Relapsing Forms of Multiple Sclerosis (RMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (GEMINI 2)

A Phase 3, Randomized, Double-blind Efficacy and Safety Study Comparing SAR442168 to Teriflunomide (Aubagio®) in Participants With Relapsing Forms of Multiple Sclerosis

Primary Objective:

To assess efficacy of daily SAR442168 compared to a daily dose of 14 mg teriflunomide (Aubagio) measured by annualized adjudicated relapse rate (ARR) in participants with relapsing forms of MS

Secondary Objective:

To assess efficacy of SAR442168 compared to teriflunomide (Aubagio) on disability progression, MRI lesions, cognitive performance and quality of life To evaluate the safety and tolerability of daily SAR442168 To evaluate pharmacodynamics (PD) of SAR442168

Study duration varied per participant in this event driven trial with a treatment duration of approximately 18 to 36 months. Participants completing the study were offered to participate in a long term safety study.

Inclusion criteria :

• The participant must be 18 to 55 years of age, inclusive, at the time of signing the informed consent

• The participant must have been diagnosed with RMS according to the 2017 revision of the McDonald diagnostic criteria

• The participant has an expanded disability status scale (EDSS) score ≤5.5 at the first Screening Visit

• The participant must have at least 1 of the following prior to screening:

  • ≥1 documented relapse within the previous year OR
  • ≥2 documented relapses within the previous 2 years, OR
  • ≥1 documented Gd enhancing lesion on an MRI scan within the previous year

• Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies

• Male participants are eligible to participate if they agree to the following during the intervention period and until accelerated elimination procedure:

  • Refrain from donating 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 as detailed below

• Agree to use a male condom and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak when having sexual intercourse with a woman of childbearing potential (WOCBP) who is not currently pregnant

  - A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions apply:

• Is not a WOCBP OR

• Is a WOCBP and agrees to use a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user dependency during the intervention period and until accelerated elimination procedure is completed (or for at least 10 days after the last dose of SAR442168, if the case was unblinded) and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during the study and for the same period of time.

  • A WOCBP must have a negative highly sensitive pregnancy test at screening and within 24hours before the first dose of study intervention.
  • If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
  • The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
  • The participant must have given written informed consent prior to undertaking any study related procedure. This includes consent to comply with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. In countries where the legal age of maturity is greater than 18 years, a specific ICF for such legally minor participants must also be signed by the participant's legally authorized representative

Exclusion criteria:

• The participant has been diagnosed with primary progressive multiplesclerosis (PPMS) according to the 2017 revision of the McDonald diagnostic criteria or with nonrelapsing secondary progressive multiplesclerosis (SPMS)

• The participant has a history of infection or may be at risk for infection including but not limited to: HIV, transplantation, live attenuated vaccines, progressive multifocal leukoencephalopathy, tuberculosis, hepatitis B or C, any persistent chronic or active recurring infection

• Clinically significant laboratory abnormalities (including evidence of liver injury) or electrocardiogram abnormalities at Screening.

• The participant has conditions or situations that would adversely affect participation in this study, including but not limited to:

  • A short life expectancy due to pre-existing health condition(s) as determined by their treating neurologist
  • Medical condition(s) or concomitant disease(s) making them nonevaluable for the primary efficacy endpoint or that would adversely affect participation in this study, as judged by the Investigator
  • A requirement for concomitant treatment that could bias the primary evaluation

• The participant has a history of or currently has concomitant medical or clinical conditions that would adversely affect participation in this study

• At screening, the participant is positive for hepatitis B surface antigen and/or hepatitis B core antibody and/or is positive for hepatitis C antibody

• The participant has any of the following:

  • A bleeding disorder or known platelet dysfunction at any time prior to the screening visit
  • A platelet count <150 000/μL at the screening visit

• The participant has a lymphocyte count below the lower limit of normal (LLN) at the screening visit

• The presence of psychiatric disturbance or substance abuse

• Prior/concomitant therapy

• The participant is receiving potent and moderate inducers of cytochrome P450 (CYP) 3A or potent inhibitors of CYP2C8 hepatic enzymes

• The participant is receiving anticoagulant/antiplatelet therapies

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