDI confirmed over at least 6 months 
• Percent change in brain volume as detected by MRI scans at the EOS compared to 
Month 6 
3.6 
SAFETY ANALYSES  
All safety analyses will be performed 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 with no testing 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. 
3.6.1 Extent of exposure  
The extent of IMP exposure will be assessed by the duration of IMP exposure and compliance 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 in the DB 
treatment period and OL period respectively: >0 to ≤24 weeks, >24 to ≤48 weeks, >48 to 
≤72 weeks, >72 to ≤96 weeks, >96 weeks. 
Additionally, the cumulative duration of treatment exposure (expressed in participant-years) will 
be provided. 
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Treatment compliance 
A given administration will be considered noncompliant 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 DB treatment period and OL period respectively. 
Treatment compliance will be summarized quantitatively and categorically: <80%, ≥80%. 
3.6.2 Adverse events  
General common rules for adverse events 
All adverse events (AEs) 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 4 categories: 
• 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 DB TE period 
• OL AEs: AEs that developed, worsened, or become serious during the OL TE period 
• Post-treatment AEs: AEs that developed, worsened, or became serious during the post-
treatment period  
Similarly, if occurring, deaths will be summarized in the pre-treatment, DB TE, OL, and post-
treatment periods.  
The primary focus of AE reporting will be on TEAEs. Pre-treatment, OL, 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, OL, 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 IMP. If the severity is missing for 1 of the TE occurrences of an AE, the severity will be 
imputed with the maximal severity of the other occurrences. If the severity is missing for all the 
occurrences, the severity will be left as missing. 
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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  
AESI category and PT 
By AESI category (protocol order) and decreasing frequency of PTsa 
PT 
By 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 TEAE will be generated presenting the number (%) of participants with: 
• Any TEAE  
• Any treatment emergent SAE 
• TEAE leading to death 
• Any TEAE leading to permanent study intervention discontinuation  
• Any treatment emergent AESI 
• Any TEAE considered by the investigator as related to study intervention 
Similar summaries for OL emergent AEs will also be provided. An additional overview summary 
including the number and rate of events will be provided in the DB treatment period and OL 
period respectively. 
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 from participants who are treated but not 
randomized, AEs leading to treatment discontinuation and severe AEs will be provided. 
Table 5 - Analyses of adverse events  
Type of AE 
MedDRA levels 
All TEAE 
Primary SOC and PT 
 
PT (incidence ≥2%) 
Severe (grade ≥3) TEAEs 
Primary SOC and PT 
 
PT 
TEAE related to IMP as per Investigator’s judgment 
Primary SOC and PT 
 
PT 
Treatment emergent SAE 
Primary SOC and PT 
 
PT 
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Type of AE 
MedDRA levels 
Treatment emergent SAE related to IMP as per Investigator’s 
judgment 
Primary SOC and PT 
Treatment emergent AESIs 
AESI category and PT 
TEAE leading to permanent study intervention discontinuation 
Primary SOC and PT 
 
PT 
TEAE leading to death (death as an outcome of the AE as reported 
by the Investigator in the AE page) 
Primary SOC and PT 
Pretreatment AE 
Overviewa 
 
Primary SOC and PT 
Post-treatment AE 
Overviewa 
 
Primary SOC and PT 
a Will include the following AE categories: any AEs, any severe (grade ≥3) AEs, 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 TE, OL, and post-treatment periods  
• Deaths in non-randomized/non-enrolled participants or randomized but not treated 
participants 
Analysis of adverse events of special interest (AESIs)  
Adverse events of special interest (AESIs) will be selected for analyses as indicated in Table 6. 
Number (%) of participants experiencing at least one event will be provided for each event of 
interest. Tables will be sorted as indicated in Table 4.  
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 in ALT >3 x ULN (confirmed) 
Dedicated CRF page (AECAT=”ALT INCREASE DATA”) and AESI 
marked “Y” 
ECG observation of atrial fibrillation or 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” 
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AESIs 
Selection 
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 units, if 
applicable. 
• Hematology:  
- 
Red blood cells and platelet: 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  
- 
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 (ALT), aspartate aminotransferase (AST), 
alkaline phosphatase, total and direct bilirubin 
• Urinalysis for quantitative analysis: specific gravity, pH 
• Vital signs: heart rate, systolic and diastolic blood pressure, weight, temperature 
• ECG variables: heart rate, PR, QRS, QT, and corrected QTcF (according to Fridericia). In 
case the ECG machine does not automatically calculate QTcF, manual calculation using 
nomogram or automatic website calculator is acceptable.  
For laboratory data reported as <xx or >yy, a numeric value of xx/2 or yy, respectively, will be 
used for quantitative analysis.  
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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 
DB treatment period and OL period respectively. These analyses will be performed using central 
measurements only for laboratory variables.  
For each laboratory parameter, vital signs parameter and ECG parameter, mean changes from 
baseline with the corresponding SE 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 DB treatment-emergent period and OL 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 DB treatment-emergent period and OL period will be summarized 
respectively 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 or AST elevation (>3 x ULN) and total bilirubin elevation 
(>2 x ULN) during the treatment-emergent period will be analyzed using the KM method.  
• The KM method will also be used to analyze time to onset of the following initial 
elevation ALT >3 x ULN, ALT >5 x ULN, ALT >8 x ULN, ALT >10 x ULN, AST >3 x 
ULN, AST >5 x ULN, AST >8 x ULN, AST >10 x ULN, total bilirubin >2 x ULN during 
the treatment-emergent period, respectively. 
• A graph of the distribution of peak values of ALT versus peak values of total bilirubin 
during the treatment-emergent period will be provided.  
• For each liver function test (eg, ALT), participants having experienced a PCSA (eg, ALT 
>5 x ULN) will be summarized using the following categories: Returned to baseline PCSA 
status (or returned to value ≤ULN in case of missing baseline) before last IMP dose, 
Returned to baseline PCSA status after last IMP dose, Never returned to baseline PCSA 
status, No assessment after elevation. This summary will be performed by categories of 
elevation ALT >3, >5, >10, >20 x ULN. 
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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 Columbia Suicide Severity Rating Scale (C-SSRS) 
during DB treatment period and OL period will be summarized respectively. A shift table for 
baseline versus during treatment and OL responses will be provided respectively according to the 
categories of no suicidal ideation or behavior, suicidal ideation, and suicidal behavior. 
3.7 
OTHER ANALYSES  
3.7.1 Other variables and/or parameters  
3.7.1.1 PK analyses  
Tolebrutinib and M2 metabolite pharmacokinetic (PK) individual parameters (at least Cmax, 
tmax, AUC0-24) and corresponding descriptive statistics (mean, geometric mean, median, SD, 
coefficient of variation, minimum, and maximum) will be determined by population PK analysis 
by the PKDM department using sampling times at Months 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 will be collected for a subset of up to 200 randomized 
participants. Flow cytometry will be used for evaluation of change (and % change) from baseline 
in lymphocyte count and phenotyping subset. Additional pharmacodynamics evaluations include 
assessment of neurofilament light chain (NfL) levels in plasma, chitinase-3-like protein 1 
(Chi3L1), and immunoglobulin (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, SD, coefficient of variation, 
minimum, and maximum.  
3.8 
INTERIM ANALYSES  
A non-binding interim futility analysis will be performed when approximately 50% of the primary 
endpoint events are observed. The futility criterion will be determined by calculating the 
predictive power, which is a weighted average of the conditional power (11). Futility of the study 
may be declared only when the predictive power for the primary endpoint is below 10%, which is 
equivalent to the condition that the hazard ratio between tolebrutinib and placebo derived from the 
primary analysis is greater than or equal to 0.92. The futility interim analysis will be conducted by 
an independent statistics group and reviewed by the DMC. Neither the Sponsor’s team nor the 
Investigator’s staff will have access to the treatment information at the individual participant level 
or group level before the study is formally unblinded after study completion or after the DMC 
recommendation and Sponsor agreement for stopping the trial. The details of the interim analysis 
will be included in the Data Monitoring Committee (DMC) SAP. 
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4 
SAMPLE SIZE DETERMINATION  
Approximately 1700 participants will be screened to achieve up to 1290 randomly assigned to 
study intervention (2:1 randomization ratio of tolebrutinib to placebo). This study is planned as 
an event-driven trial based on 6-month CDP. The study will continue until approximately 
288 events are projected to have occurred to provide 80% power to detect a 30% risk reduction in 
6-month CDP with tolebrutinib compared to placebo (2-sided α = 0.05). The following 
assumptions were used for the calculations: 2-year placebo event rate of 23.6%; annual 
discontinuation rate of 10%; constant hazard rates using a log-rank test; estimated enrollment 
period of 24 months with the last randomized participant followed for 24 months. 
Actual recruitment and disability event rates may vary; therefore, it is possible to stop with 
a reduced sample size of around 1100 and still maintain study power by extending the duration of 
the trial, if needed, to reach approximately the same number of events. For example, it could be 
that the last randomized participant is followed for around 30 months instead of 24, if necessary. 
Additional recruitment of participants will not substantially reduce the trial duration. In any case, 
the power is based on the number of events, and the actual trial duration will be dependent on the 
observed placebo rate and treatment effect. 
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5 
SUPPORTING DOCUMENTATION  
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS  
 
9-HPT: 
9-hole peg test 
AE: 
adverse event 
AESIs: 
adverse events of special interest 
ALT: 
alanine aminotransferase 
ANCOVA: 
analysis of covariance 
AST: 
aspartate aminotransferase 
ATC: 
anatomic therapeutic category 
BVL: 
brain volume loss 
CDI: 
confirmed disability improvement 
CDP: 
confirmed disability progression 
CI(s): 
confidence intervals 
CMH: 
Cochran-Mantel-Haenszel 
C-SSRS: 
Columbia Suicide Severity Rating Scale 
CVLT-II: 
California Verbal Learning Test-II 
DB: 
double-blind 
DMC: 
Data Monitoring Committee 
ECG: 
electrocardiogram 
e-CRF: 
electronic case report form 
EDSS: 
expanded disability status scale 
EOS: 
end of study 
Gd: 
Gadolinium 
GLMM: 
generalized linear mixed model 
HLGT: 
high-level group term 
HLT: 
high-level term 
IMP: 
investigational medicinal product 
KM: 
Kaplan-Meier 
LLT: 
lower-level term 
LSM: 
least squares means 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MMRM: 
mixed-effect model with repeated measures 
MRI: 
magnetic resonance imaging 
MS: 
multiple sclerosis 
MSFC-3: 
multiple sclerosis functional composite 
MSQoL-54: 
multiple sclerosis quality of life-54 
MTR: 
magnetization transfer ratio 
NCI-CTCAE: 
National Cancer Institute Common Terminology for Adverse Events 
NEDA-3: 
no evidence of disease activity-3 
NRSPMS: 
non-relapsing secondary progressive multiple sclerosis 
OL: 
open-label 
PCSA: 
potentially clinically significant abnormality 
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PD: 
pharmacodynamic 
PK: 
pharmacokinetics 
PT: 
preferred term 
ROW: 
rest of the world 
RRMS: 
relapsing-remitting multiple sclerosis 
SDMT: 
symbol digit modalities test 
SE: 
standard error 
SOC: 
system organ class 
SPMS: 
secondary progressive multiple sclerosis 
T25-FW: 
timed 25-foot walk 
TE: 
treatment-emergent 
TEAE: 
treatment-emergent adverse event 
VAS: 
visual analogue scale 
WHO-DD: 
World Health Organization-drug dictionary 
  
5.2 
APPENDIX 2 PARTICIPANT DISPOSITIONS  
The number (%) of participants included in each of the analysis populations listed in Table 3 will 
be summarized. 
Screened subjects 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 and not exposed, if applicable 
• Randomized and exposed  
- 
Completed the DB study intervention period  
- 
Did not complete the DB study intervention period including main reason for 
discontinuation and reason for withdrawal by subject 
- 
Switched to the OL tolebrutinib treatment 
- 
Completed the OL period  
- 
Did not complete the OL period including main reason for discontinuation and reason 
for withdrawal by subject 
• Completed the study  
• Did not complete the study including main reason for study discontinuation 
• Status at last contact (alive, dead) 
• Entered LTS study 
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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 study intervention discontinuation (DB and OL) and with early study discontinuation 
will be provided by country and site. Listings of other reasons for treatment 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. 
5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS  
Demographics, baseline characteristics, medical surgical history 
The following demographics 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 quantitative variable and in categories (≤40, >40; 18 to 60)  
• 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 
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• 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 
• Time since symptom onset of relapsing-remitting multiple sclerosis (RRMS) in years 
• Time since diagnosis of secondary progressive multiple sclerosis (SPMS) in years 
• Time since most recent relapse in years 
• Baseline EDSS score as a quantitative variable (average of screening and baseline scores 
when both available) 
• Disease burden at baseline (baseline EDSS ≤4.5 versus >4.5; EDSS ≤5.5 versus >5.5) 
• Baseline Gd-enhancing T1 lesion (absent, present) 
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 World Health Organization-Drug Dictionary (WHO-DD) 
using the version currently in effect at Sanofi at the time of database lock.  
• Prior medications are those the participant received prior to first IMP intake. Prior 
medications can be discontinued before first administration or can be ongoing during 
treatment period. 
• Concomitant medications are any medications received by the participant concomitantly to 
the IMP during the DB treatment and OL periods. 
• Post-treatment medications are those the participant received in the period running from 
the end of the concomitant medications period up to the end of the study.  
• 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 MS disease modifying therapy 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 medications will be summarized for the 
randomized and exposed population, by anatomic and therapeutic level. The summaries will be 
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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.  
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 48 months.  
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Table 7 - Analyses window definition of efficacy variables  
AVISIT 
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 
-40 
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 
Month 39 
1092 
1051 
1134 
 
 
1051 
1134 
 
 
Month 42 
1176 
1135 
1218 
 
 
1135 
1218 
1093 
1260 
Month 45 
1260 
1219 
1302 
 
 
1219 
1302 
 
 
Month 48 
1344 
1303 
1386 
1177 
1512 
1303 
1386 
1261 
1428 
EOS 
 
Start Day: last visit window upper limit +1 
End Day: EOS visit date 
Nominal visit (9000) 
FU for participants 
not entering 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 
except liver 
function 
tests 
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 
1092 
841 
1176 
925 
1092 
  
  
Month 39 
1092 
1051 
1134 
1051 
1134 
 
 
 
 
 
 
 
 
Month 42 
1176 
1135 
1218 
1135 
1218 
1093 
1260 
 
 
1093 
1260 
 
 
Month 45 
1260 
1219 
1302 
1219 
1302 
 
 
 
 
 
 
 
 
Month 48 
1344 
1303 
1386 
1303 
1386 
1261 
1386 
1177 
1386 
1261 
1386 
 
 
EOS 
 
Start Day: last visit window upper limit +1; End Day: EOS visit date 
Nominal visit (9000) 
 
 
Liver 
Function 
test 
 
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 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 
 
 
 
Note: Analysis windows in open-label period can follow the same rule except that the first open-label dose date is Day 1 in that period 
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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 
504 
253 
504 
 
 
 
 
Month 15 
420 
 
 
 
 
 
 
 
 
Month 18 
504 
 
 
 
 
 
 
 
 
Month 21 
588 
 
 
 
 
 
 
 
 
Month 24 
672 
505 
840 
505 
840 
 
 
 
 
Month 27 
756 
 
 
 
 
 
 
 
 
Month 30 
840 
 
 
 
 
 
 
 
 
Month 33 
924 
 
 
 
 
 
 
 
 
Month 36 
1008 
841 
1176 
841 
1176 
 
 
 
 
Month 39 
1092 
 
 
 
 
 
 
 
 
Month 42 
1176 
 
 
 
 
 
 
 
 
Month 45 
1260 
 
 
 
 
 
 
 
 
Month 48 
1344 
1177 
1386 
1177 
1386 
 
 
 
 
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 
 
 
 
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 and ECG) if they are re-allocated to scheduled visits based on the analysis 
windows defined above. 
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Version number: 3 
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5.5 
APPENDIX 5 ANALYSES SUPPORTING THE INTEGRATED SUMMARY OF SAFETY  
Below are the additional analyses supporting the integrated summary of safety. 
• Time to study intervention discontinuation for any reason (except switch to OL due to 6M-
CDP) and due to AE using the KM method 
• Exposure to study intervention by duration in participant years (≥24, ≥48, ≥72, ≥96, ≥120, 
≥144, ≥168 weeks) 
• Exposure to study intervention by subgroups in participant years  
- 
Age at screening (>40, ≤40 years) 
- 
Sex (Male or Female) 
- 
Age by sex (>40 & male, >40 & female, ≤40 & male, ≤40 & female) 
- 
Race (White, Black or African American, Asian, Other) 
- 
Weight in kg (<70, ≥70 to <90, ≥90) 
- 
BMI in kg/m2 (<25, ≥25 to <30, ≥30) 
- 
Baseline EDSS (<4, ≥4) 
- 
Geographic region (US, non-US; Eastern Europe, Western Europe, North America, 
rest of the world [ROW]) 
- 
Prior disease modifying therapy use (yes, no) 
• Most frequent TEAEs sorted by relative risk and the corresponding forest plot 
• Most frequent TEAEs sorted by risk difference and the corresponding forest plot 
• Summary of TEAEs by primary SOC 
• Summary of TEAEs by primary SOC, HLT and PT 
• TEAEs leading to permanent study intervention discontinuation by exposure intervals 
(based on 24-week intervals) 
• Incidence rate of post-treatment SAEs related to IMP 
• Summary of TE AESIs by category, primary SOC and PT 
• Summary of other TEAE groupings of interest by category, primary SOC and PT 
• Incidence rate and relative risk ratio for TE AESIs and other selected AE groupings 
(COVID-19, suicidal behavior, malignancy) and the corresponding forest plot 
• Incidence rate and risk difference for TE AESIs and other selected AE groupings 
(COVID-19, suicidal behavior, malignancy) and the corresponding forest plot 
• Detailed summary for each AESI and other AE groupings 
• Summaries of PTs occurring in at least 2/3/5% of participants on tolebrutinib and with 
a greater incidence compared to placebo by primary SOC and PT 
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Statistical Analysis Plan  
 
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Page 44 
• Boxplots and shift plots of the maximum values of ALT, AST, ALP and total bilirubin 
during treatment 
• Incidence rates of TEAEs, TE SAEs, TEAEs leading to permanent study intervention 
discontinuation and AESIs/other AE group events by subgroups with corresponding forest 
plots 
 
VV-CLIN-0642962 3.0


Statistical Analysis Plan  
 
30-Apr-2024 
SAR442168-EFC16645 - tolebrutinib 
Version number: 3 
Property of the Sanofi group - strictly confidential 
Page 45 
6 
REFERENCES  
  
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Chapman & Hall / CRC. 1999. 
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