Efficacy and Safety of Tolebrutinib in Primary Progressive Multiple Sclerosis: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to determine the **efficacy** of SAR442168, also known as tolebrutinib, compared to placebo in delaying disability progression in individuals with **Primary Progressive Multiple Sclerosis (PPMS)**. This is clinically relevant as PPMS is a form of multiple sclerosis characterized by a steady progression of neurological disability, and effective treatments are limited. Evaluating the ability of SAR442168 to slow this progression could provide a significant therapeutic advancement for patients with PPMS.

Secondary objectives include:

• Evaluating the efficacy of SAR442168 compared to placebo on clinical endpoints, magnetic resonance imaging (MRI) lesions, cognitive performance, physical function, and quality of life.
• Assessing the safety and tolerability of SAR442168.
• Evaluating the population pharmacokinetics (PK) of SAR442168 in PPMS and its relationship to efficacy and safety.
• Assessing the pharmacodynamics of SAR442168.

The clinical trial involves a total of **384 participants** diagnosed with **Primary Progressive Multiple Sclerosis** (PPMS). The study population includes both male and female subjects, aged between **18 to 55 years**. Participants were selected based on specific criteria, including a diagnosis of PPMS according to the 2017 McDonald criteria and an Expanded Disability Status Scale (EDSS) score ranging from 2.0 to 6.5 points. The trial does not involve a vulnerable population. Participants are required to have positive cerebrospinal fluid oligoclonal bands and/or an elevated Immunoglobulin G (IgG) index. Lifestyle considerations such as contraceptive use consistent with local regulations are noted, and participants must not be pregnant or breastfeeding. Additionally, participants must not have access to ocrelizumab or must have experienced intolerance or lack of efficacy with ocrelizumab treatment. The trial aims to evaluate the efficacy of SAR442168 compared to placebo in delaying disability progression in individuals with PPMS.

The clinical trial is designed as a **randomized, double-blind, controlled** study to evaluate the efficacy and safety of **Tolebrutinib** compared to placebo in participants with **Primary Progressive Multiple Sclerosis** (PPMS). The primary objective is to determine the efficacy of Tolebrutinib in delaying disability progression. The trial is expected to last until June 2025, with recruitment having commenced in November 2020. Participants will be involved in the study for a maximum treatment period of 60 days, with a daily dose of 60 mg administered orally in the form of film-coated tablets.

The study includes several key visits: an initial **screening visit** to confirm eligibility based on criteria such as age (18 to 55 years), diagnosis of PPMS according to the 2017 McDonald criteria, and specific **Expanded Disability Status Scale** (EDSS) scores. Participants must also have positive cerebrospinal fluid oligoclonal bands or an elevated Immunoglobulin G (IgG) index. Follow-up visits will be scheduled to monitor the primary endpoint of 6-month composite Confirmed Disability Progression (cCDP) and secondary endpoints, including changes in T2 hyperintense lesions by MRI, brain volume, cognitive function, and safety assessments. The **end-of-study visit** will conclude the participant's involvement, assessing the overall outcomes and any adverse events.

Participants may be withdrawn from the study if they do not adhere to the protocol, experience significant adverse effects, or if the study is terminated early for any reason. The trial is not categorized as low intervention, and it is conducted under strict regulatory compliance to ensure the integrity and reliability of the data collected. The study's design and procedures are structured to provide robust evidence on the potential benefits of Tolebrutinib in managing PPMS, contributing valuable insights into its therapeutic profile.

The clinical trial involves the administration of **Tolebrutinib**, an experimental medication, to evaluate its efficacy and safety in participants with primary progressive multiple sclerosis. **Tolebrutinib** is provided in the form of a film-coated tablet, with each tablet containing the active substance **tolebrutinib**. The medication is administered orally, with a maximum daily dose of 60 mg. The treatment period for each participant is set to a maximum of 60 days. The pharmaceutical formulation is developed by Sanofi Aventis Recherche et Développement (SAR), and the product is identified by the sponsor product code SAR442168. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

In addition to the experimental treatment, a **placebo** is used as a comparator in this double-blind study. The placebo consists of **mannitol and microcrystalline cellulose**, which are inactive substances. The placebo is also administered orally in a form that mimics the appearance and administration route of the active treatment, ensuring blinding of both participants and investigators. The placebo is utilized to assess the efficacy of **Tolebrutinib** by providing a baseline for comparison in terms of disability progression in participants with primary progressive multiple sclerosis.

The efficacy of SAR442168 in the treatment of **Primary Progressive Multiple Sclerosis (PPMS)** will be assessed through a series of primary and secondary endpoints. The primary endpoint is the 6-month composite Confirmed Disability Progression (cCDP). Secondary endpoints include the 6-month Confirmed Disability Progression (CDP), 3-month composite Confirmed Disability Progression (cCDP), changes in T2 hyperintense lesions as measured by MRI, time to onset of confirmed disability improvement (CDI), percent change in brain volume (BV), and changes in cognitive function assessed by the Symbol Digit Modalities Test (SDMT) and the California Verbal Learning Test-II (CVLT-II). Additional secondary endpoints involve changes in Multiple Sclerosis Quality of Life, safety and tolerability, population pharmacokinetics, changes in plasma neurofilament light chain (NfL), lymphocyte phenotype subsets, serum immunoglobulin levels, and serum chitinase-3 like protein 1 (Chi3L1).

These efficacy parameters will be measured and collected at specified intervals throughout the trial, with the primary focus on the 6-month and 3-month timepoints for disability progression. The use of MRI will facilitate the assessment of changes in T2 hyperintense lesions, while cognitive function will be evaluated using validated scales such as the SDMT and CVLT-II. The trial is designed to compare SAR442168 to a placebo in a randomized, double-blind manner, ensuring the reliability and validity of the efficacy assessments. The study aims to determine the efficacy of SAR442168 in delaying disability progression in participants with PPMS, with the estimated end date of the trial set for June 28, 2025.