Phase 3 Extension Study on Long-term Safety and Tolerability of Tolebrutinib in Relapsing and Progressive Multiple Sclerosis

The primary objective of this study is to determine the long-term **safety** and tolerability of tolebrutinib in participants with **relapsing multiple sclerosis** (RMS) and **progressive multiple sclerosis** (PMS). This is clinically relevant as it aims to ensure that tolebrutinib, a potential therapeutic agent, can be safely administered over an extended period, which is crucial for chronic conditions like multiple sclerosis where long-term treatment is often necessary.

Secondary objectives include assessing the long-term efficacy of open-label tolebrutinib on:

• Disability progression in participants with RMS and PMS.
• Relapse rate, specifically in participants with RMS.
• Magnetic resonance imaging (MRI) parameters in participants with RMS and PMS.

The clinical trial involves a total of **1261 participants** diagnosed with **nervous system diseases**, specifically focusing on individuals with **relapsing multiple sclerosis (RMS)** and **progressive multiple sclerosis (PMS)**. The study population includes both male and female subjects, with an age range that spans from young adults to older adults, categorized under age groups 3 and 4. Participants were selected based on their completion of previous Phase 2b or Phase 3 tolebrutinib trials, or those who temporarily discontinued due to a national emergency but completed trial visits. The trial includes a vulnerable population, indicating that special considerations are in place to ensure their safety and well-being. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data. The primary objective of the study is to assess the long-term safety and tolerability of tolebrutinib in this specific patient population.

The clinical trial is designed to evaluate the long-term safety and tolerability of **tolebrutinib** in participants with relapsing multiple sclerosis (RMS), primary progressive multiple sclerosis (PPMS), or nonrelapsing secondary progressive multiple sclerosis (NRSPMS). This is a Phase 3 extension study, employing a randomized, double-blind, controlled trial design. The trial is expected to last until August 2029, with recruitment starting in April 2024. Participants will be involved for a maximum treatment period of 36 months, depending on their specific condition and response to the treatment.

Study visits are structured to ensure comprehensive monitoring and data collection. The inclusion visit, or screening visit, will determine participant eligibility based on criteria such as completion of previous related trials or temporary discontinuation due to national emergencies. Follow-up visits will occur regularly to assess the primary endpoints, which include the number of participants experiencing adverse events, serious adverse events, and adverse events leading to permanent study intervention discontinuation. Secondary endpoints will evaluate the time to onset of confirmed disability worsening or progression, annualized relapse rate for RMS, and changes in T2-hyperintense lesions.

The end-of-study visit will conclude the participant's involvement, ensuring all necessary data is collected and any final assessments are completed. Participants may be terminated early from the study if they experience significant adverse events, fail to comply with study protocols, or withdraw consent. The trial aims to provide valuable insights into the long-term effects of tolebrutinib, contributing to the understanding and management of multiple sclerosis.

The clinical trial involves the administration of **Tolebrutinib**, an experimental medication, in the form of a film-coated tablet. Tolebrutinib is administered orally with a maximum daily dose of 60 mg. The treatment period for Tolebrutinib extends up to 36 months. This investigational drug is a chemical compound developed by Sanofi Aventis Recherche et Développement (SAR) and is identified by the sponsor product code SAR442168. Participant compliance with the dosing schedule is monitored throughout the study.

**AUBAGIO 14 mg film-coated tablets**, containing the active substance **Teriflunomide**, serve as a comparator treatment in the study. This medication is also administered orally with a maximum daily dose of 14 mg, and the treatment duration is up to 36 months. Teriflunomide is a chemical compound produced by Sanofi Winthrop Industrie.

The study includes the use of a **Matched Placebo to Test** and a **Matched Placebo for Comparator Teriflunomide**. These placebos are designed to match the appearance and administration route of the active treatments but do not contain any active pharmaceutical ingredients. The use of placebos helps to maintain blinding and assess the efficacy and safety of the experimental and comparator treatments.

**Anhydrous Cholestyramine** is utilized as an auxiliary treatment in the trial. It is a bile acid sequestrant administered orally. The pharmaceutical form is identified as PHF00169MIG, and it is classified under the ATC code C10AC01. The maximum treatment period for this auxiliary treatment is 1 month.

Another auxiliary treatment involves the use of **Magnetic Resonance Imaging Contrast Media**. This substance is administered as a solution for injection and is classified under the ATC code V08C. The contrast media is used to enhance imaging results during the trial, with a maximum treatment period of 1 month.

Additionally, an unspecified **Intestinal Adsorbent** is included as an auxiliary treatment. It is administered orally, with a pharmaceutical form identified as PHF00005MIG, and is classified under the ATC code A07B. The maximum treatment period for this auxiliary treatment is 1 month.

Efficacy in this clinical trial will be assessed using several secondary endpoints. These include the time to onset of 6-month confirmed disability worsening (CDW) for participants with relapsing multiple sclerosis (RMS) or confirmed disability progression (CDP) for those with primary progressive multiple sclerosis (PPMS) and nonrelapsing secondary progressive multiple sclerosis (NRSPMS). Additionally, the **Annualized Relapse Rate (ARR)** will be evaluated for RMS participants. The number of new and/or enlarging T2-hyperintense lesions per year will also be measured, along with changes from baseline in the total volume of T2-hyperintense lesions. For the ToleDYNAMIC substudy, changes from baseline in biomarkers will be assessed.

The collection and analysis of these efficacy parameters will be conducted at specified intervals throughout the trial. The methods for measuring these endpoints will include imaging techniques to evaluate T2-hyperintense lesions and validated scales for assessing disability progression and relapse rates. The schedule for these assessments will align with the trial's protocol, ensuring consistent and reliable data collection to evaluate the efficacy of the investigational product, tolebrutinib, in the specified patient populations.