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

Phase 3

Recruiting

• Conditions: Relapsing Multiple Sclerosis; Secondary Progressive Multiple Sclerosis; Progressive Relapsing Multiple Sclerosis
• Interventions: Drug: Tolebrutinib; Drug: Placebo; Drug: Teriflunomide

• Registration Number: NCT06372145
• Lead Sponsor: Sanofi

Brief Summary

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

Detailed Description

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.

Study Timeline

• Study First Submitted: 2024-04-15
• Study First Submitted QC: 2024-04-15
• Study Start: 2024-04-16
• Study First Posted: 2024-04-17
• Status Verified: 2025-07
• Last Update Submitted: 2025-07-04
• Last Update Posted: 2025-07-08
• Primary Completion: 2029-04-30
• Study Completion: 2029-04-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 2500

Inclusion Criteria

• Participants with RMS, PPMS, or NRSPMS who completed the Phase 2b LTS (LTS16004) or 1 of the 4 Phase 3 pivotal tolebrutinib trials (EFC16033, EFC16034, EFC16645, EFC16035) on IMP.

OR

• The Phase 2b LTS (LTS16004) or Phase 3 tolebrutinib pivotal trial participants who temporarily discontinued IMP due to a national emergency and completed the trial visits.

ToleDYNAMIC Substudy: Inclusion criteria are those of the main study

Exclusion Criteria

• Participants are excluded from the study if any of the following criteria apply:
• The participant is at risk for or has a persistent chronic, active (including fever higher than 38°C and clinically unstable), or recurring systemic infection, as judged by the Investigator
• For participants initiating OL tolebrutinib in the LTS17043 study: Participants at risk of developing or having reactivation of hepatitis, ie, results at the unblinding visit (RMS) or opt-in visit (PMS) for serological markers for hepatitis B and C viruses indicating acute or chronic infection
• Active alcohol use disorder or a history of alcohol or drug abuse within 1 year prior to the opt-in visit
• Current alcohol intake equal to or exceeding the following at the opt-in visit: more than 2 drinks per day for men and more than 1 drink per day for women
• Abnormal ECG during the opt-in visit considered in the Investigator's judgment to be clinically significant, such as QTcF >500 msec, in the context of this study.
• A bleeding disorder, known platelet dysfunction, abnormal platelet count (<100,000/microliter), history of significant bleeding event or other conditions and planned procedures that may predispose the participant to excessive bleeding during the study, as judged by the Investigator.
• For participants initiating OL tolebrutinib in the LTS17043 study: Confirmed unblinding visit (RMS) or opt-in visit (PMS) alanine aminotransferase (ALT) more than 1.5 × upper limit of normal (ULN) OR aspartate aminotransferase (AST) more than 1.5 × ULN OR alkaline phosphatase more than 2 × ULN (unless caused by non-liver-related disorder or explained by a stable chronic liver disorder) OR total bilirubin more than 1.5 × ULN (unless due to Gilbert syndrome or non-liver-related disorder).
• Acute liver disease, cirrhosis, chronic liver disease (unless considered stable for more than 6 months).
• Participants who developed clinically relevant cardiovascular, hepatic, endocrine, neuropsychiatric or other major systemic disease making implementation of the protocol or interpretation of the trial results difficult or that would put the patient at risk by participating in the trial, as judged by the Investigator.
• The participant is receiving treatment during the study period with drugs not permitted by the study protocol, including potent and moderate inducers of cytochrome P450 (CYP) 3A or potent inhibitors of CYP2C8 hepatic enzymes.

NOTE: The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

ToleDYNAMIC Substudy: Exclusion criteria are those of the main study

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Tolebrutinib	Tolebrutinib	* 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.
Tolebrutinib	Placebo	* 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.
Teriflunomide	Placebo	* 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.
Teriflunomide	Teriflunomide	* 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.

Primary Outcome Measures

Name	Time	Method
Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESIs) and AEs leading to permanent study intervention discontinuation	From baseline until the End of study approximately 3 years per participant
Number of Participants with Potentially clinically significant abnormalities (PCSAs)	From baseline until the End of study approximately 3 years per participant	Potentially clinically significant abnormalities (PCSAs) determined by laboratory tests, electrocardiogram (ECG), or vital signs and safety findings on MRI during the study period.

Secondary Outcome Measures

Name	Time	Method
Number of new and/or enlarging T2-hyperintense lesions per year	From baseline until the End of study approximately 3 years per participant
Change from baseline in total volume of T2-hyperintense lesions	From baseline until the End of study approximately 3 years per participant
Time to onset of 6-month confirmed disability worsening (CDW for RMS) or confirmed disability progression (CDP for PPMS and NRSPMS) for participants from pivotal studies	From baseline until the End of study approximately 3 years per participant	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
Annualized Relapse Rate (ARR) for RMS only	From baseline until the End of study approximately 3 years per participant	ARR during the OL treatment period assessed by confirmed protocol-defined relapses
ToleDYNAMIC substudy Change from baseline in biomarkers	From baseline until 12 months per participant

Trial Locations

Locations (314)

University of Alabama at Birmingham- Site Number : 8400013; 🇺🇸 Birmingham, Alabama, United States

North Central Neurology Associates- Site Number : 8400009; 🇺🇸 Cullman, Alabama, United States

Center for Neurology and Spine - Phoenix - North 32nd Street- Site Number : 8400089; 🇺🇸 Phoenix, Arizona, United States

University of California San Diego - La Jolla- Site Number : 8400101; 🇺🇸 La Jolla, California, United States

Collaborative Neuroscience Research- Site Number : 8400045; 🇺🇸 Los Alamitos, California, United States

Keck School of Medicine of University of Southern California- Site Number : 8400143; 🇺🇸 Los Angeles, California, United States

Private Practice - Dr. Regina Berkovich- Site Number : 8400059; 🇺🇸 West Hollywood, California, United States

University of Colorado- Site Number : 8400012; 🇺🇸 Denver, Colorado, United States

Advanced Neurology of Colorado- Site Number : 8400025; 🇺🇸 Fort Collins, Colorado, United States

MedStar Georgetown University Hospital- Site Number : 8400119; 🇺🇸 Washington, District of Columbia, United States

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