A Phase 2 Double-blind, Randomized, Placebo-controlled Study Evaluating the Effect of SAR443820 on Serum Neurofilament Levels in Participants With Multiple Sclerosis, Followed by an Open-label Long-term Extension Period
Phase: PHASE2
Conditions: Multiple Sclerosis
Sponsor: Sanofi

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According to Template: Sanofi OneDocument Version 6.0, dated 25-JUN-2021 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 04 
Protocol title: 
A Phase 2 double-blind, randomized, placebo-controlled 
study evaluating the effect of SAR443820 on serum 
neurofilament levels in participants with multiple sclerosis, 
followed by an open-label long-term extension period 
Protocol number: 
ACT16753 
Amendment number: 
04 
Compound number 
(INN/Trademark): 
SAR443820 
Not applicable 
Brief title: 
Phase 2 study of SAR443820 in participants with multiple 
sclerosis (MS) 
Acronym: 
Not Applicable 
Study phase: 
Phase 2 
Sponsor name: 
Legal registered address: 
Monitoring team’s 
representative name and 
contact information 
Regulatory agency identifier number(s): 
IND: 
EudraCT: 
NCT: 
WHO: 
EUDAMED: 
Other: 
159937 
2022-000049-34 
NCT05630547
U1111-1271-1257 
Not applicable 
Not applicable 
Date: 
13-Dec-2023 
Total number of pages: 115 
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Sanofi-Aventis Recherche & Developpement 
1 avenue Pierre Brossolette 
91380 Chilly-Mazarin, France

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Page 2 
 
PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY 
 
Document 
Country/countries 
impacted by amendment 
Date, version 
Amended Clinical Trial Protocol 04 
All 
13 Dec 2023, version 1 (electronic 7.0) 
Amended Clinical Trial Protocol 03 
All 
06 July 2023, version 1 (electronic 6.0) 
Amended Clinical Trial Protocol 02 
All 
19 May 2023, version 2 (electronic 5.0) 
Amended Clinical Trial Protocol 01 
All 
21 September 2022, version 1 (electronic 2.0) 
Original Protocol 
 
18 March 2022, version 1 (electronic 2.0) 
Amended protocol 04 (13 December 2023) 
This amended protocol (amendment 04) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
Overall rationale for the amendment 
 
An identified risk of drug induced liver injury (DILI) for SAR443820 is added based on internal 
data review of another Phase 2 study (ACT16970) testing 20 mg BID SAR443820 in patients with 
amyotrophic lateral sclerosis (ALS). 
The main purpose of protocol amendment 04 is to add 23 visits (Weeks 8, 10, 14, 18, 20, 22, 28, 
32, 40, and 44 in Part A, and Weeks 50, 54, 58, 62, 64, 66, 68, 70, 76, 80, 84, 88, and 92 in Part 
B) for liver chemistry monitoring at each added visit. Also, two diagnostic tests in case of events 
of ALT increase are made mandatory. 
Protocol amendment summary of changes table 
Section # and Name 
Description of change 
Brief rationale 
1.2 SCHEMA 
1.3.1 Part A 
1.3.2 Part B 
4.1 OVERALL DESIGN 
Added visits for liver chemistry test on Weeks 8, 10, 14, 
18, 20, 22, 28, 32, 40, and 44 in Part A and Weeks 50, 
54, 58, 62, 64, 66, 68, 70, 76, 80, 84, 88, and 92 visit in 
Part B. Added instructions on sample collecting, testing 
and results reporting at the visits added. Updated the 
Part A to include biweekly liver chemistry monitoring for 
D1 through Week 24, then monthly from Week 24 
through 48. Updated Part B to include biweekly liver 
chemistry monitoring from Week 48 through Week 72, 
then monthly Week 72 through the end of the study.  
To enable earlier detection and 
management of liver 
abnormalities to protect 
participants' safety and get 
additional liver enzyme data in 
participants with MS treated with 
20 mg OD.  
2.3.1 Risk Assessment  
2.3.3 Overall benefit/risk 
conclusion 
Added an identified risk of DILI for SAR443820. 
Added clinical data and mitigation strategy supporting the 
potential risk of ALT increase.  
 
To update the risk of SAR443820 
based on current data from the 
ongoing clinical trial and minimize 
the risk for participants. 
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Section # and Name 
Description of change 
Brief rationale 
10.6 APPENDIX 6: LIVER AND 
OTHER SAFETY: SUGGESTED 
ACTIONS AND FOLLOW UP 
ASSESSMENTS AND STUDY 
INTERVENTION 
RECHALLENGE GUIDELINES 
Updated to include mandatory hepatobiliary 
ultrasonography as part of the steps to investigate cases 
of ALT>5xULN; Hepatitis B surface antigen testing added 
to safety follow up 
Update of mandatory procedures 
for etiology investigation 
10.12 APPENDIX 12: 
PROTOCOL AMENDMENT 
HISTORY 
Summary of changes table for amendment 03 is moved 
to appendix 10.12. 
To describe the protocol 
amendment history.  
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TABLE OF CONTENTS  
AMENDED CLINICAL TRIAL PROTOCOL 04 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 4 
LIST OF TABLES ........................................................................................................................................... 9 
LIST OF FIGURES .......................................................................................................................................... 9 
1 
PROTOCOL SUMMARY ............................................................................................................... 10 
1.1 
SYNOPSIS ..................................................................................................................................... 10 
1.2 
SCHEMA ........................................................................................................................................ 16 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 17 
1.3.1 
Part A ............................................................................................................................................. 17 
1.3.2 
Part B ............................................................................................................................................. 22 
2 
INTRODUCTION............................................................................................................................ 25 
2.1 
STUDY RATIONALE ..................................................................................................................... 25 
2.2 
BACKGROUND ............................................................................................................................. 26 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 27 
2.3.1 
Risk assessment ............................................................................................................................ 27 
2.3.2 
Benefit assessment ........................................................................................................................ 29 
2.3.3 
Overall benefit/risk conclusion ....................................................................................................... 29 
3 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS ......................................................................... 31 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 33 
3.1.1 
Measurements for efficacy assessment ........................................................................................ 33 
3.1.2 
Pharmacokinetic assessments ...................................................................................................... 34 
3.1.3 
Pharmacodynamic assessments ................................................................................................... 34 
3.1.4 
Safety and tolerability assessment ................................................................................................ 35 
4 
STUDY DESIGN ............................................................................................................................ 36 
4.1 
OVERALL DESIGN ........................................................................................................................ 36 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 36 
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4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 37 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 38 
5 
STUDY POPULATION .................................................................................................................. 39 
5.1 
INCLUSION CRITERIA .................................................................................................................. 39 
5.2 
EXCLUSION CRITERIA ................................................................................................................ 40 
5.3 
LIFESTYLE CONSIDERATIONS................................................................................................... 43 
5.3.1 
Meals and dietary restrictions ........................................................................................................ 43 
5.3.2 
Caffeine, alcohol, and tobacco....................................................................................................... 43 
5.3.3 
Activity ............................................................................................................................................ 44 
5.4 
SCREEN FAILURES ..................................................................................................................... 44 
5.5 
CRITERIA FOR TEMPORARILY DELAYING 
ENROLLMENT/RANDOMIZATION/ADMINISTRATION OF STUDY INTERVENTION ................ 44 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................................... 45 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 45 
6.2 
PREPARATION, HANDLING, STORAGE, AND ACCOUNTABILITY ........................................... 46 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 46 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 48 
6.5 
DOSE MODIFICATION .................................................................................................................. 48 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY ...................... 48 
6.7 
TREATMENT OF OVERDOSE ...................................................................................................... 48 
6.8 
CONCOMITANT THERAPY .......................................................................................................... 49 
6.8.1 
Rescue medicine............................................................................................................................ 50 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 51 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 51 
7.1.1 
Permanent discontinuation ............................................................................................................ 51 
7.1.2 
Liver function stopping criteria ....................................................................................................... 52 
7.1.3 
Temporary discontinuation ............................................................................................................. 52 
7.1.4 
Rechallenge ................................................................................................................................... 52 
7.1.4.1 
Study intervention restart or rechallenge after discontinuation of study intervention .................... 52 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 53 
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7.3 
STUDY LEVEL STOPPING CRITERIA ......................................................................................... 54 
7.4 
LOST TO FOLLOW UP ................................................................................................................. 54 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 55 
8.1 
EFFICACY ASSESSMENTS ......................................................................................................... 55 
8.1.1 
Serum neurofilament response ...................................................................................................... 55 
8.1.2 
Expanded Disability Status Score .................................................................................................. 55 
8.1.2.1 
Confirmed disability progression .................................................................................................... 56 
8.1.3 
Magnetic resonance imaging ......................................................................................................... 56 
8.1.4 
Multiple sclerosis relapse assessment........................................................................................... 57 
8.1.4.1 
Definition of multiple sclerosis relapse ........................................................................................... 57 
8.1.4.2 
Unscheduled assessment visits ..................................................................................................... 58 
8.1.5 
Timed 25-foot walk test .................................................................................................................. 58 
8.1.6 
9-Hole Peg Test ............................................................................................................................. 59 
8.1.7 
Composite analysis ........................................................................................................................ 59 
8.1.7.1 
EDSS-Plus ..................................................................................................................................... 59 
8.1.8 
MSIS-29v2 ..................................................................................................................................... 59 
8.1.9 
MSWS-12 ....................................................................................................................................... 59 
8.2 
SAFETY ASSESSMENTS ............................................................................................................. 60 
8.2.1 
Physical examinations ................................................................................................................... 60 
8.2.2 
Neurological examinations ............................................................................................................. 60 
8.2.3 
Vital signs ....................................................................................................................................... 60 
8.2.4 
Electrocardiograms ........................................................................................................................ 61 
8.2.5 
Clinical safety laboratory tests ....................................................................................................... 61 
8.2.6 
Pregnancy testing .......................................................................................................................... 62 
8.2.7 
Suicidal ideation and behavior risk monitoring .............................................................................. 62 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING ................................................................................................................... 62 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 63 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 63 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 63 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 63 
8.3.5 
Pregnancy ...................................................................................................................................... 64 
8.3.6 
Cardiovascular and death events .................................................................................................. 64 
8.3.7 
Multiple sclerosis relapse reporting................................................................................................ 64 
8.3.8 
Magnetic resonance imaging ......................................................................................................... 64 
8.3.9 
Adverse events of special interest ................................................................................................. 65 
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8.3.10 
Guidelines for reporting product complaints .................................................................................. 65 
8.4 
PHARMACOKINETICS .................................................................................................................. 66 
8.5 
GENETICS ..................................................................................................................................... 66 
8.6 
BIOMARKERS ............................................................................................................................... 66 
8.7 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 67 
8.8 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS ................................................................................................................................. 67 
8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH ................................ 67 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 68 
9.1 
POPULATIONS FOR ANALYSES ................................................................................................. 68 
9.2 
STATISTICAL ANALYSES ............................................................................................................ 69 
9.2.1 
General considerations .................................................................................................................. 69 
9.2.2 
Primary endpoint(s) analyses ........................................................................................................ 69 
9.2.2.1 
Part A ............................................................................................................................................. 69 
9.2.2.2 
Part B ............................................................................................................................................. 70 
9.2.3 
Secondary endpoint(s) analyses .................................................................................................... 70 
9.2.4 
Tertiary/exploratory endpoint(s) analyses ...................................................................................... 71 
9.2.5 
Multiplicity adjustment .................................................................................................................... 71 
9.2.6 
Safety analyses .............................................................................................................................. 71 
9.2.6.1 
Adverse events .............................................................................................................................. 71 
9.2.6.2 
Laboratory variables, vital signs and electrocardiograms (ECGs) ................................................. 72 
9.2.7 
Other analyses ............................................................................................................................... 72 
9.3 
INTERIM ANALYSES .................................................................................................................... 72 
9.4 
SAMPLE SIZE DETERMINATION................................................................................................. 73 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 74 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 74 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 74 
10.1.2 
Financial disclosure ....................................................................................................................... 75 
10.1.3 
Informed consent process .............................................................................................................. 75 
10.1.4 
Data protection ............................................................................................................................... 76 
10.1.5 
Committees structure ..................................................................................................................... 78 
10.1.5.1 Study Steering Committee ............................................................................................................. 78 
10.1.5.2 Independent Data Monitoring Committee (DMC) .......................................................................... 78 
10.1.6 
Dissemination of clinical study data ............................................................................................... 78 
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10.1.7 
Data quality assurance .................................................................................................................. 79 
10.1.8 
Source documents ......................................................................................................................... 80 
10.1.9 
Study and site start and closure ..................................................................................................... 80 
10.1.10 Publication policy ........................................................................................................................... 81 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 81 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING ......................................................................... 83 
10.3.1 
Definition of AE .............................................................................................................................. 83 
10.3.2 
Definition of SAE ............................................................................................................................ 84 
10.3.3 
Recording and follow-up of AE and/or SAE ................................................................................... 86 
10.3.4 
Reporting of SAEs ......................................................................................................................... 87 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE ................................................... 88 
10.4.1 
Definitions ...................................................................................................................................... 88 
10.4.2 
Contraception guidance ................................................................................................................. 89 
10.5 
APPENDIX 5: GENETICS ............................................................................................................. 91 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: ACTIONS AND FOLLOW-UP 
ASSESSMENTS AND STUDY INTERVENTION RESTART/RECHALLENGE ............................ 92 
10.7 
APPENDIX 7: AES, ADES, SAES, SADES, USADES AND DEVICE DEFICIENCIES: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, FOLLOW-UP, 
AND REPORTING IN MEDICAL DEVICE STUDIES .................................................................... 98 
10.8 
APPENDIX 8: COUNTRY-SPECIFIC/REGION REQUIREMENTS ............................................... 98 
10.8.1 
China .............................................................................................................................................. 98 
10.8.1.1 Study objectives and endpoints ..................................................................................................... 98 
10.8.1.2 Sample storage and disposition of samples after study completion ............................................ 100 
10.8.2 
Germany ...................................................................................................................................... 100 
10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................. 101 
10.10 
APPENDIX 10: STRONG AND MODERATE CYP3A4 INHIBITORS AND STRONG 
CYP3A4 INDUCERS ................................................................................................................... 102 
10.11 
APPENDIX 11: ABBREVIATIONS ............................................................................................... 104 
10.12 
APPENDIX 12: PROTOCOL AMENDMENT HISTORY .............................................................. 106 
10.12.1 Amended protocol 01 (21 September 2022) ................................................................................ 106 
10.12.2 Amended protocol 02 (19 May 2023) .......................................................................................... 110 
10.12.3 Amended protocol 03 (06 July 2023) ........................................................................................... 112 
11 
REFERENCES............................................................................................................................. 113 
 
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LIST OF TABLES  
Table 1 - Risk assessment (identified risk of clinical significance) ................................................................ 27 
Table 2 - Objectives and endpoints ............................................................................................................... 31 
Table 3 - Summary of primary estimand ....................................................................................................... 33 
Table 4 - Study intervention(s) administered ................................................................................................ 45 
Table 5 - Schedule of PK sampling ............................................................................................................... 66 
Table 6 - Populations for analyses ................................................................................................................ 68 
Table 7 - Sample size determination ............................................................................................................. 73 
Table 8 - Protocol-required laboratory tests .................................................................................................. 81 
Table 9 - Strong and moderate CYP3A4 inhibitors and strong CYP3A4 inducers ..................................... 102 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................. 16 
 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title:  
A Phase 2 double-blind, randomized, placebo-controlled study evaluating the effect of SAR443820 on 
serum neurofilament levels in participants with multiple sclerosis, followed by an open-label long-term 
extension period 
Brief title: 
 
Phase 2 study of SAR443820 in participants with multiple sclerosis (MS) 
Rationale: 
Multiple sclerosis (MS) is a chronic autoimmune disease characterized by neuroinflammation, 
demyelination, and axonal degeneration (1). Despite the availability of several disease-modifying 
therapy (DMT) that reduce relapses, there is still a significant unmet need for therapies that target 
disease progression in relapsing and progressive forms of MS (2). Clinically, most relapsing signs 
are effectively controlled with a broad arsenal of DMTs that target the peripheral adaptive 
immune system. Even when the relapses are well-controlled, ongoing inflammatory activity in the 
central nervous system (CNS) inflicts insidious chronic damage and progressive physical 
disability predominates in absence of relapse activity (3, 4). This is particularly true for people 
with progressive forms of MS including primary progressive multiple sclerosis (PPMS) and 
secondary progressive multiple sclerosis (SPMS) leading to relentless accumulation of nervous 
system disability. This is in part due to a complex cellular and biochemical milieu that perpetuates 
mediators of inflammation, leading to neuroaxonal damage and demyelination (3, 4). 
Receptor interacting serine/threonine-protein kinase (RIPK1) is a critical signaling protein in the 
tumor necrosis factor receptor 1 (TNFR1) pathway that regulates inflammation and cell death in 
tissues throughout the body. RIPK1 is activated in response to several inflammatory stimuli, with 
subsequent initiation of a complex signaling cascade that triggers intracellular responses, 
including cytokine release, microglial activation, and necroptosis, a regulated form of cell death. 
There is evidence for RIPK1, receptor interacting serine/threonine-protein kinase 3 (RIPK3), and 
mixed lineage kinase domain-like protein (MLKL) activation in MS postmortem tissue, playing a 
role in both microglial and astrocyte inflammatory signaling and necroptosis of oligodendrocytes, 
which can be subject to RIPK1-dependent cell death. Inhibition of RIPK1 activity has been shown 
to protect against necroptotic cell death in vitro across a range of cell death models (5, 6, 7). 
Genetic and pharmacological inhibition of RIPK1 kinase ameliorated disease pathology and 
disease scores, improved animal behavior, attenuated the production of proinflammatory 
cytokines, reduced plasma neurofilament heavy chain levels, and decreased recruitment of 
immune cells in 2 animal models of MS, the experimental autoimmune encephalomyelitis (EAE), 
and cuprizone models (5 ,7), recapitulating certain aspects of immunological and degenerative 
components of MS (3, 4). These nonclinical findings coupled with observations of increased 
RIPK1 activity in human disease suggest a CNS-penetrant RIPK1 inhibitor may be beneficial in 
treating neurological diseases such as MS (5, 6, 7).  
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SAR443820 is a selective, orally bioavailable, CNS-penetrant, reversible kinase inhibitor of 
RIPK1. SAR443820 has demonstrated strong RIPK1 inhibition with high potency in vitro in 
various cell types. Dose ranging from 10 mg to 40 mg daily and 15 mg to 20 mg BID were safe 
and well tolerated. The first-in-human (FIH) single ascending dose (SAD; Study TDU16519) and 
multiple ascending dose (MAD; Study TDR16520) showed a good tolerability and 
pharmacokinetic (PK) profile (t1/2 7 to 9 hours and tmax 1 to 2 hours), a strong target engagement 
relative to the RIPK1 inhibition evidenced at peripheral level and good penetration of SAR443820 
in cerebrospinal fluid (CSF). 
Neuronal loss is a hallmark pathological feature of MS that is associated with brain atrophy, 
disease progression, and long-term disability (8, 9). Neurofilaments (heavy and light chain) are 
structural elements of axons and markers of neuronal damage. Neurofilaments are increased in the 
CSF, plasma, and serum in a range of neurological diseases including MS (10). Neurofilament 
light chain (NfL) levels have been demonstrated in numerous studies to be predictive of disease 
course and are responsive to DMTs in MS (11). Most approved and clinically effective MS 
treatments also reduce serum neurofilament light chain (sNfL) levels serving as a surrogate 
biomarker of treatment efficacy in numerous relapsing remitting multiple sclerosis (RRMS), 
PPMS, and SPMS randomized clinical trials (12, 13, 14). Therapeutic administration of a 
CNS-penetrant RIPK1 inhibitor has been demonstrated to cause dose-dependent reduction in 
disease score and plasma heavy chain neurofilament levels in the EAE animal model, 
substantiating neurofilament’s suitability for objectively measuring SAR443820’s effect on this 
marker in MS patients while evaluating the clinical and radiological signs that may respond to this 
intervention, especially the degenerative aspects that axonal injury manifests in the form of 
neurofilament elevation across the spectrum of neurological disease (7, 10, 11). 
The aim of the ACT16753 Phase 2 proof-of-concept study is to demonstrate SAR443820’s effect 
on sNfL levels when compared to placebo in participants with RRMS, SPMS, and PPMS. This 
study will also evaluate the effect of SAR443820 on clinical and imaging markers of disease 
progression and activity. Participants will be permitted to continue specified standard of care 
(SOC) background therapies (see Section 5) throughout the double-blinded treatment (Part A) and 
open-label long-term extension period (Part B). Safety and tolerability of SAR443820 will be 
monitored throughout the trial. 
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Objectives and endpoints: 
 
Part A 
  
Objectives 
Endpoints 
Primary 
 
• 
To assess the effect of SAR443820 
compared to placebo on sNfL 
• 
Week 48 sNfL levels relative to baseline 
Secondary 
 
• 
To evaluate efficacy of SAR443820 
compared to placebo on imaging and clinical 
endpoints 
• 
Cumulative number of new gadolinium (Gd)-enhancing 
T1 hyperintense lesions as detected by MRI at Week 48, 
defined as the sum of the individual number of new 
Gd-enhancing T1 hyperintense lesions at all scheduled 
visits starting after baseline up to and including the 
Week 48 visit 
• 
Cumulative number of new and/or enlarging 
T2 hyperintense lesions as detected by MRI, at Week 48, 
defined as the sum of the individual number of new and/or 
enlarging T2 lesions at all scheduled visits starting after 
baseline up to and including the Week 48 visit 
• 
Time to onset of 12 weeks confirmed disability progression 
(CDP) from baseline as assessed by the Expanded 
Disability Status Scale (EDSS) score 
• 
Time to onset of sustained 20% increase in 9-Hole Peg 
Test (9-HPT) confirmed over at least 12 weeks 
• 
Time to onset of sustained 20% increase in timed 25-foot 
walk test (T25-FW) confirmed over at least 12 weeks 
• 
Change from baseline in EDSS-Plus at Week 48 
• 
Annualized relapse rate (ARR) of RMS population 
(relapsing SPMS and RRMS) up to Week 48 
• 
To explore effect of SAR443820 compared to 
placebo on brain volume and chronic lesions 
• 
Percent change from baseline in brain volume loss (BVL) 
as detected by brain MRI at 48 weeks 
• 
Change from baseline in the volume, number, and intensity 
(T1) of slowly expanding lesions (SELs), and normalized 
T1 intensity in lesions at Weeks 12, 24, 36, and 48 
• 
Change from baseline in the total number and volume of 
non-enhancing lesions volume at Weeks 12, 24, 36, and 
48 
• 
Change from baseline in the number of phase rim lesions 
(PRL) at Weeks 12, 24, 36, and 48; among participants at 
sites with 3T capability 
• 
To assess the safety and tolerability of 
SAR443820 
• 
Incidence of AE, SAE, TEAE, PCSA in laboratory tests 
• 
To assess pharmacokinetic (PK) of 
SAR443820 
• 
Plasma concentration of SAR443820 
 
 
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Part B 
 
Objectives 
Endpoints 
Primary 
 
• 
To assess long-term trends in durability of 
sNfL 
• 
Week 96 sNfL levels relative to baseline 
Secondary 
• 
To explore the effect of SAR443820 on brain 
volume and chronic lesions 
• 
Percent change from baseline in BVL as detected by brain 
MRI at Week 96 
• 
Change from baseline in volume, number and intensity 
(T1) in SEL and normalized T1 intensity in lesions to 
Week 96 
• 
Change from baseline in the total number and volume of 
non-enhancing lesions Week 96 
• 
Change from baseline in the number of PRLs (same 
participants/centers from Part A) at Week 96 
• 
To assess the long-term safety and 
tolerability of SAR443820 
• 
Incidence of AE, SAE, TEAE, PCSA in laboratory tests, 
ECG, and vital signs during through Week 96 
• 
To evaluate long-term effect of SAR443820 
on disease progression and activity assessed 
by other clinical and imaging measures on 
physical function and patient-reported 
outcomes (PROs) 
• 
Cumulative number of new Gd-enhancing lesions as 
detected by T1-weighted MRI between 48 and 96 weeks; 
number of new or enlarging T2-hyperintense lesions on 
MRI at Week 96 relative to Week 48 
• 
Annualized relapse rate (ARR) of RMS population 
(relapsing SPMS and RRMS) up to Week 96 
• 
Time to onset of composite CDP (CCDP), confirmed over 
at least 12 weeks (3-month CCDP), by the EDSS-Plus 
composite (EDSS score increase, OR 20% increase in the 
T25-FW test, OR 20% increase in the 9-HPT) 
• 
Time to onset of 12 weeks CDP as assessed by the EDSS 
score 
• 
Time to onset of sustained 20% increase in 9-HPT 
confirmed over at least 12 weeks 
• 
Time to onset of sustained 20% increase T25-FW test 
confirmed over at least 12 weeks 
• 
Change from baseline in EDSS-Plus at Week 96 
• 
Change in MSIS-29v2 physical and psychological domains 
scoring from baseline through Week 96 
• 
Change in MSWS-12 from baseline through Week 96 
 
For China, please see Section 10.8.1 for details. 
Overall design: 
Study ACT16753 is a Phase 2, randomized, double-blind, placebo-controlled study (Part A) 
followed by an open-label, long-term extension period (Part B).  
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Brief summary:  
This is a Phase 2, randomized, double-blind, placebo-controlled 2 parallel-arm study to assess the 
effect on sNfL, safety and tolerability of 20 mg once daily (QD) oral SAR443820 compared to 
placebo in male and female participants aged 18 to 60 years with RRMS, SPMS (relapsing or 
non-relapsing), or PPMS followed by an open-label long-term extension period. 
The total study duration is approximately 100 weeks and includes the following: 
• 4-week screening period 
• 48-week double-blind treatment period (Part A) 
• 48-week open-label long-term extension period (Part B) 
Number of participants: 
Approximately 280 participants will be screened to achieve 168 participants randomly assigned at 
a 1:1 ratio to SAR443820 or placebo (based on a 40% screen failure rate). A minimum of 50% of 
study participants are required to have progressive multiple sclerosis (PMS) (PPMS and SPMS).  
Intervention groups and duration: 
Study intervention(s) 
SAR443820 OR matching placebo 
Investigational medicinal product(s)  
• Formulation: Both SAR443820 20 mg and matching placebo will be formulated in tablets 
• Route(s) of administration: Tablets will be taken orally. The suggested method for IMP 
administration is detailed in Section 6. 
• Dose regimen: 
- 
Part A: 
- 
Treatment arm: SAR443820, 20 mg QD 
- 
Placebo arm: Placebo QD 
- 
Part B: 
- 
Treatment arm: SAR443820, 20 mg QD 
Noninvestigational medicinal products(s) (NIMP) 
• Formulation: MRI contrast enhancing preparations 
• Route(s) of administration: intravenous (IV) 
• Dose regimen: as per respective country-specific labelling 
Devices 
Not applicable. 
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Poststudy access to study medication 
Part B is an open-label long-term extension period up to Week 96 in which all eligible participants 
from Part A may rollover to Part B and receive open-label IMP. In addition to this open-label 
extension, poststudy access to study medication could be provided based on local/country 
regulations. 
Duration of study intervention 
Treatment duration is up to 48 weeks each in Part A and Part B. 
Statistical considerations: 
• Primary endpoint: Week 48 sNfL levels relative to baseline  
• Main secondary endpoints:  
- 
Cumulative number of new Gd-enhancing T1 hyperintense lesions as detected by MRI 
at Week 48, defined as the sum of the individual number of new Gd-enhancing T1 
hyperintense lesions at all scheduled visits starting after baseline up to and including 
the Week 48 visit 
- 
Cumulative number of new and/or enlarging T2 hyperintense lesions as detected by 
MRI, at Week 48, defined as the sum of the individual number of new and/or enlarging 
T2 lesions at all scheduled visits starting after baseline up to and including the 
Week 48 visit 
- 
Time to onset of 12 weeks confirmed disability progression (CDP) from baseline as 
assessed by the Expanded Disability Status Scale (EDSS) score 
The reduction in sNfL levels (primary endpoint) or correlation to other covariates (main 
secondary endpoints) for participants treated with SAR443820 relative to participants receiving 
placebo will be estimated in the modified intent-to-treat (mITT) population. 
Data Monitoring/Other committee: Yes 
 
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1.2 
SCHEMA  
Figure 1 - Graphical study design  
 
Abbreviations: D = Day; n = number; QD = once daily; R = randomization; W = Week; Biweekly and monthly refers to liver chemistry monitoring visits 
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1.3 
SCHEDULE OF ACTIVITIES (SOA)  
1.3.1 Part A  
 
Procedure 
Screening (up to 4 weeks before 
Day 1)a 
Interventional period 
 
Day 1 
Week 2 
Week 4 
Week 6 
Week 8 
Week 9 
Week 10 
Week 12 
Week 14 
Week 16 
Week 18 
Week 20 
Week 22 
Week 24 
Week 28 
Week 32 
Week 36 
Week 40 
Week 44 
Week 48b 
Early discontinuation 
visit 
 
Predose 
(baseline) 
Post dose 
Day 14±3 
Day 28±3 
Day 42 ±3 
Day 44±3 
Day 56 ±3 
Day 70 ±3 
Day 84 ±3 
Day 98 ±3 
Day 112 ±3 
Day 126 ±3 
Day 140 ±3 
Day 154 ±3 
Day 168 ±3 
Day 196 ±3 
Day 224 ±3 
Day 252 ±3 
Day 280 ±3 
Day 308 ±3 
Day 336 ±3 
Visit 
1c 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility check 
(inclusion and 
exclusion criteria) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/ surgical 
history (includes 
substance usage)d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Current/new 
medical conditions 
(includes substance 
usage)d 
X 
X 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
Concomitant 
therapy and 
procedures 
recording 
 
=====================================================================================================================➔ 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Procedure 
Screening (up to 4 weeks before 
Day 1)a 
Interventional period 
 
Day 1 
Week 2 
Week 4 
Week 6 
Week 8 
Week 9 
Week 10 
Week 12 
Week 14 
Week 16 
Week 18 
Week 20 
Week 22 
Week 24 
Week 28 
Week 32 
Week 36 
Week 40 
Week 44 
Week 48b 
Early discontinuation 
visit 
 
Predose 
(baseline) 
Post dose 
Day 14±3 
Day 28±3 
Day 42 ±3 
Day 44±3 
Day 56 ±3 
Day 70 ±3 
Day 84 ±3 
Day 98 ±3 
Day 112 ±3 
Day 126 ±3 
Day 140 ±3 
Day 154 ±3 
Day 168 ±3 
Day 196 ±3 
Day 224 ±3 
Day 252 ±3 
Day 280 ±3 
Day 308 ±3 
Day 336 ±3 
Visit 
1c 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
IRT contact 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
IMP dispensation/ 
reconciliation 
X 
  
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Xe 
Xf 
Safety 
Physical 
examinationg 
X 
X 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
Neurological 
examinationh 
X 
X 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
HIV and hepatitis B 
and C screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsj 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
12-lead ECG 
X 
X 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Laboratory tests for 
hematology and 
chemistry 
X 
X 
 
X 
Xi 
X 
Xi 
Xi 
Xi 
X 
Xi 
Xi 
Xi 
Xi 
Xi 
X 
Xi 
Xi 
X 
Xi 
Xi 
X 
X 
Urine sample for 
urinalysis 
X 
X 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
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Procedure 
Screening (up to 4 weeks before 
Day 1)a 
Interventional period 
 
Day 1 
Week 2 
Week 4 
Week 6 
Week 8 
Week 9 
Week 10 
Week 12 
Week 14 
Week 16 
Week 18 
Week 20 
Week 22 
Week 24 
Week 28 
Week 32 
Week 36 
Week 40 
Week 44 
Week 48b 
Early discontinuation 
visit 
 
Predose 
(baseline) 
Post dose 
Day 14±3 
Day 28±3 
Day 42 ±3 
Day 44±3 
Day 56 ±3 
Day 70 ±3 
Day 84 ±3 
Day 98 ±3 
Day 112 ±3 
Day 126 ±3 
Day 140 ±3 
Day 154 ±3 
Day 168 ±3 
Day 196 ±3 
Day 224 ±3 
Day 252 ±3 
Day 280 ±3 
Day 308 ±3 
Day 336 ±3 
Visit 
1c 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
Urine pregnancy 
test (WOCBP only)k 
 
=====================================================================================================================➔ 
X 
Serum β-HCG test 
(WOCBP only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum FSHl and 
estradiol 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS 
questionnairem 
X 
Xm 
Xm 
 
Xm 
 
 
 
Xm 
 
 
 
 
 
Xm 
 
 
Xm 
 
 
Xm 
Xm 
AE review 
=====================================================================================================================➔ 
X 
SAE review 
=====================================================================================================================➔ 
X 
Efficacy 
EDSS 
X 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
Timed 25-foot walk 
test (T25-FW)n 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
9-hole peg test 
(9-HPT)n 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
Brain MRI with and 
without Gd 
Xo 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Xp 
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Procedure 
Screening (up to 4 weeks before 
Day 1)a 
Interventional period 
 
Day 1 
Week 2 
Week 4 
Week 6 
Week 8 
Week 9 
Week 10 
Week 12 
Week 14 
Week 16 
Week 18 
Week 20 
Week 22 
Week 24 
Week 28 
Week 32 
Week 36 
Week 40 
Week 44 
Week 48b 
Early discontinuation 
visit 
 
Predose 
(baseline) 
Post dose 
Day 14±3 
Day 28±3 
Day 42 ±3 
Day 44±3 
Day 56 ±3 
Day 70 ±3 
Day 84 ±3 
Day 98 ±3 
Day 112 ±3 
Day 126 ±3 
Day 140 ±3 
Day 154 ±3 
Day 168 ±3 
Day 196 ±3 
Day 224 ±3 
Day 252 ±3 
Day 280 ±3 
Day 308 ±3 
Day 336 ±3 
Visit 
1c 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
Clinical outcome assessment 
MSIS-29v2q 
X 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
MSWS-12q 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
Pharmacokinetics 
Blood samples for 
plasma PK 
 
 
Xr 
Xs 
 
Xt 
 
 
 
Xt 
 
 
 
 
 
 
 
 
Xt 
 
 
 
 
Pharmacodynamics/biomarkers 
Blood samples for 
sNfL 
X 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
Blood samples for 
neuro-degeneration/ 
neuro-inflammation 
markersu 
X 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
Abbreviations: 9-HPT = 9-Hole Peg Test; AE = adverse event; β-HCG = beta human chorionic gonadotropin; CCL3 = Chemokine (C-C motif) ligands 3; CCL4 = Chemokine (C-C motif) ligands 4; CHI3L1 = Chitinase 3-
like protein 1; C-SSRS = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; EDSS = Expanded Disability Status Scale; EOT = end of treatment; FSH = follicle stimulating hormone; HIV = human 
immunodeficiency virus; IL1β = Interleukin 1 beta; IL6 = Interleukin 6; IL8 = Interleukin 8; IMP = investigational medicinal product; IRT = interactive response technology; MIP1a = Macrophage Inflammatory Protein-1 
alpha; MIP1b = Macrophage Inflammatory Protein-1 beta; MRI = magnetic resonance imaging; MSIS-29v2 = Multiple Sclerosis Impact Scale-29 items version 2; MSWS-12 = Multiple Sclerosis Walking Scale-12 items; 
PK = pharmacokinetic(s); SAE = serious adverse event; SEL= slowly expanding lesions; sGFAP = serum glial fibrillary acidic protein; sNfL = serum neurofilament light chain; T25-FW = Timed 25 foot walk test; 
TNFα = tumor necrosis factor alpha; WOCBP = woman of childbearing potential 
a 
A maximum of 11 days is required to get IMP on site. The Randomization Visit date of the participants must take into consideration this constraint.  
b 
The Week 48 visit can be considered as both the last visit for Part A and the first visit for Part B. For all participants last dose of double-blind IMP should be taken the prior day. Week 48 visit will consist of 1st 
open-label (Part B) IMP. All assessments for end of Part A should be completed prior to first dose of open-label IMP. 
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c 
The Screening Visit can be performed over up to 2 days if needed (the days need not to be consecutive days) to minimize the burden on participants. 
d 
Substances include drugs of abuse, alcohol, tobacco, and caffeine.  
e 
Reconciliation of IMP dispensed in Part A and dispensation of open-label IMP in Part B will be performed at this visit (Week 48). The IMP may be dispensed in the clinic or provided for home administration via 
direct-to-patient services, except if prohibited by local regulatory authorities. 
f 
Only IMP reconciliation will be performed at this visit. 
g 
A full physical examination will be performed at the Screening Visit, and a brief physical examination will be performed at all other visits.  
h A full neurological examination will be performed at the Screening Visit, and a brief neurological examination including cranial nerves, coordination/cerebellar function, reflexes, motor function, and stance/gait will 
be performed at other visits. 
i 
Laboratory tests for liver chemistry will be conducted every two weeks (biweekly) from W2 through Week 24, every month from Week 24 through Week 48. Hence the only hematology and chemistry laboratory 
tests performed at the visits denoted with footnote "i" are liver chemistry assessments. These visits can be conducted remotely. On-site, local laboratory or home health nurse, are permitted based on availability. 
In case of remote visits, the blood sample must be collected at a local clinic or at home by a nurse, and the sample must be tested at a local lab or the central lab. In case of testing at a local lab, the study site 
staff must contact participants, within 2 working days after the results are expected to be available, to collect results of blood test. The following parameters will be investigated: alkaline phosphatase (ALP), 
alanine transaminase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and bilirubin.   
j 
Vital signs include blood pressure, heart rate, respiratory rate, and temperature. Refer to Section 8.2.3 for further details.  
k 
A urine pregnancy test will be provided direct-to-patient on a monthly basis except for the months coinciding with scheduled clinic visits (ie, Day 1 and Weeks 2, 6, 12, 24, 36, and 48), which should be conducted 
on-site, should not be older than 24 hours upon first IMP intake on Day 1. 
l 
Only for female participants, if needed, to establish menopausal status. 
m The “Since Last Visit” version of the C-SSRS will be used. 
n 
9-HPT: All individuals will complete a practice test and an actual test for both hands (1 task [right and left hand]). T25FW: the amount of time will vary for each participant. 
o 
Baseline scan can be carried out within 5 to 7 days prior to Day 1 randomization but after all other screening assessments have been completed and none have excluded the patient. 
p 
To be performed only if the previous MRI was done more than 4 weeks ago. 
q 
MSIS-29v2 and MSWS-12 will be completed by participants prior to discussion of health status or other tests, and prior to administration of IMP. MSIS-29v2 will be self-administered, with a recall/observation 
period of 2 weeks. The time to complete MSIS-29v2 is 2 to 4 minutes. MSWS-12 will be self-administered with a recall/observation period of 2 weeks. The time to complete MSWS-12 is less than 5 minutes. 
r 
Two samples will be taken within 15 minutes to-1 hour postdose and within 1-to-3 hours postdose (at least 45 minutes apart). 
s 
One sample will be taken predose (within 1-hour predose), and 1 sample will be taken within 0.5-to-3 hours postdose. 
t 
One sample will be taken predose (within 1-hour predose). 
u 
Disease biomarkers will include the followings: CHI3L1 and sGFAP (not collected in China); Cytokines and Chemokines including IL1β, IL6, IL8, TNFα, CCL3 (MIP1a), and CCL4 (MIP1b). 
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1.3.2 Part B  
 
Procedure 
Intervention period (Part B) 
Safety Follow-upb 
Early discontinuation visit 
 
Week 50 
Week 52 
Week 54 
Week 56 
Week 58 
Week 60 
Week 62 
Week 64 
Week 66 
Week 68 
Week 70 
Week 72 
Week 76 
Week 80 
Week 84 
Week 88 
Week 92 
Week 96 / 
EOT 
 
Day 350 ±7 
Day 364 ±7a 
Day 378 ±7 
Day 392 ±7 
Day 406 ±7 
Day 420 ±7 
Day 434 ±7 
Day 448 ±7 
Day 462 ±7 
Day 476 ±7 
Day 490 ±7 
Day 504 ±7 
Day 532 ±7 
Day 560 ±7 
Day 588 ±7 
Day 616 ±7 
Day 644 ±7 
Day 672 ±7/
EOT 
Visit 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
37 
38 
39 
 
Concomitant therapy 
and procedures 
recording 
=====================================================================================================================➔ 
X 
IRT contact 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
IMP dispensation/ 
reconciliationc 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Xd 
 
Xd 
Safety 
Physical examinatione 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Neurological 
examinationf 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Weight 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Vital signsg 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
12-lead ECG 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Laboratory tests for 
hematology and 
chemistry 
Xh 
X 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
X 
Xh 
Xh 
Xh 
Xh 
Xh 
X 
X 
X 
Urine sample for 
urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
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Procedure 
Intervention period (Part B) 
Safety Follow-upb 
Early discontinuation visit 
 
Week 50 
Week 52 
Week 54 
Week 56 
Week 58 
Week 60 
Week 62 
Week 64 
Week 66 
Week 68 
Week 70 
Week 72 
Week 76 
Week 80 
Week 84 
Week 88 
Week 92 
Week 96 / 
EOT 
 
Day 350 ±7 
Day 364 ±7a 
Day 378 ±7 
Day 392 ±7 
Day 406 ±7 
Day 420 ±7 
Day 434 ±7 
Day 448 ±7 
Day 462 ±7 
Day 476 ±7 
Day 490 ±7 
Day 504 ±7 
Day 532 ±7 
Day 560 ±7 
Day 588 ±7 
Day 616 ±7 
Day 644 ±7 
Day 672 ±7/
EOT 
Visit 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
37 
38 
39 
 
Urine pregnancy test 
(WOCBP only)i  
============================================================================================================================➔ 
C-SSRS questionnairej 
 
X 
 
 
 
======================================================================================➔ 
X 
AE review 
=======================================================================================================================➔ 
X 
SAE review 
=======================================================================================================================➔ 
X 
Efficacy  
EDSS 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
Timed 25-foot walk test 
(T25-FW)k 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
9-hole peg test 
(9-HPT)k 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
Brain MRI with and 
without Gd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Clinical outcome assessment 
MSIS-29v2l 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
MSWS-1l 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
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Procedure 
Intervention period (Part B) 
Safety Follow-upb 
Early discontinuation visit 
 
Week 50 
Week 52 
Week 54 
Week 56 
Week 58 
Week 60 
Week 62 
Week 64 
Week 66 
Week 68 
Week 70 
Week 72 
Week 76 
Week 80 
Week 84 
Week 88 
Week 92 
Week 96 / 
EOT 
 
Day 350 ±7 
Day 364 ±7a 
Day 378 ±7 
Day 392 ±7 
Day 406 ±7 
Day 420 ±7 
Day 434 ±7 
Day 448 ±7 
Day 462 ±7 
Day 476 ±7 
Day 490 ±7 
Day 504 ±7 
Day 532 ±7 
Day 560 ±7 
Day 588 ±7 
Day 616 ±7 
Day 644 ±7 
Day 672 ±7/
EOT 
Visit 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
37 
38 
39 
 
Pharmacodynamics/biomarkers 
Blood samples for sNfL 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
Abbreviations: 9-HPT = 9-Hole Peg Test; AE = adverse event; C-SSRS = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; EDSS = Expanded Disability Status Scale; EOT = end of treatment; 
Gd = gadolinium; IMP = investigational medicinal product; IRT = interactive response technology; MRI = magnetic resonance imaging; MSIS-29v2 = Multiple Sclerosis Impact Scale-29 items version 2; MSWS-12 = 
multiple sclerosis walking scale 12 items; SAE = serious adverse event; sNfL = serum neurofilament light chain; T25-FW = Timed 25 foot walk test; WOCBP = woman of childbearing potential 
a 
The first visit for Part B is the Week 48 Visit in Part A. First dose of open-label (Part B) IMP will be taken at that visit, upon completion of all Week 48 assessments. 
b 
The participants will attend a safety follow-up visit within 2 weeks following discontinuation of IMP, if they no longer wish to remain in the study 
c 
In addition to the IMP being dispensed in the clinic, the IMP may be dispensed for home administration via direct-to-patient services, except if prohibited by local regulatory authorities during the intervening 
3 months between site visits. 
d 
Only IMP reconciliation will be performed at this visit if participants are still on study intervention. 
e 
A brief physical examination will be performed at each visit. 
f 
A brief neurological examination including to cranial nerves, coordination/cerebellar function, reflexes, motor function, stance/gait will be performed at all visits. 
g 
Vital signs include blood pressure, heart rate, respiratory rate, and temperature. Refer to Section 8.2.3 for further details. 
h 
Only laboratory tests for liver chemistry will be conducted: every two weeks (biweekly) from Week 50 through Week 72, every month from Week 72 through Week 96. Hence the only hematology and chemistry 
laboratory tests performed at the visits denoted with the footnote “h” are liver chemistry assessments. On-site, local laboratory or home health nurse, are permitted based on availability. These can be conducted 
remotely. In such cases, the blood sample must be collected at a local clinic or at home by a nurse, and the sample must be tested at a local lab or the central lab. In case of testing at a local lab, the study site 
staff must contact participants, within 2 working days after the results are expected to be available, to collect results of blood test. The following parameters will be investigated: alkaline phosphatase (ALP), 
alanine transaminase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and bilirubin. 
i 
A urine pregnancy test will be provided direct-to-patient on a monthly basis except for the months coinciding with scheduled clinic visits (Weeks 52, 72, and 96). 
j 
The “Since Last Visit” version of the C-SSRS will be used. 
k 
9-HPT: All individuals will complete a practice test and an actual test for both hands (1 task [right and left hand]). T25FW: the amount of time will vary for each participant.    
l 
MSIS-29v2 and MSWS-12 will be completed by participants prior to discussion of health status or other tests, and prior to administration of IMP. MSIS-29v2 will be self-administered, with a recall/observation 
period of 2 weeks. The time to complete MSIS-29v2 is 2 to 4 minutes. MSWS-12 will be self-administered with a recall/observation period of 2 weeks. The time to complete MSWS-12 is less than 5 minutes. 
 
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2 
INTRODUCTION  
SAR443820 is a novel, potent, selective, CNS-penetrant RIPK1 inhibitor that is being developed 
for neurodegenerative diseases, including MS. 
2.1 
STUDY RATIONALE  
Multiple sclerosis is a chronic autoimmune disease characterized by neuroinflammation, 
demyelination, and axonal degeneration (1). Despite the availability of several DMTs that reduce 
relapses, there is still a significant unmet need for therapies that target disease progression in 
relapsing and progressive forms of MS (2). Clinically, most relapsing signs are effectively 
controlled with a broad arsenal of DMTs that target the peripheral adaptive immune system. Even 
when the relapses are well-controlled, ongoing inflammatory activity in the CNS inflicts insidious 
chronic damage and progressive physical disability predominates in absence of relapse activity 
(3, 4). This is particularly true for people with progressive forms of MS including PPMS and 
SPMS leading to relentless accumulation of nervous system disability. This is in part due to a 
complex cellular and biochemical milieu that perpetuates mediators of inflammation, leading to 
neuroaxonal damage and demyelination (3, 4). 
Receptor interacting serine/threonine-protein kinase is a critical signaling protein in the TNFR1 
pathway that regulates inflammation and cell death in tissues throughout the body. RIPK1 is 
activated in response to several inflammatory stimuli, with subsequent initiation of a complex 
signaling cascade that triggers intracellular responses, including cytokine release, microglial 
activation, and necroptosis, a regulated form of cell death. There is evidence for RIPK1, RIPK3, 
and MLKL activation in MS postmortem tissue, playing a role in both microglial and astrocyte 
inflammatory signaling and necroptosis of oligodendrocytes, which can be subject to 
RIPK1-dependent cell death. Inhibition of RIPK1 activity has been shown to protect against 
necroptotic cell death in vitro across a range of cell death models (5, 6, 7). Genetic and 
pharmacological inhibition of RIPK1 kinase ameliorated disease pathology and disease scores, 
improved animal behavior, attenuated the production of proinflammatory cytokines, reduced 
plasma neurofilament heavy chain levels, and decreased recruitment of immune cells in 2 animal 
models of MS, the EAE, and cuprizone models ( 5, 7), recapitulating certain aspects of 
immunological and degenerative components of MS (3, 4). These nonclinical findings coupled 
with observations of increased RIPK1 activity in human disease suggest a CNS-penetrant RIPK1 
inhibitor may be beneficial in treating neurological diseases such as MS ( 5, 6, 7). 
SAR443820 is a selective, orally bioavailable, CNS-penetrant, reversible kinase inhibitor of 
RIPK1. SAR443820 has demonstrated strong RIPK1 inhibition with high potency in vitro in 
various cell types. Dose ranging from 10 mg to 40 mg daily and 15 mg to 20 mg BID were safe 
and well tolerated. The FIH SAD (Study TDU16519) and MAD (Study TDR16520) showed a 
good tolerability and PK profile (t1/2 7 to 9 hours and tmax 1 to 2 hours), a strong target engagement 
relative to the RIPK1 inhibition evidenced at peripheral level and good penetration of SAR443820 
in CSF. 
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Neuronal loss is a hallmark pathological feature of MS that is associated with brain atrophy, 
disease progression, and long-term disability (7, 8, 9). Neurofilaments (heavy and light chains) are 
structural elements of axons and markers of neuronal damage. Neurofilaments are increased in the 
CSF, plasma, and serum in a range of neurological diseases including MS (10). Neurofilament 
light chain levels have been demonstrated in numerous studies to be predictive of disease course 
and are responsive to DMTs in MS (11). Most approved and clinically effective MS treatments 
also reduce sNfL levels serving as a surrogate biomarker of treatment efficacy in numerous 
RRMS, PPMS, and SPMS randomized clinical trials (12, 13, 14). Therapeutic administration of a 
CNS-penetrant RIPK1 inhibitor has been demonstrated to cause dose-dependent reduction in 
disease score and plasma heavy chain neurofilament in the EAE animal model, substantiating 
neurofilament’s suitability for objectively measuring SAR443820’s effect on this marker in MS 
patients while evaluating the clinical and radiological signs that may respond to this intervention, 
especially the degenerative aspects that axonal injury manifests in the form of neurofilament 
elevation across the spectrum of neurological disease (7, 10, 11). 
The aim of the ACT16753 Phase 2 proof-of-concept is to demonstrate SAR443820’s effects on 
sNfL levels when compared to placebo in RRMS, SPMS, and PPMS participants. This study will 
also evaluate the effect of SAR443820 on clinical and imaging markers of disease progression and 
activity. Participants will be permitted to continue specified SOC background therapies 
(see Section 5) throughout the double-blinded treatment (Part A) and open-label long-term 
extension period (Part B). Safety and tolerability of SAR443820 will be monitored throughout the 
trial. 
2.2 
BACKGROUND  
Immunomodulatory drugs have been the mainstay of MS therapy, most of which target the 
peripheral immune response, and have conferred significant benefit to patients suffering from MS 
with clinical relapses and MRI activity. 
There is still a significant unmet need for therapies that target neuroinflammation in the CNS with 
the goal of halting long-term disability and neurodegeneration in all diagnostic categories of MS 
(ie, progressive forms of the disease such as PPMS and SPMS, as well as progression in RRMS) 
(15). Even the most recent high efficacy DMTs act mainly on adaptive immunity in the periphery 
with only modest or temporary ability to slow neuroinflammatory and neurodegenerative 
processes and stop disease progression (10, 11). Therefore, development of MS treatments with 
new modes of action is of interest. 
Beyond the existing strategy to modulate cellular elements of adaptive immunity, there is 
mounting evidence that innate immunity, mediated by cells of a myeloid lineage (eg, bone 
marrow-derived monocytes, macrophages, and CNS resident microglial cells), is responsible for 
many of the neurodegenerative aspects of MS that persist in spite of the effectiveness of approved 
DMTs in preventing acute relapses (11, 15). Modulation of innate immunity has the potential to 
curtail such neuroinflammation and other manifestations of disease progression that remain 
unaddressed by current, approved therapies. 
SAR443820 has demonstrated strong RIPK1 inhibition with high potency in vitro in various cell 
types and has been investigated in 4 clinical trials. Overall, in 100 healthy participants, doses 
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ranging from 10 mg to 40 mg daily and 15 to 20 mg BID were safe and well tolerated. The FIH 
SAD (Study TDU16519) and MAD (Study TDR16520) studies showed a good tolerability and 
PK profile (t1/2 of 7 to 9 hours and tmax of 1 to 2 hours), strong target engagement relative to the 
RIPK1 inhibition evidenced at the peripheral level, and good penetration of SAR443820 in CSF. 
A preliminary PK-PD model has been developed using PD data 
 from the SAD and MAD. Typical Imax and IC50 values 
were 
% and 
 ng/mL, respectively, confirming the
 efficacy and potency of SAR443820 
on pRIPK1 inhibition. Study BDR16957 evaluated the relative bioavailability between tablet and 
capsule formulations in Part 1 and showed 
 of the SAR443820 
formulation, and in Part 2,
 of SAR443820 administered in 
fasted or fed (high-fat meal) conditions were observed. Study PKM17247 assessed safety and PK 
in East Asian healthy participants (Chinese and Japanese cohorts). 
. Refer to the SAR443820 Investigator’s 
Brochure (IB) for detailed descriptions of the chemistry, pharmacology, efficacy, and safety of 
SAR443820. 
2.3 
BENEFIT/RISK ASSESSMENT  
2.3.1 Risk assessment  
Table 1 - Risk assessment (identified risk of clinical significance)  
Identified risk of clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
Study intervention(s) 
 
 
Drug induced liver injury (DILI) 
During clinical trials with SAR443820, mild-
severe ALT increases have been reported, 
including 2 SUSARs with total bilirubin 
increase >2 ULN (DILI) reported in the ALS 
patients. These events often involved 
patients who were also taking concomitant 
medications that are known to induce liver 
function abnormalities, or who had 
concomitant diseases that could also affect 
ALT level. 
A lower percentage of ALT increases greater 
than 3xULN  have been reported in the 
ongoing phase 2 MS study (ACT16753) 
 
Hepatic impairment will be considered by 
excluding participants with moderate to 
severe hepatic impairment (see item 5 of 
Section 2.3.3). 
All participants are requested to undergo 
biweekly liver chemistry monitoring from 
D1 through Week 24, then monthly liver 
chemistry monitoring from Week 28 
through Week 48. In Part B all participants 
are requested to undergo biweekly liver 
chemistry monitoring from Week 50 
through Week 72, and then monthly liver 
chemistry monitoring through Week 96.  
Participants will be discontinued from the 
study based on ALT levels. 
Detailed instructions to be followed in case 
of the occurrence of an AESI of ALT 
increase >3 ULN are described in 
Appendix 6 in this protocol, and cover ALT 
monitoring, IMP administration, etiology 
assessment and IMP rechallenge 
Abbreviations: ALT = alanine transaminase; DILI = drug induced liver injury; IMP = investigational medicinal product. 
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Table 2 - Risk assessment (potential risk of clinical significance)  
Potential risk of clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
Study intervention(s) 
Convulsion/seizures 
Convulsions are considered a potential risk 
based on nonclinical findings in single‑dose, 
10 and 28‑day nonhuman primate toxicity 
studies and in a 6‑month rat study. 
In nonhuman primate studies, 
convulsions/tremors were observed at 
75 mg/kg in the single-dose study, at 
100 mg/kg/day in the 10-day study, and at 
60 mg/kg/day in the 28-day study. 
No convulsions were observed in the 3 or 
9-month monkey studies at dose levels up to 
 mg/kg/day (the highest dose tested in 
these studies). 
In an in vivo genetic toxicity study in rats, 
convulsions were observed after a single 
dose of 500 mg/kg and above/. In the 6- and 
9-month studies in rats, convulsions were 
noted at 400 mg/kg/day (males) and 
200 mg/kg/day (females). Convulsions and 
other findings that necessitated euthanasia 
were also observed in a single female rat 
receiving 50 mg/kg/day. 
Based on the uncertainty in the 
interspecies translatability of convulsive 
risk, a conservative safety approach to 
limit human exposure (ie, Cmax and AUC) 
was taken regarding the selected dose of 
20 mg QD, which maintained a minimum 
of a 
 to the NOAEL 
exposure (Cmax and AUC) in the 6-month 
toxicology study in rat and 9-month 
toxicology study in nonhuman primate.  
Excluding participants in whom exposure 
may be increased (participants weighing 
<45 kg, or participant with moderate or 
severe hepatic impairment). 
Moreover, to mitigate risk, participants 
with a history of noninfantile seizure will 
not be eligible to participate in this study.  
Additionally, concomitant medications 
that may increase the risk of seizure or 
increase exposure (moderate or strong 
cytochrome P450 [CYP]3A4 inhibitors or 
strong inducers of CYP3A4) are not 
allowed in the study.  
Convulsion will be considered an AESI. 
Immunomodulatory effects 
Findings consistent with immune system 
modulation were observed with SAR443820 
in the 3- and 9-month nonhuman primate 
studies. These pathological findings included 
mononuclear cell infiltrates in various tissues 
and changes in lymphoid tissues 
(increased/decreased cellularity and/or 
increased germinal centers). None of these 
microscopic findings for SAR443820 were 
considered adverse based on incidence, 
severity, and/or recoverability, as well as the 
lack of clinical pathology correlates or relevant 
clinical observations. 
Frequent monitoring via hematology 
tests, physical examinations (eg, skin, 
lymph nodes), and occurrence of 
infection TEAEs is planned. 
Serious infection will be considered an 
AESI. 
Off target potential risks  
Thrombocytopenia 
Anemia 
 
Related to other similar compounds, and to a 
potential bone marrow effect 
 
Regular CBC assessments will be 
performed. 
Skin reaction 
 
Clinical examination will be performed. 
Study procedures 
Blood drawing 
Pain or other discomfort from collection of 
blood samples  
Minimize the frequency and amount of 
blood drawing. 
Abbreviations: AESI = adverse event of special interest; ALT = alanine aminotransferase; AUC = area under the curve; CBC = complete 
blood count; Cmax = maximum plasma concentration; NOAEL = no-observable-adverse-effect level; Pop PK = population pharmacokinetic; 
QD: once daily; TEAEs = treatment-emergent adverse events 
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2.3.2 Benefit assessment  
SAR443820 is anticipated to demonstrate efficacy across multiple parameters of MS (disability 
progression in particular). Based on the mechanism and CNS penetrance of SAR443820, its 
potential to interfere with early and ongoing central inflammation that leads to activation of 
microglia, which is responsible in part for neurodegeneration, may confer protection from clinical 
sequelae and physical improvement. These benefits may further translate into cognitive 
stabilization and overall amelioration of quality of life. 
2.3.3 Overall benefit/risk conclusion  
In the completed FIH studies, SAR443820 was safe and well-tolerated up to the highest doses 
administered, ie, a single dose of 
 mg and 14-day dose of 20 mg BID in healthy volunteers who 
received SAR443820 as of November 2021. Neither convulsions, immunomodulatory effects, 
thrombocytopenia, anemia, skin reactions, nor infections were observed. In addition, a 
preliminary physiologically based pharmacokinetic (PBPK) model indicates that at the dose of 
20 mg QD, 
(RIPK1 
auto-phosphorylation inhibition test [pSer166-RIPK1] in peripheral blood mononuclear cell 
[PBMC] lysates) during the dosing interval. Convulsions believed to be SAR443820 related have 
been observed in
 at similar SAR443820 levels in 
plasma. The risk of convulsion will be mitigated through the following: 
1. limiting the dose chosen in this study with maximum plasma concentration (Cmax) and area 
under the curve (AUC)  that are 
 at the 
no-observed–adverse-effect level (NOAEL) in the
 
studies; 
2. excluding participants with a history of seizures; 
3. excluding concomitant medications that may increase the risk of seizures; 
4. excluding concomitant medications that may increase exposure (moderate or strong 
CYP3A4 inhibitors); 
5. excluding participants with moderate or severe hepatic impairment and with body weight 
<45 kg.  
In the ongoing study ACT16970, a limited number of cases meeting criteria for severe DILI have 
been reported. ALT and bilirubin levels fully recovered in these cases after stopping the IMP and 
riluzole. These blinded data suggest that DILI is an identified risk of SAR443820, in particular 
when used in combination with hepatotoxic concomitant medications. The exact mechanism is not 
known. In nonclinical studies in rats and monkeys, non-adverse microscopic changes were noted 
in the liver without ALT increases. In Phase 1 studies, there were three mild (<3 ULN) 
asymptomatic cases of ALT increase (all recovered). Risk minimization measures during the 
study include limitation of alcohol consumption, although a relationship with alcohol use has not 
been established.  
In addition, frequent monitoring of safety through hematology and liver chemistry tests, physical 
examination (eg, skin, lymph nodes), and occurrence of infections, will be implemented in both 
Parts A and B. 
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Participants in this study will be permitted to continue their current stable dose of DMT 
(see Section 5), except for those explicitly prohibited in the exclusion criteria. SAR443820 is a 
centrally acting RIPK1 inhibitor that is poised to reduce MS disease processes in the central 
nervous system and to complement the relapse-reducing effects of peripherally acting DMT’s. 
The primary endpoint of neurofilament levels measures the impact of SAR443820 on reducing 
neuronal damage, which is expected to occur over the 12-month treatment duration. It is critical 
that the trial does not deprive MS patients from taking stable dosages of selected safe and 
effective DMT’s that are expected to control relapses during the trial duration. 
Combining a centrally acting RIPK1 inhibitor such as SAR443820, with well-established MS 
therapies believed to act through separate, peripheral, immune mechanisms argues for potential 
added beneficial effects on disease processes in the central nervous system while limiting the risk 
of relapses. When considering risks associated with addition of SAR443820 on top of the allowed 
background DMTs, several safeguards were put in place to avoid risks related to overlap in 
mechanism of action, potential additive adverse effects between SAR443820 with MS 
concomitant medications, and PK drug-drug interactions. Considering the measures taken to 
minimize risk to participants in this study, the potential risks identified in association with 
SAR443820 are justified by the anticipated benefits that may be afforded to participants with MS. 
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3 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS  
Table 2 - Objectives and endpoints  
Part A 
 
Objectives 
Endpoints 
Primary 
 
• 
To assess the effect of SAR443820 
compared to placebo on sNfL 
• 
Week 48 sNfL levels relative to baseline 
Secondary 
 
• 
To evaluate efficacy of SAR443820 
compared to placebo on imaging and 
clinical endpoints 
• 
Cumulative number of new gadolinium (Gd)-enhancing 
T1 hyperintense lesions as detected by MRI at Week 48, 
defined as the sum of the individual number of new 
Gd-enhancing T1 hyperintense lesions at all scheduled visits 
starting after baseline up to and including the Week 48 visit 
• 
Cumulative number of new and/or enlarging T2 hyperintense 
lesions as detected by MRI, at Week 48, defined as the sum of 
the individual number of new and/or enlarging T2 lesions at all 
scheduled visits starting after baseline up to and including the 
Week 48 visit 
• 
Time to onset of 12 weeks confirmed disability progression 
(CDP) from baseline as assessed by the Expanded Disability 
Status Scale (EDSS) score 
• 
Time to onset of sustained 20% increase in 9-Hole Peg Test 
(9-HPT) confirmed over at least 12 weeks 
• 
Time to onset of sustained 20% increase in timed 25-foot walk 
test (T25-FW) confirmed over at least 12 weeks 
• 
Change from baseline in EDSS-Plus at Week 48 
• 
Annualized relapse rate (ARR) of RMS population (relapsing 
SPMS and RRMS) up to Week 48 
• 
To explore effect of SAR443820 
compared to placebo on brain volume 
and chronic lesions 
• 
Percent change from baseline in brain volume loss (BVL) as 
detected by brain MRI at 48 weeks 
• 
Change from baseline in the volume, number, and intensity 
(T1) of slowly expanding lesions (SELs), and normalized 
T1 intensity in lesions at Weeks 12, 24, 36, and 48 
• 
Change from baseline in the total number and volume of non-
enhancing lesions volume at Weeks 12, 24, 36, and 48 
• 
Change from baseline in the number of phase rim lesions 
(PRL) at Weeks 12, 24, 36, and 48; will be conducted at 3T 
capable sites 
• 
To assess the safety and tolerability of 
SAR443820 
• 
Incidence of AE, SAE, TEAE, PCSA in laboratory tests 
• 
To assess pharmacokinetic (PK) of 
SAR443820 
• 
Plasma concentration of SAR443820 
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Objectives 
Endpoints 
Tertiary 
 
• 
To assess the effect of SAR443820 
compared to placebo on sNfL in 
subpopulations of multiple sclerosis (MS) 
• 
Change from baseline in sNfL level in MS subpopulations 
(RRMS, SPMS, PPMS) over 48 weeks 
• 
To assess the effect of SAR443820 
compared to placebo on biomarkers of 
neurodegeneration, inflammation, and 
disease progression 
 
• 
Change from baseline compared to Week 48 in: plasma 
chitinase-3-like protein 1 (CHI3L1), serum glial fibrillary acidic 
protein (sGFAP), interleukin-1B (IL1B), IL6, IL8, Chemokine 
(C-C motif) ligands 3 (CCL3), and Chemokine (C-C motif) 
ligands 4 (CCL4) 
• 
To assess efficacy of SAR443820 
compared to placebo on patient-reported 
outcomes (PROs) assessing the physical 
and psychological impact of MS from the 
patient’s perspective (MSIS-29v2) and 
the impact of MS on the individual’s 
walking ability (MSWS-12) 
• 
Change from baseline in MSIS-29v2 physical and 
psychological domains scoring at Week 12, 24, 36, and 48 
• 
Change from baseline in MSWS-12 at Week 12, 24, 36, and 
48 
 
Part B 
 
Objectives 
Endpoints 
Primary 
 
• 
To assess long-term trends in durability 
of sNfL 
• 
Week 96 sNfL levels relative to baseline 
Secondary 
• 
To explore the effect of SAR443820 on 
brain volume and chronic lesions 
• 
Percent change from baseline in BVL as detected by brain 
MRI at Week 96 
• 
Change from baseline in volume, number and intensity (T1) in 
SEL and normalized T1 intensity in lesions to Week 96 
• 
Change from baseline in the total number and volume of non-
enhancing lesions Week 96 
• 
Change from baseline in the number of PRLs (same 
participants/centers from Part A with 3T capability) at Week 96 
• 
To assess the long-term safety and 
tolerability of SAR443820 
• 
Incidence of AE, SAE, TEAE, PCSA in laboratory tests, ECG, 
and vital signs during through Week 96 
• 
To evaluate long-term effect of 
SAR443820 on disease progression and 
activity assessed by other clinical and 
imaging measures on physical function 
and patient-reported outcomes (PROs) 
• 
Cumulative number of new Gd-enhancing lesions as detected 
by T1-weighted MRI between 48 and 96 weeks; number of 
new or enlarging T2-hyperintense lesions on MRI at Week 96 
relative to Week 48 
• 
Annualized relapse rate (ARR) of RMS population (relapsing 
SPMS and RRMS) up to Week 96 
• 
Time to onset of composite CDP (CCDP), confirmed over at 
least 12 weeks (3-month CCDP), by the EDSS Plus composite 
(EDSS score increase, OR 20% increase in the T25-FW test, 
OR 20% increase in the 9-HPT) 
• 
Time to onset of 12 weeks CDP as assessed by the EDSS 
score 
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Objectives 
Endpoints 
 
• 
Time to onset of sustained 20% increase in 9-HPT confirmed 
over at least 12 weeks  
• 
Time to onset of sustained 20% increase T25-FW test 
confirmed over at least 12 weeks 
• 
Change from baseline in EDSS Plus at Week 96 
• 
Change in MSIS-29v2 physical and psychological domains 
scoring from baseline through Week 96 
• 
Change in MSWS-12 from baseline through Week 96 
 
For China, please see Section 10.8.1 for details. 
The primary estimand defined for the primary efficacy endpoint is summarized in Table 3 below. 
The comparison of interest will be the comparison of SAR443820 versus placebo. More details 
are provided in Section 9.2. 
Table 3 - Summary of primary estimand  
Endpoint 
Estimands 
Category 
Endpoint 
Population 
Intercurrent event(s) 
handling strategy 
Population-level summary  
(analysis and missing data handling) 
Primary objective: to assess the effect of SAR443820 compared to placebo on serum neurofilaments 
Primary 
endpoint 
sNfL levels 
at Week 48 
relative to 
baseline  
mITT 
Had IMP not been 
discontinued (hypothetical 
strategy), had baseline 
DMT not been permanently 
modified (hypothetical 
strategy) 
Geometric means ratio (GMR) between 
interventions from the mixed effect model with 
repeated measures (MMRM) on 
log-transformed data. Missing data will be 
handled by MMRM under the missing at random 
(MAR) assumption 
Abbreviations: ANCOVA = analysis of covariance; DMT = disease modifying therapy; IMP = investigational medicinal product; mITT = modified 
intent-to-treat; sNfL = serum neurofilament light chain 
3.1 
APPROPRIATENESS OF MEASUREMENTS  
3.1.1 Measurements for efficacy assessment  
A hallmark feature of MS that correlates highly with disability is axonal damage and loss, which 
has been associated with brain atrophy, the ultimate diagnostic evidence of disease progression 
and plays a key role in long-term disability (8, 9). This axonal damage manifests in CSF, plasma 
and serum in the form of neurofilaments (heavy and light chain) that are lost as part of the 
neurodegenerative process in a range of neurological diseases (10). In some cases of progressive 
MS, elevated neurofilament has been reported as the only evidence of disease (16). Neurofilament 
light chain levels have been demonstrated in studies to be predictive of disease course and are 
responsive to DMTs in MS (11); therefore, serum neurofilament is chosen as the primary endpoint 
in this trial. 
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Measurement of delay of disability progression is an important clinical endpoint and is endorsed 
by regulatory guidance (17). The EDSS is widely used to measure neurological disability in 
clinical trials and routine settings (18). Due to the known fluctuation in EDSS scores, CDP 
confirmed after 12 and 24 weeks is used as an endpoint in clinical trials of progressive MS 
(19, 20). 
Due to the limited sensitivity of the EDSS to changes in upper limb function and early gait 
symptoms, the timed 25-foot walk test (T25-FW) test and the 9-hole peg test (9-HPT were added 
to the EDSS, making a composite endpoint, the EDSS-Plus (13). The EDSS-Plus is used as a 
secondary endpoint to attempt a more sensitive measurement for efficacy evaluation. 
MRI markers of inflammatory activity in the brain observed in previous clinical trials of 
progressive MS (19, 20) and RMS will be measured. The number of new Gd-enhancing T1 
hyperintense lesions will be used as a secondary endpoint, as accumulation of Gd contrast agent in 
brain tissue is related to inflammatory activity in MS patients. Also, the number of new 
T2-hyperintense lesions and change in their volume are included as secondary endpoints, as they 
reliably reflect accumulating MS lesion load over time. Additional MRI measurements include 
change in brain volume, slowly expanding/evolving lesions, and phase rim lesions, which are 
considered to be markers of the CNS degenerative process and are therefore assessed to inform on 
SAR443820’s effect on disease progression. 
Clinical relapse is the main clinical expression of RMS that constitutes up to 50% of this study 
population and will therefore be assessed due to its clinical importance and in an attempt to collect 
additional efficacy data. Although all enrolled RMS participants will be expected to be stable on 
their DMTs, MS relapses may occur. Thus, relapse data will be carefully collected and their 
impact on the primary endpoint will be assessed. 
Clinical outcome assessments are considered important for understanding the impact of treatment 
on function and wellbeing (21). In both progressive and relapsing MS, the increasing limitation 
and loss of physical function are prevalent and among the most debilitating signs and symptoms 
of the disease (22). Physical function limitations are associated with decrements in quality of life 
due to diminishing productivity and ability to perform daily activities, maintain employment, and 
maintain social roles and emotional wellbeing. Reduction of disease impact on patient-reported 
physical function is therefore important to assess in addition to the clinician assessment and 
constitutes a direct measure of treatment effectiveness, ie, whether a treatment influences how a 
participant feels or functions (23). 
3.1.2 Pharmacokinetic assessments  
Whole blood samples will be collected for measurement of the plasma concentration of 
SAR443820 as specified in the SoA. 
3.1.3 Pharmacodynamic assessments  
Blood samples will also be collected to measure changes in markers of neuroinflammation, 
plasma CHI3L1, and cytokines and chemokines including IL1β, IL6, IL8, TNFα, CCL3, and 
CCL4. Additionally, serum glial fibrillary acidic protein (GFAP) will be collected from serum as 
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a potential marker of risk of relapse, treatment response and risk of disability progression 
(Note: serum GFAP will not be collected from participants in China). 
3.1.4 Safety and tolerability assessment  
Adverse events, SAEs, treatment emergent adverse events (TEAEs), adverse events of special 
interest (AESI), electrocardiogram (ECG) measurements, vital signs, C-SSRS scores, and 
laboratory test analyses will be reported. 
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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
Study ACT16753 is a Phase 2, randomized, double-blind placebo-controlled 2 parallel-arm study 
followed by an open-label, long-term extension period. 
The study consists of 2 parts (A and B) as follows: 
Part A is a 48-week, double-blind, placebo-controlled part, preceded by a screening period of up 
to 4 weeks before Day 1. 
• The screening period will be up to 4 weeks and is designed to evaluate suitability for 
participation in the study in terms of MS diagnosis, clinical status based on EDSS, and 
safety screening evaluations. No IMP will be administered in this period. 
• The double-blind treatment period will have a total duration of 48 weeks for each 
participant and will include the following: 
- 
Participants will be randomized at 1:1 ratio to receive SAR443820 20 mg QD (n = 84) 
or matching placebo QD (n = 84). 
- 
Randomization will be stratified by MS clinical subtypes (ie, RRMS, SPMS, or PPMS) 
in order to ensure a balance between the treatment and placebo arms within each MS 
clinical subtype. Participants will attend in-clinic study assessments at baseline 
(Day 1) and Weeks 2, 4, 6, 8, 9, 10, 12, 14, 16, 18, 20, 22, 24, 28, 32, 40, 44 and 48 
(Weeks 4, 8, 9, 10, 14, 16, 18, 20, 22, 28, 32, 40, and 44 visits for liver chemistry only 
may be conducted at local labs and via home health nursing where available). 
All participants who successfully completed Part A will rollover to Part B. Participants who 
discontinue the treatment or choose not to enter Part B will have their early discontinuation or 
safety follow-up visit, respectively, up to 2 weeks after the last dose of IMP. 
Part B is an open-label, long-term extension of Part A. Part B starts from the end of Part A 
(Week 48) and continues up to Week 96. 
• The assignment of participants to study intervention in Part A will remain double-blinded 
during Part B unless there is medical need to unblind the study intervention assignment. 
• All participants will receive 20 mg QD SAR443820 in Part B. 
• Participants will attend in-clinic study assessments at Weeks 50, 52, 54, 56, 58, 60, 62, 64, 
66, 68, 70, 72, 76, 80, 84, 88, 92 and 96 (and Week 48 which is the last visit of Part A and 
first visit of Part B; Weeks 50, 54, 56, 58, 60, 62, 64, 66, 68, 70, 76, 80, 84, 88, and 92 
visits for liver chemistry only may be conducted at local labs and via home health nursing 
where available). 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
This is a Phase 2 proof-of-concept study for which a double-blind, randomized, placebo-
controlled design has been selected to minimize possible biases in the study outcome.  
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Male and female participants with a diagnosis of RRMS, SPMS or PPMS between 18 and 
60 years inclusive will be selected for this study. The age range is limited to participants 
≤60 years to increase the probability of response to treatment and reduce potential confounding 
from age-related neurofilament elevations. Participants enrolled in this study will be under stable 
conditions (absence of clinical relapse in the 8 weeks prior to screening) to capture the effect of 
treatment on chronic neuroaxonal damage reflected in sNfL levels, particularly because the 
mechanism of SAR443820 modifies disease pathology, rather than symptomology.  
Part A of this study is a randomized double-blind, placebo-controlled design, while Part B is an 
open-label long-term extension during which neurofilament, imaging, clinical and safety data will 
be collected to characterize the long-term treatment effects of SAR443820. 
4.3 
JUSTIFICATION FOR DOSE  
The dose of 20 mg QD SAR443820 is selected for this Phase 2 study to achieve the best potential 
treatment effectiveness in participants with MS and has previously demonstrated strong target 
engagement and was well tolerated in healthy participants.  
Overall, in the FIH study, SAR443820 up to a highest single dose of 
 mg and 14-day dose of 
SAR443820 20 mg BID, was found to be safe and well tolerated. In the Phase 1a SAD study, 
there were no SAEs. All the TEAEs were of mild to moderate intensity except 1 severe TEAE 
(blood creatine phosphokinase [CPK] increase of Grade 3) reported in the placebo group. 
, 
In the MAD study, no SAEs were reported. All the AEs 
reported in the MAD study were of mild to moderate intensity. At 20 mg QD, the mean observed 
Cmax and AUC0-24 at steady state are
 μM and 
μM*hour, respectively based on MAD 
study that are 
-fold lower, respectively, than the exposure at NOAEL in the 6-month rat 
toxicology study. 
The dose of 20 mg QD SAR443820 is estimated to provide a high level of target engagement 
required for obtaining a clinical effect. Internal preclinical data in animal models suggest that 
SAR443820 
 (concentration enabling a
% decrease of the 
pS166-RIPK measurement compared to that at baseline) 
activity. A preliminary PK-PD model has been developed using PD data (pS166-RIPK 
measurement in human PBMCs) from SAD and MAD studies and indicates high efficacy 
 and potency 
) of SAR443820 on pRIPK1 inhibition. Good 
penetration of SAR443820 in CSF has been observed in human with mean values of the 
CSF/unbound plasma ratio close to 1.0. A preliminary PBPK model indicates that at a dose of 
20 mg QD, 
 
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4.4 
END OF STUDY DEFINITION  
The end of the study is defined as the date of the last visit of the last participant in the study or last 
scheduled assessment and/or procedure shown in the schedule of activities (SoA) for the last 
participant in the study globally. 
A participant is considered to have completed the study if he/she has completed all periods of the 
study including the last visit or the last scheduled procedure shown in the SoA. 
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5 
STUDY POPULATION  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
INCLUSION CRITERIA  
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
I 01. Participant must be 18 to 60 years (inclusive) of age, at the time of signing the informed 
consent. 
Type of participant and disease characteristics 
I 01. Participants with a diagnosis of RRMS, SPMS (relapsing or non-relapsing), or primary 
progressive subtype according to the 2017 revision of the McDonald diagnostic criteria 
(SPMS diagnostic criteria according to [13] include an initial relapsing remitting disease 
course followed by progression with or without occasional relapses, minor remissions, and 
plateaus; progression denotes the continuous worsening of neurological impairment over at 
least 6 months). 
I 02. Participants with an Expanded Disability Status Scale score of 2-6 inclusive at screening. 
I 03. Participants who are either untreated or in the opinion of the Investigator are stable on an 
allowed DMT (interferons, glatiramer acetate, fumarates, or teriflunomide) for at least the 
past 3 months, AND not anticipated to require a change in MS treatment for the duration 
of Part A and Part B (through Week 96); in Part B changes in dose of allowed DMTs or 
transition to other allowed DMTs is permitted). 
Weight 
I 04. Participants with body weight ≥45 kg and body mass index (BMI) ≥18.0 kg/m2. 
Sex, contraceptive/barrier method, and pregnancy testing requirements 
I 05. All 
Contraceptive use by men and women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies. 
a) Male participants 
- 
Male participants are eligible to participate if they agree to the following during the 
study period and for at least 92 days following their last dose of IMP: 
- 
Refrain from donating or cryopreserving sperm 
Plus, either: 
- 
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent 
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OR 
- 
Must agree to use contraception/barrier (male condom) as detailed below: 
A male condom and an additional highly contraceptive method as described in 
Section 10.4.2 when having sexual intercourse with a woman of childbearing 
potential (WOCBP) who is not currently pregnant 
b) Female participants 
Female participants are eligible to participate if they are not pregnant or breastfeeding 
and 1 of the following conditions applies: 
- 
Are a woman of nonchildbearing potential (WONCBP) as defined in 
Section 10.4.1. 
OR 
- 
Are a WOCBP and agree to use a contraceptive method that is highly effective 
(with a failure rate of <1% per year), preferably with low user dependency, as 
described in Section 10.4.2 during the study intervention period (to be effective 
before starting the study intervention) and for at least 32 days after the last 
administration of the IMP, and agree not to donate or cryopreserve eggs (ova, 
oocytes) for the purpose of reproduction during this period. 
- 
WOCBP must have a negative highly sensitive pregnancy test within 24 hours 
before the first administration of the study intervention, see Section 8.2.6. 
- 
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive. 
Informed consent 
I 06. Participants are capable of giving signed informed consent as described in Appendix 1 
(Section 10.1) of the protocol which includes compliance with the requirements and 
restrictions listed in the informed consent form (ICF) and in this protocol. 
5.2 
EXCLUSION CRITERIA   
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
E 01. Participants with immunodeficiency syndromes or other autoimmune diseases requiring 
immunosuppressive therapy. 
E 02. Participants with a history of seizures or epilepsy (history of febrile seizure during 
childhood is allowed). 
E 03. Participants with known clinical relapse (acute or subacute episodes of new or increasing 
neurological dysfunction followed by full or partial recovery, in absence of fever or 
infection) within 8 weeks of screening (1). 
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E 04. Participants with a neurological disease history other than MS, eg, head trauma within 
3 months, cerebrovascular disease, and vascular dementia.  
E 05. Participants with a history of recent serious infection (eg, pneumonia, septicemia) within 
4 weeks of screening; an infection requiring hospitalization or intravenous antibiotics, 
antivirals, or antifungals within 4 weeks of screening; or chronic bacterial infections (such 
as tuberculosis) deemed unacceptable, as per Investigator’s judgment. 
E 06. Participants who have significant cognitive impairment, psychiatric disease, other 
neurodegenerative disorders (eg, Parkinson disease or Alzheimer disease), substance abuse 
(including a history of alcohol abuse), or any other conditions that would make the 
participants unsuitable for participating in the study or could interfere with assessment or 
completing the study in the opinion of the Investigator. 
E 07. Participants with a documented history of attempted suicide over the 24 weeks prior to the 
Screening Visit, presents with suicidal ideation of category 4 or 5 on the Columbia Suicide 
Severity Rating Scale (C-SSRS), or if in the Investigator's judgment, the participant is at 
risk for a suicide attempt. 
E 08. Participants with a history of unstable or severe cardiac, pulmonary, oncological, hepatic, 
or renal disease or another medically significant illness other than MS precluding their safe 
participation in this study. 
E 09. Participants who received a live vaccine within 14 days before the Screening Visit. 
E 10. Participants with a known history of allergy to any ingredients of SAR443820 (mannitol, 
lactose monohydrate, sodium starch glycolate, colloidal silicon dioxide, magnesium 
stearate, hypromellose, titanium dioxide, polyethylene glycol, and microcrystalline 
cellulose). 
Prior/concomitant therapy 
E 11. Participants with a current use of any medications that are moderate or strong inhibitors or 
strong inducers of CYP3A4 (see Appendix 10 [Section 10.10]). 
E 12. Participants with a current use of any of the following medications/treatments: 
fampridine/dalfampridine, ofatumumab, fingolimod, cladribine, siponimod, ponesimod, 
ozanimod, alemtuzumab, mitoxantrone, ocrelizumab, natalizumab, or similar approved 
compounds but with different trade names and any unapproved treatments or therapies for 
MS; any DMTs newly approved after January 2023 that are marketed at any time during 
the course of the double-blind study period. These medications are not allowed within 
5 half-lives before the Screening Visit and for the duration of Part A and Part B. 
If the participant has received any of the prohibited medications/treatments, washout will 
be required according to the table below (no washout is required for permitted 
medications): 
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Medication 
Exclusionary if used/used within required wash 
out period 
Systemic corticosteroids, adrenocorticotropic hormone 
4 weeks prior to the baseline MRI scan 
Plasmapheresis, fingolimod, and natalizumab (participants 
who have discontinued natalizumab in the 24 weeks prior to 
randomization should be evaluated to rule out PML) 
8 weeks prior to randomization 
B cell depleting therapies such as ocrelizumab and rituximab 
24 weeks prior to randomization or until the return of B cell 
counts to normal levels, whichever is longer 
Alemtuzumab 
4 years prior to randomization 
Other prohibited MS DMT 
5 half-lives or until the end of pharmacodynamics activity, 
whichever is longer 
Abbreviations: DMT = disease-modifying therapy; MRI = magnetic resonance imaging; MS = multiple sclerosis; PML  = progressive multifocal 
leukoencephalopathy 
 
Prior/concurrent clinical study experience 
E 13. Participants who have prior/concurrent clinical study enrollment, ie, the participant has 
taken other investigational drugs within 4 weeks or 5 half-lives, whichever is longer, 
before the first Screening Visit; concurrent or recent participation in non-interventional 
studies may be permitted. 
Diagnostic assessments 
E 14. Participants with a positive human immunodeficiency virus (HIV) antibody test. 
E 15. Participants with abnormal laboratory test(s) at the Screening Visit: 
- 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3.0 × upper 
limit of normal (ULN) 
- 
Bilirubin >1.5 × ULN; unless the participant has documented Gilbert syndrome 
(isolated bilirubin >1.5 × ULN is acceptable if bilirubin is fractionated and direct 
bilirubin <35%) 
- 
Serum albumin <3.5 g/dL 
- 
Estimated glomerular filtration rate <60 mL/min/1.73 m2 (Modification of Diet in 
Renal Disease [MDRD]) 
- 
Other abnormal laboratory values or electrocardiogram (ECG) changes that are 
deemed clinically significant as per Investigator’s judgment 
E 16. Participants with presence of hepatitis B surface antigen (HBsAg) or anti-hepatitis B core 
antibodies (HBcAb) at the Screening Visit or within 12 weeks prior to the first dose of 
study intervention. Serologies consistent with a resolved infection or vaccination, such as 
the presence of HBsAb, may not exclude potential participants from the trial. 
E 17. Participants with positive hepatitis C antibody test result at screening or within 12 weeks 
prior to starting study intervention. NOTE: participants with a positive hepatitis C antibody 
due to prior resolved disease can be enrolled, only if a confirmatory negative hepatitis C 
ribonucleic acid (RNA) test is obtained. 
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E 18. Participants with a contraindication for MRI, ie, presence of a pacemaker, metallic 
implants in high-risk areas (ie, artificial heart valves, aneurysm/vessel clips), presence of 
metallic material (eg, shrapnel) in high-risk areas, known history of allergy to gadolinium, 
or history of claustrophobia that would prevent completion of all protocol-scheduled MRI. 
Note: People with a contraindication to Gd can be enrolled into the study but cannot receive Gd 
contrast dyes during their MRI scan. 
Other exclusions 
E 19. Participants who are accommodated in an institution because of a regulatory or legal order; 
prisoners or participants who are legally institutionalized. 
E 20. Participant who are 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 21. Participants who are employees of the clinical study site or other individuals directly 
involved in the conduct of the study or are immediate family members of such individuals 
(in conjunction with Section 1.61 of the International Council for Harmonisation of Good 
Clinical Practice (ICH-GCP) Ordinance E6). 
E 22. Participants with any specific situation during study implementation/course that may raise 
ethics considerations. 
E 23. Participants with 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 24. Participant is under tutorship or curatorship; participant under safeguard of justice or 
deprived of his/her liberty by a court decision. 
E 25. Participant is unable to provide informed consent. 
 
5.3 
LIFESTYLE CONSIDERATIONS  
5.3.1 Meals and dietary restrictions  
SAR443820 can be administered without regards to meal. Participants should refrain from 
consuming grapefruit or grapefruit juice (including pomelos, exotic citrus fruits, grapefruit 
hybrids, or fruit juices) from 5 days before the start of the study intervention until 2 days after the 
final dose. 
5.3.2 Caffeine, alcohol, and tobacco  
The information of participant’s regular use of alcohol and tobacco should be recorded in the 
electronic case report form (eCRF). During the entire study, participants should be warned not to 
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consume substantial quantities of alcohol, defined as >14 grams (1 standard drink) per day in 
female participants or >28 grams (2 standard drinks) per day in male participants on a regular 
basis. 
5.3.3 Activity  
No special restrictions. 
5.4 
SCREEN FAILURES  
A screen failure occurs when a participant who consents to participate in the clinical study is not 
subsequently randomized. 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 serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Rescreening is allowed for participants who fail the initial screening at the 
Investigator’s medical judgment for any manageable reasons that caused the initial screening 
failure. Participants who fail the initial screening may be rescreened up to 2 times during the study 
recruitment period. Rescreened participants should be assigned a new identification number and 
sign a new consent form for every rescreening event. 
5.5 
CRITERIA FOR TEMPORARILY DELAYING 
ENROLLMENT/RANDOMIZATION/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 are proposed in 
Appendix 9 (Section 10.9). 
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6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY  
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  
Table 4 - Study intervention(s) administered  
Intervention label 
SAR443820 
Placebo 
Intervention name 
SAR443820 
Placebo 
Intervention description 
Tablet 
Tablet 
Type 
Drug 
Drug 
Dose formulation 
Tablet 
Tablet 
Unit dose strength(s) 
20 mg tablet 
0 mg tablet 
Dosage level(s) 
20 mg once daily 
once daily 
Route of administration 
Oral 
Oral 
Use 
Experimental 
Placebo 
IMP and NIMP 
IMP 
IMP 
Packaging and labeling 
Study intervention will be provided in wallet 
blister packaging. Each wallet blister 
packaging will be labeled as required per 
country requirement.  
Study intervention will be provided in wallet 
blister packaging. Each wallet blister 
packaging will be labeled as required per 
country requirement. 
Current name 
SAR443820 
Not Applicable 
Abbreviations: IMP = investigational medicinal product; NIMP = non-investigational product 
SAR443820 or matching placebo tablets are to be taken once daily. The IMP tablet will be taken 
orally with water. The IMP should be taken around the same time each day under the same 
condition (with or without food) throughout the study unless adjustment is specifically requested 
due to PK sampling at the Day 1, Weeks 2, 6, 12, and 36 site visits. 
SAR443820 or placebo may be supplied at the site or from the PI/site/Sponsor to the participant 
via a Sponsor-approved courier company where allowed by local regulations and agreed upon 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 
Appendix 9 (Section 10.9). 
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6.2 
PREPARATION, HANDLING, STORAGE, AND ACCOUNTABILITY  
1. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and that any discrepancies are 
reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention, and only 
authorized site staff may supply or administer study intervention. All study intervention 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access limited to 
the Investigator and authorized site staff. 
3. The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
SAR443820 and placebo tablets require no preparation and will be supplied to the study 
participants in labeled child-resistant wallets. 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) must be promptly notified to the Sponsor. 
Some deficiencies may be recorded through a complaint procedure (see Section 8.3.10). 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall the IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party (except for 
direct-to-patient [DTP] shipment, for which a courier company has been approved by the 
Sponsor), allow the IMP to be used other than as directed by this clinical trial protocol, or dispose 
of IMP in any other manner. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
• The study will be performed in a double-blind fashion for Part A. The placebo tablet will 
be identical to the SAR443820 tablet in appearance, quantity, taste, odor, and packaging. 
• All participants will be centrally assigned to a randomized study intervention using an 
interactive response technology (IRT). Before the study is initiated, the login information 
and directions for the interactive web response system (IWRS) will be provided to each 
site. The study intervention will be dispensed at the study visits summarized in the SoA. 
Returned IMP should not be redispensed to participants. 
• A randomized participant is defined as a participant from the screened population who has 
been allocated to a randomized intervention regardless of whether the intervention was 
received or not. A participant cannot be randomized more than once in the study. 
• The randomization will be stratified by MS clinical subtypes (ie, RRMS, SPMS, or 
PPMS). 
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• Due to the open-label extension period, a participant assigned to a specific arm at 
randomization may be allocated, by the IRT, to several (varying) intervention numbers 
(and corresponding intervention kit numbers) for multiple visits despite having the same 
intervention arm assignment from randomization. That is, in these cases, the 
intervention/kit number varies but the arm assignment at randomization does not change. 
• The Investigator, site staff, Sponsor monitoring team, and participants will remain blinded 
to the treatment assignment in Part A until the end of Part B. The Sponsor study team, 
except Sponsor monitors, will be unblinded after database lock of Part A. 
• The bioanalyst and the pharmacokineticist responsible for sample analysis and PK 
evaluation will be unblinded. However, they will agree not to disclose the randomization 
schedule or the individual unblinded analytical results before the official opening of the 
randomization schedule. Preliminary PK data, if needed and available during the study, 
will refer to means with descriptive statistics, and individual data will not be associated 
with any individual randomization numbers or participant numbers. 
• This is a double-blind study in which participants/care providers/ Investigators/ outcomes 
assessors, etc. are blinded to study intervention. The IRT will be programmed with 
blind-breaking instructions. In case of an emergency, the Investigator has the sole 
responsibility for determining if unblinding of a participant’s intervention assignment is 
warranted (eg, in case of available antidote). Participant safety must always be the 
first consideration in making such a determination. If the Investigator decides that 
unblinding is warranted, he/she may, at his/her discretion, contact the Sponsor to discuss 
the situation prior to unblinding a participant’s intervention assignment unless this could 
delay emergency treatment for the participant. If a participant’s intervention assignment is 
unblinded, the Sponsor must be notified within 24 hours of this occurrence. The date and 
reason for the unblinding must be recorded. 
• For regulatory reporting purposes, and if required by local health authorities, the Sponsor 
or designee will break the treatment code for all suspected unexpected serious adverse 
reactions (SUSAR) that are considered by the Investigator or Sponsor to be related to the 
study intervention. 
Methods of blinding 
Unless specified otherwise, the baseline brain MRI scan will be used as the reference to assess all 
MRI-derived endpoints. Standardized endpoint evaluation is assured by central review of brain 
MRI scans. A blinded MRI central review will be performed for all MRI-derived endpoints. All 
MRI reviewers will be blinded to treatment assignments and to other participant data. Details on 
MRI scanning and central review will be described in the central MRI Acquisition and Procedures 
manual. In addition, in accordance with standard clinical practice, during the blinded intervention 
period, the Treating Investigator can access MRI reports once a year starting at Month 12, or 
before if clinically required, through the local radiologist. 
A data monitoring committee (DMC) will be used to periodically monitor the safety of this study. 
Unblinded data will be provided for DMC review by an unblinded independent statistician. Study 
team members, Investigators, and study participants will not have access to unblinded data. 
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6.4 
STUDY INTERVENTION COMPLIANCE  
IMP accountability will be as described below: 
• Intervention units are returned by the participant at each visit. In case of DTP process, the 
intervention units can be returned by the carrier (if defined in the contract) 
• The Investigator will count the number of tablets remaining in the returned packs and 
complete the Intervention Log Form 
• The Investigator will record the dosing information on the appropriate page(s) of the case 
report form (CRF) 
• The monitor in charge of the study will then check the CRF data by comparing them with 
the IMP that he/she has retrieved and intervention log forms 
When participants are dosed at the site, they will receive study intervention directly from the 
Investigator or designee, under medical supervision. The date and time of each dose administered 
in the clinic will be recorded in the source documents. The dose of study intervention and study 
participant identification will be confirmed at the time of dosing by a member of the study site 
staff other than the person administering the study intervention.  
When participants self-administer study intervention(s) at home, compliance with study 
intervention will be assessed at each visit. Compliance will be assessed by counting returned 
tablets during the site visits and documented in the source documents and relevant form. 
Deviation(s) from the prescribed dosage regimen should be recorded. 
A record of the quantity of SAR443820 or matching placebo dispensed to and administered by 
each participant must be maintained and reconciled with study intervention and compliance 
records. Intervention start and stop dates, including dates for intervention delays and/or dose 
reductions, will also be recorded. 
6.5 
DOSE MODIFICATION  
Dose modification is not foreseen in this study. The IMP treatment may need to be interrupted or 
permanently discontinued if deemed necessary due to an AE. 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY  
Part B is an open-label long-term extension period up to Week 96 in which all eligible participants 
from Part A may rollover to Part B and receive open-label IMP. In addition to this open-label 
extension, poststudy access to study medication could be provided based on local/country 
regulations. 
6.7 
TREATMENT OF OVERDOSE  
For this study, overdose is defined as at least at least 
 mg IMP within 24 hours. 
The Sponsor does not recommend a specific treatment for an overdose, and treatment of an 
overdose will be based on the Investigator’s clinical judgment in conjunction with the Sponsor’s 
agreement. 
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In the event of an overdose, the Investigator should: 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities until the 
IMP can no longer be detected systemically (at least 2 days). Provide supportive and 
symptomatic treatment as needed. 
• Obtain a plasma sample for PK analysis as soon as possible from the date of the last dose 
of study intervention. 
• Evaluate the participant to determine whether study intervention should be interrupted or 
whether the dose should be reduced. 
• Document appropriately in the CRF.  
• Contact the Sponsor immediately. 
6.8 
CONCOMITANT THERAPY  
Any medication or vaccine (including over-the-counter or prescription medicines, recreational 
drugs, 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 the following: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
• The use of any live vaccine is prohibited within 14 days before the Screening Visit and 
during study duration. 
The Sponsor should be contacted if there are any questions regarding concomitant or prior 
therapy. 
The concomitant therapy should be reported to the Investigator and recorded on the Concomitant 
Medications electronic case report form (eCRF). The reported medications will be reviewed and 
evaluated by the Investigator or designee to determine whether they affect a participant’s 
eligibility to participate or continue to participate in the study. 
Medications for treatment of MS symptoms (eg, walking impairment, fatigue, spasticity, 
incontinence, pain) should be maintained at a stable dose prior to screening and for the duration of 
the treatment period (except those per exclusion criterion E 11), if clinically feasible. Allowed 
concomitant DMTs (ie, interferons, glatiramer acetate, fumarates, and teriflunomide) should be 
maintained at the pre-enrollment dose. Prohibited medications listed in exclusion criteria may not 
be exhaustive, and any exceptions (eg, newly marketed DMTs during the course of the study) 
should be discussed with the Medical Monitor. 
Participants must abstain from starting prescription or nonprescription drugs (including vitamins, 
recreational drugs, and dietary or herbal supplements) within 7 days (or 14 days if the drug is a 
potential enzyme inducer) or 5 half-lives (whichever is longer) before the start of study 
intervention until completion of the follow-up visit, unless, in the opinion of the Investigator and 
Sponsor, the medication will not interfere with the study. 
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Based on in vitro results, SAR443820 is mainly metabolized by CYP3A4. A 
 in 
 was observed in the presence of
 in a drug-drug interaction study. Based on PBPK modeling, administration of potent 
CYP3A4 inhibitors are 
 
. Administration of strong 
CYP3A4 inducer is predicted to decrease the SAR443820 AUC. Therefore, concomitant 
medications or substances that are strong or moderate inhibitors or strong inducers of CYP3A4 
(Appendix 10, Section 10.10, Table 9) are not allowed within the specific wash out period before 
the Screening Visit and for the duration of Part A and Part B. 
In Part A, any modifications of SOC therapy will result in participant discontinuation from the 
IMP. This includes stopping, changing the dose of allowed SOC DMTs, or switching to another 
allowed SOC DMT, or switching to a prohibited DMT (per exclusion criterion E 12). In Part B, 
changes to dose of allowed DMTs or switching to another allowed DMT will be permitted. 
The use of any live vaccine is prohibited within 14 days before the Screening Visit and during 
study duration. 
6.8.1 Rescue medicine  
For all participants that experience relapse in the case of MS relapse, rescue treatments are 
allowed as per local routine practice (eg, high dose intravenous methylprednisolone for 
3 to 5 days). Rescue treatments are defined as limited to this prescribed timeframe and medication 
and does not include transition to new permanent DMTs whether participants are switched to 
another allowed DMT or any prohibited DMT. Rescue medications must be reported in the eCRF, 
as for all other concomitant medications. The Investigator should document the discussion with 
the participant and the decision for rescue treatment in the source documentation. 
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
Discontinuation of specific sites or of the study as a whole are detailed in Appendix 1 
(Section 10.1). 
7.1 
DISCONTINUATION OF STUDY INTERVENTION   
 
7.1.1 Permanent discontinuation  
Compliance with and continuation of the study intervention is encouraged, while maintaining the 
safety of study participants and integrity of the study. In certain instances, it may be medically 
necessary for a participant to permanently discontinue study intervention. 
In case of the events listed below, permanent discontinuation of the IMP is mandatory (this list is 
not intended to be exclusive): 
• The Investigator or Sponsor determines it is in the best interest of the participant. 
• Occurrence of AEs or any other medical condition that, in the opinion of the Investigator 
or Sponsor, may jeopardize the participant’s safety or data integrity. These include, but are 
not limited to, abnormal livers tests and meeting the stopping criteria. 
• Noncompliance with the protocol, dosing regimen and visits including switching DMT or 
taking a prohibited DMT in Part A or Part B. 
• Pregnancy of a female participant. 
• Occurrence of convulsions. 
Any abnormal laboratory value or ECG parameter will be immediately rechecked for 
confirmation after 24 hours before making a decision regarding permanent discontinuation of the 
IMP for the concerned participant. 
Handling of participants after permanent intervention discontinuation 
If a participant is withdrawn from study intervention permanently, the Sponsor will be notified 
within 2 business days and the date and reason(s) for the withdrawal will be documented by the 
Investigator in the appropriate pages of the eCRF when considered as confirmed. 
Participants will be followed up according to the study procedures specified in this protocol up to 
study completion, or up to recovery or stabilization of any AE to be followed up as specified in 
this protocol, whichever comes last. 
If possible, and after the definitive discontinuation of intervention, the participants will be 
assessed using the procedure normally planned for the last treatment day with the IMP including a 
PK sample. Details are provided in the SoA (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. 
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All cases of permanent intervention discontinuation must be recorded by the Investigator in the 
appropriate pages of the eCRF when considered as confirmed. 
7.1.2 Liver function stopping criteria  
Discontinuation of study intervention for abnormal liver tests is required by the Investigator when 
a participant meets one of the conditions outlined in Section 10.6 or in the presence of abnormal 
liver chemistry test results not meeting protocol-specified stopping rules if the Investigator 
believes that it is in best interest of the participant. 
7.1.3 Temporary discontinuation  
Temporary intervention 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 (Appendix 9 [Section 10.9]). For all temporary intervention 
discontinuations, the duration should be recorded by the Investigator in the appropriate pages of 
the eCRF. Temporary discontinuation of study intervention is defined as stopping study 
intervention for a minimum of 1 day and a maximum of 2 weeks accumulative in Part A or 
8 weeks accumulative in Part B. 
7.1.4 Rechallenge  
Reinitiation of intervention with the IMP will be done under close and appropriate clinical and/or 
laboratory monitoring once the Investigator has considered according to his/her best medical 
judgment that the responsibility of the IMP(s) in the occurrence of the concerned event was 
unlikely, that there are no safety concerns, that the selection criteria for the study are still met 
(refer to Section 5.1 and Section 5.2), and the criteria for the permanent treatment discontinuation 
have not been met. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 9 [Section 10.9]. 
7.1.4.1 Study intervention restart or rechallenge after discontinuation of study 
intervention  
Do not restart/rechallenge participant with study intervention unless: 
• Ethics committee and/or IRB approval is obtained, if required, and based on local practice 
• The participant is made aware of the potential risk, and separate consent for intervention 
restart/rechallenge is signed by the participant 
• Sponsor should be notified. 
NOTE: If study intervention was interrupted for suspected intervention-induced liver injury, the 
participant should be informed of the risk of death, liver transplantation, hospitalization, and 
jaundice and re-consented before resumption of dosing. In case of confirmed drug-induced liver 
injury caused by the IMP, the rechallenge with the IMP is not permitted and the participants must 
be permanently discontinued from IMP treatment. 
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Refer to Appendix 6 (Section 10.6) for details on the restart/rechallenge process. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 9 (Section 10.9). 
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 or 
compliance reasons. 
• At the time of discontinuing from the study, if possible, an early discontinuation visit 
should be conducted, as shown in the SoA. See the SoA for data to be collected at the time 
of study discontinuation and follow-up and for any further evaluations that need to be 
completed. 
• If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records. 
For Part A and Part B, if a participant no longer wishes to take the IMP, they will be encouraged 
to remain in the study or to attend a safety follow-up visit within 2 weeks following 
discontinuation of IMP. 
NOTE: No IMP reconciliation is expected at the “Safety Follow-up” visit. 
The Investigators should discuss with them key visits to attend. The value of all their study data 
collected during their continued involvement will be emphasized as important to the public health 
value of the study. 
Participants who withdraw from the study intervention should be explicitly asked about the 
contribution of possible AEs to their decision, and any AE information elicited must be 
documented. 
All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
eCRF and in the participant’s medical records. In the medical record, at least the date of the 
withdrawal and the reason should be documented. 
In addition, a participant may withdraw his/her consent to stop participating in the study. 
Withdrawal of consent for intervention should be distinguished from withdrawal of consent for 
follow-up visits and from withdrawal of consent for non-participant contact follow-up, 
eg, medical record checks. The site should document any case of withdrawal of consent. 
Participants who have withdrawn from the study cannot be rerandomized/reallocated (treated) in 
the study. Their inclusion and intervention numbers must not be reused. 
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7.3 
STUDY LEVEL STOPPING CRITERIA  
The study may be stopped if any of the following criteria are met: 
• Cancellation of or change in the drug development program per the discretion of the 
Sponsor 
• Emergence of AEs unknown to date or increased frequency and/or severity and/or a 
duration of known AEs that makes the benefit-risk for study continuation negative 
• The results of the interim data review meet no-go criteria as detailed in the Statistical 
Analysis Plan (SAP) 
• Participant enrollment (evaluated after a reasonable amount of time) is unsatisfactory 
7.4 
LOST TO FOLLOW UP  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible, counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether 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. 
• Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants randomized, including 
those who did not get study intervention. Public sources may be searched for vital status 
information. If vital status is determined as deceased, this will be documented, and the 
participant will not be considered lost to follow-up. Sponsor personnel will not be 
involved in any attempts to collect vital status information. 
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8 
STUDY ASSESSMENTS AND PROCEDURES  
• Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count, urine tests) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and were 
performed within the timeframe defined in the SoA. 
• Safety/laboratory/analyte results that could unblind the study will not be reported to 
investigative sites or other blinded personnel until the study has been unblinded. 
• Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples. 
• If onsite visits are not feasible (due to disease progression, increased monitoring for AE 
follow-up, etc.) for visits that require sample collection only (Week 4, Week 9, Week 16, 
Week 56 or Week 60 visits), remote visits (eg, with home nurses, a home health vendor, 
etc.) may be planned for sample collection, only if the service is put in place in the country 
in which the study is being conducted. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 9 (Section 10.9).  
8.1 
EFFICACY ASSESSMENTS  
Planned timepoints for all efficacy assessments are provided in the SoA (Section 1.3). 
8.1.1 Serum neurofilament response  
Serum NfL will be collected as part of the blood specimen according to the SoA, with the mean of 
the screening and Day 1 predose sample levels serving as the baseline value for calculating NfL 
changes. sNfL samples will serve as the primary endpoint for the duration of the study in Parts A 
and B. 
8.1.2 Expanded Disability Status Score  
The Investigator will perform the EDSS assessment and will be trained and certified to perform 
the EDSS assessment in a consistent manner. Details regarding the interactive test and 
certification tool for a standardized, quantified neurological examination and assessment of 
Kurtzke’s FS and EDSS in MS will be provided to Investigators. A Level B qualification will be 
required for this study. Details regarding the interactive test and certification tool for a 
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standardized, quantified neurological examination and assessment of Kurtzke’s FS and EDSS in 
MS will be provided to Investigators. A Level B qualification will be required for this study. 
The EDSS score will be captured using an electronic EDSS tool. Quality control measures will be 
put in place to ensure scoring error detection and thus minimize the impact of any scoring and 
calculation errors. 
The Investigator will rate FS in the context of a standard neurological examination and will report 
these ratings as per the EDSS reporting instructions together with information on the participant’s 
mobility, gait, and use of assistive devices. Standard EDSS assessments of 7 functional domains 
(visual, brainstem, pyramidal [motor], cerebellar [coordination], sensory, cerebral, and 
bowel/bladder) scoring will be performed by assessing neurological symptoms in each of these 
domains. Ambulation scoring will be done to conclude the evaluation. The fatigue evaluation may 
be optionally recorded, but it will not contribute to assignment of the EDSS score. The total EDSS 
score will be assigned according to the EDSS scoring rules. 
A screening EDSS assessment must be completed to confirm eligibility, and the EDSS assessment 
must be repeated at the Randomization Visit. 
The Investigator will be informed if 12 weeks CDP is observed based on the EDSS data reported 
in the electronic database. Participants will not be informed of their EDSS scores. 
8.1.2.1 Confirmed disability progression  
Twelve-week and 24-week (3 and 6-month, respectively) CDPs are defined as an increase in 
EDSS score (defined as an increase of ≥1.0 point from the baseline EDSS score when the baseline 
score is ≤5.5 or an increase of ≥0.5 points from the baseline EDSS score when the baseline score 
is >5.5) confirmed after a 12 or 24 week interval, respectively. 
An EDSS score increase at CDP onset and confirmation at 12 weeks must be observed by the 
Investigator during routine quarterly visits. Results of all EDSS assessments obtained during 
routine or unscheduled visits over a minimum of a 12-week period will serve as the basis for 
conclusion for the endpoint. 
8.1.3 Magnetic resonance imaging  
A cranial (brain) MRI scan before and after administering the Gd contrast agent (according to 
local labeling requirements) will be performed. 
• The basic MRI scan will be performed at all sites and will consist of the following 
sequences: T2- and T1-weighted sequences before and after administering a Gd contrast 
(if there is no contraindication). 
• Basic MRI sequences will be used to evaluate following MRI-related endpoints 
(see Section 3): 
- 
change in T2-hyperintense lesion number and volume 
- 
new and enlarging T2-hyperintense lesion number and volume 
- 
Gd-enhancing T1-hypointense lesions number 
- 
brain volume 
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- 
SEL number, volume, and intensity (T1) 
- 
Total PRL number 
Additional details about the MRI assessments will be provided in the MRI acquisition and 
procedures manual. 
Due to a potential safety risk related to deposition of certain IV Gd contrast agents in the brain, 
these agents should be used in accordance with local recommendations/regulations (24). 
A study MRI acquisition and procedures manual, containing instructions for brain MRI standard 
image acquisition requirements, MRI acquisition validation, data transfer to the central review 
center, archiving and shipping, and image approval process, will be provided to all participating 
sites. Study site personnel will undergo training regarding MRI acquisition and data handling 
procedures. Training will be documented, and adherence to the manual will be monitored 
throughout the study with retraining performed as necessary. 
Unless specified otherwise, the baseline brain MRI scan will be used as the reference to assess all 
MRI-derived endpoints. Baseline MRI scans may be conducted as early as 5 to 7 days prior to 
first dose but must be completed after all other screening activities have been completed, and none 
are deemed exclusionary. Standardized endpoint evaluation is assured by central review of brain 
MRI scans. A blinded MRI central review will be performed for all MRI-derived endpoints. 
All MRI reviewers will be blinded to treatment assignments and to other participant data. Details 
on MRI scanning and central review will be described in the MRI acquisition and procedures 
manual. 
The MRI scans need to be reviewed by a local radiologist for any non-MS pathology to assure 
safety reporting as per Section 1. In the event of identification of MRI findings relevant to 
participant safety, the local radiologist will provide a report to the Investigator. Expected MS 
findings on MRI scans, not reflecting an acute safety concern for the participant, should not be 
disclosed to the Treating Investigator or to the site team if not relevant to any safety concern. Any 
safety concern noted on MRI, whether related to MS or not, shall be provided to the Investigator. 
8.1.4 Multiple sclerosis relapse assessment  
8.1.4.1 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 as follows: 
1. Be attributable to MS, 
2. Last for ≥24 hours, 
3. Be present at normal body temperature (ie, no infection, excessive exercise, or excessively 
high ambient temperature), and 
4. Be preceded by ≥30 days of clinical stability (including no previous MS relapse). 
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Note: An exacerbation or recurrence of symptoms and signs in a participant with MS that can be 
reasonably attributed to transient impairment of conduction in previously demyelinated pathways 
due to drugs (such as rarely occurs a few hours after injections of interferon beta), raised core 
body temperature (the Uhthoff phenomenon), or systemic cytokine release (such as occurs with 
the administration of alemtuzumab) will not be considered a relapse. 
Refer to Section 8.3.7 for details regarding MS relapse reporting. 
8.1.4.2 Unscheduled assessment visits  
Participants must be instructed to immediately report new neurological symptoms and recurring or 
worsening of previous symptoms to the Investigator. Any reported symptoms will be collected. If 
a participant reports symptoms that may be consistent with relapse, an unscheduled assessment 
visit to the Investigator must be scheduled as soon as possible (whenever possible within 7 days of 
the onset of the symptoms). The assessment, management, and reporting of MS relapse is made 
by the Investigator. Diagnosing MS relapses during the study will occur as follows: the 
Investigator will assess whether the reported episode is consistent with the definition of MS 
relapse. If it is consistent with the definition of MS relapse or if there is any doubt and the 
possibility of relapse cannot be ruled out, the standard neurological examination (for the EDSS 
score) will be performed by the Investigator. If the participant is not referred for EDSS 
assessment, this will be documented with an explanation of the reason. Whenever possible, the 
Investigator should perform the EDSS assessment the same day the neurological examination is 
performed. Subsequent EDSS assessments can still be utilized for confirmation of MS relapses 
but should be avoided to reduce the risk of changes in participant status between the assessments. 
All MS relapses must be reported on the MS relapse eCRF page. Multiple sclerosis relapse should 
not be reported as an AE unless, in the judgment of the Investigator, it is unusually severe or 
medically unexpected, or matches the definition of an SAE. 
Safety laboratory tests are optional for the unscheduled assessment visit if no intercurrent disease 
is suspected. If any intercurrent disease is diagnosed, it will be reported as an AE as per the safety 
reporting rules. 
The participant will be also asked to report possible relapse symptoms during scheduled quarterly 
visits. If relapse is suspected, the above decision-making and reporting rules apply. 
8.1.5 Timed 25-foot walk test  
As part of the Multiple Sclerosis Functional Composite (MSFC), the T25-FW test is currently the 
most widely implemented method to objectively quantify gait disability in clinical MS trials. The 
T25-FW test is developed to quantify changes in gait of MS patients; 1 task is completed, and the 
amount of time required depends on each patient. 
The T25-FW test will be used to assess a participant’s walking ability. The participant is directed 
to one end of a clearly marked 25-foot course and is instructed to walk 25 feet as quickly as safely 
possible with several repetitions (25, 26). The mean walk time will be used for assessment of the 
participant’s walking ability. An increase of >20% from the baseline score in the T25-FW test is 
considered as meaningful worsening (27). The Examining Investigator/rater will perform this test. 
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8.1.6 9-Hole Peg Test  
The 9-HPT will be used to assess a participant’s manual dexterity and fine motor skills. This is a 
PerfRO tool (performance outcome). A participant will be asked to place pegs into holes and 
remove them with the dominant and non-dominant hand for several repetitions (26). The mean 
time to test completion will serve as an assessment of the participant’s hand dexterity. An increase 
of >20% from the baseline score in the 9-HPT is considered meaningful worsening (27). The 
Examining Investigator/rater will perform this test. 
8.1.7 Composite analysis  
Data from the clinical assessments described above will be utilized in various composite analyses 
and endpoints to assess effects of SAR443820 on a range of clinical measures. The following 
sections provide additional details on these composite scales and related criteria for analyses. 
8.1.7.1 EDSS-Plus  
Time to onset of composite (CCDP), as assessed by composite endpoint EDSS-Plus (EDSS score, 
or T25-FW test, or 9-HPT), is to be confirmed over at least 12 and 24 weeks (28). Disability 
criteria for the individual components are defined as follows: 
• Disability progression on the EDSS is defined as an increase of ≥1.0 point from the 
baseline EDSS score when the baseline score is ≤5.5 or an increase of ≥0.5 points from the 
baseline EDSS score when the baseline score is >5.5. 
• Disability progression on the T25-FW test is defined as an increase (worsening) of ≥20% 
from the baseline score. 
• Disability progression on the 9-HPT is defined as an increase (worsening) of ≥20% from 
the baseline score. 
Refer to Section 8.1.5 and Section 8.1.6 for descriptions of T25-FW and 9-HPT, respectively. 
8.1.8 MSIS-29v2  
The Multiple Sclerosis Impact Scale with 29 items (MSIS-29v2) evaluates the specific physical 
and psychological impact of MS from a patient’s perspective (29). This patient reported outcome 
(PRO) instrument has 2 subscales: 1) a physical impact score (20 items) and 2) a psychological 
impact score (9 items). The physical and psychological impact subscales of the MSIS-29v2 range 
from 0 to 100, with higher scores indicating greater physical or psychological impact. 
8.1.9 MSWS-12  
The multiple sclerosis walking scale (MSWS-12) measures the impact of walking impairment in 
patients with MS. This PRO instrument has 12 items with a global score ranging from 0 to 100. 
A higher score indicates better quality of life (30). 
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8.2 
SAFETY ASSESSMENTS   
This section presents safety assessments other than AE which are presented in Section 1. 
Planned timepoints for all safety assessments are provided in the SoA. 
8.2.1 Physical examinations  
• A complete physical examination will include, at a minimum, assessments of the general 
appearance, head and neck, abdomen, lymph nodes, cardiovascular system, respiratory 
system, musculoskeletal system, and skin by the Investigator.  
• A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, abdomen (liver, spleen), and lymph nodes by the Investigator. 
• The extent of the physical examination can be broadened at the discretion of the 
Investigator in order to evaluate AEs or abnormal clinical laboratory test values. 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
• Any clinically significant new finding or worsening of a previous finding should be 
reported as a new AE, per Investigator judgment. 
8.2.2 Neurological examinations  
• A neurological examination will be performed and the results recorded. A complete 
examination will include, at a minimum, assessments of mental status, cranial nerves, 
motor and sensory function, reflexes, coordination, and stance/gait. 
• A brief neurological examination will include, at a minimum, assessments of cranial 
nerves, coordination/cerebellar function, reflexes, motor function, and stance/gait. 
• Investigators should pay special attention to clinical signs related to previous neurological 
illnesses, including MS. 
8.2.3 Vital signs  
• Oral, tympanic, axillary, or skin temporal temperature, heart rate, respiratory rate, and 
blood pressure will be assessed. 
• Blood pressure and heart rate measurements will be assessed with the participant in a 
supine position with a completely automated device. Manual techniques will be used only 
if an automated device is not available. 
• Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions (eg, television, cell phones). 
• Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse 
and 3 blood pressure measurements (3 consecutive blood pressure readings will be 
recorded at intervals of at least 1 minute). The average of the 3 blood pressure readings 
will be recorded. 
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8.2.4 Electrocardiograms  
• Single 12-lead ECG(s) will be obtained as outlined in the SoA (see Section 1.3) using an 
ECG machine that automatically calculates heart rate and measures PR, QRS, QT, and 
QTc intervals.  
• In case the ECG machine does not automatically calculate QTcF, manual calculation using 
the following formula (QTcF = QT/RR1/3) or an automatic website calculator 
(eg, https://reference.medscape.com/calculator/48/ecg-corrected-qt) is acceptable. 
• ECGs and (longer) rhythm strips will be obtained locally. 
• If a clinically significant finding is identified in the ECG (including, but not limited to 
changes from baseline in QTcF after enrollment), the Investigator or delegate will 
determine if the participant can continue in the study and if any change in participant 
management is needed including but not limited to referral to cardiology and/or a Holter 
monitor. The Investigator or delegate should perform the following tasks: 
- 
Review the ECG in a timely manner. 
- 
Document the interpretation and sign and date it on the ECG printout. 
- 
Record your (or appropriate qualified physician) medical opinion (“normal” or 
“abnormal”) on the study participant’s records and in the eCRF. 
- 
Assess for any symptoms of cardiac issues. 
- 
Perform an additional ECG when it is medically needed for clinical management of the 
study participant and/or in case of any safety concerns and report the findings in the 
eCRF dedicated to additional ECG forms.  
- 
Check clinically significant findings with pre-existing medical history or/and, if 
appropriate, consider an AE. 
8.2.5 Clinical safety laboratory tests  
• See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and 
the SoA (Section 1.3) for their timing and frequency. 
• The Investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory reports 
must be filed with the source documents. Abnormal laboratory findings associated with 
the underlying disease are not considered clinically significant unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
• All abnormal laboratory values considered by the Investigators to be clinically 
significantly abnormal during participation in the study or within 2 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. 
- 
If clinically significant 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 tests, as defined in Appendix 2 (Section 10.2), must 
be conducted in accordance with the laboratory manual and the SoA (Section 1.3). 
- 
If laboratory values from non-protocol specified laboratory tests 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.  
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8.2.6 Pregnancy testing  
For female participants of childbearing potential, a pregnancy test will be performed at each visit 
during the whole study period. A serum pregnancy test will be conducted at the Screening Visit, 
and a urine pregnancy test will be performed for all other visits. For WOCBP, monthly urine 
pregnancy tests will be provided directly to participants for those not coinciding with a clinic visit. 
Results should not be older than 24 hours upon intake of first dose of IMP. 
8.2.7 Suicidal ideation and behavior risk monitoring  
SAR443820 crosses the blood-brain barrier. Assessment of suicidal ideation and 
behavior/treatment-emergent suicidal ideation and behavior will be monitored during ACT16753 
using the C-SSRS. For safety reasons, the C-SSRS will be administered throughout the study by 
the Investigator or delegated to an individual who is certified to administer the scale. 
Study intervention administration must be interrupted if a participant scores “yes” on item 4 or 5 
of the Suicidal Ideation Section of the C-SSRS or “yes” on any item of the Suicidal Behavior 
Section. A mental health professional will be consulted and will decide whether the study 
intervention can be restarted and if any additional risk mitigation strategies are required 
(eg, increased monitoring, antidepressant administration). 
Participants being treated with the study intervention should be monitored appropriately and 
observed closely for suicidal ideation and behavior (SIB) or any other unusual changes in 
behavior, especially at the beginning and end of the course of intervention, or at the time of dose 
changes, either increases or decreases. Participants who experience signs of SIB, should undergo a 
risk assessment. All factors contributing to SIB should be evaluated and consideration should be 
given to discontinuation of the study intervention. 
 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING  
The definitions of AEs and SAEs can be found in Appendix 3 (Section 10.3). The definition of 
AESI is provided in Section 8.3.9. 
The definitions of unsolicited and solicited AEs can be found in Appendix 3 (Section 10.3). 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant’s legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant’s legally authorized representative) 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 caused the participant to discontinue the study intervention 
(see Section 7). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
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8.3.1 Time period and frequency for collecting AE and SAE information  
All AEs (serious or nonserious) will be collected from the signing of the ICF until the follow-up 
visit at the timepoints specified in the SoA (Section 1.3). 
All SAEs and AESI will be recorded and reported to the Sponsor or designee immediately and 
under no circumstance should this exceed 24 hours, as indicated in Appendix 3 (Section 10.3). 
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of it being 
available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the Investigator must promptly 
notify the Sponsor. 
8.3.2 Method of detecting AEs and SAEs  
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3 Follow-up of AEs and SAEs  
After the initial AE/AESI/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. At the prespecified study end-date, all SAEs and AESI 
(as defined in Section 8.3.9), will be followed until resolution, stabilization, the event is otherwise 
explained, or the participant is lost to follow-up (as defined in Section 7.4). Further information 
on follow-up procedures is provided in Appendix 3 (Section 10.3). 
8.3.4 Regulatory reporting requirements for SAEs  
• Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
• Serious adverse events that are considered expected will be specified in the IB. 
• Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to Investigators as necessary. 
• An Investigator who receives an Investigator safety report describing an SAE, SUSAR, or 
any other specific safety information (eg, summary or listing of SAEs) from the Sponsor 
will review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. It is the responsibility of the Sponsor to assess whether an 
event meets the criteria for a SUSAR, and therefore, is expedited to regulatory authorities. 
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8.3.5 Pregnancy  
• Details of all pregnancies in female participants and female partners of male participants 
will be collected after the start of study intervention and until the time period for 
post-intervention contraception determined in Section 5.1. 
• If a pregnancy is reported, the Investigator will record pregnancy information on the 
appropriate form and submit it to the Sponsor within 24 hours of learning of the pregnancy 
of a female participant or female partner of male participant after obtaining the necessary 
signed informed consent from the female partner. 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and will be reported as such. 
• The participant or female partner of male participant will be followed to determine the 
outcome of the pregnancy. The Investigator will collect follow-up information on the 
participant or female partner of a male participant and the neonate, and the information 
will be forwarded to the Sponsor. 
• Any poststudy pregnancy-related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as described in 
Section 8.3.4. While the Investigator is not obligated to actively seek this information in 
former study participants, he/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. 
8.3.6 Cardiovascular and death events  
Since the risk of cardiovascular events is low based on preclinical and Phase 1 study results, 
cardiovascular events are not AESIs and will be reported per standard safety reporting and safety 
oversight practices (including a data review by the DMC). 
Death events will be reported per standard SAE reporting rules. Every effort will be made to 
clarify the cause of death and to report the diagnosis of a fatal event as an SAE. 
8.3.7 Multiple sclerosis relapse reporting  
Multiple sclerosis relapses will be exempt from being reported as AEs except when they meet the 
definition of a SAE or are unusually severe or medically unexpected. Hospitalization for MS 
relapse, if done routinely at the site (eg, for high dose IV methylprednisolone administration), will 
not be considered as a seriousness criterion for this study. 
Data for MS relapses will be collected on the eCRF and be analyzed as part of the efficacy 
analysis. Other worsening of neurological symptoms that do not meet the definition of MS relapse 
will be reported as AEs according to general safety reporting rules. 
8.3.8 Magnetic resonance imaging  
Magnetic resonance imaging scans need to be reviewed locally for any pathology. In case of 
clinically significant findings, relevant information needs to be provided to the Investigator for 
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appropriate safety reporting. When available, a diagnosis of the pathology at cause of such MRI 
findings or the findings themselves will be reported as an AE until the diagnosis is clear.  
Multiple sclerosis findings from MRI scans do not need to be reported unless they are deemed 
unusual and thus a distinct safety finding. 
8.3.9 Adverse events of special interest  
An AESI is an AE (serious or nonserious) of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and immediate notification by the 
Investigator to the Sponsor is required. Such events may require further investigation in order to 
characterize and understand them. Adverse events of special interest may be added, modified, or 
removed during a study by protocol amendment. 
For AESI, the Sponsor is to be informed immediately (ie, within 24 hours), as per the SAE 
notification guidelines described in Appendix 3 (Section 10.3), even if a seriousness criterion is 
not met, using the corresponding pages of the CRF or screens in the eCRF: 
• 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; 
- 
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 
- 
An overdose (accidental or intentional) with the IMP is an event suspected by the 
Investigator or spontaneously notified by the participant (not based on systematic pills 
count) and defined as at least at least 
 mg IMP within 20 hours.  
Note: an asymptomatic overdose has to be reported as a standard AE. 
• Other project specific AESI(s) 
- 
Convulsions, seizures 
- 
Serious infections 
- 
Increase in ALT: see the “increase in ALT algorithm” in Appendix 6 (Section 10.6). 
8.3.10 Guidelines for reporting product complaints  
Any defect in the IMP must be reported as soon as possible by the Investigator to the monitoring 
team that will complete a product complaint form within required timelines. 
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE. 
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8.4 
PHARMACOKINETICS  
Whole blood samples will be collected for measurement of plasma concentrations of SAR443820 
as specified in the SoA (Section 1.3), which is summarized in Table 5. 
Table 5 - Schedule of PK sampling  
 
Part A 
Day 1* 
Week 2 
Week 6 
Week 12 
Week 36 
Before dose (within 1 hour predose) 
 
X 
X 
X 
X 
After dose (15 minutes to 1 hour) 
X 
 
 
 
 
After dose (1 hour to 3 hours) 
X 
 
 
 
 
After dose (30 minutes to 3 hours) 
 
X 
 
 
 
PK = Pharmacokinetics  
* At least 45 minutes between the 2 PK samples at Day 1 
Instructions for the collection and handling of biological samples will be provided by the Sponsor 
or Sponsor’s designee in a separate document. The actual date and time of each sample will be 
recorded. Pharmacokinetic samples will be tested by the Sponsor or Sponsor's designee. 
Samples collected for analyses of SAR443820 plasma concentration may also be used to evaluate 
safety or efficacy aspects related to concerns arising during or after the study. 
Pharmacokinetic samples could be used for testing analytical method performance such as 
comparability and incurred sample reproducibility and for possible exploratory analysis of drug 
metabolites. The exploratory data will not be included in the study report but will be kept on file. 
Population PK approaches will be used for SAR443820. 
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded. 
8.5 
GENETICS  
Genetics is not evaluated in this study. 
8.6 
BIOMARKERS  
Blood samples will be collected to evaluate peripheral markers of neuroinflammation and 
neurodegeneration in study subjects to evaluate the impact of treatment on these markers. 
Biomarkers will include sNfL, CHI3L1 (YKL40), sGFAP (excluding China), and specific serum 
cytokines and chemokines (IL1β, IL6, IL8, TNFα, CCL3 [MIP1a], and CCL4 [MIP1b]) known to 
be elevated in MS and could be modulated by RIPK1 inhibition. Samples will be collected 
according to the schedule described in the SoA (Section 1.3) and as detailed in the laboratory 
manual that is provided separately to sites. 
For China, please see Section 10.8.1 for details. 
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8.7 
IMMUNOGENICITY ASSESSMENTS  
Not applicable. 
8.8 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS  
Health economics OR medical resource utilization and health economics parameters are not 
evaluated in this study. 
8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH  
Future research may help further the understanding of disease subtypes, disease biology, related 
conditions, mechanism of action, or possible 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 (leftover) and/or extra (additional) clinical samples, data and samples may be used 
for future research related either to the drug, the mechanism of action, and the disease or its 
associated conditions. Such research may include, but is not limited to, performing assessments on 
DNA, RNA, proteins or metabolites. If future research on genetic material is performed, this will 
also be limited to the purpose of addressing research questions related to the drug, the mechanism 
of action, the disease or its associated conditions. 
Remaining leftover samples will be used only after the study ends, ie, end of study as defined in 
the study protocol. Additional/extra samples can be collected and used during the study conduct at 
a given timepoint (eg, at Randomization Visit) as defined in the study protocol. 
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 alignment with the information provided to participants in the ICF Part 2 
(future research). For future research projects, all biological samples and relating data to be used 
will be coded such that no participant direct identifiers will be linked to them. These 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). 
Relating data and biological samples for future research will be stored for up to 25 years after the 
end of the study. Any samples remaining at the end of retention period will be destroyed. If a 
participant requests destruction of his/her samples before the end of the retention period, the 
Investigator must notify the Sponsor (or its contract organization) in writing. In such case, 
samples will be destroyed, and related coded data will be anonymized unless otherwise required 
by applicable laws. 
Participant’s coded datasets 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 
POPULATIONS FOR ANALYSES  
The following populations for analyses are defined: 
Table 6 - Populations for analyses  
Population 
Description 
Screened 
All participants who signed the ICF. 
Randomized 
All participants from screened population who have been allocated to a randomized 
intervention by IRT regardless of whether the intervention was received. 
Exposed 
All screened participants who take at least 1 dose of study intervention. 
Intent-to-treat (ITT) 
All randomized participants. Participants will be analyzed according to the intervention 
allocated by randomization. 
Modified ITT (mITT) 
All participants from the ITT population who takes at least 1 dose of study intervention and 
with an evaluable primary endpoint. 
The primary endpoint is evaluable when the following conditions are met: 
• 
The participant has a baseline and at least 1 post-baseline sNfL assessment before 
IMP discontinuation and before permanent modification of the background DMT. 
• 
Participants will be analyzed according to the intervention allocated by 
randomization. 
Safety 
All randomized participants who take at least 1 dose of study intervention. Participants will be 
analyzed according to the intervention they actually received. 
Pharmacokinetic (PK) 
All randomized and treated participants (safety population) with at least 1 post-baseline PK 
result with adequate documentation of dosing and sampling dates and times. Participants will 
be analyzed according to the intervention they actually received. 
Open-Label Extension (OLE) 
All participants who received at least 1 dose of intervention during the open-label extension 
phase. 
Abbreviations: DMT = disease modifying therapy; ICF = informed consent form; IRT = interactive response technology; ITT = intent-to-treat; 
mITT = modified intent-to-treat; OLE = open-label extension; PK = pharmacokinetics; sNfL = serum neurofilament light chain 
Participants exposed to study intervention before or without being randomized will not be 
considered randomized and will not be included in any analysis population. The safety experience 
of these participants will be reported separately. 
Randomized participants for whom it is unclear whether they took the study intervention will be 
considered as exposed and will be included in the safety population as randomized. 
For any participant randomized more than once, only the data associated with the first 
randomization will be used in any analysis population. The safety experience associated with any 
later randomization will be reported separately. 
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9.2 
STATISTICAL ANALYSES  
The SAP will include a more technical and detailed description of the statistical analyses 
described in this section. This section is a summary of the planned statistical analyses of the most 
important endpoints including primary and main secondary endpoints in Part A and primary 
endpoint in Part B. 
9.2.1 General considerations  
The baseline value is defined as the last available value before the first dose of double-blind IMP, 
except otherwise specified. For participants randomized but not treated, the baseline value is 
defined as the last available value before randomization/enrollment. 
Unless otherwise specified, analyses will be performed by initial intervention group, ie, placebo or 
SAR443820 20 mg QD (and overall, for baseline and demographics characteristics). 
The observation period will be divided into 4 segments: 
• The pre-treatment period is defined as the period up to first IMP administration. 
• The treatment-emergent (TE) period is defined as the period from the first IMP 
administration to the last IMP administration + 14 days. The TE period includes the 
following 2 periods: 
- 
The on-treatment period is defined as the period from the first IMP administration to 
the last administration of the IMP + 1 day. 
- 
The residual treatment period is defined as the period from the end of the 
on-treatment period to the end of the TE period. 
• The post-treatment period is defined as the period from the end of the TE period. 
9.2.2 Primary endpoint(s) analyses  
9.2.2.1 Part A  
The primary endpoint will be analyzed with the primary estimand defined according to the 
following attributes: 
• Endpoint: sNfL levels at Week 48 relative to baseline 
• Treatment condition: SAR443820 will be compared to placebo, on top of background 
therapy 
• Analysis population: mITT population 
• Intercurrent events (IE): 
- 
The IMP discontinuation IE will be handled with the hypothetical strategy. The 
primary endpoint will be assessed based on assessments performed before IMP 
discontinuation. 
- 
The modification in the background DMT (either dosage or medication) IE will be 
handled with the hypothetical strategy. The primary endpoint will be assessed based 
on assessments performed before the permanent modification of the background DMT 
(as distinguished from rescue therapy, which is intermittently limited to 2 to 5 days, 
after which the original background DMT will be restored at its prerescue dose). 
• Population-level summary: geometric means ratio (GMR) between interventions. 
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The primary analytical approach will use a mixed effect model with repeated measures (MMRM) 
on natural (base ‘e’) log-transformed sNfL levels. The model will include the fixed categorical 
effects of the intervention group (SAR443820 or placebo), baseline MS type (RMS versus PMS), 
time point (Weeks 12, 24, 36, 48), treatment-by-time point interaction, MS type-by-time point 
interaction, as well as the continuous fixed covariates of log-transformed baseline sNfL levels and 
log-transformed baseline-by-time point interaction. An unstructured covariance structure will be 
used to model the within-subject errors. The Kenward-Roger (31) approximation will be used to 
estimate denominator degrees of freedom and adjust standard errors. Missing data will be handled 
by MMRM under the missing at random (MAR) assumption. The geometric mean of sNfL levels 
at Week 48 relative to baseline in each intervention group, as well as the relative reduction under 
treatment with SAR443820 compared to placebo will be estimated (estimates and 2-sided 90% 
confidence intervals [CI], respectively) through exponentiated least squared means and 
exponentiated least squared means differences. 
 
9.2.2.2 Part B  
The primary endpoint of Part B, ie, sNfL levels at Week 96 relative to baseline, will be analyzed 
using the same statistical methods described for the primary endpoint of Part A  
(see Section 9.2.2.1) for descriptive purpose only. Efficacy analyses of Part B will present 
efficacy data by initial intervention group, ie, matching placebo or SAR443820 20 mg. 
9.2.3 Secondary endpoint(s) analyses  
The secondary endpoints in Part A detailed in this section are as follows: 
• The cumulative number of new and/or enlarged T2 lesions as detected by MRI at 
Week 48, defined as the sum of the individual number of new and/or enlarging T2 lesions 
at all scheduled visits starting after baseline, up to and including the Week 48 visit will be 
analyzed through a negative binomial regression model. This model will include the 
baseline T2 lesion count as a covariate and treatment and baseline MS type (RMS versus 
PMS) as a factor. The number of scans will be also taken into account as an offset variable 
after natural logarithm transformation. The mean count/scan of new T2 lesions at Week 48 
in each intervention group, as well as the relative reduction under treatment with 
SAR443820 compared to placebo will be estimated (estimates and 95% CIs, respectively). 
The cumulative number of new T2 lesions at Week 24 and Week 36 will be analyzed 
similarly. 
• The cumulative number of new Gd-enhancing T1 hyperintense lesions as detected by MRI 
at Week 48, defined as the sum of the individual number of new Gd-enhancing T1 
hyperintense lesions at all scheduled visits starting after baseline, up to and including the 
Week 48 visit will be analyzed similarly but using the number of Gd-enhancing T1 lesions 
at baseline as a covariate. 
Other secondary endpoints analyses are defined in Section 9.2.6.1 (AE, SAE) and Section 9.2.6.2 
(laboratory abnormalities). 
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9.2.4 Tertiary/exploratory endpoint(s) analyses  
Tertiary/exploratory endpoint will be presented as descriptive data. Additional analyses may be 
done and will be detailed in the SAP. 
9.2.5 Multiplicity adjustment  
Not applicable. 
9.2.6 Safety analyses  
The analysis of safety variables will be essentially descriptive. No systematic analysis is planned. 
The summary of safety results will be presented by initial treatment group separately for Parts A 
and B. 
9.2.6.1 Adverse events  
General common rules for adverse events 
The AEs will be analyzed in the following 3 categories: 
• Pre-treatment AEs: AEs that developed, worsened, or became serious during the 
pre-treatment period 
• TEAEs: AEs that developed, worsened, or became serious during the treatment-emergent 
period 
• Post-treatment AEs: AEs that developed, worsened or became serious during the 
post-treatment period  
Similarly, deaths will be analyzed in the pre-treatment, treatment-emergent, and post-treatment 
periods.  
Analysis of all adverse events 
An AE incidence table will be provided by treatment group for all types of TEAEs: all TEAEs, all 
treatment-emergent AESI (defined with a preferred term [PT] or a prespecified grouping), all 
treatment-emergent SAEs, all TEAEs leading to permanent treatment discontinuation, and all 
TEAEs leading to death. 
The AE summaries will be generated with the number (%) of participants experiencing at least 
1 event. 
Deaths will also be analyzed. 
 
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9.2.6.2 Laboratory variables, vital signs and electrocardiograms (ECGs)  
Quantitative analyses 
When relevant, for laboratory variables, vital signs and ECG variables, descriptive statistics for 
results and changes from baseline will be provided for each planned visit, the last value and the 
worst value (minimum and/or maximum value depending on the parameter) during the 
on-treatment period. These analyses will be performed using central measurements only (when 
available) for laboratory variables and ECG variables.  
Analyses according to PCSA 
• Potentially clinically significant abnormality (PCSA) analyses will be performed based on 
the PCSA list currently in effect at Sanofi at the time of the database lock. Analyses 
according to PCSA will be performed based on the worst value during the 
treatment-emergent period using all measurements (either local or central, either 
scheduled, nonscheduled or repeated). For laboratory variables, vital signs, and ECG 
variables, the incidence of participants with at least 1 PCSA during the treatment-emergent 
period will be summarized regardless of the baseline level and according to the following 
baseline status categories: Normal/missing. 
• Abnormal according to PCSA criterion or criteria 
  
9.2.7 Other analyses  
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 9 (Section 10.9). 
The impact of the regional or national emergency declared by a governmental agency on study 
conduct will be summarized (eg, study discontinuation or discontinuation/delay/omission of the 
intervention due to the emergency). Any additional analyses and methods required to evaluate the 
impact on efficacy (eg, missing data due to the emergency) and safety will be detailed in the SAP. 
Plasma concentration over time will be summarized by time window using the number of 
available data, mean, geometric mean, standard deviation (SD), median, minimum, and maximum 
in the SAR443820 dose group. 
The population PK analyses will be presented separately from the main clinical study report 
(CSR). 
9.3 
INTERIM ANALYSES   
An interim analysis (IA) may be performed when 75% of participants have completed the 
Week 48 visit. 
 
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This IA will not have any impact on the conduct of the double-blind study period; therefore, no 
penalty is needed for the primary analysis. 
The statistical analysis plan will describe the planned interim analyses in greater detail. 
9.4 
SAMPLE SIZE DETERMINATION  
Sample size calculations were performed to ensure reasonable accuracy for the estimation of the 
ratio of the SAR443820 arm sNfL geometric mean relative to the placebo arm sNfL geometric 
mean. The width (when a GMR of 
 is observed, which corresponds to a 
% reduction relative 
to placebo) of the 2-sided 90% CI, using a coverage correction to ensure coverage probability of 
90%, is displayed for various sample sizes in Table 7: 
Table 7 - Sample size determination  
 
Log-transformed data 
Corresponding geometric mean ratio 
(GMR) 
N 
Difference 
in means 
Standard 
deviation 
(SD) 
90% 
confidence 
interval (CI) 
half width* 
Lower 
limit 
Upper 
limit 
GMR 
Lower 
limit 
Upper 
limit 
Total width 
(asymmetric) 
(*): with a coverage probability (probability that the observed interval will be no longer than the specified width) of 90%. 
For an observed 30% reduction relative to placebo, a sample size of 168 participants (to account 
for an anticipated 17% dropout rate) will provide an upper limit below 
 (
% of reduction) 
for the 2-sided 90% CI, which is deemed sufficient. 
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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS  
10.1.1 Regulatory and ethical considerations  
• This study will be conducted in accordance with the protocol and with the following: 
- 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and the applicable amendments and Council for International 
Organizations of Medical Sciences (CIOMS) international ethical guidelines. 
- 
Applicable ICH-GCP guidelines. 
- 
Applicable laws and regulations (eg, data protection law as General Data Protection 
Regulation [GDPR]). 
• The protocol, protocol amendments, ICF, Investigator’s brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
• Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard 
to study participants. 
• The Investigator will be responsible for the following: 
- 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC. 
- 
Determining whether an incidental finding (as per Sanofi policy) should be returned to 
a participant and, if it meets the appropriate criteria, to ensure the finding is returned 
(an incidental finding is a previously undiagnosed medical condition that is discovered 
unintentionally and is unrelated to the aims of the study for which the tests are being 
performed). The following should be considered when determining the return of an 
incidental finding: 
- 
The return of such information to the study participant (and/or his/her designated 
healthcare professional, if so designated by the participant) is consistent with all 
applicable national, state, or regional laws and regulations in the country where the 
study is being conducted, and 
- 
The finding reveals a substantial risk of a serious health condition or has reproductive 
importance, AND has analytical validity, AND has clinical validity. 
- 
The participant in a clinical study has the right to opt out of being notified by the 
Investigator of such incidental findings. In the event that the participant has opted out 
of being notified and the finding has consequences for other individuals, eg, the 
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finding relates to a communicable disease, Investigators should seek independent 
ethical advice before determining next steps. 
- 
In case the participant has decided to opt out, the Investigator must record in the site 
medical files that she/he does not want to know about such findings. 
- 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
- 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), European Medical Device Regulation 2017/745 for 
clinical device research (if applicable), and all other applicable local regulations. 
As applicable, according to Directive 2001/20/EC, the Sponsor will be responsible for obtaining 
approval from the Competent Authorities of the EU Member States and/or Ethics Committees, as 
appropriate, for any amendments to the clinical trial that are deemed as “substantial” (ie, changes 
which are likely to have a significant impact on the safety or physical or mental integrity of the 
clinical trial participants or on the scientific value of the trial) prior to their implementation. 
10.1.2 Financial disclosure  
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3 Informed consent process  
• The Investigator or his/her representative will explain the nature of the study to the 
participants and answer all questions regarding the study, including what happens to the 
participant when his/her participation ends (post-trial access strategy for the study). 
• Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 
21 CFR 50, local regulations, ICH guidelines, Privacy and Data Protection requirements 
including those of the GDPR and of the French law, 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. 
• In case of ICF amendment while the participants are still included in the study, they must 
be re-consented to the most current version of the ICF(s). Where participants are not in the 
study anymore, teams in charge of the amendment must define if those participants must 
or not re-consent or be informed of the amendment (eg, if the processing of personal data 
is modified, if the Sponsor changes, etc.). 
• A copy of the ICF(s) must be provided to the participant or their legally authorized 
representative, where applicable. 
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Participants who are rescreened are required to sign a new ICF. 
The ICF contains 2 separate sections that addresses the use for research of participants’ data 
and/or samples (remaining mandatory ones or new extra samples collected for optional research). 
Optional exploratory research must be detailed in the section “Optional tests/procedures” and 
future research is to be defined in Core Study Informed Consent Form (CSICF) Part 2. Each 
option is subject to an independent consent and must be confirmed by ticking a checkbox in 
CSICF Part 3. The Investigator or authorized designee will explain to each participant the 
objectives of the exploratory research and why data and samples are important for future research. 
Participants will be told that they are free to refuse to participate and may withdraw their consent 
at any time and for any reason during the storage period. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 9 (Section 10.9).  
10.1.4 Data protection  
All personal data collected and/or processed in relation to this study will be handled in 
compliance with all applicable Privacy and Data Protection laws and regulations, including the 
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. 
Participant race and ethnicity will be collected in this study because they are expected to modify 
the drug response/because they are required by regulatory agencies (eg, on the African American 
population for the US Food and Drug Administration (FDA) or on the Japanese population for the 
Pharmaceuticals and Medical Devices Agency in Japan). They will not be collected in the 
countries where this is prohibited by local regulation. 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor or its service providers will be identifiable only 
by the unique identifier; participant names or any information which would make the 
participant identifiable will not be transferred to the Sponsor. 
• The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with applicable data protection laws. The level of disclosure 
must also be explained to the participant as described in the informed consent. 
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
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• Participants must be informed that their study-related data will be used for the whole “drug 
development program”, ie, for this trial as well as for the following steps necessary for the 
development of the investigational product, including to support negotiations with payers 
and publication of results. 
Protection of data related to professionals involved in the study 
• Personal data (eg, contact details, affiliation(s) details, job title and related professional 
information, role in the study, professional resume, training records) are necessary to 
allow Sanofi to manage involvement in the study and/or the related contractual or 
pre-contractual relationship. They may be communicated to any company of the 
Sanofi group (“Sanofi”) or to Sanofi service providers, where needed. 
• Personal data can be processed for other studies and projects. At any time, objection to 
processing can be made by contacting the Sanofi Data Protection Officer (link available at 
Sanofi.com). In case of refusal to the processing of personal data by or on behalf of 
Sanofi, it will be impossible to involve the professionals in any Sanofi study. In case the 
professionals have already been involved in a Sanofi study, they will not be able to object 
to the processing of their personal data as long as they are required to be processed by 
applicable regulations. The same rule applies in case the professionals are listed on a 
regulatory agencies disqualification list. 
• Personal data can be communicated to the following recipients:  
- 
Personnel within Sanofi or partners or service providers involved in the study. 
- 
Judicial, administrative and regulatory authorities, in order to comply with legal or 
regulatory requirements and/or to respond to specific requests or orders in the 
framework of judicial or administrative procedures. Contact details and identity may 
also be published on public websites in the interest of scientific research transparency. 
• Personal data may be transferred towards entities located outside the Economic European 
Area, in countries where the legislation does not necessarily offer the same level of data 
protection or in countries not recognized by the European Commission as offering an 
adequate level of protection. Those transfers are safeguarded by Sanofi in accordance with 
the requirement of European law including, notably:  
- 
The standard contractual clauses of the European Commission for transfers towards 
our partners and service providers, 
- 
Sanofi’s Binding Corporate Rules for intra-group transfers. 
• 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 thirty (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 
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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  
10.1.5.1 Study Steering Committee  
A study Steering Committee, composed of 4 experts in the field of MS, will advise the Sponsor on 
the study design and conduct. In collaboration with the Sponsor, the committee will provide 
scientific leadership to the study to ensure that the highest standards are maintained. Details 
describing the committee processes and procedures are outlined in the Steering Committee 
charter. 
10.1.5.2 Independent Data Monitoring Committee (DMC)  
A DMC, operating independently of the Sponsor and clinical Investigators, will be responsible for 
overseeing the safety of participants throughout the study. This committee is composed of 
externally based individuals with expertise in the disease under study, biostatistics, or clinical 
research. The primary responsibilities of the DMC are to review and evaluate the safety data 
during the trial and to make appropriate recommendations to the Sponsor regarding the conduct of 
the clinical trial. 
Details describing the DMC processes and procedures are outlined in the DMC charter. To 
maintain continuous blinding and study integrity, the analysis will be conducted by an 
independent statistician who will directly transfer data to DMC members. 
10.1.6 Dissemination of clinical study data  
Study participants 
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 Clinical Trials Register (eu.ctr), and sanofi.com, as well as 
some national registries. 
In addition, results from clinical trials in participants are required to be submitted to 
peer-reviewed journals following internal company review for accuracy, fair balance and 
intellectual property. For those journals that request sharing of the analyzable data sets that are 
reported in the publication, interested researchers are directed to submit their request to 
clinicalstudydatarequest.com. 
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Individual participant data and supporting clinical documents are available for request at 
clinicalstudydatarequest.com. While making information available we continue to protect the 
privacy of participants in our clinical trials. Details on data sharing criteria and process for 
requesting access can be found at this web address: clinicalstudydatarequest.com. 
Professionals involved in the study or in the drug development program 
Sanofi undertakes the legal obligation to disclose the full name of the Investigator and his/her 
affiliated institute/ hospital’s name and location on the China Trial Disclosure website as required 
by the National Medical Products Administration (NMPA) in its guidance “Drug Clinical Trial 
Registration and Information Disclosure Management Practice (Trial Implementation)”, 
requesting name disclosure of Chinese and foreign investigational sites and Investigators in any 
eligible clinical trial.  
Sanofi may publicly disclose, and communicate to relevant authorities/institutions, the funding, 
including payments and transfers of value, direct or indirect, made to healthcare organizations and 
professionals and/or any direct or indirect advantages and/or any related information or document 
if required by applicable law, by regulation or by a code of conduct such as the “European 
Federation of Pharmaceutical Industries and Associations (EFPIA) Code on Disclosure of 
Transfers of Value from Pharmaceutical Companies to Healthcare Professionals and Healthcare 
Organizations”. 
10.1.7 Data quality assurance  
• All participant data relating to the study will be recorded on a printed or an eCRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Monitoring details describing strategy, including definition of study critical data items and 
processes (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). 
• 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. 
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10.1.8 Source documents  
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The Investigator may 
need to request previous medical records or transfer records, depending on the study. Also, 
current medical records must be available. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• 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. 
10.1.9 Study and site start and closure  
First act of recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first site open and will be the study start date. 
Study/Site termination 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for study termination by the Sponsor, as well as reasons for the early closure of a study 
site by the Sponsor or Investigator may include but are not limited to: 
• For study termination: 
- 
Information on the product leads to doubt as to the benefit/risk ratio. 
- 
Discontinuation of further study intervention development. 
• For site termination: 
- 
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor’s procedures, or GCP guidelines. 
- 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator. 
• Total number of participants included earlier than expected. 
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If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
10.1.10 Publication policy  
• The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments. 
• The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. 
In this case, a coordinating Investigator will be designated by mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS  
• The tests detailed in Table 8 will be performed by the central laboratory. 
• Local laboratory results are only required in the event that the central laboratory results are 
not available in time for either study intervention administration and/or response 
evaluation. If a local sample is required, it is important that the sample for central analysis 
is obtained at the same time. Additionally, if the local laboratory results are used to make 
either a study intervention decision or response evaluation, the results must be recorded. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
Additional tests may be performed at any time during the study as determined necessary by the 
Investigator or required by local regulations. 
Table 8 - Protocol-required laboratory tests  
Laboratory tests 
Parameters 
Hematology 
 
 
Platelet count 
 
Red blood cell (RBC) count 
 
Hemoglobin 
 
Hematocrit 
 
RBC indices: 
 
Mean corpuscular volume (MCV) 
 
Mean corpuscular hemoglobin (MCH) 
 
%Reticulocytes 
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Laboratory tests 
Parameters 
 
White blood cell (WBC) count with differential: 
 
Neutrophils 
 
Lymphocytes 
 
Monocytes 
 
Eosinophils 
 
Basophils 
Clinical chemistrya 
 
 
Blood urea nitrogen (BUN) 
 
Creatinine 
 
Glucoseb 
 
Potassium 
 
Sodium 
 
Calcium 
 
Albumin 
 
Creatine phosphokinase 
 
Aspartate aminotransferase (AST)/ Serum glutamic-oxaloacetic transaminase (SGOT) 
 
Alanine aminotransferase (ALT)/ Serum glutamic-pyruvic transaminase (SGPT) 
 
Alkaline phosphatasec 
 
Total and direct bilirubin 
 
Total protein 
Routine urinalysis 
Specific gravity 
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase by dipstick 
Microscopic examination (if blood or protein is abnormal) 
Pregnancy testing 
Serum or highly sensitive urine human chorionic gonadotropin (hCG) pregnancy test (as needed for 
women of childbearing potential)d 
Other screening tests 
Follicle-stimulating hormone and estradiol (as needed in women of nonchildbearing potential only) 
Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis C virus antibody or 
specify other tests) 
All study-required laboratory tests will be performed by a central laboratory except local urine 
pregnancy test and urinalysis (See Appendix 8 [Section 10.8]) 
Abbreviations: AESI = adverse events of special interest; ULN = upper limit of normal 
NOTES: 
a Details of the liver chemistry stopping criteria and required actions and follow-up are given in Appendix 6 (Section 10.6) (liver and other 
safety. Suggested actions and follow-up assessments [and study intervention rechallenge guidelines). All events of ALT >3, which may 
indicate liver injury, must be reported to the Sponsor in an expedited manner (refer to the section on AESIs [Section 8.3.9]). Clinical 
laboratory findings of ALT >3 ULN and bilirubin ≥2 × ULN (>35% direct bilirubin), which may suggest severe liver injury (possible Hy’s 
Law), must be reported to the Sponsor in an expedited manner. 
b Fasting glucose is preferred. Fasting/nonfasting status will be recorded at the time of blood collection for glucose assessment. 
c If alkaline phosphatase is elevated, consider fractionating.  
d Local urine testing will be standard for the protocol unless 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: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING  
10.3.1 Definition of AE  
AE definition 
• An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use 
of study intervention. 
Definition of unsolicited and solicited AE 
• An unsolicited AE is an AE that was not solicited using a participant diary and that is 
communicated by a participant who has signed the informed consent. Unsolicited AEs 
include serious and nonserious AEs. 
• Potential unsolicited AEs may be medically attended (ie, symptoms or illnesses requiring a 
hospitalization, emergency room visit, or visit to/by a health care provider). The 
participants will be instructed to contact the site as soon as possible to report medically 
attended event(s), as well as any events that, though not medically attended, are of 
participant concern. Detailed information about reported unsolicited AEs will be collected 
by qualified site personnel and documented in the participant’s records. 
• Unsolicited AEs that are not medically attended nor perceived as a concern by the 
participant will be collected during an interview with the participants and by review of 
available medical records at the next visit. 
• Solicited AEs are predefined systemic events for which the participant is specifically 
questioned, and which are noted by the participants in their diary. 
Events meeting the AE definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the Investigator (ie, not related to progression of underlying 
disease), eg: 
- 
Symptomatic and/or 
- 
Requiring either corrective treatment or consultation, and/or  
- 
Leading to IMP discontinuation or modification of dosing, and/or  
- 
Fulfilling a seriousness criterion, and/or  
- 
Defined as an AESI 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
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• New condition detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. 
• Lack of efficacy or failure of expected pharmacological action per se will not be reported 
as an AE or SAE. Such instances will be captured in the efficacy assessments. However, 
the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. 
• The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as an AE or SAE if they fulfill 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 that are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.3.2 Definition of SAE  
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or more 
of the criteria listed: 
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 admitted (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 
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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 or significant disability/incapacity 
- 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
- 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent everyday 
life functions but do not constitute a substantial disruption. 
E) Is a congenital anomaly/birth defect 
F) Is a suspected transmission of any infectious agent via an authorized medicinal 
product 
G) Other situations: 
- 
Medical or scientific judgment should be exercised by the Investigator in deciding 
whether SAE reporting is appropriate in other situations such as significant medical 
events that 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. 
Note: The following list of medically important events is intended to serve as a 
guideline for determining which condition has to be considered as a medically 
important event. The list is not intended to be exhaustive: 
- 
Intensive treatment in an emergency room or at home for: 
- 
Allergic bronchospasm 
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc) 
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc). 
- 
Development of drug dependence or drug abuse 
- 
ALT >3 × ULN + total bilirubin >2 × ULN or asymptomatic ALT increase 
>10 × ULN 
- 
Suicide attempt or any event suggestive of suicidality 
- 
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling) 
- 
Bullous cutaneous eruptions 
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10.3.3 Recording and follow-up of AE and/or SAE  
AE and SAE recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The Investigator will then record all relevant AE/SAE information. 
• 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 required form. 
• 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 one of the following categories: 
• Mild: Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• Moderate: Minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental Activities of Daily Living (ADL). Instrumental ADL refers to preparing 
meals, shopping for groceries or clothes, using the telephone, managing money, etc. 
• Severe: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling, limiting self care 
ADL. Self-care ADL refers to bathing, dressing and undressing, feeding self, using the 
toilet, taking medications, and not bedridden. 
Assessment of causality 
• The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. The Investigator will use clinical judgment to determine 
the relationship. 
• A reasonable possibility of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than that a relationship cannot be ruled 
out. 
• 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. 
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• For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to the Sponsor’s representative. However, it is 
very important that the Investigator always make an assessment of causality for every 
event before the initial transmission of the SAE data to the Sponsor’s representative. 
• The Investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor’s 
representative to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide the Sponsor’s representative with a copy of any 
postmortem findings including histopathology. 
• New or updated information will be recorded in the originally submitted documents. 
• The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
10.3.4 Reporting of SAEs  
SAE reporting to the Sponsor 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) 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 
offline 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 
offline, 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 Investigator Study File. 
SAE reporting to the Sponsor via paper data collection tool 
• Facsimile transmission of the SAE paper data collection tool is the preferred method to 
transmit this information to the Sponsor’s representative. 
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• 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 data collection tool within the designated reporting timeframes. 
• Contacts for SAE reporting can be found in Investigator Study File. 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE  
10.4.1 Definitions  
A woman is considered a WOCBP (fertile) from the time of menarche until becoming 
postmenopausal (see below) unless permanently sterile (see below). 
• A postmenopausal state is defined as the period of time after a woman has experienced no 
menses for 12 consecutive months without an alternative medical cause. 
• A high follicle stimulating hormone (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). 
• Females on HRT and whose menopausal status is in doubt will be required to use 1 of the 
nonestrogen hormonal highly effective contraception methods if they want to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation 
of postmenopausal status before study enrollment. 
Women in the following categories are considered WONCBP: 
1. Any female with permanent infertility due to one 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, gonadal 
dysgenesis), Investigator discretion should be applied to determining study entry. 
2. Postmenopausal female 
A postmenopausal state is defined as the period of time after a woman has experienced 
no menses for 12 consecutive months without an alternative medical cause. 
- 
A high follicle stimulating hormone (FSH) level in the postmenopausal range must 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT).  
- 
Females on HRT and whose menopausal status is in doubt must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment. 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
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Permanent sterilization methods include: 
• 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, gonadal dysgenesis), Investigator 
discretion should be applied to determining study entry eligibility. 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first administration of the study intervention, additional evaluations should be 
considered. 
10.4.2 Contraception guidance  
If locally required, acceptable contraceptive methods are limited to those which inhibit ovulation 
as the primary mode of action. 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly effective methodsb that have low user dependency Failure rate of <1% per year when used consistently and 
correctly. 
• 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationc 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) c 
• 
Bilateral tubal occlusion 
• 
Azoospermic partner (vasectomized or due to a medical cause) 
Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual partner of the woman 
of childbearing potential and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used.  
Note: documentation of azoospermia for a male participant can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
Highly effective methodsb that are user dependent Failure rate of <1% per year when used consistently and correctly. 
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulationc 
- 
oral 
- 
intravaginal 
- 
transdermal 
- 
injectable 
• 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
- 
oral 
- 
injectable 
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Highly effective methodsb that are user dependent Failure rate of <1% per year when used consistently and correctly. 
• 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse 
during the entire period of risk associated with the study intervention. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant. 
a Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for those 
participating in clinical studies. 
b Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when used consistently and 
correctly. 
c Male condoms must be used in addition to hormonal contraception. 
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method (LAM) are not acceptable methods of contraception for this study. Male condom and female condom should 
not be used together (due to risk of failure from friction). 
Note: Periodic abstinence (calendar, symptothermal, and postovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are not 
acceptable methods of contraception for this study. A male condom and female condom should 
not be used together (due to risk of failure from friction). 
For male study participants whose partner is a WOCBP, they agree to the following during the 
study period and for at least 92 days following their last dose of IMP: 
• Refrain from donating or cryopreserving sperm 
Plus, either: 
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent 
on a long-term and persistent basis) and agree to remain abstinent 
OR 
• Must agree to use contraception/barrier (male condom) as detailed below: 
A male condom and an additional highly contraceptive method as described above in this 
section, when having sexual intercourse with a WOCBP who is not currently pregnant 
Female participants are eligible to participate if they are not pregnant or breastfeeding and 1 of the 
following conditions applies: 
• Are a woman of nonchildbearing potential (WONCBP) as defined in Section 10.4.1. 
OR 
• Are a WOCBP and agree to use a contraceptive method that is highly effective (with a 
failure rate of <1% per year), preferably with low user dependency, as described above in 
this section during the study intervention period (to be effective before starting the study 
intervention) and for at least 32 days after the last administration of the IMP and agree not 
to donate or cryopreserve eggs (ova, oocytes) for the purpose of reproduction during this 
period. 
• WOCBP must have a negative highly sensitive pregnancy test within 24 hours before the 
first administration of the study intervention, see Section 8.2.6. 
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test 
is required. In such cases, the participant must be excluded from participation if the serum 
pregnancy result is positive. 
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COLLECTION OF PREGNANCY INFORMATION: 
For male participants with partners who could 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 the IMP. 
• 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. 
For female participants who could become pregnant: 
• The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial 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 for medical reasons 
will be reported as an AE or SAE. 
• A spontaneous abortion (occurring at 22 weeks gestational age) is always considered to be 
an SAE and will be reported as such. 
• Any poststudy pregnancy related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as described in 
Section 8.3.4. While the Investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue the study intervention or be withdrawn from the study. 
10.5 
APPENDIX 5: GENETICS  
Not applicable. 
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10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: ACTIONS AND FOLLOW-UP 
ASSESSMENTS AND STUDY INTERVENTION RESTART/RECHALLENGE  
 
Abbreviations: ANC = absolute neutrophil count; PK = pharmacokinetic; RBC = red blood cells  
Neutropenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting adverse events 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 adverse events in Section 10.3 is met. 
 
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These actions are required for ALT increase events ONLY. For all other safety events described, 
these are suggested per the Investigator’s medical judgement. 
 
Abbreviations: ALT = alanine aminotransferase; CRF = case report form; IMP = investigational medicinal product; LFT = liver function test; 
ULN = upper limit of normal 
 
*If unable to retest in 72 hours, use original lab results to decide on further reporting/monitoring/discontinuation.  
** Unless a protocol-defined criterion for permanent discontinuation is met.  
*** See box below 
Note: 
• “Baseline” refers to ALT sampled at baseline visit; or if baseline value unavailable, to the latest ALT sampled before the baseline visit. The 
algorithm does not apply to the instances of increase in ALT during screening. 
• See Section 10.3 for guidance on safety reporting. 
 
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Abbreviations: ARF = acute renal failure; BP = blood pressure; CPK = creatine phosphokinase; DIC = disseminated intravascular coagulation; 
ECG = electrocardiogram; HR = heart rate; PK = pharmacokinetics; ULN = upper limit of normal 
Increase in serum creatinine is to be recorded as an AE only if at least 1 of the criteria listed in the 
general guidelines for reporting adverse events in Section 10.3 is met. 
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Abbreviations: CK-MB = creatine kinase myocardial band; CK-MM = creatine kinase muscle; CPK = creatine phosphokinase; 
ECG = electrocardiogram; ULN = upper limit of normal 
Increase in CPK is to be recorded as an AE only if at least 1 of the criteria in the general 
guidelines for reporting adverse events in Section 10.3 is met. 
 
Abbreviations: aPTT = activated partial thromboplastin time; EDTA ethylenediamine tetraacetic acid; INR = international normalized ratio; 
PK = pharmacokinetics; PT = prothrombin time 
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10.7 
APPENDIX 7: AES, ADES, SAES, SADES, USADES AND DEVICE DEFICIENCIES: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, FOLLOW-UP, 
AND REPORTING IN MEDICAL DEVICE STUDIES  
Not applicable. 
10.8 
APPENDIX 8: COUNTRY-SPECIFIC/REGION REQUIREMENTS  
10.8.1 China  
10.8.1.1 Study objectives and endpoints  
All the objectives and endpoints for both study parts in Section 3 will be unchanged for 
participants in China except for serum glial fibrillary acidic protein (sGFAP) assessment (no 
sGFAP will be analyzed for the participants from China). 
Part A 
 
 
 
Objectives 
Endpoints 
Primary 
 
• 
To assess the effect of SAR443820 
compared to placebo on sNfL 
• 
Week 48 sNfL levels relative to baseline 
Secondary 
 
• 
To evaluate efficacy of SAR443820 
compared to placebo on imaging and 
clinical endpoints 
• 
Cumulative number of new gadolinium (Gd)-enhancing 
T1 hyperintense lesions as detected by MRI at Week 48, 
defined as the sum of the individual number of new Gd 
enhancing T1 hyperintense lesions at all scheduled visits 
starting after baseline up to and including the Week 48 visit 
• 
Cumulative number of new and/or enlarging 
T2 hyperintense lesions as detected by MRI, at Week 48, 
defined as the sum of the individual number of new and/or 
enlarging T2 lesions at all scheduled visits starting after 
baseline up to and including the Week 48 visit 
• 
Time to onset of 12 weeks confirmed disability progression 
(CDP) from baseline as assessed by the Expanded 
Disability Status Scale (EDSS) score 
• 
Time to onset of sustained 20% increase in 9-Hole Peg 
Test (9-HPT) confirmed over at least 12 weeks 
• 
Time to onset of sustained 20% increase in timed 25 foot 
walk test (T25-FW) confirmed over at least 12 weeks 
• 
Change from baseline in EDSS Plus at Week 48 
• 
ARR of RMS population (relapsing SPMS and RRMS) up 
to Week 48 
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Objectives 
Endpoints 
• 
To explore effect of SAR443820 compared 
to placebo on brain volume and chronic 
lesions 
• 
Percent change from baseline in brain volume loss (BVL) 
as detected by brain MRI at 48 weeks 
• 
Change from baseline in the volume, number, and intensity 
(T1) of slowly expanding lesions (SELs), and normalized 
T1 intensity in lesions at Weeks 12, 24, 36, and 48 
• 
Change from baseline in the total number and volume of 
non-enhancing lesions volume at Weeks 12, 24, 36, and 48 
• 
Change from baseline in the number of phase rim lesions 
(PRL) at Weeks 12, 24, 36, and 48; among participants at 
sites with 3T capability 
• 
To assess the safety and tolerability of 
SAR443820 
• 
Incidence of AE, SAE, TEAE, PCSA in laboratory tests 
• 
To assess pharmacokinetic (PK) of 
SAR443820 
• 
Plasma concentration of SAR443820 
Tertiary 
 
• 
To assess the effect of SAR443820 
compared to placebo on sNfL in 
subpopulations of multiple sclerosis (MS) 
• 
Change from baseline in sNfL level in MS subpopulations 
(RRMS, SPMS, PPMS) over 48 weeks 
• 
To assess the effect of SAR443820 
compared to placebo on biomarkers of 
neurodegeneration, inflammation, and 
disease progression 
• 
Change from baseline compared to Week 48 in: plasma 
chitinase-3-like protein 1 (CHI3L1), interleukin-1B (IL1B), 
IL6, IL8, Chemokine (C-C motif) ligands 3 (CCL3), and 
Chemokine (C-C motif) ligands 4 (CCL4) 
• 
To assess efficacy of SAR443820 
compared to placebo on patient-reported 
outcomes (PROs) assessing the physical 
and psychological impact of MS from the 
patient's perspective (MSIS-29v2) and the 
impact of MS on the individual's walking 
ability (MSWS-12) 
• 
Change from baseline in MSIS-29v2 physical and 
psychological domains scoring at Week 12, 24, 36, and 48 
• 
Change from baseline in MSWS-12 at Week 12, 24, 36, 
and 48 
Part B 
 
Objectives 
Endpoints 
Primary 
 
• 
To assess long-term trends in durability of 
sNfL 
• 
Week 96 sNfL levels relative to baseline 
Secondary 
• 
To explore the effect of SAR443820 on 
brain volume and chronic lesions 
• 
Percent change from baseline in BVL as detected by brain 
MRI at Week 96 
• 
Change from baseline in volume, number and intensity (T1) 
in SEL and normalized T1 intensity in lesions to Week 96 
• 
Change from baseline in the total number and volume of 
non-enhancing lesions Week 96 
• 
Change from baseline in the number of PRLs (same 
participants/centers from Part A) at Week 96 
• 
To assess the long-term safety and 
tolerability of SAR443820 
• 
Incidence of AE, SAE, TEAE, PCSA in laboratory tests, 
ECG, and vital signs during through Week 96 
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Objectives 
Endpoints 
• 
To evaluate long-term effect of 
SAR443820 on disease progression and 
activity assessed by other clinical and 
imaging measures on physical function 
and patient-reported outcomes (PROs) 
• 
Cumulative number of new Gd-enhancing lesions as 
detected by T1-weighted MRI between 48 and 96 weeks; 
number of new or enlarging T2-hyperintense lesions on 
MRI at Week 96 relative to Week 48 
• 
Annualized relapse rate (ARR) of RMS population 
(relapsing SPMS and RRMS) up to Week 96 
• 
Time to onset of composite CDP (CCDP), confirmed over at 
least 12 weeks (3-month CCDP), by the EDSS Plus 
composite (EDSS score increase, OR 20% increase in the 
T25-FW test, OR 20% increase in the 9-HPT) 
 
• 
Time to onset of 12 weeks CDP as assessed by the EDSS 
score 
• 
Time to onset of sustained 20% increase in 9-HPT 
confirmed over at least 12 weeks 
• 
Time to onset of sustained 20% increase T25-FW test 
confirmed over at least 12 weeks 
• 
Change from baseline in EDSS Plus at Week 96 
• 
Change in MSIS-29v2 physical and psychological domains 
scoring from baseline through Week 96 
• 
Change in MSWS-12 from baseline through Week 96 
The content of this section supersedes the content in Section 3 for the study conducted in China. 
10.8.1.2 Sample storage and disposition of samples after study completion  
Blood samples for storage to support additional tertiary objectives beyond those in the study 
protocol will not be collected for participants in China. 
All samples from participants in China will be disposed of following completion of the CSR. 
10.8.2 Germany  
Informed consent process: All references to "legally authorized representative" are not applicable 
in Germany; only participants who can give written consent themselves are included in the study. 
References to "legally authorized representative" are found in Section 1 and Section 10.1.3. 
German participant continuation into Part B will be contingent on local ethics committee 
acknowledgment of recommendation from global study Data Safety Monitoring Committee and 
continued approval. The Sponsor will provide these documents in sufficient time to limit any 
disruption to the participation of German enrollees and their transition into the Part Open label 
extension phase. 
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10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY  
The following contingencies may be implemented for the duration of the emergency (after 
Sponsor agreement is obtained). 
Study intervention 
The following contingencies may be implemented to make clinical supplies available to the 
participant for the duration of the emergency: 
• DTP supply of the IMP from the PI/site/Sponsor where allowed by local regulations and 
agreed upon by the participant. 
If a participant has to stop the IMP due to a regional or national emergency (eg, coronavirus 
disease-2019 [COVID-19]), reinitiation of the study intervention will be done under close and 
appropriate clinical/and or laboratory monitoring and following the instructions provided in 
Section 7.1.3. 
Study assessments and procedures 
During the emergency, if the site will be unable to adequately follow protocol-mandated 
procedures, alternative treatment outside the clinical trial should be proposed, and 
screening/enrollment/administration of the study intervention may be temporarily delayed. 
Attempts should be made to perform all assessments in accordance with the approved protocol to 
the fullest 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. 
The following procedures are to be considered in the event of a regional or national emergency 
declared by a governmental agency: 
• If onsite visits are not possible, remote visits (eg, with home nurses, a home health vendor, 
etc.) may be planned for the collection of possible safety and/or efficacy data, including 
1) collection of samples for screening and clinical safety analyses, 2) ECG and vital signs 
assessments, and 3) AEs. 
• If onsite visits are not possible, visit windows may be extended for assessments of safety 
and/or efficacy data that cannot be obtained remotely. 
• Use of local site or laboratory locations may be allowed when central laboratory 
assessments cannot be performed due to a government declared national emergency. 
Statistical analyses 
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 of the emergency on efficacy (eg, missing data due to the emergency) and safety will be 
detailed in the SAP. 
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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 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 laboratories). 
 
10.10 APPENDIX 10: STRONG AND MODERATE CYP3A4 INHIBITORS AND STRONG 
CYP3A4 INDUCERS  
Table 9 - Strong and moderate CYP3A4 inhibitors and strong CYP3A4 inducers  
Reason for exclusion 
Compound (INN) 
Therapeutic class 
Wash out period (day) 
Strong CYP3A4 inducer 
Apalutamide 
Antiandrogens 
21 
Avasimibe 
Other antilipemics 
5 
Phenobarbital 
Anticonvulsant 
20 
Phenytoin 
Anticonvulsant 
14 
Rifampin 
Antibiotics 
14 
Rifapentine 
Antibiotics 
14 
St John’s wort 
Herbal medicine 
14 
Carbamazepine 
Anticonvulsant 
14 
Enzalutamide 
Antiandrogens 
14 
Ivosidenib 
Cancer treatment 
19 
Lumacaftor 
Cystic fibrosis treatment 
14 
Mitotane 
Other antineoplastics 
90 
Strong or moderate CYP3A4 
inhibitor 
ACT-539313 
Hypnotic 
2 
ACT17882 
Renin inhibitor 
5 
Amprenavir 
Protease inhibitor 
3 
Aprepitant 
Antiemetics 
3 
Atazanavir, atazanavir/ritonavir 
Protease inhibitor 
2 
Berotralstat 
Cardiovascular drug 
20 
Boceprevir 
Antiviral 
1 
Casopitant 
Antiemetics 
4 
Ceritinib 
Kinase inhibitor 
10 
Cimetidine 
H-2 receptor antagonist 
1 
Ciprofloxacin 
Antibiotics 
1 
Clarithromycin 
Antibiotics 
1 
Cobicistat 
None 
1 
Conivaptan 
Diuretics 
2 
Crizotinib 
Kinase inhibitor 
9 
Danoprevir/ritonavir 
Antiviral 
2 
Darunavir, darunavir/ritonavir 
Protease inhibitor 
4 
Diltiazem 
Calcium channel blocker 
1 
Dronedarone 
Antiarrhythmic 
7 
Duvelisib 
Kinase Inhibitor 
2 
Elvitegravir/ritonavir 
AIDS treatment 
3 
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Reason for exclusion 
Compound (INN) 
Therapeutic class 
Wash out period (day) 
Erythromycin 
Antibiotic 
1 
Faldaprevir 
Antiviral 
 
8 
Fedratinib 
Kinase inhibitor 
24 
FK1706 
Central nervous system agent 
15 
Fluconazole 
Antifungal 
7 
Grapefruit juice 
N/A 
2 
Idelalisib 
Kinase inhibitor 
2 
Imatinib 
Antineoplastic agent 
5 
Indinavir, indinavir/ritonavir 
Protease inhibitor 
2 
Isavuconazole 
Antifungal 
27 
Istradefylline 
Antiparkinsonian 
18 
Itraconazole 
Antifungal 
5 
Josamycin 
Antibiotic 
1 
Ketoconazole 
Antifungal 
1 
LCL161 
Cancer treatment 
2 
Lefamulin 
Antibiotic 
2 
Letermovir 
Antiviral 
3 
Lonafarnib 
Other 
2 
Lopinavir, lopinavir/ritonavir 
Protease inhibitor 
2 
Mibefradil 
Calcium channel blocker 
5 
Mifepristone 
Antiprogestins 
18 
Nefazodone 
Antidepressant 
1 
Nelfinavir 
Protease inhibitor 
2 
Netupitant 
Antiemetic 
20 
Nilotinib 
Kinase inhibitor 
4 
Posaconazole 
Antifungal 
7 
Ravuconazole 
Antifungal 
40 
Ribociclib 
Kinase inhibitor 
7 
Ritonavir 
Protease inhibitor 
2 
Saquinavir, saquinavir/ritonavir 
Protease inhibitor 
3 
Schisandra sphenanthera 
Herbal medicine 
14 
Telaprevir 
Antiviral 
3 
Telithromycin 
Antibiotic 
3 
Tipranavir/ritonavir 
Protease inhibitor 
2 
Tofisopam 
Benzodiazepine 
1 
Troleandomycin 
Antibiotic 
1 
Tucatinib 
Kinase Inhibitor 
2 
Verapamil 
Calcium channel blocker 
1 
Voriconazole 
Antifungal 
1 
Voxelotor 
Hemoglobin inhibitor 
8 
Voxelotor 
Hemoglobin inhibitor 
2 
Voxelotor 
Hemoglobin inhibitor 
5 
 
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10.11 APPENDIX 11: ABBREVIATIONS  
 
9-HPT: 
9-hole peg test 
ADL: 
Activities of Daily Living 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALT: 
alanine aminotransferase 
ANCOVA: 
analysis of covariance 
AST: 
aspartate aminotransferase 
AUC: 
area under the curve 
AUC0-24h: 
area under the plasma concentration-time curve over the last 24-h dosing 
interval 
BID: 
twice daily 
BMI: 
body mass index 
CDP: 
confirmed disability progression 
CI: 
confidence interval 
Cmax: 
maximum plasma concentration 
CNS: 
central nervous system 
CPK: 
creatine phosphokinase 
CRF: 
case report form 
CSF: 
cerebrospinal fluid 
CSICF: 
Core Study Informed Consent Form 
CSR: 
clinical study report 
C-SSRS: 
Columbia Suicide Severity Rating Scale 
CYP: 
cytochrome P450 
DMC: 
data monitoring committee 
DMT: 
disease-modifying therapy 
DTP: 
direct-to-patient 
EAE: 
experimental autoimmune encephalomyelitis 
ECG: 
electrocardiogram 
eCRF: 
electronic case report form 
EDSS: 
Expanded Disability Status Scale 
FIH: 
first-in-human 
FSH: 
follicle stimulating hormone 
Gd: 
gadolinium 
GDPR: 
General Data Protection Regulation 
GFAP: 
glial fibrillary acidic protein 
GMR: 
geometric means ratio 
HBcAb: 
hepatitis B core antibody 
HBsAg: 
hepatitis B surface antigen 
HIV: 
human immunodeficiency virus 
HRT: 
hormonal replacement therapy 
IA: 
interim analysis 
IB: 
Investigator’s Brochure 
ICF: 
informed consent form 
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ICH-GCP: 
International Council for Harmonization of Good Clinical Practice 
IE: 
intercurrent event 
IEC: 
Independent Ethics Committees 
IMP: 
investigational medicinal product 
IRB: 
Institutional Review Boards 
IRT: 
interactive response technology 
ITT: 
intent-to-treat 
IV: 
intravenous 
MAD: 
multiple ascending dose 
MAR: 
missing at random 
MDRD: 
Modification of Diet in Renal Disease 
mITT: 
modified intent-to-treat 
MLKL: 
mixed lineage kinase domain-like protein 
MMRM: 
mixed effect model with repeated measures 
MRI: 
magnetic resonance imaging 
MS: 
multiple sclerosis 
MSIS-29v2: 
Multiple Sclerosis Impact Scale-29 items version 2 
MSWS-12: 
Multiple Sclerosis Walking Scale 12 items 
NfL: 
neurofilament light chain 
NIMP: 
noninvestigational medicinal product 
NMPA: 
National Medical Products Administration 
NOAEL: 
no-observed-adverse-effect level 
PBPK: 
physiologically based pharmacokinetic 
PCSA: 
potentially clinically significant abnormality 
PK: 
pharmacokinetic 
PML: 
progressive multifocal leukoencephalopathy 
PMS: 
progressive multiple sclerosis 
PPMS: 
primary progressive multiple sclerosis 
PRL: 
phase rim lesion(s) 
PRO: 
patient reported outcome 
QD: 
once daily 
RIPK1: 
receptor interacting serine/threonine kinase 1 
RIPK3: 
receptor interacting serine/threonine-protein kinase 3 
RNA: 
ribonucleic acid 
RRMS: 
relapsing remitting multiple sclerosis 
SAD: 
single ascending dose 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SEL: 
slowly expanding lesion(s) 
SIB: 
suicidal ideation and behavior 
sNfL: 
serum neurofilament light chain 
SoA: 
schedule of activities 
SOC: 
standard of care 
SPMS: 
secondary progressive multiple sclerosis 
SUSAR: 
suspected unexpected serious adverse reaction 
T25-FW: 
timed 25-foot walk test 
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TE: 
treatment-emergent 
TEAE: 
treatment emergent adverse event 
TNFR1: 
tumor necrosis factor receptor 1 
ULN: 
upper limit of normal 
WOCBP: 
woman of childbearing potential 
WONCBP: 
woman of nonchildbearing potential 
 
10.12 APPENDIX 12: PROTOCOL AMENDMENT HISTORY  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the table of contents (TOC). 
10.12.1 Amended protocol 01 (21 September 2022)  
This amended protocol (amendment 01) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
Overall Rationale for the Amendment 
The purpose of this amendment is to include the dose change in the study. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis; Objective and 
endpoints  
3.Objectives, endpoints, and 
estimands 
10.8.1.1 Study Objectives, 
endpoints 
Part A: Secondary objective 2, endpoint 4, wordings updated from: 
‘Change from baseline in the number of phase rim lesions (PRL) 
subset of centers with 3T capacity, 25% of participants at Weeks 12, 
24, 36, and 48’ 
To 
‘Change from baseline in the number of phase rim lesions (PRL) at 
Weeks 12, 24, 36, and 48; among participants at sites with 3T 
capability” 
Part B: the following text was deleted from the secondary objective 1, 
endpoint 4 ‘with 3T capacity, 25% of participants’ 
29v2m is replaced with “29v2” and MSWS 12m is replaced with 
“MSWS 12”. 
To add consistency in 
objectives and endpoints. 
Clarification 
Part A: tertiary objective 2, endpoint 1: updated from ‘serum’ to 
‘plasma’ for CHI3L1.  
Clarification 
1.1 Synopsis: Brief summary; 
Study interventions;  
1.1 Schema 
2.3.1 Risk assessment, Table 1 
2.3.3 Overall benefit/risk 
conclusion 
4.1 Overall design 
4.3 Justification for dose 
6. Table 4: Study intervention 
administered  
9.2.1 General consideration 
To change SAR443820 dose from 20 mg BID to 20 mg QD 
The dose of 20 mg QD 
SAR443820 is selected for 
this Phase 2 study to strike 
a balance between the 
convenience of once-a-day 
dosing while maintaining 
robust potential treatment 
effectiveness in participants 
with MS.  Target 
engagement close to 90% 
measured by pS166-RIPK 
at Ctrough  
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Section # and Name 
Description of Change 
Brief Rationale 
1.3 1 Part A, Schedule of 
Activities 
Specified ‘Brain’ for MRI with and without Gd assessment 
To add more clarity. 
Footnotes ‘n’ and ‘o’ related to brain MRI assessment was updated. 
Footnote ‘n’ updated as ‘Baseline scan can be carried out within 5 to 
7 day prior to Day 1 randomization but after all other screening 
assessment have been completed and none excluded the patient.’ 
Footnote ‘o’ updated as ‘to be performed only if the previous MRI 
was done more than 4 weeks ago.’ 
The following additional visits was added for the assessment of 
12-lead ECG: Day 1 (postdose), Week 6, and Week 12 
More frequent ECG 
monitoring required, as this 
is the first study to use to 
SAR443820 in participants 
with MS. 
Footnote ‘j’ was updated to add following wordings ‘should not be 
older than 24 hours upon first IMP intake on Day 1’ 
To add more clarity. 
1.3 1 Part A, Schedule of 
Activities 
3.1.3 Pharmacodynamic 
assessments 
8.6 Biomarkers 
10.8.1. China; study objectives 
and endpoints 
Footnote ‘t’ and other sections were updated to specify that ‘serum 
GFAP will not be collected from participants in China’ 
To add more clarity 
1.3 2 Part B, Schedule of 
Activities 
Footnote ‘b’ added ‘The participants will attend a safety follow-up 
visit within 2 weeks following discontinuation of IMP, if they no longer 
wish to remain in the study.’ 
To add more clarity 
2.3.1 Risk assessment 
Described overlap benefit risk of concomitant medications. 
To Include description to 
risk table about 
concomitant medications 
safety analysis. 
The wordings under mitigation strategy for convulsion/seizures was 
updated to include ‘6-month toxicology study in rat’ and duration of 
nonhuman primate toxicology study was updated from 3 to 6-months.  
To add more clarity to risk 
mitigation strategy. 
The following wordings under mitigation strategy for 
convulsion/seizures was updated from ‘Also, weight <45 kg should 
be avoided to not exceed the cap (as per the Pop PK model).’  
To 
‘Excluding participants in whom exposure may be increased 
(participants weighing <45 kg, or participant with moderate or severe 
hepatic impairment)’ 
To limit risk of exposure in 
participants weighing 
<45 kg, or participant with 
moderate or severe hepatic 
impairment. 
2.3.3 Overall benefit/risk 
conclusion 
Added details from 6-month rat studies. Overall benefit/risk 
conclusion updated. 
To add more clarity. 
3.1.1 Measurement for efficacy 
assessment 
The following sentence was updated from ‘Due to the known 
fluctuation in EDSS scores, CDP confirmed after 3 or 6 months is 
used as an endpoint in clinical trials of progressive MS.’ 
To 
‘Due to the known fluctuation in EDSS scores, CDP confirmed after 
12 and 24 weeks is used as an endpoint in clinical trials of 
progressive MS’ 
To add consistency 
4.1 Overall design 
The following sentence was updated and included “up to”.  
‘Participants who discontinue the treatment or choose not to enter 
Part B will have their early discontinuation or safety follow-up visit, 
respectively, up to 2 weeks after the last dose of IMP.’ 
To clarify timing of safety 
follow up visit (within 
2 weeks of discontinuation) 
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Section # and Name 
Description of Change 
Brief Rationale 
4.3 Justification for dose 
Justification of dose was update in line with rat study and non-human 
primates toxicology study. 
To add clarification. 
5.1 Inclusion criteria 
6.8 Concomitant therapy 
Inclusion criterion ‘I 04’ and concomitant therapy details were 
updated to include allowed DTMs.  
‘I 04’ was updated from: ‘Participants who in the opinion of the 
Investigator are stable on their DMT (past 3 months) AND do not 
require a change in MS treatment for the duration of Part A (through 
Week 48).’ 
To: 
‘Participants who are either untreated or in the opinion of the 
Investigator are stable on an allowed DMT (interferons, glatiramer 
acetate, fumarates, or teriflunomide) for at least the past 3 months, 
AND not anticipated to require a change in MS treatment for the 
duration of Part A and Part B (through Week 96; in Part B changes in 
dose of allowed DMTs or transition to other allowed DMTs is 
permitted)’ 
To add clarification for 
allowed DMT and to add 
duration of Part B 
5.2 Exclusion criteria 
New exclusion criterion ‘E 01’ was added: ‘Participants with 
immunodeficiency syndromes or other autoimmune diseases 
requiring immunosuppressive therapy.’ 
Added to limit enrollment of 
patients with potential 
higher risk of infections.  
Exclusion criterion ‘E 03’ was updated to replace “study enrollment” 
with “screening”. 
 
To align with DMT stability 
and ensure demonstration 
of relapse-free requirement 
Exclusion criterion ‘E 12’ was updated. 
 
To add clarification for the 
prohibited medications/ 
treatments washout period. 
5.2 Exclusion criteria 
Added following new exclusion criterion: 
‘E 24: Participant is under tutorship or curatorship; participant under 
safeguard of justice or deprived of his/her liberty by a court decision’ 
and 25 added’ 
‘E 25 Participant is unable to provide informed consent’ 
Added to ensure all 
enrolled patients are 
capable of providing 
informed consent. 
6.3 Measures to minimize bias: 
Randomization and blinding 
The following sentence was updated to add “or before if clinically 
required” 
‘In addition, in accordance with standard clinical practice, during the 
blinded intervention period, the Treating Investigator can access MRI 
reports once a year starting at Month 12, or before if clinically 
required, through the local radiologist.’ 
To add more clarity. 
6.7 Treatment of overdose 
Overdose definition updated to “overdose is defined as at least 
40 mg IMP within 24 hours.” 
To align with once daily 
dosing 
6.8 Concomitant therapy 
i
i
i
” 
To add clarification around 
strong or moderate 
inhibitors or strong inducers 
of CYP3A4. 
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Section # and Name 
Description of Change 
Brief Rationale 
7.1.1 Permanent 
discontinuation 
Update the following paragraph from: “The study intervention should 
be continued whenever possible. In rare instances, it may be 
necessary for a participant to permanently discontinue study 
intervention.”  
To  
“Compliance with and continuation of the study intervention is 
encouraged, while maintaining the safety of study participants and 
the integrity of the study. In certain instances, it may be medically 
necessary for a participant to permanently discontinue study 
intervention.” 
To add clarification. 
The following sentence was updated to add ‘Part B’: “Noncompliance 
with the protocol, dosing regimen and visits including switching DMT 
or taking a prohibited DMT in Part A” 
To add clarification. 
7.2 Participant 
discontinuation/withdrawal from 
the study 
Removed following text “This is expected to be uncommon.” From 
sentence ‘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 or compliance 
reasons.’ 
Added text “For Part A and Part B” to the following sentence: ‘For 
Part A and Part B, if a participant no longer wishes to take the IMP, 
they will be encouraged to remain in the study or to attend a safety 
follow-up visit within 2 weeks following discontinuation of IMP.’ 
To add more clarity. 
8.1.3 Magnetic resonance 
imaging 
The following text was added “according to local labeling 
requirements”. 
The following text was added: “Baseline MRI scans may be 
conducted as early as 5 to 7 days prior to first dose, but must be 
completed after all other screening activities have been completed, 
and none are deemed exclusionary.” 
To add more clarity 
8.2.6 Pregnancy testing 
The following text was added “Results should not be older than 
24 hours upon intake of first dose of IMP.” 
To add more clarity 
8.3.9 Adverse events of special 
interest 
“
 mg” replaced with “
 mg” and “12 hours” replaced with 
“24 hours” 
To align with overdose 
definition 
8.6 Biomarkers 
Added alternative name of CH13L1 as ‘YKL40’. 
To add more clarity 
9.2.1 General consideration  
“on-treatment period” was updated to add ‘+1 day’. 
Updated for consistency 
9.2.2 2 Part B 
Updated primary endpoint analyses of Part B: durability of sNfL. 
To add clarity, statistical 
methods for primary 
endpoint analyses of Part B 
updated. 
9.2.6.1 Adverse events 
The following text was added “all TEAEs leading to death.” in 
sentence “An AE incidence table will be provided by treatment group 
for all types of TEAEs: all TEAEs, all treatment-emergent AESI 
(defined with a preferred term [PT] or a prespecified grouping), all 
treatment-emergent SAEs, all TEAEs leading to permanent 
treatment discontinuation, and all TEAEs leading to death.” 
Updated to include all 
TEAEs leading to death  
9.4 Sample size determination 
Anticipated dropout rate was changed from 20% to 17%. 
To align with the sample 
size of 168 participants 
10.2 Appendix 2 clinical 
laboratory tests 
Table 8 was updated to include “except local urine pregnancy test 
and urinalysis” 
To add more clarity 
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Section # and Name 
Description of Change 
Brief Rationale 
10.4.2 Contraception guidance 
Updated contraceptive requirements for male and female 
participants. 
To align appendix 
contraceptive requirements 
with Inclusion criterion 
‘I 06’. 
11 References 
‘Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an 
expanded disability status scale (EDSS). Neurology. 
1983;33(11):1444-52’  
was replaced with 
‘Standardised Neurological Examination and Assessment of 
Kurtzke’s Functional Systems and Expanded Disability Status Scale 
Slightly modified from J.F. Kurtzke, Neurology 1983:33,1444-
52©2011 Ludwig Kappos, MD, Neurology, University Hospital Basel, 
4031 Basel, Switzerland; Version 04/10.2’ 
Update 
Throughout 
Minor editorial, typographical error corrections and document 
formatting revisions 
Minor, therefore have not 
been summarized. 
10.12.2 Amended protocol 02 (19 May 2023)  
This amended protocol (amendment 02) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
Overall rationale for the amendment 
The main purpose of the protocol amendment 02 is to add four visits (Week 4, 9 and 16 in Part A 
and Week 56 in Part B) for liver chemistry monitoring at each visit. 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of change 
Brief rationale 
1.2 SCHEMA 
1.3.1 Part A 
1.3.2 Part B 
4.1 OVERALL 
DESIGN 
Added site visits including a liver chemistry test on Week 4, 
Week 9 and Week 16 in Part A and Week 56 visit in Part B 
respectively. Added instructions on sample collecting, testing and 
results reporting at Week 4, 9, 16 and Week 56 visit. Updated the 
study schema to add Week 4, 9 and 16 visit and Week 56 visit. 
Week 60 visit in Part B changed from phone visit to on site visit. 
Increase liver chemistry monitoring 
as related to a Suspected 
Unexpected Serious Adverse 
Reaction (SUSAR) case of ALT 
and bilirubin increase in another 
Phase 2 study (ACT16970) testing 
20 mg BID SAR443820 in patients 
with amyotrophic lateral sclerosis. 
8 STUDY 
ASSESSMENTS 
AND 
PROCEDURES 
The following text was added as a bullet: 
“If onsite visits are not feasible (due to disease progression, 
increased monitoring for AE follow-up, etc.) for visits that require 
sample collection only (Week 4, Week 9, Week 16, Week 56 or 
Week 60 visits), remote visits (eg, with home nurses, a home 
health vendor, etc.) may be planned for sample collection, only if 
the service is put in place in the country in which the study is 
being conducted.” 
To provide flexibility of assessment 
when it is not feasible for 
participants to conduct site visits. 
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Section # and 
Name 
Description of change 
Brief rationale 
10.6 APPENDIX 6: 
LIVER AND 
OTHER SAFETY: 
SUGGESTED 
ACTIONS AND 
FOLLOW UP 
ASSESSMENTS 
AND STUDY 
INTERVENTION 
RECHALLENGE 
GUIDELINES 
Updated the appendix heading from: 
“Appendix 6: Liver and other Safety: Suggested Actions and 
Follow Up Assessments and Study Intervention Rechallenge 
Guidelines” 
To: 
“Appendix 6: Liver and other Safety: Actions and Follow Up 
Assessments and Study Intervention Restart/Rechallenge” 
To clarify that it is required to follow 
the procedure described in this 
appendix. 
The following text added: 
“These actions are required for ALT increase events ONLY. For 
all other safety events described, these are suggested per the 
Investigator’s medical judgement.” 
Updated the algorithm graphical chart with increased frequency 
of ALT monitoring after ALT increase and updated the guidance 
text. 
To ensure all listed tests for 
etiology analysis of ALT increase 
will be conducted and to increase 
the frequency of liver function 
monitoring after ALT increase. 
10.8 APPENDIX 8: 
COUNTRY-
SPECIFIC/REGION 
REQUIREMENTS 
Section title changed from: 
“APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS” 
to: 
“APPENDIX 8: COUNTRY-SPECIFIC/REGION 
REQUIREMENTS” 
To be compliant with Sanofi 
standards. 
10.8.2 Germany 
A new section added to define informed consent procedures for 
Germany. 
To be compliant with Sanofi 
standards. 
10.8.2 Germany 
The following text added: 
“Informed consent process: All references to "legally authorized 
representative" are not applicable in Germany; only participants 
who can give written consent themselves are included in the 
study. References to "legally authorized representative" are 
found in Section 8.3 and Section 10.1.3. 
German participant continuation into Part B will be contingent on 
local ethics committee acknowledgment of recommendation from 
global study Data Safety Monitoring Committee and continued 
approval. The Sponsor will provide these documents in sufficient 
time to limit any disruption to the participation of German 
enrollees and their transition into the Part Open label extension 
phase.” 
Added as requested by German 
ethic committee. 
10.12 APPENDIX 
12: PROTOCOL 
AMENDMENT 
HISTORY 
Summary of changes table for amendment 01 is moved to 
appendix 12. 
To describe the protocol 
amendment history.  
Throughout 
Minor editorial, typographical error corrections and document 
formatting revisions 
Minor, therefore have not been 
summarized. 
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10.12.3 
Amended protocol 03 (06 July 2023)  
This amended protocol (amendment 03) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
Overall rationale for the amendment 
The main purpose of the protocol amendment 03 is to clarify exclusion of participants with a 
history of alcohol abuse and to limit consumption of alcohol during the course of the study. 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of change 
Brief rationale 
5.2 Exclusion 
criteria 
Specifying exclusion of participants with history of alcohol abuse 
Minimize the risk of liver injury 
caused by history of alcohol 
dependence/abuse  
5.3.2 Lifestyle 
considerations, 
caffeine, alcohol 
and tobacco 
Limit for daily consumption of alcohol while in the study 
Minimize exposure to alcohol 
during the study, to not exacerbate 
potential liver injury risks of 
SAR443820 
10.12 Appendix 12: 
Protocol 
amendment history 
Updated to reflect current amended protocol. 
Update. 
Throughout 
Minor editorial, typographical error corrections and document 
formatting revisions. Updates according to Sponsor’s style guide. 
Minor, therefore have not been 
summarized. 
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11 
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