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Immunologic Factors

* Participants will receive OL tolebrunitib 60 mg once daily.
* RMS participants who are not eligible for OL tolebrutinib per Health Authority and/or ethics committee decisions on the study conduct (ie, partial hold on initiation of tolebrutinib) will continue their parent study treatment assignment as per their randomization from the parent study.

* participants will receive teriflunomide 14 mg daily
* RMS participants who are not eligible for OL tolebrutinib per Health Authority and/or ethics committee decisions on the study conduct (ie, partial hold on initiation of tolebrutinib) will continue their parent study treatment assignment (either tolebrutinib or teriflunomide) as per their randomization from the parent study. If unblinded to teriflunomide parent study treatment assignment, these RMS participants will continue teriflunomide in the LTS17043 study.

Pharmaceutical form:Tablet-Route of administration:oral

Tolebrutinib

Placebo

Trial Transparency email recommended (Toll free for US & Canada)

This is a Phase 3 extension, global, multicenter study to assess the long-term safety and tolerability of tolebrutinib in adult participants (aged ≥18 years) with RMS, PPMS, or NRSPMS who were previously enrolled in the Phase 2b LTS (LTS16004) or 1 of the 4 Phase 3 tolebrutinib pivotal trials (GEMINI 1 \[EFC16033\], GEMINI 2 \[EFC16034\], HERCULES \[EFC16645\], or PERSEUS \[EFC16035\]).

SUBSTUDY: ToleDYNAMIC substudy

Participants with relapsing MS from the Phase 2b LTS16004 parent study will continue open-label (OL) tolebrutinib.

All participants from the Phase 3 parent studies (EFC16033, EFC16034, EFC16645, and EFC16035) will learn which treatment they received in the parent study:

* If from one of the Phase 3 relapsing MS studies and on teriflunomide, an accelerated elimination procedure or a 3-month washout period is required prior to starting OL tolebrutinib. If on teriflunomide, and benefiting and recommended by the Investigator, the participant may opt to continue teriflunomide outside of the LTS17043 study, if clinically appropriate. If on tolebrutinib, the participant will continue tolebrutinib.
* All participants from one of the Phase 3 progressive MS studies will start OL tolebrutinib.
* If a participant already started OL tolebrutinib in the Phase 3 parent study this will be continued.
* RMS participants who are not eligible for OL tolebrutinib per Health Authority and/or ethics committee decisions on the study conduct (ie, partial hold on initiation of tolebrutinib) will continue their parent study treatment assignment as per their randomization from the parent study.

The treatment duration per participant will be approximately 3 years of OL tolebrutinib.

A Study to Investigate Long-term Safety and Tolerability of Tolebrutinib in Participants With Multiple Sclerosis.

An Interventional, Phase 3 Extension Study to Investigate Long-term Safety and Tolerability of Tolebrutinib in Participants With Relapsing Multiple Sclerosis, Primary Progressive Multiple Sclerosis, or Nonrelapsing Secondary Progressive Multiple Sclerosis

Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

Potentially clinically significant abnormalities (PCSAs) determined by laboratory tests, electrocardiogram (ECG), or vital signs and safety findings on MRI during the study period.

Time to onset is defined as a sustained increase from baseline EDSS (pivotal trial) of:

* RMS: ≥1.5 points when the baseline score is 0, ≥1.0 point when the baseline score is 0.5 to ≤5.5 or ≥0.5 point when the baseline score is \>5.5
* PPMS: ≥1.0 point when the baseline score is ≤5.5 or ≥0.5 point when the baseline score is \>5.5
* NRSPMS: ≥1.0 point when the baseline score is ≤5.0 or ≥0.5 point when the baseline score is \>5.0

ARR during the OL treatment period assessed by confirmed protocol-defined relapses

Sanofi

Amino Acids

Tyrosine

Placebo tablet to match SAR442168 once daily

Pharmaceutical form: Film-coated tablet Route of administration: Oral

Placebo to match Tolebrutinib

Clinical Sciences & Operations

Primary Objective:

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

Secondary Objective:

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

Study duration will vary per participant in this event driven trial with a treatment duration of approximately 24 to 48 months.

Participants completing the treatment period will be proposed to enroll in a separate long term safety study.

Nonrelapsing Secondary Progressive Multiple Sclerosis (NRSPMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168)

A Phase 3, Randomized, Double-blind, Efficacy and Safety Study Comparing SAR442168 to Placebo in Participants With Nonrelapsing Secondary Progressive Multiple Sclerosis

Time to onset of 6 months CDP defined as follows:

-Increase of ≥1.0 point from the baseline expanded disability status scale (EDSS) score when the baseline score is ≤5.0, or -Increase of ≥0.5 point when the baseline EDSS score is \>5.0 -

Time to onset of composite CDP, confirmed over at least 3 months (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 hole peg test (9 HPT)

Time to onset of 3-month CDP as assessed by EDSS score

Total number of new or enlarging T2 hyperintense lesions as detected by MRI

Time to CDI defined as ≥1.0 point decrease on the EDSS score from baseline confirmed over at least 6 months

Percent change in Brain volume loss (BVL) as detected by brain MRI at the EOS compared to month 6

Change in cognitive function at the EOS compared to baseline as assessed by the Symbol Digit Modalities Test (SDMT) and by the California Verbal Learning Test (CVLT-II)

Change in Multiple Sclerosis Quality of Life-54 (MSQoL-54) from the baseline through the EOS

Number of participants with adverse events (AEs), Serious AEs, AEs leading to permanent study intervention discontinuation, and adverse events of special interest (AESI)

Plasma concentration of SAR442168 and relevant metabolites (population PK assessment) at Months 6, 9, and 12

Change in NfL levels at the EOS compared to baseline

Changes in serum Immunoglobulin level at the EOS compared to baseline

Change in lymphocyte phenotype subsets in whole blood at the EOS compared to baseline in a subset of participants

Change in serum chitinase-3 like protein 1 (Chi3L1) at the EOS compared to baseline

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study to Investigate Long-term Safety and Tolerability of Tolebrutinib in Participants With Multiple Sclerosis.	NCT06372145	Relapsing Multi... Secondary Progr... Progressive Rel...	Tolebrutinib Placebo Teriflunomide	18 Years -	Sanofi
Nonrelapsing Secondary Progressive Multiple Sclerosis (NRSPMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168)	NCT04411641	Secondary Progr...	Tolebrutinib Placebo to matc...	18 Years - 60 Years	Sanofi
A Study to Investigate Long-term Safety and Tolerability of Tolebrutinib in Participants With Multiple Sclerosis.	NCT06372145	Relapsing Multi... Secondary Progr... Progressive Rel...	Tolebrutinib Placebo Teriflunomide	18 Years -	Sanofi

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