Long-term Extension Safety and Efficacy Study of SAR442168 in Participants With Relapsing Multiple Sclerosis
Phase: PHASE2
Conditions: Relapsing Multiple Sclerosis
Sponsor: Sanofi

 
 
 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: RDSD-002540 VERSION N° 2.0 (11-OCT-2018) based on TransCelerate CPT version 5 
Page 1 
 
AMENDED CLINICAL TRIAL PROTOCOL 10   
Protocol title: 
Long-term extension safety and efficacy study of 
SAR442168 in participants with relapsing multiple 
sclerosis 
Protocol number: 
LTS16004 
Amendment number: 
10 
Compound number 
(INN/Trademark): 
SAR442168 
Tolebrutinib/not applicable 
Study phase: 
Phase 2 
Short title: 
Long-term safety and efficacy study of tolebrutinib in 
relapsing multiple sclerosis 
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: 
2018-004731-76 
NCT: 
NCT03996291 
WHO: 
U1111-1223-4256 
Other: 
Not applicable 
Approval Date: 
20-Dec-2023 
Total number of pages: 106 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY  
 
Document 
Country/countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial Protocol 10 
All 
20 December 2023, version 1 (electronic 12.0) 
Amended Clinical Trial Protocol 09 
All 
16 November 2023, version 1 (electronic 11.0) 
Amended Clinical Trial Protocol 08 
All 
19 June 2023, version 1 (electronic 10.0) 
Amended Clinical Trial Protocol 07 
All 
12 December 2022, version 1 (electronic 9.0) 
Amended Clinical Trial Protocol 06 
All 
23 May 2022, version 1 (electronic 8.0) 
Amended Clinical Trial Protocol 05 
All 
29 July 2021, version 1 (electronic 7.0) 
Amended Clinical Trial Protocol 04 
All 
28 October 2020, version 1 (electronic 5.0) 
Amended Clinical Trial Protocol 03 
All 
02 March 2020, version 1 (electronic 4.0) 
Amended Clinical Trial Protocol 02 
All 
30 August 2019, version 2 (electronic 3.0) 
Amended Clinical Trial Protocol 01 
Czech Republic only 
26 June 2019, version 1 (electronic 1.0) 
Original Protocol 
 
18 January 2019, version 1 (electronic 1.0) 
Amended protocol 10 (20 December 2023) 
In Europe, this amended protocol (amendment 10) is considered to be non-substantial based on 
the criteria set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the 
Council of the European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
The rationale for this protocol amendment is to 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 
10.7 Appendix 7 Example of drugs 
with a potential to change with 
SAR442168 metabolism 
Updated to provide guidance to the US and any 
other sites that may be following FDA partial 
clinical hold. 
Update to provide guidance. 
10.8.1 Country specific provisions for 
the US and sites following 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. 
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Section # and Name 
Description of Change 
Brief Rationale 
10.11 Appendix 11: Protocol 
amendment history 
Updated. 
Update. 
Throughout the document 
Reformatted existing content when necessary. 
Minor, editorial, stylistic changes as necessary. 
Updated table of contents, section numbers, 
abbreviations as necessary. 
Update in accordance with 
Sponsor’s standards. 
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TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 10  ............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
DOCUMENT HISTORY ................................................................................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 4 
LIST OF TABLES ........................................................................................................................................... 9 
LIST OF FIGURES .......................................................................................................................................... 9 
1 
PROTOCOL SUMMARY ............................................................................................................... 10 
1.1 
SYNOPSIS ..................................................................................................................................... 10 
1.2 
SCHEMA ........................................................................................................................................ 13 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 14 
2 
INTRODUCTION ............................................................................................................................ 21 
2.1 
STUDY RATIONALE...................................................................................................................... 21 
2.2 
BACKGROUND ............................................................................................................................. 21 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 27 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 31 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 32 
4 
STUDY DESIGN ............................................................................................................................ 33 
4.1 
OVERALL DESIGN ........................................................................................................................ 33 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 33 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 34 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 34 
5 
STUDY POPULATION .................................................................................................................. 35 
5.1 
INCLUSION CRITERIA .................................................................................................................. 35 
5.2 
EXCLUSION CRITERIA  ............................................................................................................... 36 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 38 
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5.3.1 
Meals and dietary restrictions ........................................................................................................ 38 
5.3.2 
Caffeine, alcohol, and tobacco ....................................................................................................... 38 
5.3.3 
Activity ............................................................................................................................................ 38 
5.4 
SCREEN FAILURES...................................................................................................................... 38 
5.5 
CRITERIA FOR TEMPORARILY DELAYING ENROLLMENT AND ADMINISTRATION OF 
STUDY INTERVENTION ............................................................................................................... 38 
6 
STUDY INTERVENTION ............................................................................................................... 39 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 39 
6.1.1 
Investigational medicinal product ................................................................................................... 39 
6.1.2 
Noninvestigational medicinal product ............................................................................................ 40 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 40 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 41 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 42 
6.5 
CONCOMITANT THERAPY .......................................................................................................... 42 
6.5.1 
Rescue medicine ............................................................................................................................ 43 
6.6 
DOSE MODIFICATION .................................................................................................................. 43 
6.7 
INTERVENTION AFTER THE END OF THE STUDY ................................................................... 43 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 44 
7.1 
DISCONTINUATION OF STUDY INTERVENTION  ..................................................................... 44 
7.1.1 
Definitive discontinuation ............................................................................................................... 44 
7.1.2 
Temporary discontinuation ............................................................................................................. 45 
7.1.2.1 
Rechallenge ................................................................................................................................... 45 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 46 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 47 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 48 
8.1 
EFFICACY ASSESSMENTS  ........................................................................................................ 48 
8.1.1 
Magnetic resonance imaging assessments ................................................................................... 48 
8.1.2 
MS Relapse .................................................................................................................................... 49 
8.1.2.1 
Unscheduled assessment visits for a suspected MS relapse ........................................................ 49 
8.1.2.2 
Definition of multiple sclerosis relapse ........................................................................................... 50 
8.1.3 
Expanded Disability Status Scale (EDSS) evaluation ................................................................... 50 
 
 ...................................................................................................................................... 50 
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8.2 
SAFETY ASSESSMENTS  ............................................................................................................ 51 
8.2.1 
Physical examinations ................................................................................................................... 51 
8.2.2 
Vital signs ....................................................................................................................................... 51 
8.2.3 
Electrocardiograms ........................................................................................................................ 52 
8.2.4 
Clinical safety laboratory assessments .......................................................................................... 52 
8.2.5 
Suicidal ideation and behavior risk monitoring .............................................................................. 52 
8.2.5.1 
Columbia Suicide Severity Rating Scale ....................................................................................... 53 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........................................................... 53 
8.3.1 
Adverse event of special interest ................................................................................................... 53 
8.3.2 
Index adverse events ..................................................................................................................... 54 
8.3.3 
Time period and frequency for collecting AE and SAE information ............................................... 54 
8.3.4 
Method of detecting AEs and SAEs ............................................................................................... 54 
8.3.5 
Follow-up of AEs and SAEs ........................................................................................................... 55 
8.3.6 
Regulatory reporting requirements for SAEs ................................................................................. 55 
8.3.7 
Pregnancy ...................................................................................................................................... 55 
8.3.8 
Cardiovascular and death events .................................................................................................. 55 
8.3.9 
Multiple sclerosis relapse reporting ................................................................................................ 56 
8.3.10 
Reporting of safety findings from magnetic resonance imaging .................................................... 56 
8.3.11 
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ........... 56 
8.3.12 
Guidelines for reporting product complaints .................................................................................. 56 
8.3.12.1 Medical devices .............................................................................................................................. 56 
8.4 
TREATMENT OF OVERDOSE ...................................................................................................... 56 
8.5 
PHARMACOKINETICS .................................................................................................................. 57 
8.6 
PHARMACODYNAMICS ............................................................................................................... 57 
8.7 
GENETICS ..................................................................................................................................... 57 
8.8 
BIOMARKERS ............................................................................................................................... 58 
8.9 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS ................................................................................................................................. 58 
8.10 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH ................................ 58 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 60 
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 60 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................. 60 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 60 
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9.4 
STATISTICAL ANALYSES ............................................................................................................ 60 
9.4.1 
Efficacy analyses ........................................................................................................................... 60 
9.4.2 
Safety analyses .............................................................................................................................. 61 
9.4.3 
Other analyses ............................................................................................................................... 61 
9.5 
INTERIM ANALYSES  ................................................................................................................... 61 
9.5.1 
Independent Data Monitoring Committee  ..................................................................................... 62 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 63 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 63 
10.1.1 
Regulatory and Ethical Considerations .......................................................................................... 63 
10.1.2 
Financial disclosure........................................................................................................................ 63 
10.1.3 
Informed consent process .............................................................................................................. 64 
10.1.4 
Data protection ............................................................................................................................... 64 
10.1.5 
Committees structure ..................................................................................................................... 66 
10.1.6 
Dissemination of clinical study data ............................................................................................... 67 
10.1.7 
Data quality assurance .................................................................................................................. 67 
10.1.8 
Source documents ......................................................................................................................... 68 
10.1.9 
Study and site closure .................................................................................................................... 68 
10.1.10 Publication policy ........................................................................................................................... 69 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 69 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ................................................ 71 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION .............................................................................................................................. 75 
10.5 
APPENDIX 5: GENETICS ............................................................................................................. 78 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: ACTIONS AND FOLLOW-UP 
ASSESSMENTS ............................................................................................................................ 79 
10.7 
APPENDIX 7: LIST OF EXAMPLE DRUGS WITH A POTENTIAL TO CHANGE WITH 
SAR442168 METABOLISM ........................................................................................................... 86 
10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS .............................................................. 87 
10.8.1 
Country-specific provisions for the US and sites following FDA partial clinical hold 
conditions ....................................................................................................................................... 87 
10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................... 88 
10.9.1 
Informed consent ........................................................................................................................... 88 
10.9.2 
Study procedures ........................................................................................................................... 88 
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10.9.3 
Temporary discontinuation ............................................................................................................. 89 
10.9.4 
Statistical analysis .......................................................................................................................... 90 
10.10 
APPENDIX 10: ABBREVIATIONS ................................................................................................. 90 
10.11 
APPENDIX 11: PROTOCOL AMENDMENT HISTORY ................................................................ 91 
10.11.1 Amended protocol 01 (26 June 2019)............................................................................................ 91 
10.11.2 Amended protocol 02 (30 August 2019) ........................................................................................ 92 
10.11.3 Amended protocol 03 (02 March 2020) ......................................................................................... 94 
10.11.4 Amended protocol 04 (28 October 2020) ...................................................................................... 97 
10.11.5 Amended protocol 05 (29 July 2021) ............................................................................................. 98 
10.11.6 Amended protocol 06 (23 May 2022)........................................................................................... 101 
10.11.7 Amended protocol 07 (12 December 2022) ................................................................................. 102 
10.11.8 Amended protocol 08 (19 June 2023).......................................................................................... 103 
10.11.9 Amended protocol 09 (16 November 2023) ................................................................................. 104 
11 
REFERENCES ............................................................................................................................. 105 
 
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LIST OF TABLES  
Table 1 - A - Schedule of activities (up to Year 1) ......................................................................................... 14 
Table 2 - B - Schedule of activities (Years 2 to 4) ......................................................................................... 17 
Table 3 - C - Schedule of activities (Year 5).................................................................................................. 19 
Table 4 - Exposure ratios in repeat dose toxicity studies in rats and dogs ................................................... 24 
Table 5 - NOAELs and exposure ratios in the embryo-fetal toxicity studies ................................................. 25 
Table 6 - Objectives and endpoints ............................................................................................................... 31 
Table 7 - Overview of study interventions administered ............................................................................... 39 
Table 8 - Populations for analyses ................................................................................................................ 60 
Table 9 - Efficacy analyses ........................................................................................................................... 61 
Table 10 - Safety analyses ............................................................................................................................ 61 
Table 11 - Protocol-required laboratory assessments .................................................................................. 70 
Table 12 - Contraceptive methods allowed during the study ........................................................................ 77 
Table 13 - Clinical and MRI features suggestive of PML .............................................................................. 85 
Table 14 - Potent and moderate CYP3A inducers and potent CYP2C8 inhibitors ....................................... 86 
Table 15 - Mild, moderate, and potent inhibitors of CYP3A and CYP2C8, and moderate and potent 
inducers of CYP3A ........................................................................................................................................ 87 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................. 13 
 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title: Long-term extension safety and efficacy study of SAR442168 in participants with 
relapsing multiple sclerosis 
Short title: 
Long-term safety and efficacy study of tolebrutinib in relapsing multiple sclerosis 
Rationale: 
The Bruton’s tyrosine kinase (BTK) pathway is critical to signaling in B lymphocytes and 
myeloid cells including central nervous system (CNS) microglia. Each of these cell types has been 
implicated in the pathophysiology of multiple sclerosis (MS). Accordingly, SAR442168, a CNS 
penetrant BTK inhibitor has the potential for a dual mechanism of action by inhibiting antigen 
induced B-cell activation responsible for inflammation and by modulating maladaptive microglial 
cells linked to neuroinflammation in the brain and spinal cord. There is still a significant unmet 
need for therapies that target neuroinflammation in the CNS with a goal of halting long-term 
disability and neurodegeneration in people with relapsing multiple sclerosis (RMS), and also in 
progressive forms of the disease (primary progressive multiple sclerosis [PPMS] and secondary 
progressive multiple sclerosis [SPMS]). Even the most recent high efficacy disease-modifying 
therapies act mainly on adaptive immunity in the periphery with only modest or temporary ability 
to halt neuroinflammatory and neurodegenerative processes and stop disease progression, as also 
demonstrated by recent studies in progressive MS. 
Objectives and endpoints 
 
Objectives 
Endpoints 
Primary 
• 
To determine the long-term safety and tolerability of 
SAR442168 in RMS participants 
Adverse events (Aes), serious adverse events (SAEs), safety 
findings on magnetic resonance imaging (MRI), potentially 
clinically significant abnormalities (PCSAs) in laboratory tests, 
electrocardiogram (ECG), or vital signs during the study period. 
Secondary 
• 
To evaluate efficacy of SAR442168 on disease 
activity, assessed by clinical and imaging methods. 
• 
Number of new gadolinium (Gd)-enhancing. 
T1-hyperintense lesions by brain MRI. 
• 
Number of new or enlarging T2 lesions. 
• 
Total number of Gd-enhancing T1-hyperintense 
lesions. 
• 
Number of relapses (annualized relapse rate [ARR]) 
during the study period. 
• 
Change in Expanded Disability Status Scale 
(EDSS) score from baseline over time. 
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Overall design: 
This study is a long-term, follow-up study to determine the safety and efficacy of SAR442168. 
Participants who completed treatment with SAR442168 in the previous DRI15928 study are eligible 
for enrollment. Participants will start the treatment after informed consent as soon as possible. 
The study will consist of 2 parts: 
Part A: Double-blind period of continued treatment with the respective SAR442168 dose 
administered in the DRI15928 study.  
Until the dose of SAR442168 to be used in Phase 3 is determined, participants will continue 
treatment with their same SAR442168 dose used in the DRI15928 study. The double-blind will be 
maintained until selection of the Phase 3 dose is made based on the SAR442168 clinical studies 
including the DRI15928 study. 
Part B: Open-label period of a single-group treatment with the selected Phase 3 SAR442168 dose.  
Once the SAR442168 dose has been selected, all participants will be switched to open-label 
treatment with the selected dose. 
If the participant is not willing to switch to the selected dose of SAR442168, the participant will 
be withdrawn from the study and a follow-up visit will be performed 4 to 6 weeks after 
administration of the last study intervention. 
Disclosure Statement: This is a long-term Single Group Treatment study for participants 
previously treated in the DRI15928 study. It consists of 2 parts: Part A, which is blinded/masked 
for participants and Investigators during the double-blind period of the study, and Part B which is 
an open-label period of the study.  
Number of participants: 
There are no sample size calculations for this long-term extension study.  
All participants who completed the DRI15928 study are eligible for enrollment in the LTS16004 
study. Therefore, the maximum number of participants enrolled in the LTS16004 study will not 
exceed that of the DRI15928 study. The Sponsor enrolled 130 participants in the DRI15928 study, 
of whom 129 completed it. Based on previous trial experience, the Sponsor projects that >75% of 
those participants will opt into the LTS16004 study. 
Intervention groups and duration: 
In Part A, participants will continue to receive their previous SAR442168 dose in 1 of 4 dose 
groups. In Part B all participants will form a single dose group, the selected Phase 3 dose. 
Study intervention(s) 
Investigational medicinal product: SAR442168 
• Formulation: Part A - 2.5 or 15 mg film coated tablet; Part B - 15 or 60 mg film coated tablet. 
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• Route(s) of administration: oral. 
• Dose regimen: once daily. 
Noninvestigational medicinal products 
A radiological, signal-enhancing, intravenous (IV) contrast medium will be used for 
T1-contrast-enhanced MRI sequences. A locally approved contrast agent will be used. 
Due to a potential safety risk related to gadolinium (Gd) deposition in the brain seen with certain 
contrast agents, these agents should be used in accordance with local recommendations and 
regulations. Otherwise, use of these agents will be similar to their routine use and will be sourced 
locally. The study manual will provide more details describing their administration in this trial. 
Continued access to intervention after the end of the study 
After the end of this study, participants who successfully complete the trial on SAR442168 may 
be offered the option to participate in a Phase 3 long-term safety (LTS) study for up to 
an additional 3 years, or until SAR442168 is approved in their respective country, whichever 
comes first. Details of the Phase 3 LTS study will be described in a separate protocol. If this 
program is terminated earlier, other available RMS treatments will need to be considered at the 
discretion of the treating physician.  
Statistical considerations: 
No statistical comparisons between treatment groups will be made. Summaries using descriptive 
statistics will be provided by visit for parameters. 
Sample size calculations: 
There are no sample size calculations for this long-term extension study. Sample size will be 
based on the elective participation of participants who complete the DRI15928 study, meet the 
eligibility criteria, and enroll in this LTS16004 study.  
Primary analysis: 
The safety of long-term SAR442168 treatment will be evaluated using descriptive statistics, 
summarizing incidence of adverse events (Aes), serious adverse events (SAEs), and clinically 
significant abnormalities (PCSAs) for clinical laboratory tests, and summarizing safety findings 
on MRI, electrocardiogram (ECG), and vital signs parameters by visit. 
Analysis of secondary endpoints: 
Summaries using descriptive statistics will be provided by visit. 
Independent Hepatology Assessment Committee: Yes 
Data Monitoring Committee: Yes
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1.2 
SCHEMA  
Figure 1 - Graphical study design  
 
DRI15928 (≥Week 16 Visit) 
 
LTS16004 
Part A  
(Double-blind)
DRI15928 assigned Dose
Part B 
(Open-label)
Selected Phase 3 Dose
End of Study 
Visit
(Follow-up 
Visit)
 
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1.3 
SCHEDULE OF ACTIVITIES (SOA)  
In this clinical study, a month is considered to be a period of 4 weeks (28 days). 
Table 1 - A - Schedule of activities (up to Year 1)  
Procedure 
Screening 
Baseline/start 
of IMP 
Intervention Phase 
 
 
Month (a window of ±7 days is 
allowed for all visits after screening) 
W-6 to 
D1a 
D1a 
M1 
M3 
M6 
M9 
M12 
UNSCHn 
Premature End 
of Treatmentb 
Informed consent 
X 
 
 
 
 
 
 
If switch to Part B 
 
Visit at clinical sitec 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study IMP Administration 
SAR442168 (dispensation and 
accountability) 
 
X 
X 
X 
X 
X 
X 
If switch to Part B  
X 
(Accountability 
only) 
Safetyc 
Physical examinationd, e 
X  
X  
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
Body weight 
X 
X 
X 
X 
X 
X 
X 
If needed 
X 
Vital signse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGe 
X 
X 
X 
X 
X 
X 
X 
If needed 
X 
Hematology, biochemistrye, f  
Xg 
Xg 
X 
X 
X 
X 
X 
If needed 
X 
Urinalysise, f  
Xg 
Xg 
X 
X 
X 
X 
X 
If needed 
X 
β-HCG test (if applicable)h  
X 
X 
X 
X 
X 
X 
X 
If needed 
 
Serum FSH (if applicable)i 
X 
 
 
 
 
 
 
 
 
Suicidality assessment (C-SSRS) 
X 
X 
X 
X 
X 
X 
X 
If needed 
X 
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Procedure 
Screening 
Baseline/start 
of IMP 
Intervention Phase 
 
 
Month (a window of ±7 days is 
allowed for all visits after screening) 
W-6 to 
D1a 
D1a 
M1 
M3 
M6 
M9 
M12 
UNSCHn 
Premature End 
of Treatmentb 
Adverse event collection 
<-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------> 
Efficacy 
EDSS 
 
Xj 
 
X 
X 
X 
X 
If MS relapse suspected 
X 
MRIo 
 
Xj 
 
X 
X 
 
X 
If needed 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
Pharmacokinetics 
SAR442168 pharmacokinetic plasma 
samples 
 
 
 
 
 
 
 
If MS relapse suspected 
or in case of index AEs 
Xp 
Pharmacodynamics / Biomarkers 
Exploratory biomarkers: 
 
 
 
 
 
Xl 
 
 
 
 
 
If MS relapse suspected 
or in case of index AEs 
X  
Exploratory biomarker plasma samples 
 
 
X 
 
X 
X 
 
X 
 
X 
Abbreviations: AE: adverse event; β-HCG: beta human chorionic gonadotropin; BTK: Bruton’s tyrosine kinase; C-SSRS: Columbia Suicide Severity Rating Scale; 
 D: day; 
ECG: electrocardiogram; EDSS: Expanded Disability Status Scale; FSH: follicle-stimulating hormone; IMP: investigational medicinal product; M: month; MRI: magnetic resonance imaging; MS: multiple sclerosis; 
; 
 UNSCH: unscheduled; W; week. Note: All assessments shall be done as designated in this SoA unless not permitted according to local 
regulations. 
a The Week 16 or the follow-up visit of the DRI15928 study may serve as the screening visit for LTS16004 (only tests not done during the Week 16 or follow-up visit of the DRI15928 study will need to be completed 
during the screening visit of LTS16004). If the participant is not enrolled in to LTS16004 during such visits, screening activities for LTS16004 can be performed at any time from 6 weeks to Day 1 before IMP 
administration in the LTS16004 study. The baseline visit can be combined with the screening visit (and the last visit of the DRI15928 study). Further guidance will be provided in the Study Reference Manual. 
b The participant should return for a follow-up visit 4 to 6 weeks after premature end-of-treatment. 
c Monthly (±1 week) telephone calls will be performed between the visits to monitor for any possible safety issues during the first year of the study. If a safety event is suspected, the participant will be asked to come 
for an unscheduled on-site visit for evaluation.  
d A full physical examination must be performed at screening; a brief physical examination is sufficient thereafter. The brief physical examination should be extended as needed at the judgment of the Investigator in 
the event of new findings. 
e Sample or measurement to be performed before IMP administration. 
f 
Tests will be repeated locally after 6 weeks (±1 week) of each planned visit during the first year of the study, starting after Month 3 visit. 
g Pre-study tests may be accepted if they are performed between Week -4 and Day 1 (including Week 12 or Week 16 tests in the DRI15928 study). 
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h Urine β-HCG is sufficient unless a pregnancy is detected or the urine test is inconclusive and a serum test needs to be used for verification or only serum testing is required by local regulation or Institutional 
Review board (IRB)/International Ethics Committee (IEC).  
i 
For women suspected/reported to have developed menopause since their inclusion in the DRI15928 study, FSH testing will be performed to confirm menopause. However, the participant will continue on the highly 
effective contraception until FSH result becomes available. 
j 
The last EDSS and MRI obtained in the DRI15928 study are acceptable, if they are performed within 6 weeks prior to Day 1 of the LTS16004 study. 
k Substudy at selected sites. Assessments to be performed if feasible. 
l 
Only for participants with delay between end of the DRI15928 study and start of the LTS16004 study. 
m For selected sites and participants who consented to the procedure. Refer to Section 8.1.4 for details. This part of the study may be ended prematurely if sufficient data have been gathered. 
n Once the dose for Part B is known, an unscheduled visit should be performed as quickly as possible (if the next study visit is not due within 4 weeks) to switch participants to part B on the selected dose. 
o For systemic corticosteroids and adrenocorticotropic hormone, a 1-month interval is required prior to the MRI scan. 
p PK to be collected only if pEOT visit can be scheduled within a maximum of 24 hours after the last IMP dose. 
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Table 2 - B - Schedule of activities (Years 2 to 4)  
Procedure 
Intervention Phase 
 
 
Month (a window of ±10 days is 
allowed) 
M15 
M18 
M21 
M24 
M27 
M30 
M33 
M36 M39 M42 M45 M48 
UNSCH 
Premature 
End of 
Treatmenta 
Visit at clinical site 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
Phone call or visit at clinical site 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study IMP Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAR442168 (dispensation and 
accountability) 
X 
X 
X 
X 
X 
X 
X 
X 
Xj 
X 
Xj 
X 
 
X 
(accountability 
only) 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationb,c 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
Body weight 
 
 
 
X 
 
 
 
X 
 
 
 
X 
If needed 
X 
Vital signsc 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
12-lead ECGc 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
If needed 
X 
Hematology, biochemistryc 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
If needed 
X 
Urinalysisc 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
If needed 
X 
β-HCG test (if applicable)d  
 
 
 
X 
 
 
 
X 
 
 
 
X 
If needed 
 
Suicidality assessment (C-SSRS) 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
If needed 
X 
Adverse event collection 
<----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------> 
Efficacy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EDSS 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
If MS relapse 
suspected 
X 
MRIg, h 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
If needed 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
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Procedure 
Intervention Phase 
 
 
Month (a window of ±10 days is 
allowed) 
M15 
M18 
M21 
M24 
M27 
M30 
M33 
M36 M39 M42 M45 M48 
UNSCH 
Premature 
End of 
Treatmenta 
Pharmacokinetics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAR442168 pharmacokinetic plasma 
samples 
 
 
 
 
 
 
 
 
 
 
 
 
If MS relapse 
suspected or in case 
of index AEs 
Xi 
Pharmacodynamics / Biomarkers 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exploratory biomarkers: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If MS relapse 
suspected or in case 
of index AEs 
X 
Exploratory biomarker plasma samples 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
Abbreviations: AE: adverse event; β-HCG: beta human chorionic gonadotropin; BTK: Bruton’s tyrosine kinase; C-SSRS: Columbia Suicide Severity Rating Scale; 
 ECG: electrocardiogram; 
EDSS: Expanded Disability Status Scale; IMP: investigational medicinal product; M: month; MS: multiple sclerosis; MRI: magnetic resonance imaging; 
 
UNSCH: unscheduled. Note: All assessments shall be done as designated in this SoA unless not permitted according to local regulations. 
a The participant should return for a follow-up visit 4 to 6 weeks after premature end-of-treatment. 
b A brief physical examination is sufficient. The brief physical examination should be extended as needed at the judgment of the Investigator in the event of new findings. 
c Sample or measurement to be taken before IMP administration. 
d Urine β-HCG is sufficient unless a pregnancy is detected or the urine test is inconclusive and a serum test needs to be used for verification or only serum testing is required by local regulation or Institutional 
Review board (IRB)/International Ethics Committee (IEC).  
e Substudy at selected sites. 
f 
For selected sites and participants who consented to the procedure. Refer to Section 8.1.4 for details. This part of the study may be ended prematurely if sufficient data have been gathered. 
g For systemic corticosteroids and adrenocorticotropic hormone, a 1-month interval is required prior to the MRI scan. 
h Starting from M15 (inclusive), a window of ±21 days is acceptable for MRI. 
i 
PK to be collected only if pEOT visit can be scheduled within a maximum 24 hours after the last IMP dose. 
j 
Dispensation at site or via direct-to-patient shipment. 
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Table 3 - C - Schedule of activities (Year 5)  
Procedure 
Intervention phase 
 
 
Month (a window of ±10 days is allowed) 
M51 
M54 
M57 
M60k 
Follow-up visitk 
(8 weeks after the last IMP 
administration) 
UNSCH 
Premature End 
of Treatmenta 
Visit at clinical site 
 
X 
 
X 
X 
X 
X 
Phone call or visit at clinical site 
X 
 
X 
 
 
 
 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Study IMP Administration 
 
 
 
 
 
 
 
SAR442168 (dispensation and 
accountability) 
Xj 
X 
Xj 
X (accountability only) 
 
 
 
Safety 
 
 
 
 
 
 
 
Physical examinationb, c 
 
X 
 
X 
X 
X 
X 
Body weight 
 
 
 
X 
X 
if needed 
X 
Vital signsc 
 
X 
 
X 
X 
X 
X 
12-lead ECGc 
 
X 
 
X 
X 
if needed 
X 
Hematology, biochemistryc 
 
X 
 
X 
X 
If needed 
X 
Urinalysisc 
 
X 
 
X 
X 
If needed 
X 
β-HCG test (if applicable)d  
 
 
 
X 
 
If needed 
 
Suicidality assessment (C-SSRS) 
 
X 
 
X 
X 
If needed 
X 
Adverse event collection 
<-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------> 
Efficacy 
 
 
 
 
 
 
 
EDSS 
 
X 
 
X 
X 
If MS relapse suspected 
X 
MRIg, h 
 
 
 
X 
 
If needed 
X 
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Procedure 
Intervention phase 
 
 
Month (a window of ±10 days is allowed) 
M51 
M54 
M57 
M60k 
Follow-up visitk 
(8 weeks after the last IMP 
administration) 
UNSCH 
Premature End 
of Treatmenta 
  
 
X 
 
 
 
 
 
 
Pharmacokinetics 
 
 
 
 
 
 
 
SAR442168 pharmacokinetic plasma 
samples 
 
 
 
 
 
If MS relapse suspected or in case 
of index AEs 
Xi 
Pharmacodynamics/ Biomarkers 
 
 
 
 
 
 
 
Exploratory biomarkers: 
 
 
 
 
 
 
 
 
 
If MS relapse suspected or In case 
of index AEs 
X 
Exploratory biomarker plasma samples 
 
 
 
 
X 
 
 
X 
Abbreviations: AE: adverse event; β-HCG: beta human chorionic gonadotropin; BTK: Bruton’s tyrosine kinase; C-SSRS: Columbia Suicide Severity Rating Scale; 
; ECG: electrocardiogram; 
EDSS: Expanded Disability Status Scale; IMP: investigational medicinal product; M: month; MRI: magnetic resonance imaging; MS: multiple sclerosis; 
 
 UNSCH: unscheduled. Note: All assessments shall be done as designated in this SoA unless not permitted according to local regulations. 
a The participant should return for a follow-up visit 4 to 6 weeks after premature end-of-treatment. 
b A brief physical examination is sufficient. The brief physical examination should be extended as needed at the judgment of the Investigator in the event of new findings. 
c Sample or measurement to be taken before IMP administration. 
d Urine β-HCG is sufficient unless a pregnancy is detected or the urine test is inconclusive and a serum test needs to be used for verification or only serum testing is required by local regulation or Institutional 
Review board (IRB) / International Ethics Committee (IEC).  
e Substudy at selected sites. 
f 
For selected sites and participants who consented to the procedure. Refer to Section 8.1.4 for details. This part of the study may be ended prematurely if sufficient data have been gathered. 
g For systemic corticosteroids and adrenocorticotropic hormone, a 1 month interval is required prior to the MRI scan. 
h Starting from M15 (inclusive), a window of ±21 days is acceptable for MRI. 
i 
PK to be collected only if pEOT visit can be scheduled within a maximum 24 hours after the last IMP dose.  
j 
Dispensation at site or via direct-to-patient shipment. 
k At the M60 visit, the participants who have completed the study and remain on SAR442168 may be offered participation in a Phase 3 long-term safety study. Follow-up visit assessment only performed for those 
participants who are not taking part in the long-term safety study. 
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2 
INTRODUCTION  
SAR442168 is a brain-penetrant, selective, covalent inhibitor of BTK. SAR442168 exhibits 
activity in the experimental allergic encephalomyelitis animal model used to evaluate 
immunomodulatory agents in treating MS. 
2.1 
STUDY RATIONALE  
The BTK pathway is an important signaling pathway in B lymphocytes and CNS myeloid cells 
like microglia. Both of these cell types have been implicated in the pathophysiology of MS. BTK 
is critical for B-cell activation, differentiation, and maturation, and it also regulates the activation 
of cells from other hematopoietic lineages such as basophils, mast cells, macrophages, and 
neutrophils. Accordingly, SAR442168, a CNS-penetrant BTK inhibitor, has the potential for 
a dual mechanism of action by inhibiting antigen-induced B-cell activation responsible for 
inflammation in the periphery and meninges and by modulating maladaptive microglial cells 
linked to neuroinflammation in the brain and spinal cord. The goal of this long-term study is to 
determine the long-term safety and efficacy of SAR442168 in RMS patients and to demonstrate 
that SAR442168 benefits in MS as measured by MRI are maintained.  
Participants completing the DRI15928 study may be enrolled in this long-term extension study. 
Participants will continue on the same assigned SAR442168 dose in a double-blinded manner 
until the Phase 3 dose is selected. 
2.2 
BACKGROUND  
Immunomodulatory drugs have been the mainstay of MS therapy. The role of B cells in MS 
pathogenesis has been validated clinically by ocrelizumab, a monoclonal antibody that selectively 
depletes CD20-expressing B cells in the periphery (1). Targeting B cells represents a departure 
from the prevailing dogma based on animal models that demonstrated therapeutic benefits from 
modulating T-cell activity and positions the B cell as the centerpiece of current MS drug 
development (2). Importance of immune cells residing in the CNS is also well known (3) and 
needs to be considered in MS pathogenesis. 
There is still a significant unmet need for therapies that target neuroinflammation with a goal of 
halting long-term disability and neurodegeneration in people with RMS and with progressive 
forms of the disease (PPMS and SPMS) (4). Even the most recent high efficacy 
disease-modifying therapies act mainly on adaptive immunity in the periphery with only modest 
ability to halt neuroinflammatory and neurodegenerative processes and stop disease progression, 
as also demonstrated by recent studies in progressive MS (5, 6). Therefore, development of MS 
treatments with new modes of action is of interest. 
Beyond the existing strategy to modulate cellular elements of adaptive immunity, there is 
mounting evidence that innate immunity, mediated by myeloid cell lineages (bone marrow 
derived monocytes/macrophages and CNS-resident microglial cells), is responsible for many of 
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the neurodegenerative aspects of MS that persist in spite of the effectiveness of approved disease 
modifying therapies in preventing acute relapses (7, 8). Immunomodulation directed at innate 
immunity has potential to curtail “smoldering neuroinflammation” and other manifestations of 
disease progression that remain unaddressed by current, approved therapies. 
BTK is an important intracellular signaling mediator in cells of adaptive and innate immunity. 
Accordingly, an inhibitor of BTK signaling targets both aspects of the immune system. BTK 
inhibits signaling pathways in B lymphocytes and myeloid cells, including CNS microglia. Both 
cell types have been implicated in MS pathophysiology. Further, as BTK signaling is vital for 
maturation of B cells into antibody-secreting plasma cells, BTK inhibition can modulate both 
cellular and humoral immunity. While SAR442168 is an irreversible inhibitor of BTK, its 
pharmacological effects on B-cell function are temporary, as B cells are not depleted and normal 
signaling can be restored by ongoing protein synthesis of new BTK enzyme over the course of 
several days in the absence of exposure to the inhibitor. Finally, because SAR442168 is brain 
penetrant, it has the potential for a dual mechanism of action by inhibiting antigen-induced B cell 
activation responsible for neuroinflammation and by modulating maladaptive microglial cells 
linked to neuroinflammation in the brain and spinal cord. Thus, SAR442168 has the potential to 
provide a superior benefit-risk ratio compared to currently available MS therapies. 
Repeat-Dose Toxicity Studies:  
In a 13-week Good Laboratory Practice (GLP) toxicology study in rats, there were no adverse 
effects. The no-observed-adverse-effect-level (NOAEL) in rats was 
 mg/kg/day, the highest 
dose administered.  
A 6-month oral toxicity study of SAR442168 was conducted in Wistar rats at 
 and 
 mg/kg/day. BTK inhibition (BTKi), target-related effects on immune function included T-cell 
dependent antibody response (TDAR) findings of decreased immunoglobulin (Ig) G and IgM 
responses to antigen at 2 mg/kg/day, and nematode infestation in the rectum at 2 mg/kg/day. 
Hemorrhage in the eye, pancreas, nasal cavity, and mesenteric lymph nodes were observed at 
 mg/kg/day. BTK is expressed by human platelets and participates in platelet activation through 
collagen receptor glycoprotein VI (GPVI), suggesting a target-mediated effect of SAR442168 (9). 
Pancreatic fibrosis and inflammation were observed in male rats at 
 mg/kg/day. Similar 
pancreatic effects have been documented in rats administered other BTK inhibitors, including 
LY3337641, GDC-0853, ibrutinib, and acalabrutinib, with no published reports in any other 
species (10, 11, 12, 13, 14). The findings involved a relatively low number of islets and were not 
associated with clinical chemistry changes suggestive of abnormal glucose regulation or exocrine 
pancreas injury including amylase or lipase (10, 11). The pancreatic effects of BTKi are time-, 
species-, strain-, and sex-specific. The spectrum of these microscopic effects is consistent with 
spontaneous findings reported in control Crl:CD(SD) rats and may constitute test-article-related 
acceleration of a common background finding in older rats. Lack of clinical reports of pancreatic 
dysfunction in patients treated with ibrutinib argue that pancreatic toxicity is unlikely to occur in 
humans. Cutaneous lesions were observed in rats at 
 mg/kg/day, consisting of macroscopic 
observations and microscopic findings of erosion, ulcer, and focal acanthosis/hyperkeratosis. 
Cutaneous toxicity is commonly associated with inhibition of epidermal growth factor receptor 
(EGFR) (15, 16). SAR442168 inhibited EGFR in a kinase screening panel (IC50 4 nM) and was 
active in a cellular assay for EGFR (364 nM). As such, the cutaneous effects in rats administered 
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SAR442168 were considered possibly related to off-target inhibition of EGFR. In the lungs, 
foamy alveolar macrophages were observed at 2 mg/kg/day. This finding had no apparent impact 
on the structural integrity or function of the lung parenchyma, was considered an exacerbation of 
a spontaneous background finding in the rat and was not considered adverse. While a NOAEL 
was not observed, the adverse effects seen in the 6-month toxicity study of SAR442168 in rats are 
similar to reported exaggerated pharmacology and/or toxicity of other BTK inhibitors. The 
low-observed-adverse-effect-level (LOAEL) was mg/kg/day. The SAR442168 exposure in 
Week 26 at the LOAEL (AUC0-24) was 
 and 
 ng.h/mL, respectively, in males and females.  
In a GLP, 4-week toxicity study in dogs, the dose-limiting toxicity included lowered plasma 
protein and tissue edema, which were reversible upon discontinuation of treatment. The NOAELs 
in dogs were and  mg/kg, in females and males, respectively. In a 13-week oral toxicity study 
in dogs, the NOAEL was  mg/kg/day, the highest dose administered. 
A 9-month, oral toxicity study of SAR442168 was conducted in beagle dogs at 
 and 
mg/kg/day. Minimal to mild decreases in serum albumin concentration and A:G ratio of 
unknown mechanism were observed at 
 mg/kg/day, consistent with that seen in the 1-month 
toxicity study in dogs at 
 mg/kg/day. A single female dog at 
mg/kg/day exhibited minimal 
interstitial edema of the pancreas, which correlated with low serum albumin, suggesting that it 
may have been test article related. Decreased absolute counts and relative proportions of B cells 
(CD21+) at
 mg/kg/day females and at 
 mg/kg/day males were considered related to the 
pharmacologic mechanism of action. Microscopic findings included minimal to slight decreased 
cellularity of various lymphoid organs/tissues at 
 mg/kg/day; minimal to moderate 
congestion/hemorrhage in the mesenteric and/or retropharyngeal lymph node, stomach, colon, 
ileum, testis, and/or kidney at 
 mg/kg/day; and associated pigment consistent with hemosiderin 
in the mesenteric and/or retropharyngeal lymph nodes 
mg/kg/day and Kupffer cells in 
 mg/kg/day females and 
mg/kg/day males. As described for the rat, the minimal hemorrhage 
in various tissues was considered related to the known pharmacology of BTK inhibition (target-
related effects on platelet aggregation). Due to the mild severity of findings, and the lack of 
impact on the health and wellbeing of the animals, these effects were considered non-adverse. The 
NOAEL was considered 
 mg/kg/day. The exposure at the NOAEL (AUC0-24h) was 
and 
ng.h/mL, respectively, in males and females on Day 273 (ie, 9 months). Exposure ratios in 
the repeat dose toxicity studies are summarized in Table 4. 
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Table 4 - Exposure ratios in repeat dose toxicity studies in rats and dogs  
Species 
Type of study 
(duration/route) 
Dose 
(mg/kg/day) 
NOAEL  
(mg/kg/day) 
AUC Exposure at NOAEL (ng.hr/mL) 
(exposure ratio) 
 SAR442168a, b, c 
Rat  
28-day PO 
 
 
 
 
 
13-week PO 
 
 
 
 
6-month POc 
 
 
 
 
Dog 
28-day PO 
 
 
 
 
 
13-week PO 
 
 
 
 
9-month PO 
 
 
 
 
Abbreviations: AUC: area under the curve; F: female; M: male; NOAEL: no-observed-adverse-effect-level; PO: per os (oral).  
a AUC last for 28-day and 13- week toxicity studies; AUC 0-24 for 6- and 9-month toxicity studies. 
b SAR442168 exposure ratio based on the 
 mg (mixed fasted and fed state) in 
 ng.h/mL) 
c Low-observed–adverse-effect-level (LOAEL) exposure provided for the 26-week study in rats at Week 26 since a NOAEL was not 
identified. 
Laboratory abnormalities in animals:  
Decreased plasma proteins associated with tissue edema were observed in dogs at doses of 
 mg/kg/day (1- and 9-month toxicity studies). 
Decreased IgG and IgM responses to antigen were observed in rats at doses of 
mg/kg/day. 
Decreased absolute counts and relative proportions of B cells (CD21+) were observed in dogs at 
 mg/kg/day in females and at 
mg/kg/day in males. 
Carcinogenesis, mutagenesis, and impairment of fertility:  
Carcinogenicity studies have not yet been conducted with SAR442168.  
In genotoxicity studies, SAR442168 tested negative in an in vitro bacterial genotoxicity (Ames) 
assay. In an in vitro test for chromosome aberration, increased structural aberrations were 
observed at the highest SAR442168 concentrations tested however, these concentrations were also 
cytotoxic. SAR442168 tested negative in an in vivo rat bone marrow micronucleus test up to the 
highest dose evaluated of 
 mg/kg/day. 
In a fertility study of SAR442168 in male and female rats, there were no compound-related AEs 
on male reproductive organ weights, male and female reproductive indices, or cesarean section 
parameters. The NOAEL for parental toxicity, male and female fertility, reproductive 
performance, and early embryonic development was 
mg/kg/day, the highest dose administered. 
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In an embryo-fetal toxicity study in rats, decreased mean gravid uterine weight, increased 
post-implantation loss (early resorptions), decreased number of live fetuses, and minimal decrease 
in fetal body weight occurred at 
 mg/kg/day. There were no external, visceral, or skeletal 
malformations. The maternal NOEL was 
 mg/kg/day and the developmental NOEL was 
 mg/kg/day. On Gestation Day 12, the mean plasma AUC0-24 at the developmental NOAEL was 
 ng.h/mL for SAR442168. 
In an embryo-fetal toxicity study in rabbits, dose-related, minimally delayed ossification of the 
hyoid bone was noted at ≥5 mg/kg/day. This finding was considered non-adverse, reflecting 
a slight and transient developmental (growth) delay in a few fetuses. There were no effects on 
intrauterine parameters (eg, post-implantation loss, number of live and dead fetuses, resorptions); 
and no external, visceral, or skeletal malformations. The maternal and developmental NOAEL 
were 
 mg/kg/day. On Gestation Day 12, the mean plasma AUC0-24 at the NOAEL was 
 ng.h/mL for SAR442168.  
The NOAELs and exposure ratios in the embryo-fetal toxicity studies are summarized in Table 5.  
Table 5 - NOAELs and exposure ratios in the embryo-fetal toxicity studies  
Species 
Type of study 
(duration/route) 
Dose 
(mg/kg/day) 
Embryo-
Fetal NOAEL 
(mg/kg/day) 
AUC0-24 exposure at NOAEL 
(ng.hr/mL) 
(exposure ratio) 
 SAR442168a 
Pregnant Rat 
Embryo-fetal toxicity 
GD6-17 PO 
 
 
 
 
Pregnant rabbit 
Embryo-fetal toxicity 
GD6-19 PO 
 
 
 
 
Abbreviations: AUC: area under the curve; GD: gestation day; NOAEL: no-observed-adverse-effect level; PO: orally. 
a SAR442168 exposure ratio based on the 
 mg (mixed fasted and fed state) in 
 ng.h/mL). 
Renal and hepatic impairment: The pharmacokinetics (PK) of SAR442168 have not been 
investigated in human subjects with renal or hepatic impairment. Based on the routes of 
elimination, SAR442168 exposure may increase in participants with hepatic impairment. 
Therefore, SAR442168 should not be administered to individuals with underlying hepatic 
impairment until this has been evaluated in clinical studies. Clinically relevant differences are not 
expected when treating participants with renal impairment, as SAR442168 is not primarily 
eliminated by the renal route. 
Drug abuse and dependence: SAR442168 is not classified as a controlled substance. No data are 
available regarding the potential of SAR442168 for abuse and dependence. 
Phase 1 first-in-human single-ascending-dose/multiple-ascending-dose study: Seventy-four 
healthy participants (30 in the single ascending dose [SAD]), 40 in the multiple ascending dose 
[MAD]), and 4 in the cerebrospinal fluid [CSF] exposure phases) received up to 120 mg 
SAR442168 in the SAD phase, up to 90 mg once daily for 10 days in the MAD phase, and 
120 mg (single dose) in the CSF exposure study. No SAEs were reported in Phase 1. 
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One participant in the MAD 60 mg cohort was unblinded due to decreased platelet count. Platelet 
counts will therefore be monitored during the study. Reduction in platelets observed during the 
study did not exceed 100 x 109/L. SAR442168 is rapidly absorbed (time to reach maximum 
observed concentration [tmax] is close to 1 hour) and rapidly eliminated (elimination half-life [t1/2] 
was <2.5 hours). When 
 mg SAR442168 oral solution was administered with a moderate-fat 
meal, a mild food effect was observed with an increase of 1.55-fold in AUC and 1.37-fold in 
maximum serum concentration (Cmax) (n = 4 participants). Covalent binding enables a durable 
pharmacodynamic (PD) effect, and steady state is achieved within 5 to 10 days. Cerebrospinal 
fluid exposure has been confirmed in humans with CSF concentrations of approximately 
1.87 ng/mL at 2 hours, which is more than 10 times greater than the cell-based IC50 of 
0.18 ng/mL. 
Phase 1 relative bioavailability and food effect for a SAR442168 tablet formulation: 
A single-center, 3-period, open-label, randomized, complete crossover study was performed to 
assess the relative bioavailability and food effect for a novel SAR442168 immediate release, oral 
solid tablet formulation compared to a reference oral liquid formulation that was used in a Phase 1 
SAD/MAD study. This study was performed in a cohort of 14 healthy participants. 
milligrams of SAR442168 oral solution had a similar bioavailability to 
 mg SAR442168 
as 
 tablets in fasted conditions with a ratio (tablet/solution) of 1.0 in area under the 
concentration-time curve until the last quantifiable concentration (AUClast) and 1.03 in Cmax for 
SAR442168. When SAR442168 tablets were administered with a high fat meal, a moderate food 
effect was observed at 
 mg with an increase of 1.80-fold in AUClast and no effect on Cmax 
(a 1.18-fold increase) for SAR442168. 
New Phase 1 dose escalation single- and multiple-ascending-dose studies (TDU16831/TDR16862) 
are ongoing to obtain additional safety, tolerability and PK information on SAR442168 and 
metabolite(s), with a food effect investigation, at higher doses. These doses are higher than the dose 
range used in the initial first-in-human studies, where no maximum tolerated dose was identified. In 
addition, exposure margins with preclinical toxicity data enable higher dose exploration. The study 
aimed at evaluating the safety/tolerability and PK profiles at higher doses, food effect, and PK/PD 
(exposure-QT) analysis. Cerebrospinal fluid exposure of SAR442168 was measured after 
administering a single dose of the current Phase 3 formulation 
 to compare with exposure 
after a 
 mg dose as determined in the first-in-human study. The additional Phase 1 ECG 
evaluation at exposures above the highest clinically relevant exposure allows covering of all 
intrinsic and extrinsic factors affecting the PK of SAR442168. 
Drug-drug interactions: The potential for drug-drug interactions has been investigated in vitro 
with SAR442168 evaluated as a substrate, inhibitor, or inducer of cytochrome P450 (CYP450) 
metabolizing enzymes. The results show that SAR442168 does not significantly induce nor inhibit 
CYP450 enzymes at therapeutically relevant concentrations. Therefore, SAR442168 is unlikely to 
alter the PK of other drugs that are metabolized by these enzymes. In vitro, SAR442168 was not 
an inhibitor or a substrate of drug transporters including human OAT1, OAT3, OCT1, OCT2, 
OATP1B1, OATP1B3, BCRP, and BSEP and was a minor substrate for P glycoprotein. 
Therefore, clinically significant transporter related drug-drug interactions with SAR442168 are 
considered unlikely. 
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Based on preclinical drug metabolism studies, SAR442168 is a substrate of the CYP3A4 and 
CYP2C8 isoenzymes. In healthy participants, a potent CYP3A4 inhibitor (itraconazole 200 mg 
once daily for 4 days) increased SAR442168 (area under the curve [AUC]) exposure by 1.8-fold 
(Study INT16385), and a potent CYP2C8 inhibitor (gemfibrozil 600 mg twice daily for 6 days) 
increased SAR442168 (AUC) exposure by 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 
 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 by 6-fold 
(Study INT16726). Therefore, potent and moderate (based on prediction) CYP3A inducers are not 
permitted due to their potential to decrease SAR442168 exposure and efficacy (see the list of such 
drugs in Appendix 7, Section 10.7). 
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. 
 
 
 
  
 
 
 
 
 
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Potential risks 
SAR442168 has been studied in healthy participants and participants with RMS. In the completed 
Phase 1 clinical trials in healthy participants, oral administration of SAR442168 was generally 
safe and well tolerated.  
The results from the Phase 2b trial (DRI15928) suggest that SAR442168 is generally safe and 
well tolerated in patients with RMS. No new risks were identified in this trial. The key results are 
summarized as follows:  
• There was no death or treatment-emergent adverse event (TEAE) leading to permanent 
treatment discontinuation during the study. One treatment-emergent 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 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, and both events were 
assessed as unrelated to the study drug by the Investigators. Both participants completed 
the DRI15928 study and successfully rolled over to the long-term safety 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 by the Investigator. Details of the anatomic location and clinical presentation of the 
2 skin conditions were unavailable. The 2 events of mild microscopic hematuria were 
assessed as unrelated to the study drug.  
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• No severe infections occurred. The most frequently reported (≥3 events total) in the 
SAR442168 treatment period were upper respiratory tract infection, nasopharyngitis, 
gastroenteritis, and respiratory tract infection.  
• No clinically significant cytopenia, including thrombocytopenia and neutropenia, was 
reported or detected based on hematologic lab results, and no cardiac arrhythmia was 
observed via ECG monitoring during the study.  
Based on SAR442168 nonclinical safety data, Phase 1 results from healthy participants, Phase 2b 
results in participants with RMS, and the published data of other marketed or investigational BTK 
inhibitors for various indications, the potential risks of SAR442168 are as follows:  
• Bleeding (hemorrhage) 
• Infections 
• Cytopenia including thrombocytopenia 
• Atrial arrhythmias (atrial fibrillation and atrial flutter) 
• Liver enzymes (alanine aminotransferase and aspartate transaminase) elevation 
In the ongoing Phase 3 and LTS studies, tolebrutinib has been generally well tolerated to date. 
An identified risk for tolebrutinib has been identified as follows: 
Treatment-emergent SAEs of drug-induced liver injury (DILI) were reported in the ongoing 
Phase 3 trials; cases occurred between 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 (17, 18). 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 preceding 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 adverse event of special interest (AESI) in all ongoing and future clinical trials. 
In the preceding Phase 2b trial in 130 patients with RMS, 23.8% of participants reported only 
mild or moderate infections at the end of 12 weeks of treatment with SAR442168. No participant 
discontinued treatment due to infection or any other TEAE. At present, it is unknown if people 
with MS are at increased risk for SARS CoV-2 infection, acquiring COVID-19 or developing 
severe COVID-19 (17). 
In the current trial, eligibility criteria exclude people with known risk factors for 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 has updated 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 RMS patients, the Sponsor maintains that the trial can be conducted as planned. 
Overall benefit: risk conclusion 
No safety or tolerability concerns have been identified in the completed Phase 1 studies in healthy 
participants or the Phase 2b trial (DRI15928) in participants with RMS. In addition, the positive 
Phase 2b primary endpoint results support the potential for clinical efficacy.  
Drug-induced liver injury has been identified in the ongoing Phase 3 trials. The reported events 
occurred in Months 1 to 3 after the start of the IMP. Exclusion criteria and monitoring frequency 
have been updated in all actively recruiting protocols.  
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 6 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
• 
To determine the long-term safety and tolerability of 
SAR442168 in RMS participants 
Adverse events (AEs), serious adverse events (SAEs), safety 
findings on magnetic resonance imaging (MRI), potentially 
clinically significant abnormalities (PCSAs) in laboratory tests, 
electrocardiogram (ECG), or vital signs during the study period. 
Secondary 
• 
To evaluate efficacy of SAR442168 on disease 
activity, assessed by clinical and imaging methods. 
• 
Number of new gadolinium (Gd)-enhancing. 
T1-hyperintense lesions by brain MRI. 
• 
Number of new or enlarging T2 lesions. 
• 
Total number of Gd-enhancing T1-hyperintense 
lesions. 
• 
Number of relapses (annualized relapse rate [ARR]) 
during the study period. 
• 
Change in Expanded Disability Status Scale 
(EDSS) score from baseline over time. 
Tertiary/exploratory 
To evaluate efficacy of SAR442168 on disease activity and the 
pharmacodynamics (PD) of SAR442168.  
• 
 in case of index AEs (cytopenia 
and arrhythmias).  
• 
 
  
• 
Change in volume of T2-lesions from baseline 
over time. 
• 
Change in brain volume, including regional 
changes, over time. 
• 
Change in the number of T1‑hypointense lesions 
from Baseline over time. 
• 
Change in myelin integrity and other features of 
MRI lesions as measured by magnetization transfer 
ratio and susceptibility-weighted imaging MRI over 
time. 
• 
Proportion of participants with no new MRI disease 
activity through the end of the study. 
• 
Proportion of relapse-free participants through the 
end of the study.  
• 
 
 
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3.1 
APPROPRIATENESS OF MEASUREMENTS  
Magnetic resonance imaging markers of inflammatory activity in the brain will be collected as in 
most RMS clinical trials. Number of new Gd-enhancing T1-hyperintense lesions will be used to 
assess the efficacy of SAR442168. This radiographic outcome has been established as 
a highly-reliable predictive biomarker for clinical efficacy in pivotal studies in MS. 
Central review will be used to identify new Gd-enhancing T1-hyperintense lesions not present at 
the previous MRI. The count of new Gd-enhancing T1-hyperintense lesions will also be used as 
a secondary endpoint to detect any effect on pre-existing inflammatory foci. The number of new 
and enlarging T2 lesions, a marker of inflammatory activity and brain tissue destruction in RMS, 
will also be evaluated in central review to collect additional data with respect to the efficacy of 
SAR442168.  
Relapse-related endpoints (annualized relapse rate [ARR], proportion of relapse-free participants) 
are widely used as endpoints in clinical trials.  
The EDSS is widely used to measure neurological disability in clinical trials and routine 
settings (19). 
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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
This study is a long-term follow-up study to determine the safety and efficacy of SAR442168. 
Participants who completed treatment with SAR442168 in the previous DRI15928 study are 
eligible for enrollment. Participants will start the treatment after informed consent as soon as 
possible.  
The study will consist of 2 parts: 
Part A: Double-blind period of continued treatment with the respective SAR442168 dose 
administered in the DRI15928 study 
Until the dose of SAR442168 to be used in Phase 3 is determined, participants will continue 
treatment with their same SAR442168 dose used in the DRI15928 study. Cohort 1 of the 
DRI15928 study that exits the trial receiving placebo from Weeks 13 to 16 will receive the active 
treatment dose assigned to them at randomization and administered during Weeks 1 to 12. The 
double-blind will be maintained until the selection of the Phase 3 dose is made based on the 
SAR442168 clinical studies including the DRI15928 study.  
Part B: Open-label period of a single-group treatment with the Phase 3 dose, 60 mg SAR442168. 
All participants providing consent to Part B of the study will be switched to open-label treatment 
with the selected dose. 
If the participant is not willing to switch to the selected dose of SAR442168, the participant will 
be withdrawn from the study and a follow-up visit will be performed 4 to 6 weeks after the 
last study intervention.  
The Independent Data Monitoring Committee (IDMC) will follow safety data periodically as 
detailed in the DMC charter. Additional ad hoc IDMC reviews may occur at any time should 
a safety risk be suspected. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
Until the start of Part B of this study, participants will continue treatment with their same 
SAR442168 dose used in the DRI15928 study. The double-blind period (ie, Part A) will reduce 
the potential for bias in the evaluations and data collection to support safety and efficacy of 
several doses of SAR442168 beyond 12 weeks of treatment, and pooled analysis to evaluate 
efficacy and safety. 
Open-label treatment with the selected Phase 3 SAR442168 dose during Part B will provide 
long-term safety data on SAR442168. Efficacy data will be collected as supportive data. 
Open-label treatment should introduce minimal bias for interpreting MRI and other endpoints 
such as biomarkers and protocol defined MS relapse. Moreover, regular training of EDSS 
assessors will help minimize potential bias for interpreting disability outcomes. 
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4.3 
JUSTIFICATION FOR DOSE  
The choice of the dose of 60 mg SAR442168 taken with a meal is based on the results of the 
Phase 2b dose-finding trial for SAR442168 in participants with RMS (DRI15928).  
In this study, doses of 5, 15, 30, and 60 mg SAR442168 were tested in a 12-week double-blind 
treatment period with the number of new Gd-enhancing T1-hyperintense lesions at the end of the 
12 weeks of SAR442168 treatment as the primary endpoint. The results demonstrated 
a dose-response relationship for SAR442168 as evidenced by a reduction in the number of new 
Gd-enhancing T1-hyperintense brain lesions detected by brain MRI after 12 weeks of treatment. 
There was an 85% relative reduction in lesions at 12 weeks in the 60 mg dose group as compared 
with placebo. This was obtained from the negative binomial regression model adjusted for 
baseline Gd-enhancing T1-hyperintense lesion activity. The dose-response relationship for the 
secondary endpoint of new or enlarging T2 lesions also supported the choice of the 60 mg dose.  
Analysis of the PK data and effect of fed status on SAR442168 exposure showed a positive food 
effect with an increase in AUC0-24 of approximately 2-fold. Moreover, the correlation between the 
treatment response and the exposure to SAR442168 showed that higher exposure was associated 
with low numbers of new Gd-enhancing T1-hyperintense lesions after 12 weeks of treatment. 
Approximately half the participants took SAR442168 with food during the Phase 2b trial with no 
apparent safety or tolerability issues. Taken together, these data support the recommendation to 
take SAR442168 with a meal.  
There was no correlation between the dose of SAR442168 administered and the number of 
TEAEs. The most common events (preferred terms) observed in participants in the SAR442168 
treatment arms were headache, upper respiratory tract infection, and nasopharyngitis. There were 
low numbers of AESIs and PCSAs observed in multiple dose groups. Overall, no new risks were 
identified in this trial. 
4.4 
END OF STUDY DEFINITION  
A participant is considered to have completed the study if he/she has completed Parts A and B of 
the trial, including the last visit. 
The end of the study is defined as the date of the last visit of the last participant in the study. 
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5 
STUDY POPULATION  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
INCLUSION CRITERIA  
Participants will be enrolled in this study upon written and signed informed consent. 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
Not applicable.  
Type of participant and disease characteristics 
I 01. Participants must have completed treatment in the DRI15928 study before screening. 
I 02. Female participants must continue to use an acceptable effective contraception method of 
birth control from inclusion and until the last study dose, except if she has undergone 
sterilization at least 3 months earlier or is postmenopausal. Menopause is defined as being 
amenorrheic for ≥12 months with plasma follicle-stimulating hormone (FSH) level 
>30 UI/L. 
I 03. Deleted in Amended Protocol 03.  
I 04. Deleted in Amended Protocol 03. 
I 05. Deleted in Amended Protocol 03. 
Weight 
Not applicable. 
  Informed Consent 
I 06. The participant must have given written informed consent prior to undertaking any study 
related procedure. 
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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 confirmed concomitant laboratory or ECG abnormality or medical 
condition deemed by the Investigator incompatible with continuation of SAR442168 
treatment. 
E 02. The participant has received any live (attenuated) vaccine (including but not limited to 
varicella zoster, oral polio, and nasal influenza) between the last DRI15928 visit and the 
first treatment visit in the LTS16004 study. 
Prior/concomitant therapy 
E 03. The participant has received a non-study MS disease-modifying treatment between the 
last visit in Study DRI15928 and inclusion in Study LTS16004, which by judgment of the 
Investigator may add unjustified risk to switching back and continuing treatment with 
SAR442168. The participant has received any of the medications/treatments listed in table 
below within the specified time frame. Note: the participant may be considered eligible if 
the washout period is completed after the last dose of such non-study disease-modifying 
treatment, except for interferon or glatiramer acetate treatment. 
 
Medication 
Exclusionary if used/used within 
required wash-out period 
Systemic corticosteroids, adrenocorticotropic hormone 
1 month prior to MRI scan 
Dimethyl fumarate 
1 month prior to dosing with SAR442168 
Intravenous (IV) immunoglobulin, fingolimod, natalizumab (participants 
who have discontinued natalizumab in the 6 months prior to 
randomization should be evaluated to rule out progressive multifocal 
leukoencephalopathy) 
2 months prior to dosing with SAR442168 
Teriflunomide 
2 years prior to dosing with SAR442168 or 1 month 
prior to dosing with SAR442168 if participant 
undergoes an accelerated elimination procedure 
before randomization 
B-cell-depleting therapies such as ocrelizumab and rituximab 
6 months prior to dosing with SAR442168 or until 
return of B-cell counts to normal levels, whichever is 
longer 
Mildly to moderately immunosuppressive/chemotherapeutic 
medications such azathioprine and methotrexate 
6 months prior to dosing with SAR442168 
Highly immunosuppressive/chemotherapeutic medications: 
mitoxantrone up to 120 mg/m2 body surface area, cyclophosphamide, 
cladribine 
2 years prior to dosing with SAR442168 
Alemtuzumab 
4 years prior to dosing with SAR442168. 
Lymphoid irradiation, bone marrow transplantation, mitoxantrone (with 
evidence of cardiotoxicity following treatment, or cumulative lifetime 
dose >120 mg/m2), other strongly immunosuppressive treatments with 
very long-lasting effects. 
Any time. 
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E 04. The participant is receiving strong inducers or inhibitors of CYP3A or CYP2C8 hepatic 
enzymes. Note: Such drugs need to be stopped at least 5 half-lives before study drug 
administration. 
E 05. The participant is receiving anticoagulant/antiplatelet therapies, including: 
- 
Acetylsalicylic acid (aspirin), 
- 
Antiplatelet drugs (eg, clopidogrel), 
- 
Warfarin (vitamin K antagonist), 
- 
Heparin, including low molecular weight heparin (antithrombin agents), 
- 
Dabigatran (direct thrombin inhibitor), 
- 
Apixaban, edoxaban, rivaroxaban (direct factor Xa inhibitors). 
Note: All above drugs need to be stopped at least 5 half-lives before study drug administration 
except for aspirin, which needs to be stopped at least 8 days beforehand. 
Prior/concurrent clinical study experience 
E 06. The participant is taking part in another interventional clinical trial of another drug 
substance. 
E 07. Uncooperative behavior or any condition that could make the participant potentially 
non-adherent with the study procedures. 
Other exclusions 
E 08. The participant is accommodated in an institution because of regulatory or legal order; 
prisoners or subjects who are legally institutionalized.  
E 09. Participants 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. 
E 10. The participant is dependent on the Sponsor or Investigator (in conjunction with 
Section 1.61 of the International Council for Harmonization [ICH] Good Clinical Practice 
[GCP] Ordinance E6). 
E 11. Participants are employees of the clinical study site or other individuals directly involved 
in the conduct of the study, or immediate family members of such individuals. 
E 12. Sensitivity to any of the study interventions, or components thereof, or drug or other 
allergy that, in the opinion of the Investigator, contraindicates participation in the study. 
E 13. The participant is pregnant or is a breastfeeding woman.  
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5.3 
LIFESTYLE CONSIDERATIONS  
5.3.1 Meals and dietary restrictions  
The IMP shall be taken with meals. Whenever possible, the mealtime (eg, breakfast, lunch, etc) 
should be consistent throughout the study. The typical time of day at which the IMP is 
administered will be collected at each visit. In case the mealtime for IMP administration needs to 
be changed, a gap of a minimum of 12 hours between 2 doses should be maintained. 
5.3.2 Caffeine, alcohol, and tobacco  
For each visit, participants will abstain from ingesting caffeine- or xanthine-containing products 
(eg, coffee, tea, cola drinks, and chocolate) for 2 hours before the on-site study drug 
administration. 
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. 
For each visit, participants will abstain from alcohol for 24 hours before the on-site study drug 
administration. 
5.3.3 Activity  
Not applicable. 
5.4 
SCREEN FAILURES  
Screen failures are defined as participants who consent to participate in the LTS16004 study but 
cannot continue due to eligibility criteria. The likelihood of screen failure in this extension study 
is very low. 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) will not be 
rescreened, unless they fail due to a medical condition which precludes continuation of the 
intervention, which is expected to resolve. In such case screening examinations can be repeated 
within 6 weeks to re-evaluate eligibility. 
5.5 
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 
Section 10.9, Appendix 9: Contingency measures for a regional or national emergency that is 
declared by a governmental agency should be considered for screening, enrollment, 
randomization, and administration of the study intervention. 
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6 
STUDY INTERVENTION  
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. 
6.1 
STUDY INTERVENTION(S) ADMINISTERED  
This study intervention includes an investigational medicinal product (IMP) and 
a noninvestigational medicinal product (NIMP). 
6.1.1 Investigational medicinal product  
In study Part A participants will continue their previous SAR442168 dose in one of 4 dose groups as 
in the DRI15928 study. Participants in Cohort 1 of the DRI15928 study that exited the trial after 
receiving placebo from Weeks 13 to 16 will receive the active treatment dose assigned to them at 
randomization and administered during Weeks 1 to 12. During Part A, to maintain blinding, 
participants will receive 4 tablets once per day in a blinded fashion. The 4 tablets taken daily consist 
of some combination of 2.5 mg, 15 mg, or placebo to achieve the assigned dose. In Part B all 
participants will form a single dose group assigned to receive the selected Phase 3 dose. The IMP 
should be administered with a meal. The meal (breakfast, lunch, or dinner) should be consistent in 
terms of time throughout the study. Details for the interventions are provided in Table 7. 
Table 7 - Overview of study interventions administered  
ARM name 
IMP 
NIMP 
Intervention name 
SAR442168 
Contrast medium 
Type 
Drug 
Diagnostic Test 
Dose formulation 
Film coated tablet 
Not applicable 
Unit dose strength(s) 
2.5 or 15 mg tablets (Part A) 
15 or 60 mg tablets (Part B) 
Not applicable 
Dosage level(s) 
In study Part A participants will continue 
previous SAR442168 dose in one of 4 dose 
groups. In Part B all participants will receive 
60 mg dose. 
A radiological, signal-enhancing, 
intravenous contrast medium will be 
used for T1 contrast enhanced MRI 
sequences. A locally approved medium 
will be used. 
Route of administration 
Oral 
IV injection 
IMP and NIMP 
IMP 
NIMP 
Packaging and labeling 
The IMP will be packaged in wallets, which will 
further be packaged in Part A into visit boxes. 
Each wallet and box will be labeled as 
required per country requirements. 
Not applicable 
[Current/Former 
name(s) or alias(es)] 
Not applicable 
Not applicable 
Abbreviations: IMP: investigational medicinal product; IV: intravenous; NIMP: noninvestigational medicinal product. 
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Investigational medicinal product will be dispensed at regular site visits or at an unscheduled visit 
at the time of the switch to Part B. 
Between the protocol-scheduled on-site visits, interim visits may be required for IMP dispensing. 
As an alternative to these visits, SAR442168 may be supplied from the site to the participant via 
a Sponsor-approved courier company (direct-to-patient shipment) where allowed by local 
regulations and approved by the participant. 
For a regional or national emergency declared by a governmental agency that results in travel 
restrictions, confinement, or restricted site access, contingency measures are included in 
Section 10.9, Appendix 9: Contingency measures for a regional or national emergency that is 
declared by a governmental agency.  
6.1.2 Noninvestigational medicinal product  
A radiological, signal-enhancing, IV contrast medium will be used for T1 contrast-enhanced MRI 
sequences. A locally approved contrast agent will be used. 
Due to a potential safety risk related to deposition of certain IV Gd contrast agents in the brain, 
these agents should be used in accordance with local recommendations and regulations (20). 
Otherwise, use of these agents will be similar to their routine use and will be sourced locally. The 
study manual will provide more details of their administration. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
1. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for IMPs received and any discrepancies are reported and 
resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive IMPs and only authorized site staff 
may supply or administer IMPs. All IMPs 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 IMP accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records). 
4. Further guidance and information for the final disposition of unused IMPs are provided in 
the Pharmacy Manual. 
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 8.3.12). 
Under no circumstances will the Investigator supply IMP to a third party (except for direct-to-patient 
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. 
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6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
In the DRI15928 study, participants will be centrally assigned to 1 of 8 arms (4 dose groups in 
each of the 2 cohorts at equal ratio to start with SAR442168 (in Cohort 1) or placebo (in Cohort 2) 
period before cross-over, using an IVRS/IWRS.  
During the double-blind period of LTS16004 study, participants will continue treatment with the 
dose of SAR442168 assigned during the DRI15928 study. Investigators will remain blinded to 
each participant’s assigned cohort (sequence) and dose during the double-blind period of the 
study. 
Blind break (IVRS/IWRS) 
The IVRS/IWRS will be programmed with blind-breaking instructions. In case of an emergency, 
the Investigator has the sole responsibility for determining if unblinding of a participant’s 
treatment assignment is warranted. Participant safety must always be the first consideration in 
making such a determination. If the Investigator decides that unblinding is warranted, the 
Investigator should make every effort to contact the Sponsor prior to unblinding a participant’s 
treatment assignment unless this could delay emergency treatment of the participant. If 
a participant’s treatment assignment is unblinded, the Sponsor must be notified within 24 hours 
after breaking the blind. The date and reason that the blind was broken must be recorded in the 
source documentation and case report form, as applicable. 
Methods of blinding 
During the double-blind period of this study, this study is blinded for SAR442168 dose. 
Participants will continue treatment with their same SAR442168 dose used in the DRI15928 
study. 
During the double-blind period of this study, Investigators will not have access to MRI data 
except for any non-MS related findings, which will be communicated in order to evaluate the 
safety of the participant. The radiology service for the site will be in charge of timely reporting of 
any non-MS findings on MRI to the Investigator. 
The IDMC will be used to periodically monitor safety data from this study. During the double-
blind period of this study, unblinded data will be provided for IDMC review by an unblinded 
independent statistician. Study team members, Investigators, and study participants will not have 
access to unblinded data. 
Once the dose for the Part B is selected, all participants will be switched to the open-label 
treatment with this selected dose. From this point, the Investigators will be provided the results of 
the MRI reports. With yearly MRI being the standard in normal clinical practice for proper 
management of MS patients, Investigators will be provided MRI reports in the unlikely event that 
the DRI15928 and Part A of the LTS16004 study stretch longer than a year. 
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6.4 
STUDY INTERVENTION COMPLIANCE  
At the end of each on-site visit, the participants will receive IMP quantities up to the next visit 
(onsite or phone visit) as well as a diary where they will record all doses not taken at the 
investigational site. The diary will be kept as source data in the participant’s study file. 
It is the responsibility of the Investigator to check the participant’s compliance to the IMP. 
Participant’s compliance is tracked by counting dispensed and unused tablets at each on-site visit 
and checking with the completed participant diary after baseline until the end-of-treatment visit. 
The Investigator (or authorized delegate) will complete the appropriate pages of the electronic 
case report form (eCRF) and IMP source document logs by recording the numbers and dates of 
doses taken (or not) by the participant. The monitor in charge of the clinical trial will check the 
case report form data by comparing the recorded data with the retrieved IMP kit, participant diary, 
and data recorded on the IMP source document logs and in the eCRF. 
6.5 
CONCOMITANT THERAPY  
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with: 
• Reason for use. 
• Dates of administration including start and end dates. 
• Dosage information including dose and frequency. 
Participants must abstain from taking prescription or nonprescription herbal medications 
containing St. John’s wort extract within 14 days 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.  
Therapies for MS noted in the exclusion criterion E03 are not permitted after randomization while 
the participant is receiving study treatment. Short-term use (3 to 5 days) of glucocorticoids 
(eg, for MS relapse treatment or an acute illness) and local corticosteroids (eg, cutaneous, nasal, 
ocular, otic, intra-articular) are allowed. 
It is recommended that symptomatic treatments for MS (eg, walking, fatigue, spasticity, 
incontinence, pain) and/or significant non-drug treatment such as physical therapy, should be 
maintained at a stable dose or schedule for the duration of the treatment period, if clinically 
feasible.  
Live (attenuated) vaccines should not be administered during the intervention period. 
Paracetamol/acetaminophen, at doses of ≤3 grams/day and acetylsalicylic acid (aspirin) 
≤81 mg/day are permitted for use at any time during the study. A short courses (up to 5 days) of 
NSAIDs (other than acetylsalicylic acid >81 mg/day), preferably selective cyclooxygenase-2 
inhibitors at the lowest effective dose, may be given during the course of the study if clinically 
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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. Other concomitant 
medication may be considered on a case-by-case basis by the Investigator in consultation with the 
medical monitor if required. 
In addition, Section 5.2 contains a list of prohibited anticoagulant/antiplatelet therapies in this 
study. 
CYP inhibitor/inducer 
Potent and moderate inducers of CYP3A or potent inhibitors of CYP2C8 hepatic enzymes are not 
allowed throughout the study (Appendix 7, Section 10.7).  
The Sponsor should be contacted if there are any questions regarding concomitant or prior 
therapy. 
6.5.1 Rescue medicine  
Not applicable. 
6.6 
DOSE MODIFICATION  
Dose reduction is not foreseen in this study. Participants, Investigators, and the Sponsor’s team 
will be blinded with respect to assigned dose levels during the double-blind period of the study. 
Treatment might need to be interrupted or permanently discontinued if deemed necessary due to 
an AE (Section 10.3 and Section 8.3). 
6.7 
INTERVENTION AFTER THE END OF THE STUDY  
After the end of this study, participants who successfully complete the trial on SAR442168 may 
be offered the option to participate in a Phase 3 LTS study for up to an additional 3 years, or until 
SAR442168 is approved in their respective country, whichever comes first. Details of the Phase 3 
LTS study will be described in a separate protocol.  
If this program is terminated earlier, other available RMS treatments will need to be considered at 
discretion of treating physician. 
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
Withdrawal of consent for treatment should be distinguished from (additional) withdrawal of 
consent for follow-up visits and from withdrawal of consent for nonparticipant contact 
(eg, medical record checks) follow up. The site should document any case of withdrawal of 
consent. 
7.1 
DISCONTINUATION OF STUDY INTERVENTION   
7.1.1 Definitive discontinuation  
The IMP should be continued whenever possible. 
In case the IMP is stopped, it should be determined whether the stop can be made temporarily; 
definitive IMP discontinuation should be a last resort. Any IMP discontinuation must be fully 
documented in the eCRF. In any case, the participant should remain in the study as long as 
possible. 
Definitive intervention discontinuation is any intervention discontinuation associated with the 
definitive decision from the Investigator not to re-expose the participant to the IMP at any time 
during the study, or from the participant not to be re-exposed to the IMP, whatever the reason. 
Discontinuation of study intervention for abnormal liver function should be considered by the 
Investigator when a participant meets one of the conditions outlined in Section 10.6 or if the 
Investigator believes that it is in best interest of the participant.  
If a clinically significant finding is identified in the ECG (including, but not limited to changes 
from baseline in QT interval corrected using Fridericia’s formula [QTcF]) after enrollment, the 
Investigator or qualified designee will determine if the participant can continue in the study and if 
any change in participant management is needed. Review of ECG findings by a cardiologist needs 
to be taken into consideration for a decision of a definitive discontinuation of study intervention 
because of ECG changes. This review of the ECG printed at the time of collection must be 
documented. Any new clinically relevant finding should be reported as an AE.  
See the schedule of activities (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. 
Any abnormal laboratory value or ECG parameter will be confirmed within 24 hours to inform 
the decision whether to discontinue the IMP for the concerned participant. 
In case of premature discontinuation of the intervention, the end-of-treatment visit will be 
conducted. 
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Handling of participants after definitive intervention discontinuation 
Participants will be followed-up according to the study procedures specified in this protocol up to 
the scheduled date of study completion, or up to recovery or stabilization of any AE to be 
followed-up as specified in this protocol, whichever comes last. 
If possible, and after the definitive discontinuation of intervention, the participants will be 
assessed using the procedure normally planned for the last dosing day with the IMP including 
a PK sample if the pEOT visit can be scheduled within a maximum of 24 hours after the last IMP 
dose. Details are provided in the SoA (Section 1.3). All cases of definitive intervention 
discontinuation must be recorded by the Investigator in the appropriate pages of the eCRF when 
considered as confirmed. 
7.1.2 Temporary discontinuation  
Temporary discontinuation of the IMP may be considered by the Investigator because of 
suspected AEs and/or laboratory abnormalities and/or ECG abnormalities AEs or disruption of the 
clinical trial due to a regional or national emergency declared by a governmental agency 
(Appendix 9 [Section 10.9: Contingency measures for a regional or national emergency that is 
declared by a governmental agency]) 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. For all temporary discontinuations, the duration should be recorded by the 
Investigator in the appropriate pages of the eCRF.  
Temporary discontinuation of the IMP decided by the Investigator corresponds to more than 
one missed dose. 
The following shall lead to temporary treatment discontinuation: 
• Cytopenia: follow Sanofi algorithm for neutropenia and thrombocytopenia as per 
Appendix 6 (Section 10.6). 
• Serum creatinine, creatine phosphokinase (CPK) and liver enzyme increase: follow 
corresponding Sanofi 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. 
Analysis of missed doses will be described in the Statistical Analysis Plan. 
7.1.2.1 Rechallenge  
Re-initiation of intervention with the IMP will be done under close and appropriate clinical/and or 
laboratory monitoring once the Investigator has considered, based on his/her medical judgment, 
that the responsibility of the IMP(s) in the occurrence of the concerned event was unlikely and if 
the selection criteria for the study are still met (refer to Section 5.1). For any SAE deemed to be 
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related to the IMP or with an unknown cause, the IMP should be permanently withdrawn, and 
participants will not be rechallenged. However, participants should continue regular study visits 
until study completion. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 10.9, Appendix 9: Contingency measures for a regional or national 
emergency that is declared by a governmental agency. 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY  
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, or 
administrative reasons.  
• 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. 
• 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. 
The Investigators should discuss with the participants about the 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 sections 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 participation 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 re-enrolled 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/she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• Before a participant is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
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. 
• Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue the 
study intervention. 
• Adherence to the study design requirements, including those specified in the SoA 
(Section 1.3), is essential 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) or during the DRI15928 study and obtained before signing the informed consent 
form (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 (Section 1.3). 
• In case of premature discontinuation of study intervention, the end-of-treatment visit will 
be conducted. 
• The maximum amount of blood collected from each participant over the duration of the 
study, including any extra assessments that may be required, will not exceed 200 mL. 
Additional repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 10.9, Appendix 9: Contingency measures for a regional or national 
emergency that is declared by a governmental agency. 
8.1 
EFFICACY ASSESSMENTS   
8.1.1 Magnetic resonance imaging assessments  
Cranial (brain) MRI with and without Gd contrast will be performed. Basic MRIs will be 
performed for all participants at all study sites and will consist of T2- and T1-weighted sequences 
without and with Gd contrast. 
Due to a potential safety risk related to deposition of certain IV Gd contrast agents in the brain, 
these agents should be used in accordance with local recommendations/regulations (20). 
The study manual containing instructions for standard image acquisition requirements for brain 
MRI, data transfer to the central review center, archiving, and shipping will be provided to all 
participating sites. Study site personnel will undergo training regarding MRI acquisition and data 
handling procedures, training will be documented, and adherence to the manual will be monitored 
throughout the study with retraining performed as necessary. 
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Number of new and total number of T1 Gd-enhancing hyperintense as well as new/enlarging T2 
lesions will be evaluated at the visits specified in the SoA (Section 1.3), comparing lesion count to 
that from the previous MRI scan.  
Unless specified otherwise, the baseline brain MRI will be used as the reference to assess all MRI 
derived endpoints. The last MRI obtained in the DRI15928 study, if performed within 6 weeks 
prior to Day 1 of the LTS16004 study, will be acceptable as the baseline MRI for this study. 
Standardized endpoint evaluation will be assured by central review of brain MRI scans. Blinded 
central review will be performed for all MRI-derived endpoints. In Part A, MRI reviewers will be 
blinded to treatment assignments and to other participant data. In Part B, MRI reviewers will not 
be blinded. Details on MRI testing and central review will be described in the study manual. 
Spinal MRIs may be required if spine MS lesions are suspected by the Investigator. Spinal MRIs 
will be evaluated locally and reported in the eCRF. No central review will be performed for spinal 
MRIs. 
Magnetic resonance imaging scans need to be reviewed locally for any non-MS pathology to 
assure safety reporting as per Section 8.3.6. In case of detection of non-MS findings in Part A, the 
MRI report needs to be communicated to the Treating Investigator, without disclosing normal MS 
findings to Investigators or to the site team if not relevant to any safety concern. In Part B, 
Investigators will receive MRI reports from the central MRI reader at regular intervals.  
Details of MRI sequences, including exploratory sequences, will be provided in study reference 
manuals. 
8.1.2 MS Relapse  
8.1.2.1 Unscheduled assessment visits for a suspected MS relapse  
Participants must be instructed to immediately report new neurological symptoms and recurring or 
worsening of previous symptoms to the Investigator. Any reported symptoms will be collected. If 
a participant reports symptoms that may be consistent with relapse, an unscheduled assessment 
visit with the Investigator will be scheduled as soon as possible (whenever possible within 7 days 
of onset of symptoms). The Investigator will assess whether the reported episode is consistent 
with the definition of MS relapse (see Section 8.1.2.2). If it is consistent with the definition of MS 
relapse or if there is any doubt and relapse cannot be ruled out, an EDSS assessment should be 
performed and PK and 
 samples will be collected. 
All MS relapses are to be reported on the MS relapse eCRF page. Multiple sclerosis relapse 
should not be reported as an AE/SAE unless, in the judgment of the Investigator, it is unusually 
severe or medically unexpected (see Section 8.3.6 for reporting rules). 
Unscheduled visits as detailed in the SoA (Section 1.3) must be categorized as being related to 
MS (or not), and additional examinations or laboratory tests are needed for safety follow up and 
optimal treatment decisions. 
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8.1.2.2 Definition of multiple sclerosis relapse  
For the purposes of this study, MS relapse is defined as acute, new neurological symptoms or 
worsening of previous neurological symptoms with an objective change on neurological 
examination. Symptoms must: 
• Be attributable to MS. 
• Last for ≥24 hours, with or without recovery. 
• Be present at normal body temperature (ie, no infection, excessive exercise, or excessively 
high ambient temperature), and 
• Be preceded by ≥30 days of clinical stability (including no previous MS relapse). 
Note: An exacerbation or recurrence of symptoms and signs that can be reasonably attributed 
to transient impairment of conduction in previously demyelinated pathways due to drugs (such 
as rarely occurs a few hours after injection of interferon beta), raised core body temperature 
(the Uhthoff phenomenon), or systemic cytokine release will not be considered a relapse. 
It is at the Investigator’s discretion and responsibility to choose the best treatment option for any 
MS relapse, such as a high dose glucocorticoid treatment course. 
Analysis of relapses will be detailed in the Statistical Analysis Plan. 
8.1.3 Expanded Disability Status Scale (EDSS) evaluation  
The Investigator will perform the EDSS evaluation (19) as indicated in the SoA (Section 1.3). All 
Investigators will be trained and certified to perform the EDSS in a consistent manner. 
EDSS scores will be captured on paper. Details will be included in the study manual. 
The Investigator will rate functional systems in the context of a standard neurological examination 
and will report these ratings as per the EDSS reporting instructions together with information on 
the participant’s mobility, gait, and use of assistive devices. Standard EDSS assessments of 
neurological symptoms in each of 7 functional domains (visual, brainstem, pyramidal [motor], 
cerebellar [coordination], sensory, cerebral and bowel/bladder) will be performed. Ambulation 
will also be scored as part of the evaluation. Fatigue may optionally be evaluated and if measured, 
it will contribute to the EDSS score. Details of EDSS assessment and scoring are described in the 
study manual. 
 
  
 
 
 
 
 
 
  
 
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8.2 
SAFETY ASSESSMENTS   
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
The definitions of AEs and SAEs can be found in Appendix 3 (Section 10.3). For the purpose of 
this protocol, MS relapses (Section 8.1.2) are waived from reporting as AEs except if they meet 
the criteria of an SAE. Nonserious MS relapses will be collected on a special eCRF page and will 
be analyzed as an efficacy endpoint. Following an MS relapse assessment, (Section 8.1.2), events 
that are concluded as not meeting the criteria of an MS relapse will be reported as AEs. 
The last EDSS and MRI obtained in the DRI15928 study are acceptable if they are performed 
within 6 weeks prior to Day 1 of the LTS16004 study. 
8.2.1 Physical examinations  
• A complete physical examination will include, at a minimum, assessments of general 
appearance, head and neck, abdomen, lymph nodes, skin (signs of bleeding include 
bruises, petechial rash), cardiovascular, respiratory, gastrointestinal, musculoskeletal, and 
neurological systems. Height and weight will also be measured and recorded. Details will 
be provided in the study manual. 
• A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen).  
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
• Any new finding or worsening of previous finding should be reported as a new AE. 
• The SoA (Section 1.3) provides a schedule of physical examinations. A full examination 
should be performed whenever the Investigator judges a need for complete evaluation of 
the participant. 
8.2.2 Vital signs  
• Temperature, pulse rate, respiratory rate, and blood pressure will be assessed. The same 
method for temperature measurement should be used throughout the study. 
• Blood pressure and pulse measurements will be assessed in sitting or supine position with 
a completely automated device. Same position measurements should be used throughout 
the study for the same participant. Manual techniques will be used only if an automated 
device is not available. 
• Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions (eg, television, cell phones). 
• Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse, 
3 blood pressure measurements (3 consecutive blood pressure readings will be recorded at 
intervals of at least 1 minute), and respiratory rate. The average of the 3 blood pressure 
readings will be recorded on the eCRF. 
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8.2.3 Electrocardiograms  
Single 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. At least one longer rhythm monitoring recording of ≥30 sec needs to be part of each 
ECG testing. The ECG will be reviewed by a cardiologist for confirmation of abnormality and 
clinical evaluation. Refer to Section 7 for QTcF withdrawal criteria and any additional QTcF 
readings that may be necessary. In case the ECG machine does not automatically calculate QTcF, 
manual calculation using a nomogram or an automatic website calculator 
(eg, https://reference.medscape.com/calculator/48/ecg-corrected-qt) is acceptable. 
8.2.4 Clinical safety laboratory assessments  
See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and to the 
SoA (Section 1.3) for the timing and frequency. 
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. 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 4 weeks after the last dose of study intervention should be repeated until the 
values return to normal or baseline or are no longer considered clinically significant by the 
Investigator or medical monitor. 
• If such values do not return to normal/baseline within a period of time judged reasonable 
by the Investigator, the etiology should be identified and the Sponsor notified. 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), must be 
conducted in accordance with the laboratory manual and the SoA.  
• 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 CRF.  
8.2.5 Suicidal ideation and behavior risk monitoring  
SAR442168 is considered to be CNS-active, and therefore routine suicide risk monitoring will be 
performed. The Columbia Suicide Severity Rating Scale (C-SSRS) and thorough clinical 
evaluation of complaints will be used for suicide risk assessment. Any observation or event of 
clinical importance will be reported as AEs. 
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8.2.5.1 Columbia Suicide Severity Rating Scale  
The C-SSRS will be used to assess the lifetime suicidality of a participant and to track suicidal 
events through the study. The structured interview prompts recollection of suicidal ideation, 
including the intensity of the ideation, behavior and attempts with actual/potential lethality. The 
scale will be administered by the Investigator or a qualified designee at the time points indicated 
in the SoA (Section 1.3).  
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
8.3.1 Adverse 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 
- 
Pregnancy occurring in a female participant entered in the clinical trial or in a female 
partner of a male participant entered in the clinical trial. It will be qualified as an SAE 
only if it fulfills one of the seriousness criteria (see Appendix 3 [Section 10.3]), 
- 
In the event of pregnancy in a female participant, IMP should be discontinued,  
- 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined (See Appendix 4 
[Section 10.4]). 
• Symptomatic overdose (serious or nonserious) with IMP/ NIMP 
- 
An overdose (accidental or intentional) with the IMP/NIMP is an event suspected by 
the Investigator or spontaneously notified by the participant (not based on systematic 
pills count) and defined as at least twice the intended dose within the intended 
therapeutic interval (eg, ≥2 tablets of the IMP within a 12-hour interval). 
• Increase in alanine transaminase (ALT) 
- 
Any increase of ALT >3 x upper limit of normal (ULN). 
• Other project specific AESI(s) 
- 
ECG observation of atrial fibrillation or atrial flutter 
- 
Severe infection that may or may not meet seriousness criteria (eg, a severe 
opportunistic infection) 
- 
Moderate or severe hemorrhagic events, 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 x 109/L (see Appendix 6, Section 10.6 for 
management flow chart). 
The definitions of AEs and SAEs can be found in Appendix 3 (Section 10.3).  
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Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention (see Section 7). 
8.3.2 Index adverse events  
The following are considered as index AEs for which PK and PD 
 sample(s) 
will be collected: cytopenias (eg, thrombocytopenia, neutropenia) and cardiac arrhythmias (atrial 
fibrillation and atrial flutter). 
8.3.3 Time period and frequency for collecting AE and SAE information  
All SAEs will be collected from the ICF until the last study 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).  
During Visit 1, the ongoing AEs/SAEs from the DRI15928 study and any AE/SAE that occurred 
between the final visit of the DRI15928 study and Visit 1 of the LTS16004 study are also to be 
recorded. 
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. 
8.3.4 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. 
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8.3.5 Follow-up of AEs and SAEs  
After the initial AE/AESI/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. At the prespecified study end date, all SAEs, and 
nonserious AESIs (as defined in Section 10.3), will be followed until resolution, stabilization, the 
event is otherwise explained, or the participant is lost to follow up (as defined in Section 7.3). 
Further information on follow-up procedures is given in Appendix 3 (Section 10.3). 
8.3.6 Regulatory reporting requirements for SAEs  
• Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRBs)/Independent Ethics Committees (IEC), and Investigators. 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
• Adverse events that are considered expected will be specified in the reference safety 
information. 
• An Investigator who receives an Investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will review 
and then file it along with the IB and will notify the IRB/IEC, if appropriate according to 
local requirements. 
8.3.7 Pregnancy  
Details of all pregnancies in female participants and female partners of male participants will be 
collected after the start of study intervention and until the last visit of the study. 
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of learning 
of the pregnancy and should follow the procedures outlined in Appendix 4 (Section 10.4). 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, and ectopic pregnancy) are considered SAEs. 
8.3.8 Cardiovascular and death events  
Atrial fibrillation and atrial flutter are AESIs in this study and subject to expedited reporting to the 
Sponsor. All other cardiovascular events will be reported per standard safety reporting and safety 
oversight practices (including data review by the IDMC).  
Death events will be reported per standard SAE reporting rules. Every effort will be done to 
clarify the cause of death and to report the diagnosis of the fatal event as an SAE. 
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8.3.9 Multiple sclerosis relapse reporting  
Multiple sclerosis relapses, determined from the evaluations described in Section 8.1.2, as with all 
efficacy endpoints, will be exempt from being reported as AEs except when they meet the 
definition of an SAE. Hospitalization for MS relapse, if done routinely at the site (eg, for high 
dose IV methylprednisolone), will not be considered as a seriousness criterion for this study. 
Multiple sclerosis relapses will be collected on the eCRF and be analyzed as part of the efficacy 
analysis. 
Other worsening of neurological symptoms that do not meet the definition of MS relapse will be 
reported as AEs according to general safety reporting rules. 
8.3.10 Reporting of safety findings from magnetic resonance imaging  
Magnetic resonance imaging scans should be reviewed locally for any non-MS pathology. In case 
of such findings, the relevant information needs to be provided to the Investigator for appropriate 
safety reporting and to ensure the appropriate management of the participant’s identified safety 
finding. When available, a diagnosis of pathology as a cause of such MRI findings or the findings 
themselves will be reported as an AE until the diagnosis is clear. 
Multiple sclerosis findings on MRI should not be reported as AEs unless they are deemed unusual 
and thus a distinct safety finding. 
8.3.11 Disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs  
See Section 8.3.9 and Section 8.3.10. 
8.3.12 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. 
8.3.12.1 Medical devices  
Not applicable. 
8.4 
TREATMENT OF OVERDOSE  
To date, no specific antidote or detoxification measure can be recommended for an overdose of 
SAR442168. In case of a suspected overdose, the participant should be treated symptomatically.  
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In the event of an overdose, the Investigator should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities until study 
intervention can no longer be detected systemically and activity is over (at least 9 days). 
3. If feasible, 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. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on clinical evaluation of the participant. 
8.5 
PHARMACOKINETICS  
Whole blood samples of approximately 2 mL will be collected for measurement of plasma 
concentrations of SAR442168 in the event of either a suspected MS relapse or an index AE or at 
the pEOT visit, if feasible (only if the pEOT visit can be scheduled within a maximum of 24 hours 
after the last IMP dose). 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. Time of the last meal before PK sampling will be collected to document any meal 
influence on PK parameters. 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). 
During the double-blind period of the study, drug concentration information that may unblind the 
study will not be reported to investigative sites or blinded personnel. 
8.6 
PHARMACODYNAMICS  
Venous blood samples of approximately 6 mL will be collected for measurement of 
 
in the event of either a suspected MS relapse or an index AE. 
 
 will be prepared from whole blood 
. Samples of 
blood for 
 will be collected in all participants from sites selected by their 
capability to send them rapidly to the central laboratory for processing. The details 
 
 and bioanalytical methods will be specified in the study manual. 
 
 will be reported using descriptive statistics. 
8.7 
GENETICS  
Genetics is not evaluated in this study.  
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8.8 
BIOMARKERS  
Plasma and serum samples for biomarker research are required and will be collected from all 
participants in this study as specified in the SoA (Section 1.3). 
Samples from all participants will be tested for 
 
 to evaluate their associations with observed clinical responses. 
Detailed procedures of sample preparation, storage, shipment, and destruction of these samples 
will be described in the specific laboratory manual. 
8.9 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS  
Not applicable. 
8.10 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH  
Future research may help further the understanding of disease subtypes, disease biology, related 
conditions, drug response and toxicity, and can help identify new drug targets or biomarkers that 
predict participant response to treatment. Therefore, data and biological samples will be stored 
and used for future research when consented to by participants (see Section 10.1.3) unless 
prohibited by local laws or IRBs/IECs (in such case, consent for future use of sample will not be 
included in the local ICF).  
For participants who consent to the storage and use of their data and remaining and/or extra 
clinical samples, data and samples may be used after the study ends for future research related 
either to the study intervention, the mechanism of action, and the disease or its associated 
conditions. Such research may include, but is not limited to, performing assessments on 
 
. If future research on genetic material is performed, this will also 
be limited to the purpose of addressing research questions related to 
 
 
In the event future research is conducted for other purposes, the study participants will be 
informed of those purposes and will be given means to object to those research projects. 
Data and samples will be used in compliance with the information provided to participants in the 
ICF Part 2 (future research). 
All study participant data and samples will be coded such that no participant direct identifiers will 
be linked to them. Coded data and samples may be transferred to a Sponsor site (or a subcontractor 
site), which may be located outside of the country where the study is conducted. The Sponsor 
adopts safeguards for protecting participant confidentiality and personal data (see Section 10.1.4). 
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The samples will be stored for a maximum of 15 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. 
Relating data and biological samples will be stored for future research for up to 25 years after the 
end of the study. If data are still considered of important scientific value after this period, coded 
data already available will be anonymized unless otherwise required by applicable laws (the same 
will apply to the data of a study participant who has requested the destruction of his/her samples). 
Participant’s coded data sets provided to researchers for a specific research project will be 
available to the researchers for a maximum of 2 years after the end of their specific project (end of 
project is defined by publication of the results or finalization of the future research project report). 
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9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES  
This is a long-term safety and efficacy follow-up study for participants who have been treated 
with SAR442168, therefore, there is no statistical hypothesis assumed.  
9.2 
SAMPLE SIZE DETERMINATION  
There are no sample size calculations for this long-term extension study.  
All participants who complete the DRI15928 study will be eligible for enrollment in the 
LTS16004 study. The Sponsor enrolled 130 participants in the DRI15928 study, 129 of whom 
completed that study. 
9.3 
POPULATIONS FOR ANALYSES  
For purposes of analysis, the following populations are defined (Table 8): 
Table 8 - Populations for analyses  
Population 
Description 
Enrolled/safety 
All participants who sign the informed consent form. 
Efficacy 
All participants who sign the informed consent form and receive at least 1 dose of 
SAR442168 in this study. 
 
9.4 
STATISTICAL ANALYSES  
The statistical analysis plan will be developed and finalized before database lock, or an ad hoc 
interim analysis, and will describe the participant populations to be included in the analyses, and 
procedures for accounting for missing, unused, and spurious data. This section is a summary of 
the planned statistical analyses of the primary and secondary endpoints. 
9.4.1 Efficacy analyses  
All efficacy analyses will be performed on the Efficacy Population. 
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Table 9 - Efficacy analyses  
Endpoint 
Statistical Analysis Methods 
Secondary endpoints: 
• 
Number of new Gd-enhancing T1-hyperintense lesions by 
brain MRI. 
• 
Number of new or enlarging T2 lesions. 
• 
Total number of Gd-enhancing. T1-hyperintense lesions. 
• 
Number of relapses (ARR) during the study period. 
• 
Change in EDSS score from baseline over time. 
Overall summary using descriptive statistics, by visit. 
Exploratory 
The exploratory efficacy endpoints listed in Section 3 
will be descriptively summarized. 
Abbreviations: ARR: annualized relapse rate; EDSS: Expanded Disability Status Scale; Gd: gadolinium. 
9.4.2 Safety analyses  
All safety analyses will be performed on the Safety Population. 
Table 10 - Safety analyses  
Endpoint 
Statistical analysis methods 
Adverse events - AEs, SAEs 
Overall summaries of incidence using descriptive statistics. 
Clinical laboratory tests - PCSAs 
Overall summaries of incidence using descriptive statistics, by visit. 
Safety findings on MRI 
Overall summaries using descriptive statistics, by visit. 
ECG 
Overall summaries using descriptive statistics by visit for parameters. 
Vital signs 
Overall summaries using descriptive statistics by visit for parameters. 
Abbreviations: AE: adverse event; ECG: electrocardiogram; MRI: magnetic resonance imaging; PCSA: potentially clinically significant 
abnormalities; SAE: serious adverse event.  
9.4.3 Other analyses  
Pharmacokinetics and PD analyses will be described in the statistical analysis plan finalized 
before database lock. Pharmacokinetic data from the DRI15928 study will be considered for the 
analysis in this LTS16004 study.  
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 10.9, Appendix 9: Contingency measures for a regional or national 
emergency that is declared by a governmental agency. 
9.5 
INTERIM ANALYSES   
The Statistical Analysis Plan will describe any ad hoc and interim analyses in greater detail. 
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9.5.1 Independent Data Monitoring Committee  
An IDMC will follow safety data periodically as detailed in the IDMC Charter until the dose 
selection is completed. Monitoring frequency will be reduced if no major safety issues are 
identified. Additional ad hoc IDMC reviews may occur at any time should a safety risk be 
suspected. Unblinded IDMC reports will be provided by an independent unblinded statistician for 
IDMC data reviews during the Part A period.  
The IDMC will be convened when the DRI15928 study results are available, and the IDMC may 
recommend stopping one or more SAR442168 dose levels in the LTS16004 study before the dose 
of SAR442168 to be used in Phase 3 is determined due to safety reasons (including lack of 
efficacy) and switch participants to another dose level. 
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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS  
10.1.1 Regulatory and Ethical Considerations  
• This study will be conducted in accordance with the protocol and with the following: 
- 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and the applicable amendments and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines, 
- 
Applicable ICH GCP Guidelines, 
- 
Applicable laws and regulations. 
• The protocol, protocol amendments, ICF, IB, and other relevant documents 
(eg, advertisements) must be submitted to the health authorities (competent regulatory 
authority) as required by local regulation and to an IRB/IEC by the Investigator and 
reviewed and approved- when applicable - by those health authorities and the IRB/IEC 
before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
• The Investigator will be responsible for the following: 
- 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC; 
- 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures, 
- 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations. 
10.1.2 Financial disclosure  
Investigators and 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. 
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10.1.3 Informed consent process  
• The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study. 
• Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study center. 
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
• A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative. 
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 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. 
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. 
Protection of participant data 
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. 
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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 United States Food and Drug 
Administration or on Japanese population for the Pharmaceuticals and Medical Devices Agency 
in Japan). 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 
• The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must also 
be explained to the participant. 
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor shall take all appropriate measures to safeguard and prevent 
access to this data by any unauthorized third party. 
• 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. 
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• 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.  
• 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 Committees structure  
Independent Data Monitoring Committee 
An IDMC, operating independently of the Sponsor and clinical Investigators, will be responsible 
for overseeing the safety of participants throughout the study. This committee is composed of 
externally-based individuals with expertise in the disease under study, biostatistics, or clinical 
research. The primary responsibilities of the IDMC are to review and evaluate the safety data and 
to assess futility through an interim analysis during the course of the trial and to make appropriate 
recommendations to the Sponsor regarding the conduct of the clinical trial. 
Details describing the IDMC processes and procedures are outlined in the IDMC charter. To 
maintain continuous blinding and study integrity, the analysis will be conducted by 
an independent statistician who will directly transfer data to IDMC members, and measures will 
be taken to ensure the validity of the data. 
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Independent Hepatology Assessment Committee 
An expert committee of 3 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. 
For those journals that request sharing of the analyzable data sets that are reported in the 
publication, interested researchers are directed to submit their request to vivli.org. 
Individual participant data and supporting clinical documents are available for request at vivli.org. 
While making information available we continue to protect the privacy of participants in our 
clinical trials. Details on data sharing criteria and process for requesting access can be found at 
this web address: vivli.org. 
Professionals involved in the study or in the drug development program 
Sanofi 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 electronic CRF 
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 CRF. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
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• 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). 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF 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 reported on the CRF or 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 study manual. 
10.1.9 Study and site closure  
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
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Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of participants by the Investigator 
• Discontinuation of further study intervention development 
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 11 will be performed by the central or local laboratory (as mentioned 
in the table). 
Additional tests may be performed at any time during the study as determined necessary by the 
Investigator or required by local regulations.  
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Table 11 - Protocol-required laboratory assessments  
Laboratory 
assessments 
 
Parameters 
Hematology (central) 
Platelet count  
Red blood cell (RBC) count 
Hemoglobin 
Hematocrit 
RBC indices: 
MCV 
MCH 
% reticulocytes 
White blood cell (WBC) count 
with differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Clinical chemistry 
(central)a  
Blood urea nitrogen 
(BUN) 
Potassium 
Aspartate 
aminotransferase (AST)/ 
serum glutamic-
oxaloacetic transaminase 
(SGOT) 
Total and direct 
bilirubin 
 
Creatinine 
Sodium 
Alanine 
aminotransferase 
(ALT)/ serum glutamic-
pyruvic transaminase 
(SGPT) 
Total protein 
 
Glucose 
Calcium 
Alkaline phosphatase 
Serum FSH 
Serum human 
chorionic 
gonadotropin (HCG) 
pregnancy test 
 
Creatine 
phosphokinase 
(CPK)b 
 
 
 
Routine urinalysis 
(central) 
• 
Specific gravity 
• 
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase by 
dipstick 
• 
Microscopic examination (if blood or protein) 
Other screening tests 
(local) 
• 
Urine human chorionic gonadotropin (HCG) pregnancy test (as needed for women of 
childbearing potential)c  
The results of each locally done test must be entered into the eCRF. 
NOTES: 
a Details of liver chemistry stopping criteria and required actions and follow-up assessments after observations of ALT >3 × ULN are given 
in Appendix 6, Section 10.6. Clinical laboratory findings of ALT 3 × upper limit of normal (ULN) and bilirubin 2 × ULN (>35% direct 
bilirubin) or ALT 3 × ULN and international normalized ratio (INR) >1.5, if INR measured that may suggest severe liver injury must be 
reported as an SAE. 
b Required in Year 1 only 
c Local urine testing is sufficient unless a pregnancy is detected or the urine test is inconclusive and a serum test needs to be used for 
verification, or only serum testing is required by local regulation or IRB/IEC.  
Investigators must document their review of each laboratory safety report. 
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10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING  
DEFINITION OF AE 
AE definition 
• An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
Events meeting the AE definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the Investigator (ie, not related to progression of underlying 
disease),  
• 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. 
• 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. Also, "lack of 
efficacy" or "failure of expected pharmacological action" also constitutes 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. 
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• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
DEFINITION OF SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A 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 
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f) 
Other situations: 
- 
Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the participant or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition. These events should usually be 
considered serious. 
- 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
RECORDING AND FOLLOW-UP OF AE AND/OR SAE 
AE and SAE recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The Investigator will then record all relevant AE/SAE information in the CRF. 
• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor’s representative in lieu of completion of the AE/SAE CRF 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 intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories: 
• Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities. 
• Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
• Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with a SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
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An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe. 
Assessment of causality 
• The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
• A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• The Investigator will use clinical judgment to determine the relationship. 
• 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 Sponsor’s representative with a copy of any 
post-mortem findings including histopathology. 
• New or updated information will be recorded in the originally completed CRF. 
• The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
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REPORTING OF SAES 
SAE reporting to the Sponsor’s representative via an electronic data collection tool 
• The primary mechanism for reporting an SAE to the Sponsor’s representative will be the 
electronic data collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) in order to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes available. 
• After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, then the site can report this information on a paper SAE form (see next section) or 
to the Sponsor’s representative by telephone. 
• Contacts for SAE reporting can be found in the study manual. 
SAE reporting to the Sponsor’s representative via paper CRF 
• Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the Sponsor’s representative. 
• In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service. 
• Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames. 
• Contacts for SAE reporting can be found in the study manual. 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION  
DEFINITIONS: 
Woman of childbearing potential 
A woman is considered fertile following menarche and until becoming post-menopausal 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. 
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Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
- 
Documented hysterectomy 
- 
Documented bilateral salpingectomy 
- 
Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), Investigator discretion 
should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s: review of the participant’s medical 
records, medical examination, or medical history interview. 
3. Postmenopausal female 
- 
A postmenopausal state is defined as no menses for ≥12 months with plasma FSH 
level >30 UI/L or as per laboratory reference range. 
- 
A high FSH level in the postmenopausal range may be used to confirm 
a postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy (HRT). However, in the absence of ≥12 months of amenorrhea, 
a single FSH measurement is insufficient. 
- 
Females on HRT and whose menopausal status is in doubt will be required to use 
one of the acceptable non-estrogen hormonal contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
CONTRACEPTION GUIDANCE: 
Male participants 
None. 
Female participants 
Female participants of childbearing potential are eligible to participate if they agree to use 
an acceptable effective contraception method consistently and correctly as described in Table 12. 
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Table 12 - Contraceptive methods allowed during the study 
Highly effective contraceptive methods that are user dependenta 
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation 
• 
Oral  
• 
Intravaginal  
• 
Transdermal 
• 
Injectable 
Progestogen only hormonal contraception associated with inhibition of ovulation 
• 
Oral 
• 
Injectable 
Highly effective methods that are user independenta 
Implantable progestogen only hormonal contraception associated with inhibition of ovulation 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 
Acceptable methodsb 
• 
Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary mode of action 
• 
Male or female condom with or without spermicidec 
• 
Cervical cap, diaphragm, or sponge with spermicide 
• 
A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide (double-barrier 
methods)d 
Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception 
should be used. 
Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study intervention. The reliability of sexual abstinence needs to be evaluated in relation 
to the duration of the study and the preferred and usual lifestyle of the participant. 
NOTES:  
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local regulations 
regarding the use of contraceptive methods for participants participating in clinical studies. 
b 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 amenorrhoea method (LAM) are not acceptable methods of 
contraception.  
c Male condoms and female condoms should not be used together (due to risk of failure with friction).  
d If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited to 
those that inhibit ovulation as the primary mode of action. 
PREGNANCY TESTING: 
• WOCBP should only be included after a confirmed menstrual period and a negative highly 
sensitive urine or serum pregnancy test. 
• Additional pregnancy testing should be performed at time points specified in the SoA 
(Section 1.3) and as required locally. 
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• Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected. 
COLLECTION OF PREGNANCY INFORMATION: 
Male participants with partners who become pregnant 
• The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive SAR442168. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure. 
Female participants who become pregnant 
• The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on the 
appropriate form and submitted to the Sponsor within 24 hours of learning of 
a participant's pregnancy. The participant will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the participant and the 
neonate and the information will be forwarded to the Sponsor. Generally, follow-up will 
not be required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or absence 
of anomalies) or indication for the procedure. 
• Any pregnancy complication or elective termination of a pregnancy will be reported as 
an AE or SAE. A spontaneous abortion is always considered to be an SAE and will be 
reported as such. Any post-study pregnancy related SAE considered reasonably related to 
the study intervention by the Investigator will be reported to the Sponsor as described in 
Section 8.3.6. 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. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study. 
10.5 
APPENDIX 5: GENETICS  
No additional genetic test will be collected in this study. Results of genetic tests from the 
DRI15928 study will be used for data analyses for any correlation with efficacy or safety. 
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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 Section 10.3 is met. 
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Thrombocytopenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting AEs in Section 10.3 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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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 Section 10.3 is met. 
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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 Section 10.3 is met. 
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SUSPECTED PML 
If either the clinical presentation or MRI features of a participant are suggestive of PML, the 
following diagnostic and action algorithm is recommended. 
 
Abbreviations: CSF, cerebrospinal fluid; Gd, gadolinium; IMP, investigational medicinal product; JCV, John Cunningham virus; MRI, magnetic 
resonance imaging; PCR, polymerase chain reaction; PML, progressive multifocal leukoencephalopathy 
Clinical manifestations or MRI lesions features suspicious for PML are proposed in Table 13 
(based on [21] and [22]). 
Table 13 - 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 on imaging, the local radiologist will directly inform the 
Investigator and a central review of the MRI is not 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 diagnostic workup and treatment plan. 
• The detection of John Cunningham virus (JCV) DNA in the CSF of a patient with clinical 
and MRI features suggestive of PML establishes the diagnosis of PML. 
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• 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: LIST OF EXAMPLE DRUGS WITH A POTENTIAL TO CHANGE WITH 
SAR442168 METABOLISM  
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 14). 
Additionally, participants in the US 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 15). 
Please note that the lists provided in Table 14 and Table 15 are not exhaustive and that the product 
information of drugs intended for concomitant use should be consulted. 
Table 14 - Potent and moderate CYP3A inducers and potent CYP2C8 inhibitors  
Potent CYP3A Inducers: 
Rifampin 
Carbamazepine 
St John's Wort extract 
Phenobarbital 
Avasimibe 
Lumacaftor 
Rifapentine 
 
Phenytoin 
 
Potent CYP2C8 Inhibitors: 
Gemfibrozil 
Clopidogrel 
Moderate CYP3A Inducers: 
Semagacestat 
Asunaprevir/beclabuvir/daclatasvir 
Cenobamate 
Nafcillin 
Lesinurad 
Telotristat ethyl 
Bosentan 
Elagolix 
Thioridazine 
Rifabutin 
 
  
 
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Table 15 - Mild, moderate, and potent inhibitors of CYP3A and CYP2C8, and moderate and potent 
inducers of CYP3A  
CYP2C8 inhibitors 
Potent 
Moderate 
Mild 
Clopidogrel 
Gemfibrozil  
Trimethoprim 
Sulfamethoxazole 
trimethoprim 
Fluvoxamine 
CYP3A inducers 
Potent 
Moderate 
Avasimibe 
Rifampin 
Carbamazepine 
Lumacaftor 
Phenobarbital 
Phenytoin 
Rifapentine  
St. John's Wort 
Elagolix 
Cenobamate 
Nafcillin 
Asunaprevir/beclabuvir/daclatasvir 
Lesinurad 
Bosentan 
Thioridazine  
Rifabutin 
CYP3A inhibitors 
Potent 
Moderate 
Mild 
Clarithromycin 
Itraconazole 
Ketoconazole 
Nirmatrelvir and ritonavir 
Fluoxetine 
Grapefruit juice 
Ciprofloxacin 
Diltiazem 
Erythromycin 
Fluconazole 
Verapamil 
Sertraline 
Alprazolam 
Atorvastatin 
Amlodipine 
Cimetidine 
Ranitidine 
Roxithromycin 
Ginkgo biloba 
Isoniazid 
 
10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS  
Only Part A of this protocol, the double-blind period of continued treatment with the respective 
SAR442168 dose administered in the DRI15928 study, applies to the Czech Republic. For Part B, 
the open-label period of a single-group treatment with the selected Phase 3 SAR442168 dose, 
a substantial amendment will be submitted with the defined optimal dose and rationale for the 
dose supported by clinical data from Study DRI15928 and by preclinical data. See Section 4 for 
details. 
10.8.1 Country-specific provisions for the US 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 7, Section 10.7). 
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. 
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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: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY  
A regional or national emergency declared by a governmental agency (eg, public health 
emergency, natural disaster, pandemic, terrorist attack) may prevent access to the clinical trial 
site. 
Contingency procedures are suggested below for an emergency that prevents access to the study 
site, to ensure the safety of the participants, to consider continuity of the clinical study conduct, 
protect trial integrity, and assist in maintaining compliance with Good Clinical Practice in 
Conduct of Clinical Trials Guidance. Sponsor agreement MUST be obtained prior to the 
implementation of these procedures for the duration of the emergency; this agreement must be 
provided in writing by the Sponsor and will be kept in the Investigator file. 
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. 
During the emergency, if the site will be unable to adequately follow protocol-mandated 
procedures, screening and enrollment may be temporarily delayed/halted.  
Attempts should be made to perform all assessments in accordance with the approved protocol to 
the extent possible. In case this is not possible due to a temporary disruption caused by 
an emergency, focus should be given to assessments necessary to ensure the safety of participants 
and those important to preserving the main scientific value of the study. 
10.9.1 Informed consent  
For a regional or national emergency declared by a governmental agency, contingency procedures 
may be implemented for the duration of the emergency. The participant or their legally authorized 
representative should be verbally informed prior to initiating any changes that are to be 
implemented for the duration of the emergency (eg, study visit delays/treatment extension, use of 
local labs), and the verbal information given to the participant should be documented in the 
participant’s medical record.  
10.9.2 Study procedures  
Procedures to be considered in the event of a regional or national emergency declared by 
a governmental agency: 
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1. New screenings during a regional or national emergency declared by a governmental 
agency can be performed only if allowed by local competent authorities and after 
Sponsor’s agreement is obtained. Rescreening will be permitted when the situation 
normalizes and only if allowed by local competent authorities and after Sponsor’s 
agreement is obtained.  
2. If on-site visits or alternative location (out of participant’s home) are not possible, all visits 
from Week 1 (including those planned to be done on site) 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) other safety assessment (at least serum creatinine for eGFR calculation), 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 on-site planned visit to collect 
safety data and concomitant treatment. All data collected remotely will be properly documented in 
the participant’s medical record and the study CRF. 
For all assessments which will not be performed remotely, the assessment windows will be 
extended until participants may access the site.  
If on-site 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 on-site planned 
visit to collect safety data and concomitant treatment. 
Contingencies implemented due to emergency will be documented in the participant’s medical 
record. 
10.9.3 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.  
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10.9.4 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 
Statistical Analysis Plan. 
10.10 APPENDIX 10: ABBREVIATIONS 
AE: 
adverse event(s) 
ALT: 
alanine transaminase 
ARR: 
annualized relapse rate 
AUClast: 
area under the concentration-time curve until the last quantifiable concentration 
BTK: 
Bruton's tyrosine kinase 
CFR: 
Code of Federal Regulations 
 
 
Cmax: 
maximum serum concentration 
CNS: 
central nervous system 
CSF: 
cerebrospinal fluid 
C-SSRS:
Columbia Suicide Severity Rating Scale 
CYP450:
cytochrome P450 
DILI:
drug-induced liver injury 
eCRF:
electronic case report form 
FSH:
follicle-stimulating hormone 
GCP:
Good Clinical Practice 
Gd:
gadolinium 
GLP:
Good Laboratory Practice 
HCG:
human chorionic gonadotropin 
HRT:
hormonal replacement therapy 
IC50:
half maximal inhibitory concentration 
ICF:
informed consent form 
ICH:
International Council for Harmonisation 
IEC:
Independent Ethics Committees 
Ig:
immunoglobulin 
IMP:
investigational medicinal product 
IRB:
Institutional Review Board 
IV:
intravenous 
IVRS:
interactive voice response system 
IWRS:
interactive web response system 
JCV:
John Cunningham virus 
LOAEL:
low observed adverse effect level 
LTS:
long-term safety 
MAD:
multiple ascending dose 
MRI:
magnetic resonance imaging 
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MS: 
multiple sclerosis 
NIMP: 
noninvestigational medicinal product 
NOAEL: 
no observed adverse effect level 
PCSAs: 
potentially clinically significant abnormalities 
PD: 
pharmacodynamics(s) 
PK: 
pharmacokinetic(s) 
PML: 
progressive multifocal leukoencephalopathy 
PPMS: 
primary progressive multiple sclerosis 
QTcF: 
QT interval corrected using Fridericia's formula 
RMS: 
relapsing multiple sclerosis 
SAD: 
single ascending dose 
SAE: 
serious adverse event(s) 
 
 
SoA: 
schedule of activities 
SPMS: 
secondary progressive multiple sclerosis 
t1/2: 
elimination half life 
TDAR: 
T-cell dependent antibody response 
TEAE: 
treatment-emergent adverse event 
tmax: 
time to reach maximum observed concentration 
ULN: 
upper limit of normal 
 
10.11 APPENDIX 11: PROTOCOL AMENDMENT HISTORY  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC).  
10.11.1 
Amended protocol 01 (26 June 2019)  
This amended protocol (amendment 01) was 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 because it did not significantly impact the safety or physical/mental integrity 
of participants or the scientific value of the study.  
OVERALL RATIONALE FOR THE AMENDMENT  
This protocol (amendment 01) was amended in response to a request from the Czech Republic 
Health Authority for a clear statement that only Part A of the protocol will be implemented in the 
Czech Republic until a substantial amendment, including the dose choice and rationale for dose 
choice for Part B, is approved.  
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Protocol amendment summary of changes table for amended protocol 01 
Section # and Name 
Description of Change 
Brief Rationale 
Section 10.8 Appendix 8: 
Country-specific 
requirements 
Specification that only Part A of the protocol will be 
implemented in the Czech Republic until a substantial 
amendment including the dose choice and rationale for 
dose choice for Part B is approved. 
Response to Czech Republic 
Health Authority request. 
10.11.2 
Amended protocol 02 (30 August 2019)  
In Europe, this amended protocol (amendment 02) 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 because it significantly impacted the safety or physical/mental 
integrity of participants. 
OVERALL RATIONALE FOR THE AMENDMENT  
This protocol (amendment 02) was primarily amended in response to comments from health 
authorities and ethics committees during the initial clinical trial application process. Furthermore, 
Sanofi Genzyme used that opportunity to update with new available information. 
Protocol amendment summary of changes table for amended protocol 02 
Section # and Name 
Description of Change 
Brief Rationale 
All 
Reformatting of existing content throughout the 
document, when necessary. 
Minor editorial changes are not described in the table 
below. 
Update in accordance with sanofi-
aventis standards 
 
Cover page 
Addition of IND and NCT numbers 
Clarification 
Section 1.1  
Synopsis 
 
Addition of “film coated” tablet (# in the ‘Intervention 
groups and duration’ section) 
Consistency with the IB 
Addition of “safety findings on MRI” (#in the ‘Primary 
analysis’ section) 
Consistency with the IB 
Section 1.3  
Schedule of activities 
Addition of “If needed” in the UNSCH column for MRI 
(Tables 1 and 2) 
Clarification 
 
Update of footnotes for Tables 1 (e, f, h), 2 (d), and 3 (d) 
Clarification 
Section 2.2 
Background 
Revision and update of the entire section with new 
information from the 6- and 9-month toxicology report, as 
well as embryofetal studies, with the addition of the 
inclusion of tables NOAELs and exposure ratios 
Change of "thrombocytopenia" for "decreased platelet 
count" (#section Phase 1 first-in-human single-
ascending-dose/multiple-ascending-dose study') 
Inclusion of new information from 
the animal toxicology studies 
 
Clarification 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 2.3 
Benefits and risks 
Revision of the entire section 
Update with new information 
 
Change of "thrombocytopenia" for "decreased platelet 
count" 
Clarification 
Section 5.1 
Inclusion criteria I 02 
Clarification that the effective method of birth control 
should be taken from inclusion and up to 2 months after 
the last study dose  
Alignment with changes made to 
the DRI15928 study  
 
Menopause is defined as being amenorrheic for 
≥12 months as supposed to 2 ≥years 
Correction of error 
Section 5.2 
Exclusion criterion E03 
Deletion of teriflunomide plasma level values before 
randomization 
Alignment with the Aubagio 
washout leaflet instructions that 
blood level of 0.02 mg/L is 
applicable only to participants 
seeking to achieve pregnancy 
Section 5.2 
Exclusion criterion E05 
Deletion of the dose of aspirin (>80mg/day) 
All doses for aspirin prohibited 
Section 5.2 
Exclusion criterion E12 
Deletion of this exclusion criteria: “Any specific situation 
during study implementation/course that may rise ethics 
considerations”. 
Alignment with changes made to 
the DRI15928 study 
Section 5.2 
Exclusion criterion E13 
Addition of the below criteria as E13: “The participant is 
pregnant or is a breastfeeding woman”. 
Alignment with changes made to 
the DRI15928 study  
Section 5.3.1 
Meals and dietary 
constrictions 
Clarification that the IMP can be taken with or without 
food; and the time of day and whether IMP is taken with 
or without food should be as consistent as possible 
throughout the study. Usual time of day and way of 
administration (with or without food) will be recorded at 
every study visit. 
Alignment with changes made to 
the DRI15928 study  
Section 6.1.1 
Investigational medicinal 
product 
Clarification that the time of day and whether IMP is 
taken with or without food should be as consistent as 
possible throughout the study 
Alignment with changes made to 
the DRI15928 study  
Section 6.3 
Methods of blinding 
Addition that once the dose for the Part B is selected, all 
participants will be switched to the open-label treatment 
with this selected dose. From this point, the investigators 
will be provided the results of the MRI reports. With 
yearly MRI being the standard in normal clinical practice 
for proper management of MS patients, investigators will 
be provided MRI reports in the unlikely event that the 
DRI15928 and Part A of the LTS16004 study stretch 
longer than a year. 
Clarification following the HA’s 
request. 
Section 6.5 
Concomitant therapy 
Clarification that NSAIDs can be given during the course 
of the study, proton pump inhibitors should be avoided, 
and antacids and H2-receptor antagonists should be 
staggered 
Alignment with changes made to 
the DRI15928 study  
Section 7.1.2.1 
Rechallenge 
Addition of clarification to not rechallenge participants 
after SAEs attributable to the IMP or with unknown cause 
in the DRI study 
Clarification following the HA’s 
request  
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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.1.1 
MRI assessments 
Addition that in Part A, MRI reviewers will be blinded to 
treatment assignments and to other participant data. In 
part B, MRI reviewers will not be blinded 
Clarification 
Section 8.2.5 
Suicidal ideation and 
behavior risk monitoring 
Addition that SAR442168 is considered to be CNS-
active, and therefore routine suicide risk monitoring will 
be performed 
Alignment of text with the 
DRI15928 study and clarification 
for C-SSRS 
Section 9.4.1 
Efficacy analyses 
Addition of footnote in Table 9. 
Clarification 
Section 9.4.2 
Safety analyses 
Addition of footnote in Table 10 
Clarification 
Section 10.1.1 
Regulatory and Ethical 
considerations 
(#bulletpoint 2) 
Original text modified as “the protocol, protocol 
amendments, ICF, IB, and other relevant documents 
(eg, advertisements) must be submitted to the health 
authorities (competent regulatory authority) as required 
by local regulation and to an IRB/IEC by the Investigator 
and reviewed and approved – when applicable- by those 
health authorities and the IRB/IEC before the study is 
initiated”. 
Alignment with changes made to 
the DRI15928 study and as a 
request by the HA. 
Section 10.4 
Contraception guidance 
(#Table 10) 
Deletion of footnote 
Alignment with the revised 
inclusion criterion I 02 
Section 10.8 
Appendix 8 
Creation of appendix “List of example drugs with a 
potential to affect plasma exposure of SAR442168 via 
reduction of gastric acid” 
Alignment with changes made to 
the DRI15928 study 
Section 10.11 
Appendix 11 (Protocol 
amendment history) 
Addition of reasons for amended protocol 01 
Update of the protocol 
amendment history 
 
10.11.3 
Amended protocol 03 (02 March 2020)  
In Europe, this amended protocol (amendment 03) is considered to be substantial based on the 
criteria set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the 
Council of the European Union because it significantly impacts the safety or physical/mental 
integrity of participants. 
OVERALL RATIONALE FOR THE AMENDMENT 
This protocol is amended based on the efficacy and safety findings from the DRI5928 trial, which 
demonstrated that the dose of 60 mg taken with a meal is the most appropriate dose for further 
investigation. This is the recommended dose for Part B of this study (LTS16004). Furthermore, 
the Sponsor uses this opportunity to update with new available information. 
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Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Throughout the document 
Reformatting of existing content throughout the 
document, when necessary. 
Minor, editorial changes are done throughout the 
document as necessary. 
Update in accordance with sanofi-
aventis standards. 
 
Cover page 
Addition of ‘not applicable’ for ‘other’ identifier number. 
Clarification. 
1.1 Synopsis 
# Intervention groups and 
duration 
Addition of 60 mg dose following dose selection for 
further investigations based on Phase 2b data 
(DRI15928). 
Availability of Phase 2b data. 
1.1 Synopsis 
# Post-trial access to study 
medication 
Clarification that ‘the study will continue up to 5 years or 
until SAR442168 is approved…’ 
Clarification. 
1.3 Schedule of activities 
Table 1 - A:  
- Modification of footnotes ‘a’, e’, and ‘g’. 
- Addition of footnotes ‘m’ and ‘n’. 
- Addition of “If switch to part B” in the UNSCH column for 
informed consent and IMP administration rows. 
- Annotations for screening and baseline check boxes in 
hematology, biochemistry and urinalysis assessments 
were corrected to ‘g’. 
- Annotation "e" for exploratory biomarker plasma 
samples assessments was shifted to ‘Exploratory 
biomarker plasma samples 
 from 
‘baseline visit’. 
Table 2 - B: 
- Addition of footnote ‘f. 
- Addition of year 4 checkbox for MRI in the event of 
premature EOT. 
Table 3 – C: 
- Footnote ‘f’ was newly inserted. 
- Annotation ‘a’ removed from ‘follow-up visit’ column. 
Tables 1-A, 2-B, 3-C: 
- Additional efficacy endpoint 
 added. 
- Addition of note to clarify that all assessments shall be 
done as designated in this SoA unless not permitted 
according to local regulations added in tables 1- A, 2-B, 
and 3-C. 
- Table heading ‘phase’ changes to ‘procedure”. 
Clarifications and correction of 
errors from the LTS16004 
amended protocol 02. 
2.2 Background 
Nonclinical data updated. 
New information updated. 
2.3 Benefit/Risk Assessment 
Update of the safety profile with information from the 
DRI15928 trial. 
New information updated. 
3 Objectives and Endpoints 
Addition of 
 as a tertiary/exploratory 
endpoint. 
Addition of new assessment as 
a pilot study in a subset of 
participants before inclusion in the 
Phase 3 studies. 
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Section # and Name 
Description of Change 
Brief Rationale 
4.1 Overall design 
Addition of 60 mg dose following the dose selection for 
Phase 3 studies. 
Update with new information. 
4.3 Justification for Dose 
Update with information from the DRI15928 trial. 
Update with new information and 
per commitment to the Health 
Authorities (HAs). 
5.1 Inclusion criteria 
# I 02 
 
Modification of inclusion criterion 02. 
 
No safety concerns identified in 
the embryo-fetal studies. 
# I 03, I 04, and I 05  
Deletion of inclusion criteria 03, 04, and 05. 
No safety concerns identified in 
the embryo-fetal studies. 
5.3.1 Meals and dietary 
restrictions 
New recommendations that the IMP should be taken with 
meals whenever possible. The meal (eg, breakfast, 
lunch, etc.) should be consistent throughout the study. 
The typical time of day at which the IMP is administered 
will be collected at each visit. 
Update following new PK 
information. 
6.1.1 investigational 
medicinal product 
New recommendations that the IMP should be taken with 
meals and that it will be dispensed at regular site visits or 
at an unscheduled visit at the time of the switch to Part B.  
Update of table 7 with dosing information following the 
dose selection from the DRI15928 trial.  
Availability of Phase 2 data. 
6.7 Intervention after the End 
of the Study 
Clarification that ‘the study will continue up to 5 years or 
until SAR442168 is approved…’. 
Clarification. 
 
Subsection added. 
New assessment for tertiary 
endpoint. 
10.2 Appendix 2: Clinical 
Laboratory Tests 
#Table11 
Deletion of “urine drug screen” from the  
routine urinalysis subsection. 
Urine drug screen is not part of 
the routine urinalysis. 
10.4 Appendix 4: 
Contraceptive Guidance And 
Collection Of Pregnancy 
Information 
Guidance updated. 
Deleted contraception guidance for male participants. 
No safety concerns identified in 
the embryo-fetal studies. 
10.8 Appendix 8: List Of 
Example Drugs With A 
Potential To Affect Plasma 
Exposure Of SAR442168 Via 
Reduction Of Gastric Acid 
Addition of list of example drugs with a potential to affect 
plasma exposure of SAR442168 via reduction of gastric 
acid. 
Correction of error from the 
LTS16004 amended protocol 02. 
10.10 Appendix 10: 
Abbreviations 
New abbreviations added. 
To harmonize the list of 
abbreviations with the body of the 
protocol. 
11 References 
List updated. 
To harmonize the list of 
references with the body of the 
protocol. 
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10.11.4 
Amended protocol 04 (28 October 2020)  
In Europe, this amended protocol (amendment 04) is considered to be nonsubstantial 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 because it does not significantly impact the safety or 
physical/mental integrity of participants. 
OVERALL RATIONALE FOR THE AMENDMENT 
This protocol is amended primarily to add an additional timepoint for MRI assessment.  
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3 Schedule of 
activities 
MRI at Month 18 added in Table 2-B. 
 removed from screening, unscheduled, 
Month 60, premature end-of-treatment, and follow-up 
visits.  
Table 1, footnote c: A window of ±1 week is applied to 
monthly phone calls in Year 1. 
Exploratory biomarkers added to premature end-of-
treatment visit in Table 2.  
“If needed” removed from exploratory biomarkers for 
unscheduled visits in Table 3.  
Reference to footnote c, “Sample or measurement to be 
taken before IMP administration”, added to exploratory 
biomarkers. 
Tables 1 to 3, footnotes, m, f, and f (respectively) edited 
to reflect that the 
portion of the study may be 
terminated early if sufficient data are gathered. 
A month is defined as 4 weeks. 
Additional efficacy assessment. 
Correction of errors. 
 
 
 
Clarifications. 
 
 
 
 
 
 
 
 
 
Section 1.3 Schedule of 
activities 
 
Language regarding 
periods clarified in 
Tables 1, 2, and 3 and 
  
Clarification. 
Section 5.5 Criteria for 
temporarily delaying 
enrollment and administration 
of study intervention 
Section added to allow flexibility in case of a regional or 
national emergency declared by a governmental agency. 
COVID-19. 
Section 6.1.1 Investigational 
medicinal product 
Section 7.1.2.1 Rechallenge 
Section 8 Study assessments 
and procedures 
Section 9.4.3 Other analyses 
Reference added to Appendix 10: Contingency measures 
for a regional or national emergency that is declared by 
a governmental agency. 
COVID-19. 
8.1.3 Expanded Disability 
Status Scale (EDSS) 
evaluation 
Fatigue, if measured, will contribute to the EDSS score. 
Correction. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 10.10 Appendix 10: 
Contingency measures for 
a regional or national 
emergency that is declared 
by a governmental agency 
Appendix added containing contingency measures for 
a regional or national emergency that is declared by 
a governmental agency. 
COVID-19. 
Throughout the document 
Reformatting of existing content when necessary. 
Minor, editorial, stylistic changes as necessary. 
Update table of contents, section numbers as necessary. 
Update in accordance with 
Sponsor’s standards. 
10.11.5 
Amended protocol 05 (29 July 2021)  
In Europe, this amended protocol (amendment 05) is considered to be substantial based on the 
criteria set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the 
Council of the European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
The primary reason for this amendment is the availability of new information from drug-drug 
interaction studies.  
 
Section # and Name 
Description of Change 
Brief Rationale 
Title page and 1.1 Synopsis 
Added INN, substituted tolebrutinib for SAR442168 in 
short title. 
Reflection of new INN. 
1.3 Schedule of Activities, 
footnote 
Footnote o (Table 1-A) and g (Tables 2-B and 3-C): 
Clarified the interval required between the use of 
a systemic corticosteroid and MRI scan. 
Footnote h (Tables 2-B and 3-C): Increased the 
window to ±21 days for MRI starting from M15. 
Footnote p (Table 1-A) and i (Tables 2-B and 3-C): 
timing of PK clarified. 
Alignment with exclusion criterion E03. 
 
 
To increase flexibility. 
 
Clarification. 
2.2 Background 
Update with information about new studies. 
Update of the drug-drug interaction profile. 
Update so that information is current. 
Update based on outcomes from PK 
results of drug-drug interaction studies. 
2.3 Benefit/risk assessment 
Added assessment of risks for trial participants due 
to COVID-19. 
COVID-19 pandemic. 
5.3.1 Meals and dietary 
restrictions 
Clarification of IMP administration details to specify 
that a gap of a minimum of 12 hours between 
2 doses should be maintained in case the mealtime 
of IMP administration needs to be changed. 
Removed the restrictions related to consumption of 
grapefruit or grapefruit juice. 
Clarification of the minimum time 
between 2 IMP doses. 
 
 
Update based on outcomes from PK 
results of drug-drug interaction studies 
investigating concomitant use of 
SAR442168 with drugs such as 
itraconazole. 
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Section # and Name 
Description of Change 
Brief Rationale 
6.5 Concomitant therapy 
Added abstention from prescription or 
nonprescription herbal medications containing 
St. John’s wort extract. 
Added 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, cutaneous, nasal, ocular, otic, 
intra-articular). 
Added that live (attenuated) vaccines should not be 
administered during the intervention period. 
Updated language regarding symptomatic treatment 
and NSAIDs. 
Added information about CYP inhibitors/inducers. 
St. John’s wort is a CYP3A inducer. 
Abstention is to prevent potential loss 
of efficacy. 
Clarification for use of cutaneous 
corticosteroids and short-term 
corticosteroids. 
 
 
Alignment with exclusion criterion E02. 
 
Clarity. 
 
Update based on outcomes from PK 
results of drug-drug interaction studies. 
6.5 Concomitant therapy 
Clarified that treatments excluded in E03 cannot be 
used during the study. 
Clarification. 
6.5 Concomitant therapy 
10.7 Appendix 7: List of 
example drugs with 
a potential to change 
SAR442168 metabolism 
10.8 Appendix 8: List of 
example drugs with 
a potential to affect plasma 
exposure of SAR442168 
via reduction of gastric acid 
Updated for antacid drugs: Removed restrictions 
related to antacid drugs as concomitant use of 
proton-pump inhibitors (PPIs), H2 receptor 
antagonists, and antacids is allowed. 
Updated guidance for CYP inhibitors/inducers: potent 
or moderate inducers of CYP3A or potent inhibitors 
of CYP2C8 hepatic enzymes are not permitted 
throughout the study. 
Clarified whether concomitant use of potent CYP3A 
inhibitors is allowed.  
Deleted Appendix 8. 
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.  
7.1.1 Definitive 
discontinuation 
8.5 Pharmacokinetic 
To add that collection of the pharmacokinetic (PK) 
sample at premature end of treatment (pEOT) visit, if 
the visit can be scheduled within a maximum 24 
hours from the last IMP dose. 
Clarity. 
7.1.2 Temporary 
discontinuation 
Added the possibility of temporary discontinuation 
due to a regional or national emergency or a need for 
a prohibited concomitant medication. Specified 
events of serum creatinine, creatine phosphokinase, 
and liver enzymes increase, cytopenias, cardiac 
arrythmias, and suicidality as reasons for temporary 
discontinuation.  
Flexibility. Clarity. 
8.1.1 Magnetic resonance 
imaging assessments 
Allowed Investigators to see regular MRI reports 
during the open label part of the study. 
Flexibility. 
8.1.2.2 Definition of multiple 
sclerosis relapse 
Specified that a relapse must be preceded by at least 
30 days of clinical stability and last for >24 hours, 
with or without recovery. 
Clarity 
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Section # and Name 
Description of Change 
Brief Rationale 
8.2.3 Electrocardiograms 
Added allowance of manual calculation of QT interval 
corrected using Fridericia’s formula (QTcF). 
Specified that “longer” ECG recording means 
≥30 sec.  
To allow flexibility, as some automated 
electrocardiograms do not provide this 
parameter. All other electrocardiogram 
parameters will be automatically 
provided. Clarity. 
8.3.1 Adverse events of 
special interest 
Updated definitions of project-specific adverse 
events of special interest related to cardiac and 
moderate or severe hemorrhagic events, severe 
infection, and thrombocytopenia. Definition of 
overdose is revised. 
Removed requirement for asymptomatic overdoses 
to be reported as AESIs. 
Clarity. 
 
 
 
 
Update of template. 
8.3.10 Reporting of safety 
findings from magnetic 
resonance imaging 
Clarified safety reporting. 
Clarity. 
8.4 Treatment of overdose 
Corrected the language to clarify that plasma sample 
for PK analysis is to be obtained within 24 hours of 
the last documented IMP dose (rather than the last 
dose of SAR442168). 
Correction of error. 
8.5 Pharmacokinetics 
Added optional additional PK samples, eg, for 
retesting or if clinically indicated. 
Flexibility. 
10.2 Appendix 2: Clinical 
laboratory tests 
Table 11: Footnote a was updated to clarify clinical 
laboratory abnormalities for liver injury. 
Clarity. 
Section 10.4 Appendix 4: 
Contraceptive guidance 
and collection of pregnancy 
information 
Added “or as per laboratory reference range” to 
definition of high FSH level for post-menopausal 
status. 
Clarity. 
10.6: Appendix 6: Liver and 
other safety: actions and 
follow-up assessments 
Changed section title from “suggested actions” to 
“actions.” Added clarifying guidance before 
algorithms. Updated thrombocytopenia algorithm. 
Updated ALT algorithm. Added suspected PML 
algorithm. 
Title, guidance, ALT algorithm clarified. 
Thrombocytopenia algorithm updated 
to align with CTCAE standards. PML 
algorithm added to align with trials in 
the Phase 3 program. 
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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10.11.6 
Amended protocol 06 (23 May 2022)  
Amended protocol 06 (23 May 2022) 
In Europe, 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 amendment is to update the liver monitoring to mitigate risk of drug-
induced liver injury and to change the time between onsite visits to every 6 months after the 
Month 36 visit. 
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 
added. 
To evaluate on an ongoing basis 
cases of potential liver injury. 
1.3 Schedule of Activities 
On site visits changed to every 6 months after M36 
visit with phone calls between 2 onsite visits 
To increase flexibility. 
2.3 Benefit/risk assessment. 
Text related to drug-induced liver injury identified in 
an ongoing Phase 3 trial added. 
Update. 
5.3.2 Alcohol, caffeine, and 
tobacco 
Recommendation for alcohol consumption during 
study updated. 
To mitigate the risk of DILI. 
6.1.1 Investigational medicinal 
product 
IMP supply to the participant via a Sponsor-approved 
courier company defined as direct to patient shipment 
Clarification. 
6.2 Preparation/handling/ 
storage/accountability 
Duties and taxes paid shipment replaced by direct-to-
patient shipment 
Correction. 
6.4 Study intervention 
compliance 
Participant will receive IMP up to next visit (on site or 
phone call visit) 
Clarification. 
7.2 Participant 
discontinuation/withdrawal 
from the study 
Sentence “The participant will be permanently 
discontinued both from the study intervention and 
from the study at that time” removed. 
Correction. Participant will be 
followed up to the scheduled date 
of study completion. 
8 Study assessments and 
procedures 
Maximum amounts of blood to be collected updated. 
Update for accuracy.  
10.6 Appendix 6: Liver and 
other safety: actions and 
follow-up assessments 
ALT algorithm and related instructions updated. 
Updated monitoring request as per 
new exclusion threshold for ALT 
level in actively recruiting studies 
10.10 Appendix 11: Abbreviations 
Updated. 
Update. 
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Section # and Name 
Description of Change 
Brief Rationale 
10.11: Appendix 12: Protocol 
amendment history 
Updated. 
Update. 
Throughout the document 
Reformatting of existing content when necessary. 
Minor, editorial, stylistic changes as necessary. 
Updated table of contents, section numbers, 
references, abbreviations as necessary. 
Update in accordance with 
Sponsor’s standards. 
10.11.7 
Amended protocol 07 (12 December 2022)  
In Europe, this amended protocol (amendment 07) is considered to be substantial based on the 
criteria set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the 
Council of the European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
The rationale for this protocol amendment is to clarify information about drug-induced liver 
injury (DILI) and update the ALT increase algorithm in relation to the risk of DILI. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Cover page 
Sponsor disclaimer added at ‘Sponsor name’. 
‘Not applicable’ added at ‘Trademark’. 
Update. 
1.3 Schedule of activities 
(SoA) (Table 2 and Table 3) 
Phone call procedure updated to clarify that this can 
also be a visit at the clinical site. 
Update. 
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 
Increase in ALT algorithm flowchart and related 
instructions updated.  
Update. 
10.11: Appendix 12: Protocol 
amendment history 
Updated. 
Update. 
10.11.5 Amended protocol 
05 (29 July 2021) 
Added statement related to consideration of changes to 
be substantial and overall rationale for the amendment. 
Correction. 
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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10.11.8 
Amended protocol 08 (19 June 2023)  
In Europe, 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 add the option for participants to continue to 
receive SAR442168 (tolebrutinib) in a separate clinical trial. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis, and 
6.7 Intervention after the End 
of the Study 
Added the option for the participants to roll over in 
a Phase 3 LTS clinical trial. 
To provide a continued treatment 
option in a Phase 3 long term 
study that will also include 
participants from Phase 3 trials. 
1.1 Synopsis 
Revised “Post-trial access to study medication” to 
“Continued access to intervention after the end of the 
study” 
Clarification. 
1.3 Schedule of activities 
(SoA) (Table 3) 
Footnote k added. 
To clarify the last visit for 
participants rolling over in 
a Phase 3 LTS. 
2.3 Benefit/risk assessment 
Removed “all” for the identified risk for tolebrutinib and 
removed “to mitigate risk for hepatic injury”. 
Update to keep consistency with 
Investigator’s Brochure. 
8.3.1 Adverse event of special 
interest 
Acute hypersensitivity/anaphylaxis removed from list of 
adverse events of special interest. 
Found to be unnecessary due to 
lack of safety signal in previous 
studies. 
8.10 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. 
10.1.3 Informed consent 
process 
Clarification of informed consent process. 
To keep consistency with ICF 
and Sponsor standards related to 
data privacy guidelines. 
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. 
10.1.6 Dissemination of 
clinical study data 
Sharing of information about funding made to healthcare 
organizations and healthcare professionals clarified. 
To be compliant with Sanofi 
standards. 
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Section # and Name 
Description of Change 
Brief Rationale 
10.4 Appendix 4: 
Contraceptive guidance and 
collection of pregnancy 
information 
Clarification of highly effective and acceptable methods 
of contraception. 
Clarification. 
10.7 Appendix 7: List of 
example drugs with 
a potential to change with 
SAR442168 metabolism 
Removed the reference to www.druginteractioninfo.org 
 
 
 
 
Removed Modifinil from the list of moderate CYP3A 
Inducers. 
Only keeping the 
recommendation for the sites to 
refer to the drug label for 
metabolic interactions. 
 
Correction of error as, according 
to the label, modafinil is a weak 
CYP3A inducer, and therefore 
not prohibited. 
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. 
10.11.9 
Amended protocol 09 (16 November 2023)  
In Europe, this amended protocol (amendment 09) is considered to be substantial based on the 
criteria set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the 
Council of the European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
The rationale for this protocol amendment is to update the testing requirements in the “Increase in 
ALT algorithm”, as per health authority request.  
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
10.6 Appendix 6: Liver and 
other safety: actions and 
follow up assessments 
Increase in ALT algorithm related assessments updated; 
Rechallenge restrictions updated. 
 
Update 
Throughout the document 
Reformatting of existing content when necessary. 
Updated table of contents, abbreviations as necessary. 
Update in accordance with 
Sponsor’s standards. 
 
 
 
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11 
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